Hepatitis

According to estimates, between 2.7 and 3.9 million people are infected with hepatitis C virus (HCV) in the US, with worldwide infection estimated to be about 185 million people.^1-3 The majority of patients infected with HCV develop a chronic infection, which is the leading cause of liver-related complications in the Western world, including cirrhosis, hepatocellular carcinoma, and the need for liver transplantation.⁴ In addition to the direct effects HCV has on the liver, extrahepatic complications can occur, often related to the immune-mediated mechanism of cryoglobulinemia, such as vasculitis, renal disease, and palpable purpura. Additionally, > 70 studies globally have associated HCV with insulin resistance and worsening glycemic control.^5,6

The prevalence of patients infected with HCV that have comorbid type 2 diabetes mellitus (T2DM) is estimated to be about 30%.^7,8 The landmark cross-sectional National Health and Nutrition Examination Survey III study found the prevalence of T2DM among HCV patients in the US aged > 40 years to be about 3-fold higher than those without HCV.⁹ These findings were further supported by a Taiwanese prospective community-based cohort study that found a higher incidence of T2DM in HCV-positive patients compared with HCV negative patients (hazard ratio [HR], 1.7; 95% CI, 1.3-2.1).¹⁰ This relationship appears to be separate from the diabetogenic effect of cirrhosis itself as a significantly higher prevalence of DM has been observed in people with HCV when compared with people with cirrhosis due to other etiologies.¹¹ Although the mechanism for this relationship is not fully understood and is likely multifactorial, it is believed to primarily be an effect of the HCV core protein increasing phosphorylation of insulin receptor substrate-1.^6,12,13 The increased presence of the inflammatory cytokine, tumor necrosis factor-α, is also believed to play a role in the effects on insulinreceptor substrate-1 as well as mediating hepatic insulin resistance, stimulating lipolysis, down-regulating peroxisome proliferator-activated receptor-γ, and interfering with β-cell function.^14-17

The relationship between HCV and T2DM has been further established by measured improvements in insulin resistance among patients undergoing HCV treatment with the pre-2011 standard of care—peginterferon and ribavirin.Kawaguchi and colleagues found sustained treatment responders to have a significant decrease in both the homeostatic model assessment-insulin resistance (HOMA-IR) score, representing insulin resistance, and the HOMA-β score, representing β-cell function.¹⁸ Improvements in the HOMA-IR score were further validated by Kim and colleagues and a nested cohort within the Hepatitis C Long-term Treatment against Cirrhosis (HALT-C) trial.^19,20 Furthermore, Romero-Gómez and colleagues found that patients achieving a cure from HCV treatment defined as a sustained virologic response (SVR) had a nearly 50% reduced risk of impaired fasting glucose or T2DM over a mean posttreatment follow-up of 27 months.²¹

The recent development of direct-acting antivirals (DAAs) has marked significant HCV treatment advances in terms of efficacy and tolerability, leading current guidelines to emphasize that nearly all patients with HCV would benefit from treatment.²² Despite these guidelines, issues have been documented throughout the US with payors often limiting this costly treatment to only those with advanced fibrotic disease.²³ Although the benefits of HCV treatment on reducing liver-related morbidity and mortality may be most appreciated in individuals with advanced fibrotic liver disease, improvements in insulin resistance would suggest potential morbidity and mortality benefits beyond the liver in many more at-risk individuals.²⁴

Increasingly, cases are being reported of new DAA regimens having a significant impact on reducing insulin resistance as demonstrated by marked decreases in antihyperglycemic requirements, fasting blood glucose, and hemoglobin A_1c (HbA_1c).^25-30 One striking case describes a patient being able to de-escalate his regimen from 42 daily units of insulin to a single oral dipeptidyl peptidase-4 inhibitor while maintaining goal HbA_1c level over a 2-year time period.³¹ A database-driven study of veterans found a mean HbA_1c drop of 0.37% in its overall included cohort of patients with T2DM who achieved SVR from HCV DAA treatment.³²

Despite these data, the individual predictability and variable magnitude of improved insulin resistance based on baseline HbA_1c remains unknown. The objective of this study was to assess the impact of HCV treatment with short course DAAs on glucose control in veteran patients with T2DM at a single center.

Methods

This retrospective cohort study was performed at the Department of Veterans Affairs (VA) Northeast Ohio Healthcare System (VANEOHS) in Cleveland. This study received approval from the VANEOHS Institutional Review Board. Retrospective patient data were collected from the Veterans Health Administration (VHA) Computerized Patient Record System (CPRS) electronic health record. Collectively, the VHA has treated > 100,000 patients with DAAs, making it the largest provider of HCV treatment in the US. VANEOHS has treated nearly 2,000 patients with DAAs, rendering it one of the largest single-institution cohorts to be able to examine the effects of HCV treatment on subpopulations, such as patients with T2DM.

Patient Population

Patients were identified using ICD-9/10 codes for T2DM and medication dispense history of hepatitis C DAAs. Patients were included if they had a diagnosis of T2DM, were initiated on a hepatitis C DAA between February 1, 2014 to September 26, 2016. To be eligible, patients were required to have both a baseline HbA_1c within 6 months prior to starting HCV treatment as well as a HbA_1c within 4 months posttreatment. The HCV treatment included were new short-course DAAs, including sofosbuvir, simeprevir, ombitasvir/paritaprevir/ritonavir ± dasabuvir, ledipasvir/sofosbuvir, elbasvir/grazoprevir, and sofosbuvir/velpatasvir. Patients were excluded if they were not on any antihyperglycemic medications at the start of HCV treatment or did not complete a full HCV treatment course.

Baseline Characteristics

Pertinent demographic data collected at baseline included patient age, gender, HCV genotype, and presence of advanced fibrotic liver disease (defined as a Metavir fibrosis stage 4 on liver biopsy, transient elastography > 12.5 kPa, or radiologic evidence of cirrhosis). HCV treatment initiation and completion dates were collected along with treatment response at 12 weeks posttreatment. Patients were considered to have achieved SVR12 if their hepatitis C viral load remained undetectable at posttreatment day 77 or thereafter. Treatment relapse was defined as a patient who achieved an undetectable HCV RNA by the end of treatment but subsequently had detectable HCV RNA following treatment cessation.

Outcome Measures

Baseline HbA_1c was defined as the HbA_1c drawn closest to the date of HCV treatment initiation, at least 6 months prior to treatment. Immediate posttreatment HbA_1c was defined as HbA_1c drawn up to 4 months posttreatment, and sustained HbA_1c was captured up to 18 months posttreatment. Antihyperglycemic medication regimens and doses were collected at baseline, the end of treatment, and 3 months posttreatment via medication dispense history as well as provider notes documented in CPRS. Changes in antihyperglycemic medications were defined as net de-escalation, escalation, or no change. De-escalation of antihyperglycemic medication was defined as an overall decrease in dose, decrease in number of medications, or discontinuation of insulin (eg, if same overall number of medications but insulin was changed to an oral antihyperglycemic would have been considered a de-escalation). No change was defined as no overall change in insulin dose, or number of medications (eg, including patients who may have changed from one oral antihyperglycemic to another while overall number of medications did not change). Escalation was defined as an increase in dose, increase in number of medications, or initiation of insulin.

The primary endpoint was the change in HbA_1c up to 4 months posttreatment in patients achieving SVR12. Secondary endpoints included the sustained change in HbA_1c up to 12- and 18-months posttreatment, as well as change in antihyperglycemic medications from baseline to the end of HCV treatment and from baseline to 3 months posttreatment in patients achieving SVR12. Lastly, the changes in HbA_1c and net changes in antihyperglycemic medications were compared among patients who achieved SVR12 and those who relapsed.

Statistical Analysis

The anticipated sample size after inclusion and exclusion for this study was 160 patients. As HbA_1c is a continuous variable and tested prior to treatment and up to 18-months posttreatment, a paired dependent 2-sided t test was used for this study. For a paired dependent t test with an α of 0.05 and a power of 80%, a sample size of 160 would be able to detect a moderately small, but clinically relevant effect size of 0.22. Descriptive statistics were used for secondary outcomes. For categorical data, frequencies and percentages are provided.

Results

A total of 437 patients were identified as having a diagnosis of T2DM and being prescribed a HCV DAA, of which 157 patients met inclusion criteria. The 280 excluded patients included 127 who were not on antihyperglycemics at the start of HCV treatment, 147 who did not have HbA_1c data within the specified time frame, 4 were excluded due to delayed treatment initiation outside of the study time period, and 2 self-discontinued HCV treatment due to adverse drug reactions.

Baseline Demographics

The majority of patients were male (96%), primarily African American (56%), with a mean age of 62 years (Table 1). 

Metformin was the most commonly prescribed antihyperglycemic medication (62%), followed by insulin (54%), and sulfonylureas (40%) (Table 2). 

Primary and Secondary Endpoints

There was a significant immediate HbA_1c lowering of 0.67% (from 7.67% to 7.00%; P < .001) in patients who achieved SVR12 over a mean of 2-months posttreatment (Figure 1).

In the overall cohort of patients achieving SVR12, the HbA_1c lowering was not sustained at 18 months posttreatment. However, a subanalysis demonstrated that patients with baseline HbA_1c ≥ 8%, ≥ 9%, and ≥ 10% had an increasingly larger HbA_1c Δ upon HCV treatment completion; the change in HbA_1c for these subcohorts did remain significant at sustained time points. Patients with a baseline HbA_1c ≥ 8%, ≥ 9%, and ≥ 10%, showed 18-month posttreatment HbA_1c decreases of 1.65% (P < .001), 2.28% (P = .004), and 3.63% (P = .003), respectively (Figure 3). 

Discussion

The immediate reduction in HbA_1c following HCV treatment observed in this study of -0.67% is clinically significant and contrasts with the expected rise in HbA_1c seen with normal disease progression. The results from this study are comparable to HbA_1c reductions seen with certain oral, antihyperglycemic medications, such as DPP-4 inhibitors, meglitinides, and SGLT-2 inhibitors that have an average HbA_1c lowering of 0.5% to 1%. This effect was increasingly magnified in patients with a higher baseline HbA_1c.

The sustained effect on HbA_1c may have not been seen in the overall cohort achieving SVR12 due to the fairly well-controlled mean baseline HbA_1c for this older patient cohort. In addition to improvements in HbA_1c, one-third of patients achieving SVR12 required de-escalation of concomitant antihyperglycemic medications. The de-escalation of antihyperglycemics may have made the sustained HbA_1c impact underappreciated in the overall cohort. There were also limited sustained HbA_1c data to evaluate at the time the review was completed.

Despite the clinically significant magnitude of HbA_1c change, this study suggests that this effect is not predictable for all patients with DM achieving SVR12 from HCV treatment. Nineteen percent (28/147) of these patients neither had a decrease in their HbA_1c nor a de-escalation of their antihyperglycemic treatment. Patients whose T2DM onset preceded or was independent of the diabetogenic effects of HCV may be more likely to have insulin resistance unaffected by hepatitis C viral clearance. Notably, the small number of treatment relapses in this study limits this group’s ability to serve as a comparator. However, one may expect a treatment relapse to have an initial decrease in insulin resistance while the hepatitis C viral load decreases below the level of detectability, yet the effects not be sustained once the HCV relapses.

Of the 35 patients who had their HbA_1c decrease to < 6% following HCV treatment, concerningly 29 (83%) had either no change or even had an escalation in their antihyperglycemic regimen. This lack of de-escalation occurred despite 45% (13/29) of these patients continuing insulin posttreatment. These patients may be at a particularly high risk for hypoglycemia. Given the mean age of patients was 62 years, extremely tight glycemic control typically is not the goal for this older patient population with numerous comorbidities and high potential for hypoglycemia unawareness.

This raises concerns that patients with T2DM undergoing HCV treatment experience a new heightened risk of hypoglycemia, particularly if neither patients or providers managing DM are aware of the high potential for decreased antihyperglycemic needs upon achieving hepatitis C virologic response. It is important that these providers are aware of the mean decreased insulin resistance achieved from hepatitis C viral clearance. Providers managing DM should advise frequent serum blood glucose monitoring with close follow-up to allow for medication adjustments to prevent hypoglycemic episodes occurring during and after HCV treatment.

Limitations

The limitations of this study included small sample sizes in subgroups, and the retrospective design prohibited the ability to quantify and describe hypoglycemic events that may have occurred as a result of HCV treatment. In addition, the documentation of medication changes in CPRS may not have fully accounted for adjustments or self-discontinuations of DM medications. An alternative definition for change in antihyperglycemic medications may have accounted for the variable HbA_1c-lowering between oral antihyperglycemic medications.

Finally, hemoglobin was not collected to account for any impact ribavirin-associated anemia may have had on the immediate posttreatment HbA_1c values. Phase 3 DAA trials have demonstrated that between 7% and 9% of patients on ribavirin-containing DAA regimens are expected to have a hemoglobin < 10 g/dL during the HCV treatment course.^33-36 Ribavirin-containing regimens may minimally impact the immediate posttreatment HbA_1c result, but not necessarily the 12- or 18-month posttreatment HbA_1c levels due to the reversible nature of this adverse effect (AE) following discontinuation of ribavirin.

Future studies may be strengthened by controlling for possible confounders such as concomitant ribavirin, adherence to antihyperglycemic medications, comorbidities, years since initial DM diagnosis, and lifestyle modifications, including a decrease of alcohol consumption. A prospective study also may include data on hypoglycemic events and further determine the sustained response by including an 18- or 24-month posttreatment HbA_1c in the protocol.

Conclusion

The findings of this study validate the significant HbA_1c changes post-HCV treatment described in the recent veteran database study.³² However, the current study’s validated patient chart data provide a better understanding of the changes made to antihyperglycemic regimens. This also is the first study describing this phenomenon of improved insulin resistance to only be observed in approximately 80% of patients infected with HCV and comorbid T2DM. Furthermore, the variable magnitude of HbA_1c impact reliant on baseline HbA_1c is informative for individual patient management. In addition to the direct benefits for the liver on hepatitis C viral eradication, improvements in HbA_1c and the de-escalation of antihyperglycemic regimens may be a benefit of receiving HCV treatment.

The improved DM control achieved with hepatitis C viral eradication may represent an opportunity to prevent progressive DM and cardiovascular AEs. Additionally, HCV treatment may be able to prevent the onset of T2DM in patients at risk. Arguably HCV treatment has significant benefits in terms of health outcomes, quality of life, and long-term cost avoidance to patients beyond the well-described value of decreasing liver-related morbidity and mortality. This may be an incentive for payers to improve access to HCV DAAs by expanding eligibility criteria beyond those with advanced fibrotic liver disease.

Acknowledgments
This material is the result of work supported with the resources and the use of facilities at the VA Northeast Ohio Healthcare System.

According to estimates, between 2.7 and 3.9 million people are infected with hepatitis C virus (HCV) in the US, with worldwide infection estimated to be about 185 million people.^1-3 The majority of patients infected with HCV develop a chronic infection, which is the leading cause of liver-related complications in the Western world, including cirrhosis, hepatocellular carcinoma, and the need for liver transplantation.⁴ In addition to the direct effects HCV has on the liver, extrahepatic complications can occur, often related to the immune-mediated mechanism of cryoglobulinemia, such as vasculitis, renal disease, and palpable purpura. Additionally, > 70 studies globally have associated HCV with insulin resistance and worsening glycemic control.^5,6

The prevalence of patients infected with HCV that have comorbid type 2 diabetes mellitus (T2DM) is estimated to be about 30%.^7,8 The landmark cross-sectional National Health and Nutrition Examination Survey III study found the prevalence of T2DM among HCV patients in the US aged > 40 years to be about 3-fold higher than those without HCV.⁹ These findings were further supported by a Taiwanese prospective community-based cohort study that found a higher incidence of T2DM in HCV-positive patients compared with HCV negative patients (hazard ratio [HR], 1.7; 95% CI, 1.3-2.1).¹⁰ This relationship appears to be separate from the diabetogenic effect of cirrhosis itself as a significantly higher prevalence of DM has been observed in people with HCV when compared with people with cirrhosis due to other etiologies.¹¹ Although the mechanism for this relationship is not fully understood and is likely multifactorial, it is believed to primarily be an effect of the HCV core protein increasing phosphorylation of insulin receptor substrate-1.^6,12,13 The increased presence of the inflammatory cytokine, tumor necrosis factor-α, is also believed to play a role in the effects on insulinreceptor substrate-1 as well as mediating hepatic insulin resistance, stimulating lipolysis, down-regulating peroxisome proliferator-activated receptor-γ, and interfering with β-cell function.^14-17

The relationship between HCV and T2DM has been further established by measured improvements in insulin resistance among patients undergoing HCV treatment with the pre-2011 standard of care—peginterferon and ribavirin.Kawaguchi and colleagues found sustained treatment responders to have a significant decrease in both the homeostatic model assessment-insulin resistance (HOMA-IR) score, representing insulin resistance, and the HOMA-β score, representing β-cell function.¹⁸ Improvements in the HOMA-IR score were further validated by Kim and colleagues and a nested cohort within the Hepatitis C Long-term Treatment against Cirrhosis (HALT-C) trial.^19,20 Furthermore, Romero-Gómez and colleagues found that patients achieving a cure from HCV treatment defined as a sustained virologic response (SVR) had a nearly 50% reduced risk of impaired fasting glucose or T2DM over a mean posttreatment follow-up of 27 months.²¹

The recent development of direct-acting antivirals (DAAs) has marked significant HCV treatment advances in terms of efficacy and tolerability, leading current guidelines to emphasize that nearly all patients with HCV would benefit from treatment.²² Despite these guidelines, issues have been documented throughout the US with payors often limiting this costly treatment to only those with advanced fibrotic disease.²³ Although the benefits of HCV treatment on reducing liver-related morbidity and mortality may be most appreciated in individuals with advanced fibrotic liver disease, improvements in insulin resistance would suggest potential morbidity and mortality benefits beyond the liver in many more at-risk individuals.²⁴

Increasingly, cases are being reported of new DAA regimens having a significant impact on reducing insulin resistance as demonstrated by marked decreases in antihyperglycemic requirements, fasting blood glucose, and hemoglobin A_1c (HbA_1c).^25-30 One striking case describes a patient being able to de-escalate his regimen from 42 daily units of insulin to a single oral dipeptidyl peptidase-4 inhibitor while maintaining goal HbA_1c level over a 2-year time period.³¹ A database-driven study of veterans found a mean HbA_1c drop of 0.37% in its overall included cohort of patients with T2DM who achieved SVR from HCV DAA treatment.³²

Despite these data, the individual predictability and variable magnitude of improved insulin resistance based on baseline HbA_1c remains unknown. The objective of this study was to assess the impact of HCV treatment with short course DAAs on glucose control in veteran patients with T2DM at a single center.

Methods

This retrospective cohort study was performed at the Department of Veterans Affairs (VA) Northeast Ohio Healthcare System (VANEOHS) in Cleveland. This study received approval from the VANEOHS Institutional Review Board. Retrospective patient data were collected from the Veterans Health Administration (VHA) Computerized Patient Record System (CPRS) electronic health record. Collectively, the VHA has treated > 100,000 patients with DAAs, making it the largest provider of HCV treatment in the US. VANEOHS has treated nearly 2,000 patients with DAAs, rendering it one of the largest single-institution cohorts to be able to examine the effects of HCV treatment on subpopulations, such as patients with T2DM.

Patient Population

Patients were identified using ICD-9/10 codes for T2DM and medication dispense history of hepatitis C DAAs. Patients were included if they had a diagnosis of T2DM, were initiated on a hepatitis C DAA between February 1, 2014 to September 26, 2016. To be eligible, patients were required to have both a baseline HbA_1c within 6 months prior to starting HCV treatment as well as a HbA_1c within 4 months posttreatment. The HCV treatment included were new short-course DAAs, including sofosbuvir, simeprevir, ombitasvir/paritaprevir/ritonavir ± dasabuvir, ledipasvir/sofosbuvir, elbasvir/grazoprevir, and sofosbuvir/velpatasvir. Patients were excluded if they were not on any antihyperglycemic medications at the start of HCV treatment or did not complete a full HCV treatment course.

Baseline Characteristics

Pertinent demographic data collected at baseline included patient age, gender, HCV genotype, and presence of advanced fibrotic liver disease (defined as a Metavir fibrosis stage 4 on liver biopsy, transient elastography > 12.5 kPa, or radiologic evidence of cirrhosis). HCV treatment initiation and completion dates were collected along with treatment response at 12 weeks posttreatment. Patients were considered to have achieved SVR12 if their hepatitis C viral load remained undetectable at posttreatment day 77 or thereafter. Treatment relapse was defined as a patient who achieved an undetectable HCV RNA by the end of treatment but subsequently had detectable HCV RNA following treatment cessation.

Outcome Measures

Baseline HbA_1c was defined as the HbA_1c drawn closest to the date of HCV treatment initiation, at least 6 months prior to treatment. Immediate posttreatment HbA_1c was defined as HbA_1c drawn up to 4 months posttreatment, and sustained HbA_1c was captured up to 18 months posttreatment. Antihyperglycemic medication regimens and doses were collected at baseline, the end of treatment, and 3 months posttreatment via medication dispense history as well as provider notes documented in CPRS. Changes in antihyperglycemic medications were defined as net de-escalation, escalation, or no change. De-escalation of antihyperglycemic medication was defined as an overall decrease in dose, decrease in number of medications, or discontinuation of insulin (eg, if same overall number of medications but insulin was changed to an oral antihyperglycemic would have been considered a de-escalation). No change was defined as no overall change in insulin dose, or number of medications (eg, including patients who may have changed from one oral antihyperglycemic to another while overall number of medications did not change). Escalation was defined as an increase in dose, increase in number of medications, or initiation of insulin.

The primary endpoint was the change in HbA_1c up to 4 months posttreatment in patients achieving SVR12. Secondary endpoints included the sustained change in HbA_1c up to 12- and 18-months posttreatment, as well as change in antihyperglycemic medications from baseline to the end of HCV treatment and from baseline to 3 months posttreatment in patients achieving SVR12. Lastly, the changes in HbA_1c and net changes in antihyperglycemic medications were compared among patients who achieved SVR12 and those who relapsed.

Statistical Analysis

The anticipated sample size after inclusion and exclusion for this study was 160 patients. As HbA_1c is a continuous variable and tested prior to treatment and up to 18-months posttreatment, a paired dependent 2-sided t test was used for this study. For a paired dependent t test with an α of 0.05 and a power of 80%, a sample size of 160 would be able to detect a moderately small, but clinically relevant effect size of 0.22. Descriptive statistics were used for secondary outcomes. For categorical data, frequencies and percentages are provided.

Results

A total of 437 patients were identified as having a diagnosis of T2DM and being prescribed a HCV DAA, of which 157 patients met inclusion criteria. The 280 excluded patients included 127 who were not on antihyperglycemics at the start of HCV treatment, 147 who did not have HbA_1c data within the specified time frame, 4 were excluded due to delayed treatment initiation outside of the study time period, and 2 self-discontinued HCV treatment due to adverse drug reactions.

Baseline Demographics

The majority of patients were male (96%), primarily African American (56%), with a mean age of 62 years (Table 1). 

Metformin was the most commonly prescribed antihyperglycemic medication (62%), followed by insulin (54%), and sulfonylureas (40%) (Table 2). 

Primary and Secondary Endpoints

There was a significant immediate HbA_1c lowering of 0.67% (from 7.67% to 7.00%; P < .001) in patients who achieved SVR12 over a mean of 2-months posttreatment (Figure 1).

In the overall cohort of patients achieving SVR12, the HbA_1c lowering was not sustained at 18 months posttreatment. However, a subanalysis demonstrated that patients with baseline HbA_1c ≥ 8%, ≥ 9%, and ≥ 10% had an increasingly larger HbA_1c Δ upon HCV treatment completion; the change in HbA_1c for these subcohorts did remain significant at sustained time points. Patients with a baseline HbA_1c ≥ 8%, ≥ 9%, and ≥ 10%, showed 18-month posttreatment HbA_1c decreases of 1.65% (P < .001), 2.28% (P = .004), and 3.63% (P = .003), respectively (Figure 3). 

Discussion

The immediate reduction in HbA_1c following HCV treatment observed in this study of -0.67% is clinically significant and contrasts with the expected rise in HbA_1c seen with normal disease progression. The results from this study are comparable to HbA_1c reductions seen with certain oral, antihyperglycemic medications, such as DPP-4 inhibitors, meglitinides, and SGLT-2 inhibitors that have an average HbA_1c lowering of 0.5% to 1%. This effect was increasingly magnified in patients with a higher baseline HbA_1c.

The sustained effect on HbA_1c may have not been seen in the overall cohort achieving SVR12 due to the fairly well-controlled mean baseline HbA_1c for this older patient cohort. In addition to improvements in HbA_1c, one-third of patients achieving SVR12 required de-escalation of concomitant antihyperglycemic medications. The de-escalation of antihyperglycemics may have made the sustained HbA_1c impact underappreciated in the overall cohort. There were also limited sustained HbA_1c data to evaluate at the time the review was completed.

Despite the clinically significant magnitude of HbA_1c change, this study suggests that this effect is not predictable for all patients with DM achieving SVR12 from HCV treatment. Nineteen percent (28/147) of these patients neither had a decrease in their HbA_1c nor a de-escalation of their antihyperglycemic treatment. Patients whose T2DM onset preceded or was independent of the diabetogenic effects of HCV may be more likely to have insulin resistance unaffected by hepatitis C viral clearance. Notably, the small number of treatment relapses in this study limits this group’s ability to serve as a comparator. However, one may expect a treatment relapse to have an initial decrease in insulin resistance while the hepatitis C viral load decreases below the level of detectability, yet the effects not be sustained once the HCV relapses.

Of the 35 patients who had their HbA_1c decrease to < 6% following HCV treatment, concerningly 29 (83%) had either no change or even had an escalation in their antihyperglycemic regimen. This lack of de-escalation occurred despite 45% (13/29) of these patients continuing insulin posttreatment. These patients may be at a particularly high risk for hypoglycemia. Given the mean age of patients was 62 years, extremely tight glycemic control typically is not the goal for this older patient population with numerous comorbidities and high potential for hypoglycemia unawareness.

This raises concerns that patients with T2DM undergoing HCV treatment experience a new heightened risk of hypoglycemia, particularly if neither patients or providers managing DM are aware of the high potential for decreased antihyperglycemic needs upon achieving hepatitis C virologic response. It is important that these providers are aware of the mean decreased insulin resistance achieved from hepatitis C viral clearance. Providers managing DM should advise frequent serum blood glucose monitoring with close follow-up to allow for medication adjustments to prevent hypoglycemic episodes occurring during and after HCV treatment.

Limitations

The limitations of this study included small sample sizes in subgroups, and the retrospective design prohibited the ability to quantify and describe hypoglycemic events that may have occurred as a result of HCV treatment. In addition, the documentation of medication changes in CPRS may not have fully accounted for adjustments or self-discontinuations of DM medications. An alternative definition for change in antihyperglycemic medications may have accounted for the variable HbA_1c-lowering between oral antihyperglycemic medications.

Finally, hemoglobin was not collected to account for any impact ribavirin-associated anemia may have had on the immediate posttreatment HbA_1c values. Phase 3 DAA trials have demonstrated that between 7% and 9% of patients on ribavirin-containing DAA regimens are expected to have a hemoglobin < 10 g/dL during the HCV treatment course.^33-36 Ribavirin-containing regimens may minimally impact the immediate posttreatment HbA_1c result, but not necessarily the 12- or 18-month posttreatment HbA_1c levels due to the reversible nature of this adverse effect (AE) following discontinuation of ribavirin.

Future studies may be strengthened by controlling for possible confounders such as concomitant ribavirin, adherence to antihyperglycemic medications, comorbidities, years since initial DM diagnosis, and lifestyle modifications, including a decrease of alcohol consumption. A prospective study also may include data on hypoglycemic events and further determine the sustained response by including an 18- or 24-month posttreatment HbA_1c in the protocol.

Conclusion

The findings of this study validate the significant HbA_1c changes post-HCV treatment described in the recent veteran database study.³² However, the current study’s validated patient chart data provide a better understanding of the changes made to antihyperglycemic regimens. This also is the first study describing this phenomenon of improved insulin resistance to only be observed in approximately 80% of patients infected with HCV and comorbid T2DM. Furthermore, the variable magnitude of HbA_1c impact reliant on baseline HbA_1c is informative for individual patient management. In addition to the direct benefits for the liver on hepatitis C viral eradication, improvements in HbA_1c and the de-escalation of antihyperglycemic regimens may be a benefit of receiving HCV treatment.

The improved DM control achieved with hepatitis C viral eradication may represent an opportunity to prevent progressive DM and cardiovascular AEs. Additionally, HCV treatment may be able to prevent the onset of T2DM in patients at risk. Arguably HCV treatment has significant benefits in terms of health outcomes, quality of life, and long-term cost avoidance to patients beyond the well-described value of decreasing liver-related morbidity and mortality. This may be an incentive for payers to improve access to HCV DAAs by expanding eligibility criteria beyond those with advanced fibrotic liver disease.

Acknowledgments
This material is the result of work supported with the resources and the use of facilities at the VA Northeast Ohio Healthcare System.

According to estimates, between 2.7 and 3.9 million people are infected with hepatitis C virus (HCV) in the US, with worldwide infection estimated to be about 185 million people.^1-3 The majority of patients infected with HCV develop a chronic infection, which is the leading cause of liver-related complications in the Western world, including cirrhosis, hepatocellular carcinoma, and the need for liver transplantation.⁴ In addition to the direct effects HCV has on the liver, extrahepatic complications can occur, often related to the immune-mediated mechanism of cryoglobulinemia, such as vasculitis, renal disease, and palpable purpura. Additionally, > 70 studies globally have associated HCV with insulin resistance and worsening glycemic control.^5,6

The prevalence of patients infected with HCV that have comorbid type 2 diabetes mellitus (T2DM) is estimated to be about 30%.^7,8 The landmark cross-sectional National Health and Nutrition Examination Survey III study found the prevalence of T2DM among HCV patients in the US aged > 40 years to be about 3-fold higher than those without HCV.⁹ These findings were further supported by a Taiwanese prospective community-based cohort study that found a higher incidence of T2DM in HCV-positive patients compared with HCV negative patients (hazard ratio [HR], 1.7; 95% CI, 1.3-2.1).¹⁰ This relationship appears to be separate from the diabetogenic effect of cirrhosis itself as a significantly higher prevalence of DM has been observed in people with HCV when compared with people with cirrhosis due to other etiologies.¹¹ Although the mechanism for this relationship is not fully understood and is likely multifactorial, it is believed to primarily be an effect of the HCV core protein increasing phosphorylation of insulin receptor substrate-1.^6,12,13 The increased presence of the inflammatory cytokine, tumor necrosis factor-α, is also believed to play a role in the effects on insulinreceptor substrate-1 as well as mediating hepatic insulin resistance, stimulating lipolysis, down-regulating peroxisome proliferator-activated receptor-γ, and interfering with β-cell function.^14-17

The relationship between HCV and T2DM has been further established by measured improvements in insulin resistance among patients undergoing HCV treatment with the pre-2011 standard of care—peginterferon and ribavirin.Kawaguchi and colleagues found sustained treatment responders to have a significant decrease in both the homeostatic model assessment-insulin resistance (HOMA-IR) score, representing insulin resistance, and the HOMA-β score, representing β-cell function.¹⁸ Improvements in the HOMA-IR score were further validated by Kim and colleagues and a nested cohort within the Hepatitis C Long-term Treatment against Cirrhosis (HALT-C) trial.^19,20 Furthermore, Romero-Gómez and colleagues found that patients achieving a cure from HCV treatment defined as a sustained virologic response (SVR) had a nearly 50% reduced risk of impaired fasting glucose or T2DM over a mean posttreatment follow-up of 27 months.²¹

The recent development of direct-acting antivirals (DAAs) has marked significant HCV treatment advances in terms of efficacy and tolerability, leading current guidelines to emphasize that nearly all patients with HCV would benefit from treatment.²² Despite these guidelines, issues have been documented throughout the US with payors often limiting this costly treatment to only those with advanced fibrotic disease.²³ Although the benefits of HCV treatment on reducing liver-related morbidity and mortality may be most appreciated in individuals with advanced fibrotic liver disease, improvements in insulin resistance would suggest potential morbidity and mortality benefits beyond the liver in many more at-risk individuals.²⁴

Increasingly, cases are being reported of new DAA regimens having a significant impact on reducing insulin resistance as demonstrated by marked decreases in antihyperglycemic requirements, fasting blood glucose, and hemoglobin A_1c (HbA_1c).^25-30 One striking case describes a patient being able to de-escalate his regimen from 42 daily units of insulin to a single oral dipeptidyl peptidase-4 inhibitor while maintaining goal HbA_1c level over a 2-year time period.³¹ A database-driven study of veterans found a mean HbA_1c drop of 0.37% in its overall included cohort of patients with T2DM who achieved SVR from HCV DAA treatment.³²

Despite these data, the individual predictability and variable magnitude of improved insulin resistance based on baseline HbA_1c remains unknown. The objective of this study was to assess the impact of HCV treatment with short course DAAs on glucose control in veteran patients with T2DM at a single center.

Methods

This retrospective cohort study was performed at the Department of Veterans Affairs (VA) Northeast Ohio Healthcare System (VANEOHS) in Cleveland. This study received approval from the VANEOHS Institutional Review Board. Retrospective patient data were collected from the Veterans Health Administration (VHA) Computerized Patient Record System (CPRS) electronic health record. Collectively, the VHA has treated > 100,000 patients with DAAs, making it the largest provider of HCV treatment in the US. VANEOHS has treated nearly 2,000 patients with DAAs, rendering it one of the largest single-institution cohorts to be able to examine the effects of HCV treatment on subpopulations, such as patients with T2DM.

Patient Population

Patients were identified using ICD-9/10 codes for T2DM and medication dispense history of hepatitis C DAAs. Patients were included if they had a diagnosis of T2DM, were initiated on a hepatitis C DAA between February 1, 2014 to September 26, 2016. To be eligible, patients were required to have both a baseline HbA_1c within 6 months prior to starting HCV treatment as well as a HbA_1c within 4 months posttreatment. The HCV treatment included were new short-course DAAs, including sofosbuvir, simeprevir, ombitasvir/paritaprevir/ritonavir ± dasabuvir, ledipasvir/sofosbuvir, elbasvir/grazoprevir, and sofosbuvir/velpatasvir. Patients were excluded if they were not on any antihyperglycemic medications at the start of HCV treatment or did not complete a full HCV treatment course.

Baseline Characteristics

Pertinent demographic data collected at baseline included patient age, gender, HCV genotype, and presence of advanced fibrotic liver disease (defined as a Metavir fibrosis stage 4 on liver biopsy, transient elastography > 12.5 kPa, or radiologic evidence of cirrhosis). HCV treatment initiation and completion dates were collected along with treatment response at 12 weeks posttreatment. Patients were considered to have achieved SVR12 if their hepatitis C viral load remained undetectable at posttreatment day 77 or thereafter. Treatment relapse was defined as a patient who achieved an undetectable HCV RNA by the end of treatment but subsequently had detectable HCV RNA following treatment cessation.

Outcome Measures

Baseline HbA_1c was defined as the HbA_1c drawn closest to the date of HCV treatment initiation, at least 6 months prior to treatment. Immediate posttreatment HbA_1c was defined as HbA_1c drawn up to 4 months posttreatment, and sustained HbA_1c was captured up to 18 months posttreatment. Antihyperglycemic medication regimens and doses were collected at baseline, the end of treatment, and 3 months posttreatment via medication dispense history as well as provider notes documented in CPRS. Changes in antihyperglycemic medications were defined as net de-escalation, escalation, or no change. De-escalation of antihyperglycemic medication was defined as an overall decrease in dose, decrease in number of medications, or discontinuation of insulin (eg, if same overall number of medications but insulin was changed to an oral antihyperglycemic would have been considered a de-escalation). No change was defined as no overall change in insulin dose, or number of medications (eg, including patients who may have changed from one oral antihyperglycemic to another while overall number of medications did not change). Escalation was defined as an increase in dose, increase in number of medications, or initiation of insulin.

The primary endpoint was the change in HbA_1c up to 4 months posttreatment in patients achieving SVR12. Secondary endpoints included the sustained change in HbA_1c up to 12- and 18-months posttreatment, as well as change in antihyperglycemic medications from baseline to the end of HCV treatment and from baseline to 3 months posttreatment in patients achieving SVR12. Lastly, the changes in HbA_1c and net changes in antihyperglycemic medications were compared among patients who achieved SVR12 and those who relapsed.

Statistical Analysis

The anticipated sample size after inclusion and exclusion for this study was 160 patients. As HbA_1c is a continuous variable and tested prior to treatment and up to 18-months posttreatment, a paired dependent 2-sided t test was used for this study. For a paired dependent t test with an α of 0.05 and a power of 80%, a sample size of 160 would be able to detect a moderately small, but clinically relevant effect size of 0.22. Descriptive statistics were used for secondary outcomes. For categorical data, frequencies and percentages are provided.

Results

A total of 437 patients were identified as having a diagnosis of T2DM and being prescribed a HCV DAA, of which 157 patients met inclusion criteria. The 280 excluded patients included 127 who were not on antihyperglycemics at the start of HCV treatment, 147 who did not have HbA_1c data within the specified time frame, 4 were excluded due to delayed treatment initiation outside of the study time period, and 2 self-discontinued HCV treatment due to adverse drug reactions.

Baseline Demographics

The majority of patients were male (96%), primarily African American (56%), with a mean age of 62 years (Table 1). 

Metformin was the most commonly prescribed antihyperglycemic medication (62%), followed by insulin (54%), and sulfonylureas (40%) (Table 2). 

Primary and Secondary Endpoints

There was a significant immediate HbA_1c lowering of 0.67% (from 7.67% to 7.00%; P < .001) in patients who achieved SVR12 over a mean of 2-months posttreatment (Figure 1).

In the overall cohort of patients achieving SVR12, the HbA_1c lowering was not sustained at 18 months posttreatment. However, a subanalysis demonstrated that patients with baseline HbA_1c ≥ 8%, ≥ 9%, and ≥ 10% had an increasingly larger HbA_1c Δ upon HCV treatment completion; the change in HbA_1c for these subcohorts did remain significant at sustained time points. Patients with a baseline HbA_1c ≥ 8%, ≥ 9%, and ≥ 10%, showed 18-month posttreatment HbA_1c decreases of 1.65% (P < .001), 2.28% (P = .004), and 3.63% (P = .003), respectively (Figure 3). 

Discussion

The immediate reduction in HbA_1c following HCV treatment observed in this study of -0.67% is clinically significant and contrasts with the expected rise in HbA_1c seen with normal disease progression. The results from this study are comparable to HbA_1c reductions seen with certain oral, antihyperglycemic medications, such as DPP-4 inhibitors, meglitinides, and SGLT-2 inhibitors that have an average HbA_1c lowering of 0.5% to 1%. This effect was increasingly magnified in patients with a higher baseline HbA_1c.

The sustained effect on HbA_1c may have not been seen in the overall cohort achieving SVR12 due to the fairly well-controlled mean baseline HbA_1c for this older patient cohort. In addition to improvements in HbA_1c, one-third of patients achieving SVR12 required de-escalation of concomitant antihyperglycemic medications. The de-escalation of antihyperglycemics may have made the sustained HbA_1c impact underappreciated in the overall cohort. There were also limited sustained HbA_1c data to evaluate at the time the review was completed.

Despite the clinically significant magnitude of HbA_1c change, this study suggests that this effect is not predictable for all patients with DM achieving SVR12 from HCV treatment. Nineteen percent (28/147) of these patients neither had a decrease in their HbA_1c nor a de-escalation of their antihyperglycemic treatment. Patients whose T2DM onset preceded or was independent of the diabetogenic effects of HCV may be more likely to have insulin resistance unaffected by hepatitis C viral clearance. Notably, the small number of treatment relapses in this study limits this group’s ability to serve as a comparator. However, one may expect a treatment relapse to have an initial decrease in insulin resistance while the hepatitis C viral load decreases below the level of detectability, yet the effects not be sustained once the HCV relapses.

Of the 35 patients who had their HbA_1c decrease to < 6% following HCV treatment, concerningly 29 (83%) had either no change or even had an escalation in their antihyperglycemic regimen. This lack of de-escalation occurred despite 45% (13/29) of these patients continuing insulin posttreatment. These patients may be at a particularly high risk for hypoglycemia. Given the mean age of patients was 62 years, extremely tight glycemic control typically is not the goal for this older patient population with numerous comorbidities and high potential for hypoglycemia unawareness.

This raises concerns that patients with T2DM undergoing HCV treatment experience a new heightened risk of hypoglycemia, particularly if neither patients or providers managing DM are aware of the high potential for decreased antihyperglycemic needs upon achieving hepatitis C virologic response. It is important that these providers are aware of the mean decreased insulin resistance achieved from hepatitis C viral clearance. Providers managing DM should advise frequent serum blood glucose monitoring with close follow-up to allow for medication adjustments to prevent hypoglycemic episodes occurring during and after HCV treatment.

Limitations

The limitations of this study included small sample sizes in subgroups, and the retrospective design prohibited the ability to quantify and describe hypoglycemic events that may have occurred as a result of HCV treatment. In addition, the documentation of medication changes in CPRS may not have fully accounted for adjustments or self-discontinuations of DM medications. An alternative definition for change in antihyperglycemic medications may have accounted for the variable HbA_1c-lowering between oral antihyperglycemic medications.

Finally, hemoglobin was not collected to account for any impact ribavirin-associated anemia may have had on the immediate posttreatment HbA_1c values. Phase 3 DAA trials have demonstrated that between 7% and 9% of patients on ribavirin-containing DAA regimens are expected to have a hemoglobin < 10 g/dL during the HCV treatment course.^33-36 Ribavirin-containing regimens may minimally impact the immediate posttreatment HbA_1c result, but not necessarily the 12- or 18-month posttreatment HbA_1c levels due to the reversible nature of this adverse effect (AE) following discontinuation of ribavirin.

Future studies may be strengthened by controlling for possible confounders such as concomitant ribavirin, adherence to antihyperglycemic medications, comorbidities, years since initial DM diagnosis, and lifestyle modifications, including a decrease of alcohol consumption. A prospective study also may include data on hypoglycemic events and further determine the sustained response by including an 18- or 24-month posttreatment HbA_1c in the protocol.

Conclusion

The findings of this study validate the significant HbA_1c changes post-HCV treatment described in the recent veteran database study.³² However, the current study’s validated patient chart data provide a better understanding of the changes made to antihyperglycemic regimens. This also is the first study describing this phenomenon of improved insulin resistance to only be observed in approximately 80% of patients infected with HCV and comorbid T2DM. Furthermore, the variable magnitude of HbA_1c impact reliant on baseline HbA_1c is informative for individual patient management. In addition to the direct benefits for the liver on hepatitis C viral eradication, improvements in HbA_1c and the de-escalation of antihyperglycemic regimens may be a benefit of receiving HCV treatment.

The improved DM control achieved with hepatitis C viral eradication may represent an opportunity to prevent progressive DM and cardiovascular AEs. Additionally, HCV treatment may be able to prevent the onset of T2DM in patients at risk. Arguably HCV treatment has significant benefits in terms of health outcomes, quality of life, and long-term cost avoidance to patients beyond the well-described value of decreasing liver-related morbidity and mortality. This may be an incentive for payers to improve access to HCV DAAs by expanding eligibility criteria beyond those with advanced fibrotic liver disease.

Acknowledgments
This material is the result of work supported with the resources and the use of facilities at the VA Northeast Ohio Healthcare System.

Hepatitis B is a viral infection caused by the hepatitis B virus (HBV), which is transmitted through percutaneous (ie, puncture through the skin) or mucosal (ie, direct contact with mucous membranes) exposure to infectious blood or body fluids. Hepatitis B virus can cause chronic infection, resulting in cirrhosis of the liver, liver cancer, liver failure, and death. Persons with chronic infection also serve as the main reservoir for continued HBV transmission.¹

Individuals at highest risk for infection include those born in geographic regions with a high prevalence of HBV, those with sexual partners or household contacts with chronic HBV infection, men who have sex with men (MSM), those with HIV, and individuals who inject drugs. Pregnant women also are a population of concern given the potential for perinatal transmission.²

About 850,000 to 2.2 million people in the US (about 0.3% of the civilian US population) are chronically infected with HBV.³ The prevalence of chronic HBV is much higher (10%-19%) among Asian Americans, those of Pacific Island descent, and other immigrant populations from highly endemic countries.⁴ In the US, HBV is responsible for 2,000 to 4,000 preventable deaths annually, primarily from cirrhosis, liver cancer, and hepatic failure.⁴ In the civilian US population, reported cases of acute HBV decreased 0.3% from 2011 to 2012, increased 5.4% in 2013 with an 8.5% decrease in 2014, and a 20.7% increase in 2015.⁴ Injection drug use is likely driving the most recent increase.⁵

Not all individuals exposed to HBV will develop chronic infection, and the risk of chronic HBV infection depends on an individual’s age at the time of exposure. For example, about 95% of infants exposed to HBV perinatally will develop a chronic infection compared with 5% of exposed adults.⁶ Of those with chronic HBV, a small proportion will develop cirrhosis and/or hepatocellular carcinoma (HCC) with increasing risk as viral DNA concentrations increase. Additional risk factors for cirrhosis include being older, male, having a persistently elevated alanine transaminase, viral superinfections, HBV reversion/reactivation, genotype, and various markers of disease severity (HCC).⁶ Of note, chronic HBV infection may cause HCC even in the absence of cirrhosis.⁷ In addition, immunosuppression (eg, from cancer chemotherapy) may allow HBV reactivation, which may result in fulminant hepatic failure. In the Veterans Health Affairs (VHA) health care system, about 17% of those with known chronic HBV also carry a diagnosis of cirrhosis.

Vaccination is the mainstay of efforts to prevent HBV infection. The first commercially available HBV vaccine was approved by the FDA in 1981, with subsequent FDA approval in 1986 of a vaccine manufactured using recombinant DNA technology.⁸ In 1991, the Advisory Committee on Immunization Practices (ACIP) recommended universal childhood vaccination for HBV, with subsequent recommendations for vaccination of adolescents and adults in high-risk groups in 1995, and in 1999 all remaining unvaccinated children aged ≤ 19 years.⁹ Military policy has been to provide hepatitis B immunization to personnel assigned to the Korean peninsula since 1986 and to all recruits since 2001.¹⁰

Following publication of an Institute of Medicine/National Academies of Sciences, Engineering, and Medicine (NASEM) report, in 2011 the US Department of Health and Human Services (HHS) released the first National Viral Hepatitis Action Plan.¹¹ The current HHS Action Plan, along with the NASEM National Strategy for the Elimination of Hepatitis B and C: Phase Two Report, commissioned by the US Centers for Disease Control and Prevention (CDC), outlines a national strategy to prevent new viral hepatitis infections; reduce deaths and improve the health of people living with viral hepatitis; reduce viral hepatitis health disparities; and coordinate, monitor, and report on implementation of viral hepatitis activities.¹² The VA is a critical partner in this federal collaborative effort to achieve excellence in viral hepatitis care.

In August 2016, the HIV, Hepatitis, and Related Conditions Programs in the VA Office of Specialty Care Services convened a National Hepatitis B Working Group consisting of VA subject matter experts (SMEs) and representatives from the VA Central Office stakeholder program offices, with a charge of developing a strategic plan to ensure excellence in HBV prevention, care, and management across the VHA. The task included addressing supportive processes and barriers at each level of the organization through a public health framework and using a population health management approach.

The VA National Strategic Plan for Excellence in HBV Care was focused on the following overarching aims:

• Characterizing the current state of care for veterans with HBV in VA care;
• Developing and disseminating clinical guidance on high-quality care for patients with HBV;
• Developing population data and informatics tools to streamline the identification and monitoring of patients with chronic HBV; and
• Evaluating VHA care for patients with HBV over time.

Care for Veterans With HBV at the VA

The VA health care system is America’s largest integrated health care system, providing care at 1,243 health care facilities, including 170 medical centers and 1,063 outpatient sites of care serving 9 million enrolled veterans each year.¹³ As of January 2018, there were 10,743 individuals with serologic evidence for chronic HBV infection in VA care, based on a definition of 2 or more detectable surface antigen (sAg) or hepatitis B DNA tests recorded at least 6 months apart.¹ About 2,000 additional VA patients have a history of a single positive sAg test. These patients have unclear HBV status and require a second sAg test to determine whether they have a chronic infection.

The prevalence of HBV infection among veterans in VA care is slightly higher than that in the US civilian population at 0.4%.¹⁴ Studies of selected subpopulations of veterans have found high seropositivity of prior or chronic HBV infection among homeless veterans and veterans admitted to a psychiatric hospital.^15,16 The data from 2015 suggest that homeless veterans have a chronic HBV infection rate of 1.0%.¹⁴ Of those with known chronic HBV infection, the plurality are white (40.4%) or African American (40.2%), male (92.4%), with a mean age of 59.9 (SD 12.0) years. According to National HIV, Hepatitis and Related Conditions Data and Analysis Group personal correspondence, the geographic territories with the largest chronic HBV caseload include the Southeast, Gulf Coast, and West Coast. As of January 2018, 1,210 veterans in care have HBV-related cirrhosis.

HBV Screening in VA

The current VA HBV screening guidelines follow those of the US Preventive Services Task Force (USPSTF).¹⁷ HBV screening is recommended for unvaccinated individuals in high-risk groups, such as patients with HIV or hepatitis C virus (HCV), those on hemodialysis, those with elevated alanine transaminase/aspartate transaminase of unknown etiology, those on immunosuppressive therapy, injection drug users, the MSM population, people with household contact with an HBV-infected person, people born to an HBV-infected mother, those with risk factors for HBV exposure prior to vaccination, pregnant women, and people born in highly endemic areas regardless of vaccination status.² The VHA recommends against standardized risk assessment and laboratory screening for HBV infection in the asymptomatic general patient population. However, if risk factors become known during the course of providing usual clinical care, then laboratory screening should be considered.²

Of the 6.1 million VHA users in fiscal year (FY) 2016, 26% have received HBV testing, an increase from 21.8% in FY 2013, despite enrollment of nearly 500,000 new VA users since that time. Screening rates for HBV among veterans in VHA care with HIV and HCV are > 94%.¹⁸ The VHA screening rates for HBV for veterans receiving immunosuppressive therapy, who inject drugs, or who have sexually transmitted infection are estimated to be 43.9%, 53.5%, and 51.4%, respectively.¹⁸ Testing for HBV sAg in homeless US veterans is estimated at 52.8% using data from a 2015 prevalence study.¹⁴

HBV Care and VA Antiviral Treatment

In a study of an HBV care cascade, Serper and colleagues reviewed a cohort of veterans in the VA with HBV. About 50% of the patients with known chronic HBV in the VA system from 1999 to 2013 had received infectious diseases or gastroenterology/hepatology specialty care in the previous 2 years.¹⁹ Follow-up data from the National HIV, Hepatitis and Related Conditions Data and Analysis Group indicated that this remains the case: 52.3% of patients with documented chronic HBV had received specialty care from VA sources in the prior 2 years. Serper and colleagues also reported that among veterans in VHA care with chronic HBV infection and cirrhosis from 1999 to 2013, annual imaging was < 50%, and initiation of antiviral treatment was only 39%. Antiviral therapy and liver imaging were both independently associated with lower mortality for patients with HBV and cirrhosis.¹⁹

A review of studies that evaluated the delivery of care for patients with HBV in U.S. civilian populations, including retrospective reviews of private payer claims databases and chart reviews, the Kaiser Permanente claims database, and community gastrointestinal (GI) practice chart reviews, revealed similar practice patterns with those in the VA.²⁰ Across the US, rates of antiviral therapy and HCC surveillance for those with HBV cirrhosis were low, ranging from 14% to 50% and 19% to 60%, respectively. Several of these studies also found that being seen by an HBV specialist was associated with improved care.²⁰

Antiviral treatment of individuals with cirrhosis and chronic HBV infection can reduce the risk of progression to decompensated cirrhosis and liver cancer. Among current VA patients with HBV cirrhosis, 62.4% received at least 1 month of HBV antiviral medication in the prior year. Additionally, biannual liver imaging is recommended in this population to screen for the development of HCC. According to National HIV, Hepatitis and Related Conditions Data and Analysis Group personal correspondence, nationally, 51.2% of individuals with HBV cirrhosis had received at least one instance of liver imaging within the past 6 months, and 71.2% received imaging within the past 12 months.

Prevention of HBV Infection and Sequelae

Vaccination rates in the US vary by age group, with higher immunization rates among those born after 1991 than the rates of those born earlier. Data from the National Health and Nutrition Examination Survey from 1988 to 2012 reported 33% immunity among veterans aged < 50 years and 6% among those aged ≥ 50 years.²¹ In addition to individuals who received childhood vaccination in the 1990s, all new military recruits assigned to the Korean Peninsula were vaccinated for HBV as of 1986, and those joining the military after 2002 received mandatory vaccination.

The VA follows the ACIP/CDC hepatitis B immunization guidelines.^22-24 The VA currently recommends HBV immunization among previously unvaccinated adults at increased risk of contracting HBV infection and for any other adult who is seeking protection from HBV infection. The VA also offers general recommendations for prevention of transmission between veterans with known chronic HBV to their household, sexual, or drug-using partners. Transmission prevention guidelines also provide recommendations for vaccination of pregnant women with HBV risk factors and women at risk for HBV infection during pregnancy.²²

HBV Care Guidance

One of the core tasks of the VA National Hepatitis B Working Group, given its broad, multidisciplinary expertise in HBV, was developing general clinical guidelines for the provision of high-quality care for patients with HBV. The group reviewed current literature and scientific evidence on care for patients with HBV. The working group relied heavily on the VA’s national guidelines for HBV screening and immunization, which are based on recommendations from the USPSTF, ACIP, CDC, and professional societies. The professional society guidelines included the American Association for the Study of Liver Disease’s Guidelines for Treatment of Chronic Hepatitis B, the America College of Gastroenterology’s Practice Guidelines: Evaluation of Abnormal Liver Chemistries, the American Gastroenterological Association Institute’s Guidelines for Prevention and Treatment of Hepatitis B Reactivation during Immunosuppressive Drug Therapy, and CDC’s Guidelines for Screening Pregnant Women for HBV.^19,22-27

The working group identified areas for HBV quality improvement that were consistent with the VA and professional guidelines, specific and measurable using VA data, clinically relevant, feasible, and achievable in a defined time period. Areas for targeted improvement will include testing for HBV among high-risk patients, increasing antiviral treatment and HCC surveillance of veterans with HBV-related cirrhosis, decreasing progression of chronic HBV to cirrhosis, and expanding prevention measures, such as immunization among those at high risk for HBV and prevention of HBV reactivation.

At a national level, development of specific and measurable quality of care indicators for HBV will aid in assessing gaps in care and developing strategies to address these gaps. A broader discussion of care for patients with HBV quality with front-line health care providers (HCPs) will be paired with increased education and providing clinical support tools for those HCPs and facilities without access to specialty GI services.

Clinical pharmacists will be critical targets for the dissemination of guidance for HBV care paired with clinical informatics support tools and clinical educational opportunities. As of 2015, there were about 7,700 clinical pharmacists in the VHA and 3,200 had a scope of practice that included prescribing authority. As a result, 20% of HCV prescriptions in the VA in fiscal year 2015 were written by a clinical pharmacy specialist.²⁸ Since then, the VA has expanded the education and support of clinical pharmacists in the care of patients with HCV and advanced liver disease, making them uniquely suited to provide additional support for a complex, low-prevalence disease like HBV.

Identification and Monitoring

The HBV working group and the VA Viral Hepatitis Technical Advisory Group are working with field HCPs to develop several informatics tools to promote HBV case identification and quality monitoring. These groups identified several barriers to HBV case identification and monitoring. The following informatics tools are either available or in development to reduce these barriers:

1. A local clinical case registry of patients with HBV infection based on ICD codes, which allows users to create custom reports to identify, monitor, and track care;
2. Because of the risk of HBV reactivation in patients with chronic HBV infection who receive anti-CD20 agents, such as rituximab, a medication order check to improve HBV screening among veterans receiving anti-CD20 medication;
3. Validated patient reports based on laboratory diagnosis of HBV, drawn from all results across the VHA since 1999, made available to all facilities;
4. Interactive reports summarizing quality of care for patients with HBV infection, based on facility-level indicators in development by the national HBV working group, will be distributed and enable geographic comparison;
5. An HBV immunization clinical reminder that will prompt frontline HCPs to test and vaccinate; and
6. An HBV clinical dashboard that will enable HCPs and facilities to identify all their HBV-positive veterans and track their care and outcomes over time.

Evaluating VA Care for Patients with HBV

As indicators of quality of HBV care are refined for VA patients and the health care delivery system, guidance will be made broadly available to frontline HCPs and administrators. The HBV quality of care recommendations will be paired with a suite of clinical informatics tools and virtual educational trainings to ensure that VA HCPs and facilities can streamline care for patients with HBV infection as much as possible. Quality improvement will be measured nationally each year, and strategies to address persistent variability and gaps in care will be developed in collaboration with the VA SME’s, facilities, and HCPs.

Conclusion

Hepatitis B virus is at least as prevalent among veterans who are cared for at VA facilities as it is in the US civilian population. Although care for patients with HBV infection in the VA is similar to care for patients with HBV infection in the community, the VA recognizes areas for improved HBV prevention, testing, care, and treatment. The VA has begun a continuous quality improvement strategic plan to enhance the level of care for patients with HBV infection in VA care. Centralized coordination and communication of VA data combined with veteran- and field-centered policies and operational planning and execution will allow clinically relevant improvements in HBV diagnosis, treatment, and prevention among veterans served by VA.

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Hepatitis B is a viral infection caused by the hepatitis B virus (HBV), which is transmitted through percutaneous (ie, puncture through the skin) or mucosal (ie, direct contact with mucous membranes) exposure to infectious blood or body fluids. Hepatitis B virus can cause chronic infection, resulting in cirrhosis of the liver, liver cancer, liver failure, and death. Persons with chronic infection also serve as the main reservoir for continued HBV transmission.¹

Individuals at highest risk for infection include those born in geographic regions with a high prevalence of HBV, those with sexual partners or household contacts with chronic HBV infection, men who have sex with men (MSM), those with HIV, and individuals who inject drugs. Pregnant women also are a population of concern given the potential for perinatal transmission.²

About 850,000 to 2.2 million people in the US (about 0.3% of the civilian US population) are chronically infected with HBV.³ The prevalence of chronic HBV is much higher (10%-19%) among Asian Americans, those of Pacific Island descent, and other immigrant populations from highly endemic countries.⁴ In the US, HBV is responsible for 2,000 to 4,000 preventable deaths annually, primarily from cirrhosis, liver cancer, and hepatic failure.⁴ In the civilian US population, reported cases of acute HBV decreased 0.3% from 2011 to 2012, increased 5.4% in 2013 with an 8.5% decrease in 2014, and a 20.7% increase in 2015.⁴ Injection drug use is likely driving the most recent increase.⁵

Not all individuals exposed to HBV will develop chronic infection, and the risk of chronic HBV infection depends on an individual’s age at the time of exposure. For example, about 95% of infants exposed to HBV perinatally will develop a chronic infection compared with 5% of exposed adults.⁶ Of those with chronic HBV, a small proportion will develop cirrhosis and/or hepatocellular carcinoma (HCC) with increasing risk as viral DNA concentrations increase. Additional risk factors for cirrhosis include being older, male, having a persistently elevated alanine transaminase, viral superinfections, HBV reversion/reactivation, genotype, and various markers of disease severity (HCC).⁶ Of note, chronic HBV infection may cause HCC even in the absence of cirrhosis.⁷ In addition, immunosuppression (eg, from cancer chemotherapy) may allow HBV reactivation, which may result in fulminant hepatic failure. In the Veterans Health Affairs (VHA) health care system, about 17% of those with known chronic HBV also carry a diagnosis of cirrhosis.

Vaccination is the mainstay of efforts to prevent HBV infection. The first commercially available HBV vaccine was approved by the FDA in 1981, with subsequent FDA approval in 1986 of a vaccine manufactured using recombinant DNA technology.⁸ In 1991, the Advisory Committee on Immunization Practices (ACIP) recommended universal childhood vaccination for HBV, with subsequent recommendations for vaccination of adolescents and adults in high-risk groups in 1995, and in 1999 all remaining unvaccinated children aged ≤ 19 years.⁹ Military policy has been to provide hepatitis B immunization to personnel assigned to the Korean peninsula since 1986 and to all recruits since 2001.¹⁰

Following publication of an Institute of Medicine/National Academies of Sciences, Engineering, and Medicine (NASEM) report, in 2011 the US Department of Health and Human Services (HHS) released the first National Viral Hepatitis Action Plan.¹¹ The current HHS Action Plan, along with the NASEM National Strategy for the Elimination of Hepatitis B and C: Phase Two Report, commissioned by the US Centers for Disease Control and Prevention (CDC), outlines a national strategy to prevent new viral hepatitis infections; reduce deaths and improve the health of people living with viral hepatitis; reduce viral hepatitis health disparities; and coordinate, monitor, and report on implementation of viral hepatitis activities.¹² The VA is a critical partner in this federal collaborative effort to achieve excellence in viral hepatitis care.

In August 2016, the HIV, Hepatitis, and Related Conditions Programs in the VA Office of Specialty Care Services convened a National Hepatitis B Working Group consisting of VA subject matter experts (SMEs) and representatives from the VA Central Office stakeholder program offices, with a charge of developing a strategic plan to ensure excellence in HBV prevention, care, and management across the VHA. The task included addressing supportive processes and barriers at each level of the organization through a public health framework and using a population health management approach.

The VA National Strategic Plan for Excellence in HBV Care was focused on the following overarching aims:

• Characterizing the current state of care for veterans with HBV in VA care;
• Developing and disseminating clinical guidance on high-quality care for patients with HBV;
• Developing population data and informatics tools to streamline the identification and monitoring of patients with chronic HBV; and
• Evaluating VHA care for patients with HBV over time.

Care for Veterans With HBV at the VA

The VA health care system is America’s largest integrated health care system, providing care at 1,243 health care facilities, including 170 medical centers and 1,063 outpatient sites of care serving 9 million enrolled veterans each year.¹³ As of January 2018, there were 10,743 individuals with serologic evidence for chronic HBV infection in VA care, based on a definition of 2 or more detectable surface antigen (sAg) or hepatitis B DNA tests recorded at least 6 months apart.¹ About 2,000 additional VA patients have a history of a single positive sAg test. These patients have unclear HBV status and require a second sAg test to determine whether they have a chronic infection.

The prevalence of HBV infection among veterans in VA care is slightly higher than that in the US civilian population at 0.4%.¹⁴ Studies of selected subpopulations of veterans have found high seropositivity of prior or chronic HBV infection among homeless veterans and veterans admitted to a psychiatric hospital.^15,16 The data from 2015 suggest that homeless veterans have a chronic HBV infection rate of 1.0%.¹⁴ Of those with known chronic HBV infection, the plurality are white (40.4%) or African American (40.2%), male (92.4%), with a mean age of 59.9 (SD 12.0) years. According to National HIV, Hepatitis and Related Conditions Data and Analysis Group personal correspondence, the geographic territories with the largest chronic HBV caseload include the Southeast, Gulf Coast, and West Coast. As of January 2018, 1,210 veterans in care have HBV-related cirrhosis.

HBV Screening in VA

The current VA HBV screening guidelines follow those of the US Preventive Services Task Force (USPSTF).¹⁷ HBV screening is recommended for unvaccinated individuals in high-risk groups, such as patients with HIV or hepatitis C virus (HCV), those on hemodialysis, those with elevated alanine transaminase/aspartate transaminase of unknown etiology, those on immunosuppressive therapy, injection drug users, the MSM population, people with household contact with an HBV-infected person, people born to an HBV-infected mother, those with risk factors for HBV exposure prior to vaccination, pregnant women, and people born in highly endemic areas regardless of vaccination status.² The VHA recommends against standardized risk assessment and laboratory screening for HBV infection in the asymptomatic general patient population. However, if risk factors become known during the course of providing usual clinical care, then laboratory screening should be considered.²

Of the 6.1 million VHA users in fiscal year (FY) 2016, 26% have received HBV testing, an increase from 21.8% in FY 2013, despite enrollment of nearly 500,000 new VA users since that time. Screening rates for HBV among veterans in VHA care with HIV and HCV are > 94%.¹⁸ The VHA screening rates for HBV for veterans receiving immunosuppressive therapy, who inject drugs, or who have sexually transmitted infection are estimated to be 43.9%, 53.5%, and 51.4%, respectively.¹⁸ Testing for HBV sAg in homeless US veterans is estimated at 52.8% using data from a 2015 prevalence study.¹⁴

HBV Care and VA Antiviral Treatment

In a study of an HBV care cascade, Serper and colleagues reviewed a cohort of veterans in the VA with HBV. About 50% of the patients with known chronic HBV in the VA system from 1999 to 2013 had received infectious diseases or gastroenterology/hepatology specialty care in the previous 2 years.¹⁹ Follow-up data from the National HIV, Hepatitis and Related Conditions Data and Analysis Group indicated that this remains the case: 52.3% of patients with documented chronic HBV had received specialty care from VA sources in the prior 2 years. Serper and colleagues also reported that among veterans in VHA care with chronic HBV infection and cirrhosis from 1999 to 2013, annual imaging was < 50%, and initiation of antiviral treatment was only 39%. Antiviral therapy and liver imaging were both independently associated with lower mortality for patients with HBV and cirrhosis.¹⁹

A review of studies that evaluated the delivery of care for patients with HBV in U.S. civilian populations, including retrospective reviews of private payer claims databases and chart reviews, the Kaiser Permanente claims database, and community gastrointestinal (GI) practice chart reviews, revealed similar practice patterns with those in the VA.²⁰ Across the US, rates of antiviral therapy and HCC surveillance for those with HBV cirrhosis were low, ranging from 14% to 50% and 19% to 60%, respectively. Several of these studies also found that being seen by an HBV specialist was associated with improved care.²⁰

Antiviral treatment of individuals with cirrhosis and chronic HBV infection can reduce the risk of progression to decompensated cirrhosis and liver cancer. Among current VA patients with HBV cirrhosis, 62.4% received at least 1 month of HBV antiviral medication in the prior year. Additionally, biannual liver imaging is recommended in this population to screen for the development of HCC. According to National HIV, Hepatitis and Related Conditions Data and Analysis Group personal correspondence, nationally, 51.2% of individuals with HBV cirrhosis had received at least one instance of liver imaging within the past 6 months, and 71.2% received imaging within the past 12 months.

Prevention of HBV Infection and Sequelae

Vaccination rates in the US vary by age group, with higher immunization rates among those born after 1991 than the rates of those born earlier. Data from the National Health and Nutrition Examination Survey from 1988 to 2012 reported 33% immunity among veterans aged < 50 years and 6% among those aged ≥ 50 years.²¹ In addition to individuals who received childhood vaccination in the 1990s, all new military recruits assigned to the Korean Peninsula were vaccinated for HBV as of 1986, and those joining the military after 2002 received mandatory vaccination.

The VA follows the ACIP/CDC hepatitis B immunization guidelines.^22-24 The VA currently recommends HBV immunization among previously unvaccinated adults at increased risk of contracting HBV infection and for any other adult who is seeking protection from HBV infection. The VA also offers general recommendations for prevention of transmission between veterans with known chronic HBV to their household, sexual, or drug-using partners. Transmission prevention guidelines also provide recommendations for vaccination of pregnant women with HBV risk factors and women at risk for HBV infection during pregnancy.²²

HBV Care Guidance

One of the core tasks of the VA National Hepatitis B Working Group, given its broad, multidisciplinary expertise in HBV, was developing general clinical guidelines for the provision of high-quality care for patients with HBV. The group reviewed current literature and scientific evidence on care for patients with HBV. The working group relied heavily on the VA’s national guidelines for HBV screening and immunization, which are based on recommendations from the USPSTF, ACIP, CDC, and professional societies. The professional society guidelines included the American Association for the Study of Liver Disease’s Guidelines for Treatment of Chronic Hepatitis B, the America College of Gastroenterology’s Practice Guidelines: Evaluation of Abnormal Liver Chemistries, the American Gastroenterological Association Institute’s Guidelines for Prevention and Treatment of Hepatitis B Reactivation during Immunosuppressive Drug Therapy, and CDC’s Guidelines for Screening Pregnant Women for HBV.^19,22-27

The working group identified areas for HBV quality improvement that were consistent with the VA and professional guidelines, specific and measurable using VA data, clinically relevant, feasible, and achievable in a defined time period. Areas for targeted improvement will include testing for HBV among high-risk patients, increasing antiviral treatment and HCC surveillance of veterans with HBV-related cirrhosis, decreasing progression of chronic HBV to cirrhosis, and expanding prevention measures, such as immunization among those at high risk for HBV and prevention of HBV reactivation.

At a national level, development of specific and measurable quality of care indicators for HBV will aid in assessing gaps in care and developing strategies to address these gaps. A broader discussion of care for patients with HBV quality with front-line health care providers (HCPs) will be paired with increased education and providing clinical support tools for those HCPs and facilities without access to specialty GI services.

Clinical pharmacists will be critical targets for the dissemination of guidance for HBV care paired with clinical informatics support tools and clinical educational opportunities. As of 2015, there were about 7,700 clinical pharmacists in the VHA and 3,200 had a scope of practice that included prescribing authority. As a result, 20% of HCV prescriptions in the VA in fiscal year 2015 were written by a clinical pharmacy specialist.²⁸ Since then, the VA has expanded the education and support of clinical pharmacists in the care of patients with HCV and advanced liver disease, making them uniquely suited to provide additional support for a complex, low-prevalence disease like HBV.

Identification and Monitoring

The HBV working group and the VA Viral Hepatitis Technical Advisory Group are working with field HCPs to develop several informatics tools to promote HBV case identification and quality monitoring. These groups identified several barriers to HBV case identification and monitoring. The following informatics tools are either available or in development to reduce these barriers:

1. A local clinical case registry of patients with HBV infection based on ICD codes, which allows users to create custom reports to identify, monitor, and track care;
2. Because of the risk of HBV reactivation in patients with chronic HBV infection who receive anti-CD20 agents, such as rituximab, a medication order check to improve HBV screening among veterans receiving anti-CD20 medication;
3. Validated patient reports based on laboratory diagnosis of HBV, drawn from all results across the VHA since 1999, made available to all facilities;
4. Interactive reports summarizing quality of care for patients with HBV infection, based on facility-level indicators in development by the national HBV working group, will be distributed and enable geographic comparison;
5. An HBV immunization clinical reminder that will prompt frontline HCPs to test and vaccinate; and
6. An HBV clinical dashboard that will enable HCPs and facilities to identify all their HBV-positive veterans and track their care and outcomes over time.

Evaluating VA Care for Patients with HBV

As indicators of quality of HBV care are refined for VA patients and the health care delivery system, guidance will be made broadly available to frontline HCPs and administrators. The HBV quality of care recommendations will be paired with a suite of clinical informatics tools and virtual educational trainings to ensure that VA HCPs and facilities can streamline care for patients with HBV infection as much as possible. Quality improvement will be measured nationally each year, and strategies to address persistent variability and gaps in care will be developed in collaboration with the VA SME’s, facilities, and HCPs.

Conclusion

Hepatitis B virus is at least as prevalent among veterans who are cared for at VA facilities as it is in the US civilian population. Although care for patients with HBV infection in the VA is similar to care for patients with HBV infection in the community, the VA recognizes areas for improved HBV prevention, testing, care, and treatment. The VA has begun a continuous quality improvement strategic plan to enhance the level of care for patients with HBV infection in VA care. Centralized coordination and communication of VA data combined with veteran- and field-centered policies and operational planning and execution will allow clinically relevant improvements in HBV diagnosis, treatment, and prevention among veterans served by VA.

Click here to read the digital edition.

Hepatitis B is a viral infection caused by the hepatitis B virus (HBV), which is transmitted through percutaneous (ie, puncture through the skin) or mucosal (ie, direct contact with mucous membranes) exposure to infectious blood or body fluids. Hepatitis B virus can cause chronic infection, resulting in cirrhosis of the liver, liver cancer, liver failure, and death. Persons with chronic infection also serve as the main reservoir for continued HBV transmission.¹

Individuals at highest risk for infection include those born in geographic regions with a high prevalence of HBV, those with sexual partners or household contacts with chronic HBV infection, men who have sex with men (MSM), those with HIV, and individuals who inject drugs. Pregnant women also are a population of concern given the potential for perinatal transmission.²

About 850,000 to 2.2 million people in the US (about 0.3% of the civilian US population) are chronically infected with HBV.³ The prevalence of chronic HBV is much higher (10%-19%) among Asian Americans, those of Pacific Island descent, and other immigrant populations from highly endemic countries.⁴ In the US, HBV is responsible for 2,000 to 4,000 preventable deaths annually, primarily from cirrhosis, liver cancer, and hepatic failure.⁴ In the civilian US population, reported cases of acute HBV decreased 0.3% from 2011 to 2012, increased 5.4% in 2013 with an 8.5% decrease in 2014, and a 20.7% increase in 2015.⁴ Injection drug use is likely driving the most recent increase.⁵

Not all individuals exposed to HBV will develop chronic infection, and the risk of chronic HBV infection depends on an individual’s age at the time of exposure. For example, about 95% of infants exposed to HBV perinatally will develop a chronic infection compared with 5% of exposed adults.⁶ Of those with chronic HBV, a small proportion will develop cirrhosis and/or hepatocellular carcinoma (HCC) with increasing risk as viral DNA concentrations increase. Additional risk factors for cirrhosis include being older, male, having a persistently elevated alanine transaminase, viral superinfections, HBV reversion/reactivation, genotype, and various markers of disease severity (HCC).⁶ Of note, chronic HBV infection may cause HCC even in the absence of cirrhosis.⁷ In addition, immunosuppression (eg, from cancer chemotherapy) may allow HBV reactivation, which may result in fulminant hepatic failure. In the Veterans Health Affairs (VHA) health care system, about 17% of those with known chronic HBV also carry a diagnosis of cirrhosis.

Vaccination is the mainstay of efforts to prevent HBV infection. The first commercially available HBV vaccine was approved by the FDA in 1981, with subsequent FDA approval in 1986 of a vaccine manufactured using recombinant DNA technology.⁸ In 1991, the Advisory Committee on Immunization Practices (ACIP) recommended universal childhood vaccination for HBV, with subsequent recommendations for vaccination of adolescents and adults in high-risk groups in 1995, and in 1999 all remaining unvaccinated children aged ≤ 19 years.⁹ Military policy has been to provide hepatitis B immunization to personnel assigned to the Korean peninsula since 1986 and to all recruits since 2001.¹⁰

Following publication of an Institute of Medicine/National Academies of Sciences, Engineering, and Medicine (NASEM) report, in 2011 the US Department of Health and Human Services (HHS) released the first National Viral Hepatitis Action Plan.¹¹ The current HHS Action Plan, along with the NASEM National Strategy for the Elimination of Hepatitis B and C: Phase Two Report, commissioned by the US Centers for Disease Control and Prevention (CDC), outlines a national strategy to prevent new viral hepatitis infections; reduce deaths and improve the health of people living with viral hepatitis; reduce viral hepatitis health disparities; and coordinate, monitor, and report on implementation of viral hepatitis activities.¹² The VA is a critical partner in this federal collaborative effort to achieve excellence in viral hepatitis care.

In August 2016, the HIV, Hepatitis, and Related Conditions Programs in the VA Office of Specialty Care Services convened a National Hepatitis B Working Group consisting of VA subject matter experts (SMEs) and representatives from the VA Central Office stakeholder program offices, with a charge of developing a strategic plan to ensure excellence in HBV prevention, care, and management across the VHA. The task included addressing supportive processes and barriers at each level of the organization through a public health framework and using a population health management approach.

The VA National Strategic Plan for Excellence in HBV Care was focused on the following overarching aims:

• Characterizing the current state of care for veterans with HBV in VA care;
• Developing and disseminating clinical guidance on high-quality care for patients with HBV;
• Developing population data and informatics tools to streamline the identification and monitoring of patients with chronic HBV; and
• Evaluating VHA care for patients with HBV over time.

Care for Veterans With HBV at the VA

The VA health care system is America’s largest integrated health care system, providing care at 1,243 health care facilities, including 170 medical centers and 1,063 outpatient sites of care serving 9 million enrolled veterans each year.¹³ As of January 2018, there were 10,743 individuals with serologic evidence for chronic HBV infection in VA care, based on a definition of 2 or more detectable surface antigen (sAg) or hepatitis B DNA tests recorded at least 6 months apart.¹ About 2,000 additional VA patients have a history of a single positive sAg test. These patients have unclear HBV status and require a second sAg test to determine whether they have a chronic infection.

The prevalence of HBV infection among veterans in VA care is slightly higher than that in the US civilian population at 0.4%.¹⁴ Studies of selected subpopulations of veterans have found high seropositivity of prior or chronic HBV infection among homeless veterans and veterans admitted to a psychiatric hospital.^15,16 The data from 2015 suggest that homeless veterans have a chronic HBV infection rate of 1.0%.¹⁴ Of those with known chronic HBV infection, the plurality are white (40.4%) or African American (40.2%), male (92.4%), with a mean age of 59.9 (SD 12.0) years. According to National HIV, Hepatitis and Related Conditions Data and Analysis Group personal correspondence, the geographic territories with the largest chronic HBV caseload include the Southeast, Gulf Coast, and West Coast. As of January 2018, 1,210 veterans in care have HBV-related cirrhosis.

HBV Screening in VA

The current VA HBV screening guidelines follow those of the US Preventive Services Task Force (USPSTF).¹⁷ HBV screening is recommended for unvaccinated individuals in high-risk groups, such as patients with HIV or hepatitis C virus (HCV), those on hemodialysis, those with elevated alanine transaminase/aspartate transaminase of unknown etiology, those on immunosuppressive therapy, injection drug users, the MSM population, people with household contact with an HBV-infected person, people born to an HBV-infected mother, those with risk factors for HBV exposure prior to vaccination, pregnant women, and people born in highly endemic areas regardless of vaccination status.² The VHA recommends against standardized risk assessment and laboratory screening for HBV infection in the asymptomatic general patient population. However, if risk factors become known during the course of providing usual clinical care, then laboratory screening should be considered.²

Of the 6.1 million VHA users in fiscal year (FY) 2016, 26% have received HBV testing, an increase from 21.8% in FY 2013, despite enrollment of nearly 500,000 new VA users since that time. Screening rates for HBV among veterans in VHA care with HIV and HCV are > 94%.¹⁸ The VHA screening rates for HBV for veterans receiving immunosuppressive therapy, who inject drugs, or who have sexually transmitted infection are estimated to be 43.9%, 53.5%, and 51.4%, respectively.¹⁸ Testing for HBV sAg in homeless US veterans is estimated at 52.8% using data from a 2015 prevalence study.¹⁴

HBV Care and VA Antiviral Treatment

In a study of an HBV care cascade, Serper and colleagues reviewed a cohort of veterans in the VA with HBV. About 50% of the patients with known chronic HBV in the VA system from 1999 to 2013 had received infectious diseases or gastroenterology/hepatology specialty care in the previous 2 years.¹⁹ Follow-up data from the National HIV, Hepatitis and Related Conditions Data and Analysis Group indicated that this remains the case: 52.3% of patients with documented chronic HBV had received specialty care from VA sources in the prior 2 years. Serper and colleagues also reported that among veterans in VHA care with chronic HBV infection and cirrhosis from 1999 to 2013, annual imaging was < 50%, and initiation of antiviral treatment was only 39%. Antiviral therapy and liver imaging were both independently associated with lower mortality for patients with HBV and cirrhosis.¹⁹

A review of studies that evaluated the delivery of care for patients with HBV in U.S. civilian populations, including retrospective reviews of private payer claims databases and chart reviews, the Kaiser Permanente claims database, and community gastrointestinal (GI) practice chart reviews, revealed similar practice patterns with those in the VA.²⁰ Across the US, rates of antiviral therapy and HCC surveillance for those with HBV cirrhosis were low, ranging from 14% to 50% and 19% to 60%, respectively. Several of these studies also found that being seen by an HBV specialist was associated with improved care.²⁰

Antiviral treatment of individuals with cirrhosis and chronic HBV infection can reduce the risk of progression to decompensated cirrhosis and liver cancer. Among current VA patients with HBV cirrhosis, 62.4% received at least 1 month of HBV antiviral medication in the prior year. Additionally, biannual liver imaging is recommended in this population to screen for the development of HCC. According to National HIV, Hepatitis and Related Conditions Data and Analysis Group personal correspondence, nationally, 51.2% of individuals with HBV cirrhosis had received at least one instance of liver imaging within the past 6 months, and 71.2% received imaging within the past 12 months.

Prevention of HBV Infection and Sequelae

Vaccination rates in the US vary by age group, with higher immunization rates among those born after 1991 than the rates of those born earlier. Data from the National Health and Nutrition Examination Survey from 1988 to 2012 reported 33% immunity among veterans aged < 50 years and 6% among those aged ≥ 50 years.²¹ In addition to individuals who received childhood vaccination in the 1990s, all new military recruits assigned to the Korean Peninsula were vaccinated for HBV as of 1986, and those joining the military after 2002 received mandatory vaccination.

The VA follows the ACIP/CDC hepatitis B immunization guidelines.^22-24 The VA currently recommends HBV immunization among previously unvaccinated adults at increased risk of contracting HBV infection and for any other adult who is seeking protection from HBV infection. The VA also offers general recommendations for prevention of transmission between veterans with known chronic HBV to their household, sexual, or drug-using partners. Transmission prevention guidelines also provide recommendations for vaccination of pregnant women with HBV risk factors and women at risk for HBV infection during pregnancy.²²

HBV Care Guidance

One of the core tasks of the VA National Hepatitis B Working Group, given its broad, multidisciplinary expertise in HBV, was developing general clinical guidelines for the provision of high-quality care for patients with HBV. The group reviewed current literature and scientific evidence on care for patients with HBV. The working group relied heavily on the VA’s national guidelines for HBV screening and immunization, which are based on recommendations from the USPSTF, ACIP, CDC, and professional societies. The professional society guidelines included the American Association for the Study of Liver Disease’s Guidelines for Treatment of Chronic Hepatitis B, the America College of Gastroenterology’s Practice Guidelines: Evaluation of Abnormal Liver Chemistries, the American Gastroenterological Association Institute’s Guidelines for Prevention and Treatment of Hepatitis B Reactivation during Immunosuppressive Drug Therapy, and CDC’s Guidelines for Screening Pregnant Women for HBV.^19,22-27

The working group identified areas for HBV quality improvement that were consistent with the VA and professional guidelines, specific and measurable using VA data, clinically relevant, feasible, and achievable in a defined time period. Areas for targeted improvement will include testing for HBV among high-risk patients, increasing antiviral treatment and HCC surveillance of veterans with HBV-related cirrhosis, decreasing progression of chronic HBV to cirrhosis, and expanding prevention measures, such as immunization among those at high risk for HBV and prevention of HBV reactivation.

At a national level, development of specific and measurable quality of care indicators for HBV will aid in assessing gaps in care and developing strategies to address these gaps. A broader discussion of care for patients with HBV quality with front-line health care providers (HCPs) will be paired with increased education and providing clinical support tools for those HCPs and facilities without access to specialty GI services.

Clinical pharmacists will be critical targets for the dissemination of guidance for HBV care paired with clinical informatics support tools and clinical educational opportunities. As of 2015, there were about 7,700 clinical pharmacists in the VHA and 3,200 had a scope of practice that included prescribing authority. As a result, 20% of HCV prescriptions in the VA in fiscal year 2015 were written by a clinical pharmacy specialist.²⁸ Since then, the VA has expanded the education and support of clinical pharmacists in the care of patients with HCV and advanced liver disease, making them uniquely suited to provide additional support for a complex, low-prevalence disease like HBV.

Identification and Monitoring

The HBV working group and the VA Viral Hepatitis Technical Advisory Group are working with field HCPs to develop several informatics tools to promote HBV case identification and quality monitoring. These groups identified several barriers to HBV case identification and monitoring. The following informatics tools are either available or in development to reduce these barriers:

1. A local clinical case registry of patients with HBV infection based on ICD codes, which allows users to create custom reports to identify, monitor, and track care;
2. Because of the risk of HBV reactivation in patients with chronic HBV infection who receive anti-CD20 agents, such as rituximab, a medication order check to improve HBV screening among veterans receiving anti-CD20 medication;
3. Validated patient reports based on laboratory diagnosis of HBV, drawn from all results across the VHA since 1999, made available to all facilities;
4. Interactive reports summarizing quality of care for patients with HBV infection, based on facility-level indicators in development by the national HBV working group, will be distributed and enable geographic comparison;
5. An HBV immunization clinical reminder that will prompt frontline HCPs to test and vaccinate; and
6. An HBV clinical dashboard that will enable HCPs and facilities to identify all their HBV-positive veterans and track their care and outcomes over time.

Evaluating VA Care for Patients with HBV

As indicators of quality of HBV care are refined for VA patients and the health care delivery system, guidance will be made broadly available to frontline HCPs and administrators. The HBV quality of care recommendations will be paired with a suite of clinical informatics tools and virtual educational trainings to ensure that VA HCPs and facilities can streamline care for patients with HBV infection as much as possible. Quality improvement will be measured nationally each year, and strategies to address persistent variability and gaps in care will be developed in collaboration with the VA SME’s, facilities, and HCPs.

Conclusion

Hepatitis B virus is at least as prevalent among veterans who are cared for at VA facilities as it is in the US civilian population. Although care for patients with HBV infection in the VA is similar to care for patients with HBV infection in the community, the VA recognizes areas for improved HBV prevention, testing, care, and treatment. The VA has begun a continuous quality improvement strategic plan to enhance the level of care for patients with HBV infection in VA care. Centralized coordination and communication of VA data combined with veteran- and field-centered policies and operational planning and execution will allow clinically relevant improvements in HBV diagnosis, treatment, and prevention among veterans served by VA.

Click here to read the digital edition.

VA Hepatitis C Treatment Progress

Lisa Backus, MD. For a long time the US Department of Veterans Affairs (VA) has approached hepatitis C virus (HCV) care in a comprehensive way. We have done extensive screening to look for people with HCV infection. Even before birth cohort testing was recommended by the Centers for Disease Control and Prevention (CDC), the VA had aggressive HCV screening programs.

From the VA Corporate Data Warehouse, we know that the VA has screened more than 80% of people who are in the 1945 to 1965 birth cohort in VA care. Over time, HCV prevalence has been dropping in screened veterans and by extension in those who remain to be screened. Based on internal modeling, the VA estimates that only 6,000 to 7,000 veterans in the 1945 to 1965 birth cohort remain to be found if we could somehow screen everyone in that group.

On the treatment side, the VA has provided an unparalleled amount of care. In data from the Clinical Case Registry: HCV, as of February 2018 the VA has started more than 104,000 veterans on direct-acting antiviral (DAA) treatment. When the DAAs first became available, we estimated that there were about 165,000 people who were HCV viremic and who needed to be treated. By the end of January 2018, that number was down to about 35,000 people. The VA has done an unbelievably good job of finding people, getting them into care, and treating them.

Samuel Ho, MD. I agree with Dr. Backus. The VA has done an excellent job over the past few years in treating a very significant proportion of our patients with HCV. In addition to the extensive screening efforts, I want to emphasize that going back to about the year 2000, the VA has been very active in supporting the establishment of HCV clinics within every VA medical center to identify and engage patients in treatment. At that time, of course, the treatment was with pegylated interferon and ribavirin, which was very challenging. The VA support consisted of funding 4 hepatitis C Resource Centers (HCRCs) nationwide, which were located in Minneapolis, Portland/Seattle, New Haven, and San Francisco.

The HCRCs reached out to every VA facility in the country, developed networks of health care providers (HCPs), trained them, and educated them regarding the HCV treatments and strategies to engage patients in care, especially the large numbers with comorbidities, such as psychiatric problems and substance use disorders. This highly engaged network of local HCV clinic providers was set up and running and was well poised to take advantage of the interferon-free DAAs when they became available in late 2013 and early 2014. With the continuing leadership of David Ross, MD, and many others at the national level, the VA then supported the development of HCV Innovation Teams in every VISN that continued the efforts to support local quality improvement initiatives related to HCV care.

That being said, the VA still has challenges. There are a significant number of people who have barriers to receiving treatment. For example, here at the VA San Diego Healthcare System, Dr. John Dever and our other colleagues looked at 481 patients who were high priority to get started on HCV treatment, because they were all believed to be a high risk for cirrhosis due to their Fibrosis-4 (FIB4) scores and other characteristics.¹

We really worked hard on that group, and of the ones who were eligible for treatment, 30% were either unwilling or unable to engage in care over a yearlong follow-up with multiple attempts at outreach. In comparison with patients who became engaged or were engaged in care, these nonengaged patients were significantly more likely to be homeless, have other comorbidities, or active alcohol and/or drug use. Not surprisingly, they had obvious barriers to engaging in care.

Further efforts need to be made to focus on these patients, maybe with innovative ideas and strategies for outreach to get them into treatment or to bring treatment to them. I’m not sure exactly as to what the best approach would be. There is ongoing research in that regard, but it still is a challenge.

Erica Trimble, NP. Our experience at VA San Francisco Health Care System is similar. If we actively reach out to veterans already engaged in primary care, we can usually engage them in the liver clinic as well. However, there are quite a number of veterans who engage regularly with HUD-VASH (US Department of House and Urban Development-VA Supportive Housing program) and other homeless veteran services but have no primary or specialty care engagement. These veterans are very difficult to reach.

We are collaborating with HUD-VASH social workers to see if there are more creative ways to connect with these veterans. Some of the ideas include having liver providers visit veteran housing locations, having HUD-VASH social workers convey messages to difficult-to-reach veterans, and problem-solving specific transportation issues that present barriers to care.

Christina Dickson, PharmD. At the VA Maryland Health Care System Baltimore VA Medical Center, we hear from veterans in our education classes about the various myths that are still out there in the community about HCV. Some of these myths are the reason that veterans may avoid seeking treatment or even attending the HCV clinic appointments. Some veterans say they didn’t come in previously because they thought they would need a liver biopsy or because their doctor told them they had to be completely sober in order to be considered for treatment. These can be major deterrents that keep patients away despite our outreach efforts. In addition to miseducation in the community, there also is still a reluctance to talk about HCV and the risk factors. Many patients don’t want to discuss their history or are concerned about their partners finding out, so they instead choose to ignore it altogether. The negative stigma of HCV is still present even in some of our HCPs.

Just as VA San Francisco is working to engage its homeless population, we are looking to work with mental health and substance abuse programs. More and more is being written about the importance of working with such teams and even colocating the HCV clinic with their services. For example, in Baltimore, the methadone clinic is 2 floors above our clinic. Some of the remaining viremic patients will go to the methadone clinic in the morning and then leave despite having an appointment just 2 floors down. Offering HCV services at the same time, in the same area may help to engage veterans to consider their liver health.

Ms. Trimble. VA San Francisco has been fortunate to have the assistance of our opiate replacement clinic staff as well; this is particularly helpful since many veterans visit the opiate replacement clinic daily for medications and know the staff there very well. The staff facilitate communication with the liver clinic, execute warm handoffs to the liver clinic, and provide daily dispensing of hepatitis C medications for a number of veterans who have more difficulty with medication adherence. It has worked very well.

Dr. Ho. I think what you both are pointing out is very important—these patients require teamwork. A multidisciplinary group of HCPs working together in a collaborative, integrated care model has been demonstrated to significantly improve HCV engagement, care, and treatment in these highly comorbid patients.² Whenever we can work together and build teams and recruit other HCPs in these other clinics, it will really pay off.

Dr. Backus. At VA Palo Alto Health Care System, we also run a program integrated with our 28-day and 90-day residential rehabilitation programs. We realized that those residential treatment programs were a place to reach people who we were having difficulties starting treatment. It was a perfect situation because if you were there for 28 days, we could nearly guarantee that at the very least the patient was going to get 28 days of medications. Particularly now with some of the shorter treatment courses, we only have to get a patient to take another 28 days, which is very doable. Clearly, for the people who are in 90-day programs, the full 8-week or 12-week course of treatment could be completed during the rehabilitation. In addition, we started out at a good place because the programs already screened automatically for HCV on admission to the program, so it was easy to identify people who had HCV.

Ms. Trimble. Specialty Care Access Network-Extension for Community Healthcare Outcomes (SCAN-ECHO) also can help with outreach. Alexander Monto, MD, and Helen Yee, PharmD, conduct weekly SCAN-ECHO video telehealth conferences with outlying HCPs from other clinics. The outlying HCPs submit cases for hepatitis C treatment consideration; then they take the recommendations from their discussion with Dr. Monto and Dr. Yee but lead the treatment with their patients.

Over time, with this ongoing mentoring, the participating providers have gained a lot of expertise in hepatitis C and serve as a local resource for their clinics. One of the clinics is in Eureka, California, which is nearly 300 miles away. In contrast, the other main clinic that participates is the downtown clinic. It serves the most urban and difficult-to-reach patients. The familiarity and rapport that the downtown clinic providers have with their patients allow them to more effectively engage patients for treatment initiation and follow-up.

Dr. Dickson. Our catchment area includes West Virginia, and we do telehealth for one of the sites, which has a number of 20-year-old and 30-year-old patients. In this slightly different population it is again a challenge getting and keeping them engaged as they go through the pretreatment evaluation. Some say that there may be a benefit to getting them on treatment as quickly as possible so that they don’t have time to disengage. The age difference brings about different barriers. We have to think outside the box on how to reach out to these patients. They work, they have kids, and they don’t feel ill right now. And many are active injection drug users. Trying to get them engaged in health care in general and on HCV treatment is the next big challenge.

Health Care Provider Education

Dr. Dickson. When we reach out to viremic veterans who’ve never been to our clinic, we will sometimes find comments such as, “patient not interested” or “patient still drinking” or no comment at all in the electronic health record primary care notes. So we began to focus our HCV education not only on veterans but also the providers. Some HCPs don’t consider the benefits of referring patients to the clinic for at least the opportunity to receive education on HCV, learning if there is any scarring on their liver, and learning about their options for treatment should they choose to proceed. We are continuing to meet with HCPs in all areas to let them know what’s offered in the HCV clinics. In addition, we have found that direct contact from our HCV clinic to veterans who were not interested is very successful. We get a chance to show that the VA cares and explain what our clinic offers and find that they are more than willing to arrange an appointment with us.

Ms. Trimble. I agree. We have successfully treated many veterans who are still using alcohol or drugs, and the VA supports considering any patient for treatment regardless of substance use; however, not all providers are aware of this. One of the other main education points for patients and providers is that they need not have severe liver disease to be considered for treatment. In the past, typically only patients with moderate to advanced liver fibrosis were considered for treatment, but this approach has changed in the past couple years.

Dr. Ho. I would agree that there still is a need to educate HCPs who may have had a presentation or read something on HCV a year or 2 ago. It’s now possible to treat almost all patients with HCV. It really has been fantastic, but not everyone is aware of it right now. That means we need to continue to be active with our colleagues and get them on the team. It is very helpful to increase enthusiasm if we can publicize new data and information coming out about the success in the VA of these DAA regimens.

Dr. Backus. There was a time when the DAAs first came out and the prices were higher and there was concern about the funding. At that time, we were treating only people with more advanced liver disease. Now we are treating everyone regardless of how advanced their liver disease is, but occasionally at VA Palo Alto I’ve run into providers who say, “The patient didn’t have cirrhosis, so I didn’t refer.” Education still needs to happen. It can be a little confusing because there was a time when we were not treating everyone. Now we are, and we have to make sure to get out this message.

Dr. Dickson. For patients with unstable comorbidities, HCPs may make the choice against HCV treatment. In the Baltimore clinic, we have case managers who will work with such patients and get to know them very well. Many times we do more than just cure their HCV. We also help them with their other conditions because we see them so often, such as helping with their pill boxes and encouraging them since they can see their liver enzymes getting better. There is a lot to be said for case management, the hands-on contact, and the concern that we can show these veterans. It helps not just the HCV but also their blood pressure and cholesterol are now controlled. We hear so many thanks from the veterans that come through our program. It might have taken a lot of work to get them to treatment, but in the end, they’re better overall.

Next Steps in HCV Care

Dr. Backus. The most pressing next step is becoming really creative and integrative about how to reach the more difficult-to-treat patients with comorbidities and reach the less-engaged populations. It is probably going to take some change in the models of care. For example, we are going to have to set up a clinic that is colocated in an opioid replacement therapy clinic or in the rehabilitation program. HCV care is going to have to evolve.

I think there is another issue that Dr. Dickson pointed out. Although it is small and really only occurs in some regions, there is a young population of people with HCV. Some of the models of care that we have used may not work with this population, and we have to recognize that this will be an ongoing issue. Care for these patients will look different. For example, clinics may need to provide child care for this younger population.

Cancer is another important issue. Many of these people have cirrhosis, and even if we cure their HCV, we have to remain cognizant that they still have cirrhosis and potentially need screening for hepatocellular carcinoma. They also may need care for their cirrhosis or counseling about ongoing alcohol use, because even though their HCV was cured, continued alcohol use is not good for their cirrhosis.

Those 3 issues are still in the immediate future of HCV care in the VA. The World Health Organization has a goal for eliminating HCV. One could hope that maybe we could get there; it may be possible through screening, treatment, and prevention strategies. If we are lucky, we could put ourselves out of a job. I don’t see that happening, but it’s a hope.

Ms. Trimble. Are we seeing the same trend in new infections in young injection drug using veterans that are being seen in the nonveteran population nationally?

Dr. Backus. We have looked at this quite closely. The CDC came out with a report recently that showed a substantial increase in HCV cases in people aged 20 to 39 years. At the VA, we have not seen that uptick. The VA rates of new infections or new diagnosis of infections in peopled aged 20 to 39 years are pretty stable. The VA screening rates in people who were born after 1965 is in the high 70% range—nearly as high as in the cohort of people born between 1945 and 1965. As a result, the VA has excellent internal data about the incidence of infections in younger populations. In the VA, we are not seeing this sort of massive increase in incidence in younger populations. Definitely, there are new young injection drug users in the VA who are contracting HCV but not what the CDC is reporting in other parts of the country.⁴

Ms. Trimble. That’s really interesting.

Dr. Ho. Part of that has been the fact that if you’re a VA patient, you had to have been engaged at some point with the VA with access to its extensive psychiatric mental health and substance use disorder treatment infrastructure. I wonder if the availability of these services is a factor that can be protecting our patients from this recent upsurge in injection drug use.

Dr. Dickson. For our VISN, we do have smaller sites with a number of their remaining viremic veterans in this young cohort who are indeed proving to be a challenge to link to care in the HCV clinics. We continue to brainstorm ideas to determine and overcome their barriers to treatment. The VA is excellent at connecting all of us nationwide, so we look forward to hearing from other sites in a similar situation on how they are overcoming this challenge. Because when you look outside the VA, many are wondering what to do and how to engage these patients.

Dr. Backus. One of the amazing things about HCV treatment is how effective it has been. Traditionally the real-world effectiveness for medications is not nearly as good as the clinical trial efficacy. Clinical trials have extra resources, specially trained doctors and nurses, and tend to recruit engaged and cooperative patients. Often, there has been a stepdown between the clinical efficacy from the trials and what we see in the real world. A pleasant surprise about DAA treatment at the VA is that the clinical effectiveness we see in the real world almost matches the amazing results seen in clinical trials. That also has been critical to the success that we are seeing. The medications are powerful, and even outside the settings of a clinical trial, they work incredibly well.

Dr. Ho. I agree. You, Dr. Backus, along with Pam Belperio, PharmD, George Ioannou MD, MS, and other VA researchers have done excellent work in documenting the real-world effectiveness of these medications in the VA system. It was surprising but not unexpected.^5-7 It is due to the VA’s excellent clinical infrastructure and that it provides an integrated system for caring for these patients. It is a measure of that success.

Dr. Dickson. The multidisciplinary teams are a major part of that. I don’t think we could care and support the veterans that we have, especially the challenging ones, the ones who are resistant, without having nursing, social work, mental health, and pharmacy involved. It’s just a huge team effort. That is what I love about caring for patients at the VA—it’s always been supportive of the multidisciplinary aspect of looking at this disease.

Click here to read the digital edition.

VA Hepatitis C Treatment Progress

Lisa Backus, MD. For a long time the US Department of Veterans Affairs (VA) has approached hepatitis C virus (HCV) care in a comprehensive way. We have done extensive screening to look for people with HCV infection. Even before birth cohort testing was recommended by the Centers for Disease Control and Prevention (CDC), the VA had aggressive HCV screening programs.

From the VA Corporate Data Warehouse, we know that the VA has screened more than 80% of people who are in the 1945 to 1965 birth cohort in VA care. Over time, HCV prevalence has been dropping in screened veterans and by extension in those who remain to be screened. Based on internal modeling, the VA estimates that only 6,000 to 7,000 veterans in the 1945 to 1965 birth cohort remain to be found if we could somehow screen everyone in that group.

On the treatment side, the VA has provided an unparalleled amount of care. In data from the Clinical Case Registry: HCV, as of February 2018 the VA has started more than 104,000 veterans on direct-acting antiviral (DAA) treatment. When the DAAs first became available, we estimated that there were about 165,000 people who were HCV viremic and who needed to be treated. By the end of January 2018, that number was down to about 35,000 people. The VA has done an unbelievably good job of finding people, getting them into care, and treating them.

Samuel Ho, MD. I agree with Dr. Backus. The VA has done an excellent job over the past few years in treating a very significant proportion of our patients with HCV. In addition to the extensive screening efforts, I want to emphasize that going back to about the year 2000, the VA has been very active in supporting the establishment of HCV clinics within every VA medical center to identify and engage patients in treatment. At that time, of course, the treatment was with pegylated interferon and ribavirin, which was very challenging. The VA support consisted of funding 4 hepatitis C Resource Centers (HCRCs) nationwide, which were located in Minneapolis, Portland/Seattle, New Haven, and San Francisco.

The HCRCs reached out to every VA facility in the country, developed networks of health care providers (HCPs), trained them, and educated them regarding the HCV treatments and strategies to engage patients in care, especially the large numbers with comorbidities, such as psychiatric problems and substance use disorders. This highly engaged network of local HCV clinic providers was set up and running and was well poised to take advantage of the interferon-free DAAs when they became available in late 2013 and early 2014. With the continuing leadership of David Ross, MD, and many others at the national level, the VA then supported the development of HCV Innovation Teams in every VISN that continued the efforts to support local quality improvement initiatives related to HCV care.

That being said, the VA still has challenges. There are a significant number of people who have barriers to receiving treatment. For example, here at the VA San Diego Healthcare System, Dr. John Dever and our other colleagues looked at 481 patients who were high priority to get started on HCV treatment, because they were all believed to be a high risk for cirrhosis due to their Fibrosis-4 (FIB4) scores and other characteristics.¹

We really worked hard on that group, and of the ones who were eligible for treatment, 30% were either unwilling or unable to engage in care over a yearlong follow-up with multiple attempts at outreach. In comparison with patients who became engaged or were engaged in care, these nonengaged patients were significantly more likely to be homeless, have other comorbidities, or active alcohol and/or drug use. Not surprisingly, they had obvious barriers to engaging in care.

Further efforts need to be made to focus on these patients, maybe with innovative ideas and strategies for outreach to get them into treatment or to bring treatment to them. I’m not sure exactly as to what the best approach would be. There is ongoing research in that regard, but it still is a challenge.

Erica Trimble, NP. Our experience at VA San Francisco Health Care System is similar. If we actively reach out to veterans already engaged in primary care, we can usually engage them in the liver clinic as well. However, there are quite a number of veterans who engage regularly with HUD-VASH (US Department of House and Urban Development-VA Supportive Housing program) and other homeless veteran services but have no primary or specialty care engagement. These veterans are very difficult to reach.

We are collaborating with HUD-VASH social workers to see if there are more creative ways to connect with these veterans. Some of the ideas include having liver providers visit veteran housing locations, having HUD-VASH social workers convey messages to difficult-to-reach veterans, and problem-solving specific transportation issues that present barriers to care.

Christina Dickson, PharmD. At the VA Maryland Health Care System Baltimore VA Medical Center, we hear from veterans in our education classes about the various myths that are still out there in the community about HCV. Some of these myths are the reason that veterans may avoid seeking treatment or even attending the HCV clinic appointments. Some veterans say they didn’t come in previously because they thought they would need a liver biopsy or because their doctor told them they had to be completely sober in order to be considered for treatment. These can be major deterrents that keep patients away despite our outreach efforts. In addition to miseducation in the community, there also is still a reluctance to talk about HCV and the risk factors. Many patients don’t want to discuss their history or are concerned about their partners finding out, so they instead choose to ignore it altogether. The negative stigma of HCV is still present even in some of our HCPs.

Just as VA San Francisco is working to engage its homeless population, we are looking to work with mental health and substance abuse programs. More and more is being written about the importance of working with such teams and even colocating the HCV clinic with their services. For example, in Baltimore, the methadone clinic is 2 floors above our clinic. Some of the remaining viremic patients will go to the methadone clinic in the morning and then leave despite having an appointment just 2 floors down. Offering HCV services at the same time, in the same area may help to engage veterans to consider their liver health.

Ms. Trimble. VA San Francisco has been fortunate to have the assistance of our opiate replacement clinic staff as well; this is particularly helpful since many veterans visit the opiate replacement clinic daily for medications and know the staff there very well. The staff facilitate communication with the liver clinic, execute warm handoffs to the liver clinic, and provide daily dispensing of hepatitis C medications for a number of veterans who have more difficulty with medication adherence. It has worked very well.

Dr. Ho. I think what you both are pointing out is very important—these patients require teamwork. A multidisciplinary group of HCPs working together in a collaborative, integrated care model has been demonstrated to significantly improve HCV engagement, care, and treatment in these highly comorbid patients.² Whenever we can work together and build teams and recruit other HCPs in these other clinics, it will really pay off.

Dr. Backus. At VA Palo Alto Health Care System, we also run a program integrated with our 28-day and 90-day residential rehabilitation programs. We realized that those residential treatment programs were a place to reach people who we were having difficulties starting treatment. It was a perfect situation because if you were there for 28 days, we could nearly guarantee that at the very least the patient was going to get 28 days of medications. Particularly now with some of the shorter treatment courses, we only have to get a patient to take another 28 days, which is very doable. Clearly, for the people who are in 90-day programs, the full 8-week or 12-week course of treatment could be completed during the rehabilitation. In addition, we started out at a good place because the programs already screened automatically for HCV on admission to the program, so it was easy to identify people who had HCV.

Ms. Trimble. Specialty Care Access Network-Extension for Community Healthcare Outcomes (SCAN-ECHO) also can help with outreach. Alexander Monto, MD, and Helen Yee, PharmD, conduct weekly SCAN-ECHO video telehealth conferences with outlying HCPs from other clinics. The outlying HCPs submit cases for hepatitis C treatment consideration; then they take the recommendations from their discussion with Dr. Monto and Dr. Yee but lead the treatment with their patients.

Over time, with this ongoing mentoring, the participating providers have gained a lot of expertise in hepatitis C and serve as a local resource for their clinics. One of the clinics is in Eureka, California, which is nearly 300 miles away. In contrast, the other main clinic that participates is the downtown clinic. It serves the most urban and difficult-to-reach patients. The familiarity and rapport that the downtown clinic providers have with their patients allow them to more effectively engage patients for treatment initiation and follow-up.

Dr. Dickson. Our catchment area includes West Virginia, and we do telehealth for one of the sites, which has a number of 20-year-old and 30-year-old patients. In this slightly different population it is again a challenge getting and keeping them engaged as they go through the pretreatment evaluation. Some say that there may be a benefit to getting them on treatment as quickly as possible so that they don’t have time to disengage. The age difference brings about different barriers. We have to think outside the box on how to reach out to these patients. They work, they have kids, and they don’t feel ill right now. And many are active injection drug users. Trying to get them engaged in health care in general and on HCV treatment is the next big challenge.

Health Care Provider Education

Dr. Dickson. When we reach out to viremic veterans who’ve never been to our clinic, we will sometimes find comments such as, “patient not interested” or “patient still drinking” or no comment at all in the electronic health record primary care notes. So we began to focus our HCV education not only on veterans but also the providers. Some HCPs don’t consider the benefits of referring patients to the clinic for at least the opportunity to receive education on HCV, learning if there is any scarring on their liver, and learning about their options for treatment should they choose to proceed. We are continuing to meet with HCPs in all areas to let them know what’s offered in the HCV clinics. In addition, we have found that direct contact from our HCV clinic to veterans who were not interested is very successful. We get a chance to show that the VA cares and explain what our clinic offers and find that they are more than willing to arrange an appointment with us.

Ms. Trimble. I agree. We have successfully treated many veterans who are still using alcohol or drugs, and the VA supports considering any patient for treatment regardless of substance use; however, not all providers are aware of this. One of the other main education points for patients and providers is that they need not have severe liver disease to be considered for treatment. In the past, typically only patients with moderate to advanced liver fibrosis were considered for treatment, but this approach has changed in the past couple years.

Dr. Ho. I would agree that there still is a need to educate HCPs who may have had a presentation or read something on HCV a year or 2 ago. It’s now possible to treat almost all patients with HCV. It really has been fantastic, but not everyone is aware of it right now. That means we need to continue to be active with our colleagues and get them on the team. It is very helpful to increase enthusiasm if we can publicize new data and information coming out about the success in the VA of these DAA regimens.

Dr. Backus. There was a time when the DAAs first came out and the prices were higher and there was concern about the funding. At that time, we were treating only people with more advanced liver disease. Now we are treating everyone regardless of how advanced their liver disease is, but occasionally at VA Palo Alto I’ve run into providers who say, “The patient didn’t have cirrhosis, so I didn’t refer.” Education still needs to happen. It can be a little confusing because there was a time when we were not treating everyone. Now we are, and we have to make sure to get out this message.

Dr. Dickson. For patients with unstable comorbidities, HCPs may make the choice against HCV treatment. In the Baltimore clinic, we have case managers who will work with such patients and get to know them very well. Many times we do more than just cure their HCV. We also help them with their other conditions because we see them so often, such as helping with their pill boxes and encouraging them since they can see their liver enzymes getting better. There is a lot to be said for case management, the hands-on contact, and the concern that we can show these veterans. It helps not just the HCV but also their blood pressure and cholesterol are now controlled. We hear so many thanks from the veterans that come through our program. It might have taken a lot of work to get them to treatment, but in the end, they’re better overall.

Next Steps in HCV Care

Dr. Backus. The most pressing next step is becoming really creative and integrative about how to reach the more difficult-to-treat patients with comorbidities and reach the less-engaged populations. It is probably going to take some change in the models of care. For example, we are going to have to set up a clinic that is colocated in an opioid replacement therapy clinic or in the rehabilitation program. HCV care is going to have to evolve.

I think there is another issue that Dr. Dickson pointed out. Although it is small and really only occurs in some regions, there is a young population of people with HCV. Some of the models of care that we have used may not work with this population, and we have to recognize that this will be an ongoing issue. Care for these patients will look different. For example, clinics may need to provide child care for this younger population.

Cancer is another important issue. Many of these people have cirrhosis, and even if we cure their HCV, we have to remain cognizant that they still have cirrhosis and potentially need screening for hepatocellular carcinoma. They also may need care for their cirrhosis or counseling about ongoing alcohol use, because even though their HCV was cured, continued alcohol use is not good for their cirrhosis.

Those 3 issues are still in the immediate future of HCV care in the VA. The World Health Organization has a goal for eliminating HCV. One could hope that maybe we could get there; it may be possible through screening, treatment, and prevention strategies. If we are lucky, we could put ourselves out of a job. I don’t see that happening, but it’s a hope.

Ms. Trimble. Are we seeing the same trend in new infections in young injection drug using veterans that are being seen in the nonveteran population nationally?

Dr. Backus. We have looked at this quite closely. The CDC came out with a report recently that showed a substantial increase in HCV cases in people aged 20 to 39 years. At the VA, we have not seen that uptick. The VA rates of new infections or new diagnosis of infections in peopled aged 20 to 39 years are pretty stable. The VA screening rates in people who were born after 1965 is in the high 70% range—nearly as high as in the cohort of people born between 1945 and 1965. As a result, the VA has excellent internal data about the incidence of infections in younger populations. In the VA, we are not seeing this sort of massive increase in incidence in younger populations. Definitely, there are new young injection drug users in the VA who are contracting HCV but not what the CDC is reporting in other parts of the country.⁴

Ms. Trimble. That’s really interesting.

Dr. Ho. Part of that has been the fact that if you’re a VA patient, you had to have been engaged at some point with the VA with access to its extensive psychiatric mental health and substance use disorder treatment infrastructure. I wonder if the availability of these services is a factor that can be protecting our patients from this recent upsurge in injection drug use.

Dr. Dickson. For our VISN, we do have smaller sites with a number of their remaining viremic veterans in this young cohort who are indeed proving to be a challenge to link to care in the HCV clinics. We continue to brainstorm ideas to determine and overcome their barriers to treatment. The VA is excellent at connecting all of us nationwide, so we look forward to hearing from other sites in a similar situation on how they are overcoming this challenge. Because when you look outside the VA, many are wondering what to do and how to engage these patients.

Dr. Backus. One of the amazing things about HCV treatment is how effective it has been. Traditionally the real-world effectiveness for medications is not nearly as good as the clinical trial efficacy. Clinical trials have extra resources, specially trained doctors and nurses, and tend to recruit engaged and cooperative patients. Often, there has been a stepdown between the clinical efficacy from the trials and what we see in the real world. A pleasant surprise about DAA treatment at the VA is that the clinical effectiveness we see in the real world almost matches the amazing results seen in clinical trials. That also has been critical to the success that we are seeing. The medications are powerful, and even outside the settings of a clinical trial, they work incredibly well.

Dr. Ho. I agree. You, Dr. Backus, along with Pam Belperio, PharmD, George Ioannou MD, MS, and other VA researchers have done excellent work in documenting the real-world effectiveness of these medications in the VA system. It was surprising but not unexpected.^5-7 It is due to the VA’s excellent clinical infrastructure and that it provides an integrated system for caring for these patients. It is a measure of that success.

Dr. Dickson. The multidisciplinary teams are a major part of that. I don’t think we could care and support the veterans that we have, especially the challenging ones, the ones who are resistant, without having nursing, social work, mental health, and pharmacy involved. It’s just a huge team effort. That is what I love about caring for patients at the VA—it’s always been supportive of the multidisciplinary aspect of looking at this disease.

Click here to read the digital edition.

VA Hepatitis C Treatment Progress

Lisa Backus, MD. For a long time the US Department of Veterans Affairs (VA) has approached hepatitis C virus (HCV) care in a comprehensive way. We have done extensive screening to look for people with HCV infection. Even before birth cohort testing was recommended by the Centers for Disease Control and Prevention (CDC), the VA had aggressive HCV screening programs.

From the VA Corporate Data Warehouse, we know that the VA has screened more than 80% of people who are in the 1945 to 1965 birth cohort in VA care. Over time, HCV prevalence has been dropping in screened veterans and by extension in those who remain to be screened. Based on internal modeling, the VA estimates that only 6,000 to 7,000 veterans in the 1945 to 1965 birth cohort remain to be found if we could somehow screen everyone in that group.

On the treatment side, the VA has provided an unparalleled amount of care. In data from the Clinical Case Registry: HCV, as of February 2018 the VA has started more than 104,000 veterans on direct-acting antiviral (DAA) treatment. When the DAAs first became available, we estimated that there were about 165,000 people who were HCV viremic and who needed to be treated. By the end of January 2018, that number was down to about 35,000 people. The VA has done an unbelievably good job of finding people, getting them into care, and treating them.

Samuel Ho, MD. I agree with Dr. Backus. The VA has done an excellent job over the past few years in treating a very significant proportion of our patients with HCV. In addition to the extensive screening efforts, I want to emphasize that going back to about the year 2000, the VA has been very active in supporting the establishment of HCV clinics within every VA medical center to identify and engage patients in treatment. At that time, of course, the treatment was with pegylated interferon and ribavirin, which was very challenging. The VA support consisted of funding 4 hepatitis C Resource Centers (HCRCs) nationwide, which were located in Minneapolis, Portland/Seattle, New Haven, and San Francisco.

The HCRCs reached out to every VA facility in the country, developed networks of health care providers (HCPs), trained them, and educated them regarding the HCV treatments and strategies to engage patients in care, especially the large numbers with comorbidities, such as psychiatric problems and substance use disorders. This highly engaged network of local HCV clinic providers was set up and running and was well poised to take advantage of the interferon-free DAAs when they became available in late 2013 and early 2014. With the continuing leadership of David Ross, MD, and many others at the national level, the VA then supported the development of HCV Innovation Teams in every VISN that continued the efforts to support local quality improvement initiatives related to HCV care.

That being said, the VA still has challenges. There are a significant number of people who have barriers to receiving treatment. For example, here at the VA San Diego Healthcare System, Dr. John Dever and our other colleagues looked at 481 patients who were high priority to get started on HCV treatment, because they were all believed to be a high risk for cirrhosis due to their Fibrosis-4 (FIB4) scores and other characteristics.¹

We really worked hard on that group, and of the ones who were eligible for treatment, 30% were either unwilling or unable to engage in care over a yearlong follow-up with multiple attempts at outreach. In comparison with patients who became engaged or were engaged in care, these nonengaged patients were significantly more likely to be homeless, have other comorbidities, or active alcohol and/or drug use. Not surprisingly, they had obvious barriers to engaging in care.

Further efforts need to be made to focus on these patients, maybe with innovative ideas and strategies for outreach to get them into treatment or to bring treatment to them. I’m not sure exactly as to what the best approach would be. There is ongoing research in that regard, but it still is a challenge.

Erica Trimble, NP. Our experience at VA San Francisco Health Care System is similar. If we actively reach out to veterans already engaged in primary care, we can usually engage them in the liver clinic as well. However, there are quite a number of veterans who engage regularly with HUD-VASH (US Department of House and Urban Development-VA Supportive Housing program) and other homeless veteran services but have no primary or specialty care engagement. These veterans are very difficult to reach.

We are collaborating with HUD-VASH social workers to see if there are more creative ways to connect with these veterans. Some of the ideas include having liver providers visit veteran housing locations, having HUD-VASH social workers convey messages to difficult-to-reach veterans, and problem-solving specific transportation issues that present barriers to care.

Christina Dickson, PharmD. At the VA Maryland Health Care System Baltimore VA Medical Center, we hear from veterans in our education classes about the various myths that are still out there in the community about HCV. Some of these myths are the reason that veterans may avoid seeking treatment or even attending the HCV clinic appointments. Some veterans say they didn’t come in previously because they thought they would need a liver biopsy or because their doctor told them they had to be completely sober in order to be considered for treatment. These can be major deterrents that keep patients away despite our outreach efforts. In addition to miseducation in the community, there also is still a reluctance to talk about HCV and the risk factors. Many patients don’t want to discuss their history or are concerned about their partners finding out, so they instead choose to ignore it altogether. The negative stigma of HCV is still present even in some of our HCPs.

Just as VA San Francisco is working to engage its homeless population, we are looking to work with mental health and substance abuse programs. More and more is being written about the importance of working with such teams and even colocating the HCV clinic with their services. For example, in Baltimore, the methadone clinic is 2 floors above our clinic. Some of the remaining viremic patients will go to the methadone clinic in the morning and then leave despite having an appointment just 2 floors down. Offering HCV services at the same time, in the same area may help to engage veterans to consider their liver health.

Ms. Trimble. VA San Francisco has been fortunate to have the assistance of our opiate replacement clinic staff as well; this is particularly helpful since many veterans visit the opiate replacement clinic daily for medications and know the staff there very well. The staff facilitate communication with the liver clinic, execute warm handoffs to the liver clinic, and provide daily dispensing of hepatitis C medications for a number of veterans who have more difficulty with medication adherence. It has worked very well.

Dr. Ho. I think what you both are pointing out is very important—these patients require teamwork. A multidisciplinary group of HCPs working together in a collaborative, integrated care model has been demonstrated to significantly improve HCV engagement, care, and treatment in these highly comorbid patients.² Whenever we can work together and build teams and recruit other HCPs in these other clinics, it will really pay off.

Dr. Backus. At VA Palo Alto Health Care System, we also run a program integrated with our 28-day and 90-day residential rehabilitation programs. We realized that those residential treatment programs were a place to reach people who we were having difficulties starting treatment. It was a perfect situation because if you were there for 28 days, we could nearly guarantee that at the very least the patient was going to get 28 days of medications. Particularly now with some of the shorter treatment courses, we only have to get a patient to take another 28 days, which is very doable. Clearly, for the people who are in 90-day programs, the full 8-week or 12-week course of treatment could be completed during the rehabilitation. In addition, we started out at a good place because the programs already screened automatically for HCV on admission to the program, so it was easy to identify people who had HCV.

Ms. Trimble. Specialty Care Access Network-Extension for Community Healthcare Outcomes (SCAN-ECHO) also can help with outreach. Alexander Monto, MD, and Helen Yee, PharmD, conduct weekly SCAN-ECHO video telehealth conferences with outlying HCPs from other clinics. The outlying HCPs submit cases for hepatitis C treatment consideration; then they take the recommendations from their discussion with Dr. Monto and Dr. Yee but lead the treatment with their patients.

Over time, with this ongoing mentoring, the participating providers have gained a lot of expertise in hepatitis C and serve as a local resource for their clinics. One of the clinics is in Eureka, California, which is nearly 300 miles away. In contrast, the other main clinic that participates is the downtown clinic. It serves the most urban and difficult-to-reach patients. The familiarity and rapport that the downtown clinic providers have with their patients allow them to more effectively engage patients for treatment initiation and follow-up.

Dr. Dickson. Our catchment area includes West Virginia, and we do telehealth for one of the sites, which has a number of 20-year-old and 30-year-old patients. In this slightly different population it is again a challenge getting and keeping them engaged as they go through the pretreatment evaluation. Some say that there may be a benefit to getting them on treatment as quickly as possible so that they don’t have time to disengage. The age difference brings about different barriers. We have to think outside the box on how to reach out to these patients. They work, they have kids, and they don’t feel ill right now. And many are active injection drug users. Trying to get them engaged in health care in general and on HCV treatment is the next big challenge.

Health Care Provider Education

Dr. Dickson. When we reach out to viremic veterans who’ve never been to our clinic, we will sometimes find comments such as, “patient not interested” or “patient still drinking” or no comment at all in the electronic health record primary care notes. So we began to focus our HCV education not only on veterans but also the providers. Some HCPs don’t consider the benefits of referring patients to the clinic for at least the opportunity to receive education on HCV, learning if there is any scarring on their liver, and learning about their options for treatment should they choose to proceed. We are continuing to meet with HCPs in all areas to let them know what’s offered in the HCV clinics. In addition, we have found that direct contact from our HCV clinic to veterans who were not interested is very successful. We get a chance to show that the VA cares and explain what our clinic offers and find that they are more than willing to arrange an appointment with us.

Ms. Trimble. I agree. We have successfully treated many veterans who are still using alcohol or drugs, and the VA supports considering any patient for treatment regardless of substance use; however, not all providers are aware of this. One of the other main education points for patients and providers is that they need not have severe liver disease to be considered for treatment. In the past, typically only patients with moderate to advanced liver fibrosis were considered for treatment, but this approach has changed in the past couple years.

Dr. Ho. I would agree that there still is a need to educate HCPs who may have had a presentation or read something on HCV a year or 2 ago. It’s now possible to treat almost all patients with HCV. It really has been fantastic, but not everyone is aware of it right now. That means we need to continue to be active with our colleagues and get them on the team. It is very helpful to increase enthusiasm if we can publicize new data and information coming out about the success in the VA of these DAA regimens.

Dr. Backus. There was a time when the DAAs first came out and the prices were higher and there was concern about the funding. At that time, we were treating only people with more advanced liver disease. Now we are treating everyone regardless of how advanced their liver disease is, but occasionally at VA Palo Alto I’ve run into providers who say, “The patient didn’t have cirrhosis, so I didn’t refer.” Education still needs to happen. It can be a little confusing because there was a time when we were not treating everyone. Now we are, and we have to make sure to get out this message.

Dr. Dickson. For patients with unstable comorbidities, HCPs may make the choice against HCV treatment. In the Baltimore clinic, we have case managers who will work with such patients and get to know them very well. Many times we do more than just cure their HCV. We also help them with their other conditions because we see them so often, such as helping with their pill boxes and encouraging them since they can see their liver enzymes getting better. There is a lot to be said for case management, the hands-on contact, and the concern that we can show these veterans. It helps not just the HCV but also their blood pressure and cholesterol are now controlled. We hear so many thanks from the veterans that come through our program. It might have taken a lot of work to get them to treatment, but in the end, they’re better overall.

Next Steps in HCV Care

Dr. Backus. The most pressing next step is becoming really creative and integrative about how to reach the more difficult-to-treat patients with comorbidities and reach the less-engaged populations. It is probably going to take some change in the models of care. For example, we are going to have to set up a clinic that is colocated in an opioid replacement therapy clinic or in the rehabilitation program. HCV care is going to have to evolve.

I think there is another issue that Dr. Dickson pointed out. Although it is small and really only occurs in some regions, there is a young population of people with HCV. Some of the models of care that we have used may not work with this population, and we have to recognize that this will be an ongoing issue. Care for these patients will look different. For example, clinics may need to provide child care for this younger population.

Cancer is another important issue. Many of these people have cirrhosis, and even if we cure their HCV, we have to remain cognizant that they still have cirrhosis and potentially need screening for hepatocellular carcinoma. They also may need care for their cirrhosis or counseling about ongoing alcohol use, because even though their HCV was cured, continued alcohol use is not good for their cirrhosis.

Those 3 issues are still in the immediate future of HCV care in the VA. The World Health Organization has a goal for eliminating HCV. One could hope that maybe we could get there; it may be possible through screening, treatment, and prevention strategies. If we are lucky, we could put ourselves out of a job. I don’t see that happening, but it’s a hope.

Ms. Trimble. Are we seeing the same trend in new infections in young injection drug using veterans that are being seen in the nonveteran population nationally?

Dr. Backus. We have looked at this quite closely. The CDC came out with a report recently that showed a substantial increase in HCV cases in people aged 20 to 39 years. At the VA, we have not seen that uptick. The VA rates of new infections or new diagnosis of infections in peopled aged 20 to 39 years are pretty stable. The VA screening rates in people who were born after 1965 is in the high 70% range—nearly as high as in the cohort of people born between 1945 and 1965. As a result, the VA has excellent internal data about the incidence of infections in younger populations. In the VA, we are not seeing this sort of massive increase in incidence in younger populations. Definitely, there are new young injection drug users in the VA who are contracting HCV but not what the CDC is reporting in other parts of the country.⁴

Ms. Trimble. That’s really interesting.

Dr. Ho. Part of that has been the fact that if you’re a VA patient, you had to have been engaged at some point with the VA with access to its extensive psychiatric mental health and substance use disorder treatment infrastructure. I wonder if the availability of these services is a factor that can be protecting our patients from this recent upsurge in injection drug use.

Dr. Dickson. For our VISN, we do have smaller sites with a number of their remaining viremic veterans in this young cohort who are indeed proving to be a challenge to link to care in the HCV clinics. We continue to brainstorm ideas to determine and overcome their barriers to treatment. The VA is excellent at connecting all of us nationwide, so we look forward to hearing from other sites in a similar situation on how they are overcoming this challenge. Because when you look outside the VA, many are wondering what to do and how to engage these patients.

Dr. Backus. One of the amazing things about HCV treatment is how effective it has been. Traditionally the real-world effectiveness for medications is not nearly as good as the clinical trial efficacy. Clinical trials have extra resources, specially trained doctors and nurses, and tend to recruit engaged and cooperative patients. Often, there has been a stepdown between the clinical efficacy from the trials and what we see in the real world. A pleasant surprise about DAA treatment at the VA is that the clinical effectiveness we see in the real world almost matches the amazing results seen in clinical trials. That also has been critical to the success that we are seeing. The medications are powerful, and even outside the settings of a clinical trial, they work incredibly well.

Dr. Ho. I agree. You, Dr. Backus, along with Pam Belperio, PharmD, George Ioannou MD, MS, and other VA researchers have done excellent work in documenting the real-world effectiveness of these medications in the VA system. It was surprising but not unexpected.^5-7 It is due to the VA’s excellent clinical infrastructure and that it provides an integrated system for caring for these patients. It is a measure of that success.

Dr. Dickson. The multidisciplinary teams are a major part of that. I don’t think we could care and support the veterans that we have, especially the challenging ones, the ones who are resistant, without having nursing, social work, mental health, and pharmacy involved. It’s just a huge team effort. That is what I love about caring for patients at the VA—it’s always been supportive of the multidisciplinary aspect of looking at this disease.

Click here to read the digital edition.

Hepatitis A virus (HAV) can result in acute infection characterized by fatigue, nausea, jaundice (yellowing of the skin) and, rarely, acute liver failure and death.^1,2 In the US, HAV yearly incidence (per 100,000) has decreased from 11.7 cases in 1996 to 0.4 cases in 2015, largely due to the 2006 recommendations from the Centers for Disease Control and Prevention (CDC) that all infants receive HAV vaccination.^3,4

In 2017, multiple HAV outbreaks occurred in Arizona, California, Colorado, Kentucky, Michigan, and Utah with infections concentrated among those who were homeless, used illicit drugs (both injection and noninjection), or had close contact with these groups (Table 1).^5-7 

In response, the CDC has recommended the administration of HAV vaccine or immune globulin (IG) as postexposure prophylaxis (PEP) to people in high-risk groups including unvaccinated individuals exposed to HAV within the prior 2 weeks.⁵ While the Veterans Health Administration (VHA) in the Department of Veteran’s Affairs (VA) has not noted a significant increase in the number of reported HAV infections, there have been cases of hospitalization within the VA health care system due to HAV in at least 2 of the outbreak areas. The VA facilities in outbreak areas are responding by supporting county disease-control measures that include ensuring handwashing stations and vaccinations for high-risk, in-care populations and employees in direct contact with patients at high risk for HAV.

This review provides information on HAV transmission and clinical manifestations, guidelines on the prevention of HAV infection, and baseline data on current HAV susceptibility and immunization rates in the VHA.

Transmission and Clinical Manifestations

Hepatitis A virus is primarily transmitted by ingestion of small amounts of infected stool (ie, fecal-oral route) via direct person-to-person contact or through exposure to contaminated food or water.^9,10 Groups at high risk of HAV infection include those in direct contact with HAV-infected individuals, users of injection or non-injection drugs, men who have sex with men (MSM), travelers to high-risk countries, individuals with clotting disorders, and those who work with nonhuman primates.¹¹ Individuals who are homeless are susceptible to HAV due to poor sanitary conditions, and MSM are at increased risk of HAV acquisition via exposure to infected stool during sexual activity.

Complications of acute HAV infection, including fulminant liver failure and death, are more common among patients infected with hepatitis B virus (HBV) or hepatitis C virus (HCV).^12,13 While infection with HIV does not independently increase the risk of HAV acquisition, about 75% of new HIV infections in the US are among MSM or IV drug users who are at increased risk of HAV infection.¹⁴ In addition, duration of HAV viremia and resulting HAV transmissibility may be increased in HIV-infected individuals.^15-17

After infection, HAV remains asymptomatic (the incubation period) for an average of 28 days with a range of 15 to 50 days.^18,19 Most children younger than 6 years remain asymptomatic while older children and adults typically experience symptoms including fever, fatigue, poor appetite, abdominal pain, dark urine, clay-colored stools, and jaundice.^2,20,21 Symptoms typically last less than 2 months but can persist or relapse for up to 6 months in 10% to 15% of symptomatic individuals.^22,23 Those with HAV infection are capable of viral transmission from the beginning of the incubation period until about a week after jaundice appears.²⁴ Unlike HBV and HCV, HAV does not cause chronic infection.

Fulminant liver failure, characterized by encephalopathy, jaundice, and elevated international normalized ratio (INR), occurs in < 1% of HAV infections and is more common in those with underlying liver disease and older individuals.^13,25-27 In one retrospective review of fulminant liver failure from HAV infection, about half of the patients required liver transplantation or died within 3 weeks of presentation.¹²

Other than supportive care, there are no specific treatments for acute HAV infection. However, the CDC recommends that healthy individuals aged between 1 and 40 years with known or suspected exposure to HAV within the prior 2 weeks receive 1 dose of a single-antigen HAV vaccination. The CDC also recommends that recently exposed individuals aged < 1 year or > 40 years, or patients who are immunocompromised, have chronic liver disease (CLD), or are allergic to HAV vaccine or a vaccine component should receive a single IG injection. In addition, the CDC recommends that health care providers report all cases of acute HAV to state and local health departments.²⁸

In patients with typical symptoms of acute viral hepatitis (eg, headache, fever, malaise, anorexia, nausea, vomiting, abdominal pain, and diarrhea) and either jaundice or elevated serum aminotransferase levels, confirmation of HAV infection is required with either a positive serologic test for immunoglobulin M (IgM) anti-HAV antibody or an epidemiologic link (eg, recent household or close contact) to a person with laboratory-confirmed HAV.⁵ Serum IgM anti-HAV antibodies are first detectable when symptoms begin and remain detectable for about 3 to 6 months.^29,30 Serum immunoglobulin G (IgG) anti-HAV antibodies, which provide lifelong protection against reinfection, appear as symptoms improve and persist indefinitely.^31,32 Therefore, the presence of anti-HAV IgG and the absence of anti-HAV IgM is indicative of immunity to HAV via past infection or vaccination.

HAV Prevention in The VHA

The mainstay of HAV prevention is vaccination with 2 doses of inactivated, single-antigen hepatitis A vaccine or 3 doses of combination (HAV and HBV) vaccine.¹¹ Both single antigen and combination HAV vaccines are safe in immunocompromised and pregnant patients.^33-39 The HAV vaccination results in 100% anti-HAV IgG seropositivity among healthy individuals, although immunogenicity might be lower for those who are immunocompromised or with CLD.^31,40-47 The VHA recommends HAV immunization, unless contraindicated, for previously unvaccinated 

In addition to vaccination, addressing risk factors for HAV infection and its complications could reduce the burden of disease. For instance, recent outbreaks highlight that homeless individuals and users of injection and noninjection drugs are particularly vulnerable to infections transmitted via fecal-oral contamination. Broad strategies to address homelessness and related sanitation concerns are needed to help reduce the likelihood of future HAV outbreaks.⁴⁹ Specific measures to combat HAV include providing access to clean water, adequate hygiene, and clean needles for people who inject drugs.¹¹ Hepatitis A virus can be destroyed by heating food to ≥ 185 °F for at least 1 minute, chlorinating contaminated water, or cleaning contaminated surfaces with a solution of household bleach and water.⁵⁰ Moreover, it is important to identify and treat risk factors for complications of HAV infection. This includes identifying individuals with HCV and ensuring that they are immune to HAV, given data that HCV-infected individuals are at increased risk of fulminant hepatic failure from HAV.^12,13

Active-duty service members have long been considered at higher risk of HAV infections due to deployments in endemic areas and exposure to contaminated food and water.^51,52 Shortly after the FDA approved HAV vaccination in 1995, the Department of Defense (DoD) mandated screening and HAV immunization for all incoming active-duty service members and those deployed to areas of high endemicity.⁵³ However, US veterans who were discharged before the adoption of universal HAV vaccination remain at increased risk for HAV infection, particularly given the high prevalence of CLD, homelessness, and substance use disorder (SUD) in this cohort.^54-56 Given the importance of HAV prevention for high-risk individuals, an analysis was performed to determine rates of HAV vaccination and testing within VA-enrolled individuals with selected risk factors for HAV acquisition or complications.

Methods

A cross-sectional analysis of veterans in VA care from June 1, 2016 to June 1, 2017 was performed to determine national rates of HAV susceptibility among patients with HCV exposure, homelessness, SUD, or HIV infection. The definitions of homelessness, SUD (alcohol, cannabis, opioid, sedatives, hallucinogens, inhalants, stimulants, or tobacco), and HIV infection were based on the presence of appropriate ICD-9 or ICD-10 codes. History of HCV exposure was based on a positive HCV antibody test. Presence of HAV vaccination was determined based on CPT codes for administration of the single-antigen HAV vaccination or combination HAV/HBV vaccination.

While HIV infection is not independently considered an indication for HAV vaccination, the authors included this group given its high proportion of patients with other risk factors, including MSM and IV drug use. All data were obtained from the VA Corporate Data Warehouse (CDW), a comprehensive national repository of all laboratory, diagnosis, and prescription results (including vaccines) within the VHA since 1999.

Hepatitis A virus nonsusceptibility was defined as (1) documented receipt of HAV vaccination within the VHA; (2) anti-HAV IgG antibody testing within the VHA; or (3) active-duty service after October 1997. It was considered likely that patients who received HAV testing either showed evidence of HAV immunity (eg, positive anti-HAV IgG) or were anti-HAV IgG negative and subsequently immunized. Therefore, patients with anti-HAV IgG antibody testing were counted presumptively as nonsusceptible. The DoD implemented a universal HAV vaccination policy in 1995, therefore, 1997 was chosen as a time at which the military’s universal HAV vaccination campaign was likely to have achieved near 100% vaccination coverage of active-duty military.

Results

The cohort included 5,896,451 patients in VA care, including 381,628 (6.5%) who were homeless, 455,344 (7.7%) with SUD, 225,889 (3.8%) with a lifetime history of positive HCV antibody (indicating past HCV exposure), and 29,166 (0.5%) with HIV infection.

There was wide geographic variability in rates of HAV susceptibility (Figure 1). 

Discussion

Widespread HAV vaccination has decreased the incidence of HAV infection in the US dramatically. Nevertheless, recent outbreaks demonstrate that substantial population susceptibility and associated risk for HAV-related morbidity and mortality remains, particularly in high-risk populations. Although the VHA has not experienced a significant increase in acute HAV infections to date, this cross-sectional analysis highlights that a large proportion of VA patients in traditionally high-risk groups remain susceptible to HAV infection.

Strengths

Strengths of this analysis include a current reflection of HAV susceptibility within the national VHA, thus informing HAV testing and vaccination strategies. This study also involves a very large cohort, which is possible because the VHA is the largest integrated healthcare system in the US. Lastly, because the VHA uses electronic medical records, there was nearly complete capture of HAV vaccinations and testing obtained through the VHA.

Limitations

This cross-sectional analysis has several potential limitations. First, findings may not be generalizable outside the VHA. In addition, determination of homelessness, substance abuse, and HIV infection were based on ICD-9 and ICD-10 codes, which have been used in previous studies but may be subject to misclassification. The authors deliberately included all patients with positive HCV antibody testing to include those with current or prior risk factors for HAV acquisition. This population does not reflect patients with HCV viremia who received HAV testing or vaccination. Lastly, misattribution of HAV susceptibility could have occurred if patients with negative HAV IgG results were not vaccinated or if patients previously received HAV vaccination outside the VHA.

Conclusion

To mitigate the risk of future HAV outbreaks, continued efforts should be made to increase vaccination among high-risk groups, improve awareness of additional prevention measures, and address risk factors for HAV acquisition, particularly in areas with active outbreaks. Further study is suggested to identify geographic areas with large caseloads of at-risk patients and to highlight best practices utilized by VHA facilities that achieved high vaccine coverage rates. Recommended approaches likely will need to include efforts to improve hygiene and reduce risks for HAV exposure associated with SUD and homelessness.

Click here to read the digital edition.

Hepatitis A virus (HAV) can result in acute infection characterized by fatigue, nausea, jaundice (yellowing of the skin) and, rarely, acute liver failure and death.^1,2 In the US, HAV yearly incidence (per 100,000) has decreased from 11.7 cases in 1996 to 0.4 cases in 2015, largely due to the 2006 recommendations from the Centers for Disease Control and Prevention (CDC) that all infants receive HAV vaccination.^3,4

In 2017, multiple HAV outbreaks occurred in Arizona, California, Colorado, Kentucky, Michigan, and Utah with infections concentrated among those who were homeless, used illicit drugs (both injection and noninjection), or had close contact with these groups (Table 1).^5-7 

In response, the CDC has recommended the administration of HAV vaccine or immune globulin (IG) as postexposure prophylaxis (PEP) to people in high-risk groups including unvaccinated individuals exposed to HAV within the prior 2 weeks.⁵ While the Veterans Health Administration (VHA) in the Department of Veteran’s Affairs (VA) has not noted a significant increase in the number of reported HAV infections, there have been cases of hospitalization within the VA health care system due to HAV in at least 2 of the outbreak areas. The VA facilities in outbreak areas are responding by supporting county disease-control measures that include ensuring handwashing stations and vaccinations for high-risk, in-care populations and employees in direct contact with patients at high risk for HAV.

This review provides information on HAV transmission and clinical manifestations, guidelines on the prevention of HAV infection, and baseline data on current HAV susceptibility and immunization rates in the VHA.

Transmission and Clinical Manifestations

Hepatitis A virus is primarily transmitted by ingestion of small amounts of infected stool (ie, fecal-oral route) via direct person-to-person contact or through exposure to contaminated food or water.^9,10 Groups at high risk of HAV infection include those in direct contact with HAV-infected individuals, users of injection or non-injection drugs, men who have sex with men (MSM), travelers to high-risk countries, individuals with clotting disorders, and those who work with nonhuman primates.¹¹ Individuals who are homeless are susceptible to HAV due to poor sanitary conditions, and MSM are at increased risk of HAV acquisition via exposure to infected stool during sexual activity.

Complications of acute HAV infection, including fulminant liver failure and death, are more common among patients infected with hepatitis B virus (HBV) or hepatitis C virus (HCV).^12,13 While infection with HIV does not independently increase the risk of HAV acquisition, about 75% of new HIV infections in the US are among MSM or IV drug users who are at increased risk of HAV infection.¹⁴ In addition, duration of HAV viremia and resulting HAV transmissibility may be increased in HIV-infected individuals.^15-17

After infection, HAV remains asymptomatic (the incubation period) for an average of 28 days with a range of 15 to 50 days.^18,19 Most children younger than 6 years remain asymptomatic while older children and adults typically experience symptoms including fever, fatigue, poor appetite, abdominal pain, dark urine, clay-colored stools, and jaundice.^2,20,21 Symptoms typically last less than 2 months but can persist or relapse for up to 6 months in 10% to 15% of symptomatic individuals.^22,23 Those with HAV infection are capable of viral transmission from the beginning of the incubation period until about a week after jaundice appears.²⁴ Unlike HBV and HCV, HAV does not cause chronic infection.

Fulminant liver failure, characterized by encephalopathy, jaundice, and elevated international normalized ratio (INR), occurs in < 1% of HAV infections and is more common in those with underlying liver disease and older individuals.^13,25-27 In one retrospective review of fulminant liver failure from HAV infection, about half of the patients required liver transplantation or died within 3 weeks of presentation.¹²

Other than supportive care, there are no specific treatments for acute HAV infection. However, the CDC recommends that healthy individuals aged between 1 and 40 years with known or suspected exposure to HAV within the prior 2 weeks receive 1 dose of a single-antigen HAV vaccination. The CDC also recommends that recently exposed individuals aged < 1 year or > 40 years, or patients who are immunocompromised, have chronic liver disease (CLD), or are allergic to HAV vaccine or a vaccine component should receive a single IG injection. In addition, the CDC recommends that health care providers report all cases of acute HAV to state and local health departments.²⁸

In patients with typical symptoms of acute viral hepatitis (eg, headache, fever, malaise, anorexia, nausea, vomiting, abdominal pain, and diarrhea) and either jaundice or elevated serum aminotransferase levels, confirmation of HAV infection is required with either a positive serologic test for immunoglobulin M (IgM) anti-HAV antibody or an epidemiologic link (eg, recent household or close contact) to a person with laboratory-confirmed HAV.⁵ Serum IgM anti-HAV antibodies are first detectable when symptoms begin and remain detectable for about 3 to 6 months.^29,30 Serum immunoglobulin G (IgG) anti-HAV antibodies, which provide lifelong protection against reinfection, appear as symptoms improve and persist indefinitely.^31,32 Therefore, the presence of anti-HAV IgG and the absence of anti-HAV IgM is indicative of immunity to HAV via past infection or vaccination.

HAV Prevention in The VHA

The mainstay of HAV prevention is vaccination with 2 doses of inactivated, single-antigen hepatitis A vaccine or 3 doses of combination (HAV and HBV) vaccine.¹¹ Both single antigen and combination HAV vaccines are safe in immunocompromised and pregnant patients.^33-39 The HAV vaccination results in 100% anti-HAV IgG seropositivity among healthy individuals, although immunogenicity might be lower for those who are immunocompromised or with CLD.^31,40-47 The VHA recommends HAV immunization, unless contraindicated, for previously unvaccinated 

In addition to vaccination, addressing risk factors for HAV infection and its complications could reduce the burden of disease. For instance, recent outbreaks highlight that homeless individuals and users of injection and noninjection drugs are particularly vulnerable to infections transmitted via fecal-oral contamination. Broad strategies to address homelessness and related sanitation concerns are needed to help reduce the likelihood of future HAV outbreaks.⁴⁹ Specific measures to combat HAV include providing access to clean water, adequate hygiene, and clean needles for people who inject drugs.¹¹ Hepatitis A virus can be destroyed by heating food to ≥ 185 °F for at least 1 minute, chlorinating contaminated water, or cleaning contaminated surfaces with a solution of household bleach and water.⁵⁰ Moreover, it is important to identify and treat risk factors for complications of HAV infection. This includes identifying individuals with HCV and ensuring that they are immune to HAV, given data that HCV-infected individuals are at increased risk of fulminant hepatic failure from HAV.^12,13

Active-duty service members have long been considered at higher risk of HAV infections due to deployments in endemic areas and exposure to contaminated food and water.^51,52 Shortly after the FDA approved HAV vaccination in 1995, the Department of Defense (DoD) mandated screening and HAV immunization for all incoming active-duty service members and those deployed to areas of high endemicity.⁵³ However, US veterans who were discharged before the adoption of universal HAV vaccination remain at increased risk for HAV infection, particularly given the high prevalence of CLD, homelessness, and substance use disorder (SUD) in this cohort.^54-56 Given the importance of HAV prevention for high-risk individuals, an analysis was performed to determine rates of HAV vaccination and testing within VA-enrolled individuals with selected risk factors for HAV acquisition or complications.

Methods

A cross-sectional analysis of veterans in VA care from June 1, 2016 to June 1, 2017 was performed to determine national rates of HAV susceptibility among patients with HCV exposure, homelessness, SUD, or HIV infection. The definitions of homelessness, SUD (alcohol, cannabis, opioid, sedatives, hallucinogens, inhalants, stimulants, or tobacco), and HIV infection were based on the presence of appropriate ICD-9 or ICD-10 codes. History of HCV exposure was based on a positive HCV antibody test. Presence of HAV vaccination was determined based on CPT codes for administration of the single-antigen HAV vaccination or combination HAV/HBV vaccination.

While HIV infection is not independently considered an indication for HAV vaccination, the authors included this group given its high proportion of patients with other risk factors, including MSM and IV drug use. All data were obtained from the VA Corporate Data Warehouse (CDW), a comprehensive national repository of all laboratory, diagnosis, and prescription results (including vaccines) within the VHA since 1999.

Hepatitis A virus nonsusceptibility was defined as (1) documented receipt of HAV vaccination within the VHA; (2) anti-HAV IgG antibody testing within the VHA; or (3) active-duty service after October 1997. It was considered likely that patients who received HAV testing either showed evidence of HAV immunity (eg, positive anti-HAV IgG) or were anti-HAV IgG negative and subsequently immunized. Therefore, patients with anti-HAV IgG antibody testing were counted presumptively as nonsusceptible. The DoD implemented a universal HAV vaccination policy in 1995, therefore, 1997 was chosen as a time at which the military’s universal HAV vaccination campaign was likely to have achieved near 100% vaccination coverage of active-duty military.

Results

The cohort included 5,896,451 patients in VA care, including 381,628 (6.5%) who were homeless, 455,344 (7.7%) with SUD, 225,889 (3.8%) with a lifetime history of positive HCV antibody (indicating past HCV exposure), and 29,166 (0.5%) with HIV infection.

There was wide geographic variability in rates of HAV susceptibility (Figure 1). 

Discussion

Widespread HAV vaccination has decreased the incidence of HAV infection in the US dramatically. Nevertheless, recent outbreaks demonstrate that substantial population susceptibility and associated risk for HAV-related morbidity and mortality remains, particularly in high-risk populations. Although the VHA has not experienced a significant increase in acute HAV infections to date, this cross-sectional analysis highlights that a large proportion of VA patients in traditionally high-risk groups remain susceptible to HAV infection.

Strengths

Strengths of this analysis include a current reflection of HAV susceptibility within the national VHA, thus informing HAV testing and vaccination strategies. This study also involves a very large cohort, which is possible because the VHA is the largest integrated healthcare system in the US. Lastly, because the VHA uses electronic medical records, there was nearly complete capture of HAV vaccinations and testing obtained through the VHA.

Limitations

This cross-sectional analysis has several potential limitations. First, findings may not be generalizable outside the VHA. In addition, determination of homelessness, substance abuse, and HIV infection were based on ICD-9 and ICD-10 codes, which have been used in previous studies but may be subject to misclassification. The authors deliberately included all patients with positive HCV antibody testing to include those with current or prior risk factors for HAV acquisition. This population does not reflect patients with HCV viremia who received HAV testing or vaccination. Lastly, misattribution of HAV susceptibility could have occurred if patients with negative HAV IgG results were not vaccinated or if patients previously received HAV vaccination outside the VHA.

Conclusion

To mitigate the risk of future HAV outbreaks, continued efforts should be made to increase vaccination among high-risk groups, improve awareness of additional prevention measures, and address risk factors for HAV acquisition, particularly in areas with active outbreaks. Further study is suggested to identify geographic areas with large caseloads of at-risk patients and to highlight best practices utilized by VHA facilities that achieved high vaccine coverage rates. Recommended approaches likely will need to include efforts to improve hygiene and reduce risks for HAV exposure associated with SUD and homelessness.

Click here to read the digital edition.

Hepatitis A virus (HAV) can result in acute infection characterized by fatigue, nausea, jaundice (yellowing of the skin) and, rarely, acute liver failure and death.^1,2 In the US, HAV yearly incidence (per 100,000) has decreased from 11.7 cases in 1996 to 0.4 cases in 2015, largely due to the 2006 recommendations from the Centers for Disease Control and Prevention (CDC) that all infants receive HAV vaccination.^3,4

In 2017, multiple HAV outbreaks occurred in Arizona, California, Colorado, Kentucky, Michigan, and Utah with infections concentrated among those who were homeless, used illicit drugs (both injection and noninjection), or had close contact with these groups (Table 1).^5-7 

In response, the CDC has recommended the administration of HAV vaccine or immune globulin (IG) as postexposure prophylaxis (PEP) to people in high-risk groups including unvaccinated individuals exposed to HAV within the prior 2 weeks.⁵ While the Veterans Health Administration (VHA) in the Department of Veteran’s Affairs (VA) has not noted a significant increase in the number of reported HAV infections, there have been cases of hospitalization within the VA health care system due to HAV in at least 2 of the outbreak areas. The VA facilities in outbreak areas are responding by supporting county disease-control measures that include ensuring handwashing stations and vaccinations for high-risk, in-care populations and employees in direct contact with patients at high risk for HAV.

This review provides information on HAV transmission and clinical manifestations, guidelines on the prevention of HAV infection, and baseline data on current HAV susceptibility and immunization rates in the VHA.

Transmission and Clinical Manifestations

Hepatitis A virus is primarily transmitted by ingestion of small amounts of infected stool (ie, fecal-oral route) via direct person-to-person contact or through exposure to contaminated food or water.^9,10 Groups at high risk of HAV infection include those in direct contact with HAV-infected individuals, users of injection or non-injection drugs, men who have sex with men (MSM), travelers to high-risk countries, individuals with clotting disorders, and those who work with nonhuman primates.¹¹ Individuals who are homeless are susceptible to HAV due to poor sanitary conditions, and MSM are at increased risk of HAV acquisition via exposure to infected stool during sexual activity.

Complications of acute HAV infection, including fulminant liver failure and death, are more common among patients infected with hepatitis B virus (HBV) or hepatitis C virus (HCV).^12,13 While infection with HIV does not independently increase the risk of HAV acquisition, about 75% of new HIV infections in the US are among MSM or IV drug users who are at increased risk of HAV infection.¹⁴ In addition, duration of HAV viremia and resulting HAV transmissibility may be increased in HIV-infected individuals.^15-17

After infection, HAV remains asymptomatic (the incubation period) for an average of 28 days with a range of 15 to 50 days.^18,19 Most children younger than 6 years remain asymptomatic while older children and adults typically experience symptoms including fever, fatigue, poor appetite, abdominal pain, dark urine, clay-colored stools, and jaundice.^2,20,21 Symptoms typically last less than 2 months but can persist or relapse for up to 6 months in 10% to 15% of symptomatic individuals.^22,23 Those with HAV infection are capable of viral transmission from the beginning of the incubation period until about a week after jaundice appears.²⁴ Unlike HBV and HCV, HAV does not cause chronic infection.

Fulminant liver failure, characterized by encephalopathy, jaundice, and elevated international normalized ratio (INR), occurs in < 1% of HAV infections and is more common in those with underlying liver disease and older individuals.^13,25-27 In one retrospective review of fulminant liver failure from HAV infection, about half of the patients required liver transplantation or died within 3 weeks of presentation.¹²

Other than supportive care, there are no specific treatments for acute HAV infection. However, the CDC recommends that healthy individuals aged between 1 and 40 years with known or suspected exposure to HAV within the prior 2 weeks receive 1 dose of a single-antigen HAV vaccination. The CDC also recommends that recently exposed individuals aged < 1 year or > 40 years, or patients who are immunocompromised, have chronic liver disease (CLD), or are allergic to HAV vaccine or a vaccine component should receive a single IG injection. In addition, the CDC recommends that health care providers report all cases of acute HAV to state and local health departments.²⁸

In patients with typical symptoms of acute viral hepatitis (eg, headache, fever, malaise, anorexia, nausea, vomiting, abdominal pain, and diarrhea) and either jaundice or elevated serum aminotransferase levels, confirmation of HAV infection is required with either a positive serologic test for immunoglobulin M (IgM) anti-HAV antibody or an epidemiologic link (eg, recent household or close contact) to a person with laboratory-confirmed HAV.⁵ Serum IgM anti-HAV antibodies are first detectable when symptoms begin and remain detectable for about 3 to 6 months.^29,30 Serum immunoglobulin G (IgG) anti-HAV antibodies, which provide lifelong protection against reinfection, appear as symptoms improve and persist indefinitely.^31,32 Therefore, the presence of anti-HAV IgG and the absence of anti-HAV IgM is indicative of immunity to HAV via past infection or vaccination.

HAV Prevention in The VHA

The mainstay of HAV prevention is vaccination with 2 doses of inactivated, single-antigen hepatitis A vaccine or 3 doses of combination (HAV and HBV) vaccine.¹¹ Both single antigen and combination HAV vaccines are safe in immunocompromised and pregnant patients.^33-39 The HAV vaccination results in 100% anti-HAV IgG seropositivity among healthy individuals, although immunogenicity might be lower for those who are immunocompromised or with CLD.^31,40-47 The VHA recommends HAV immunization, unless contraindicated, for previously unvaccinated 

In addition to vaccination, addressing risk factors for HAV infection and its complications could reduce the burden of disease. For instance, recent outbreaks highlight that homeless individuals and users of injection and noninjection drugs are particularly vulnerable to infections transmitted via fecal-oral contamination. Broad strategies to address homelessness and related sanitation concerns are needed to help reduce the likelihood of future HAV outbreaks.⁴⁹ Specific measures to combat HAV include providing access to clean water, adequate hygiene, and clean needles for people who inject drugs.¹¹ Hepatitis A virus can be destroyed by heating food to ≥ 185 °F for at least 1 minute, chlorinating contaminated water, or cleaning contaminated surfaces with a solution of household bleach and water.⁵⁰ Moreover, it is important to identify and treat risk factors for complications of HAV infection. This includes identifying individuals with HCV and ensuring that they are immune to HAV, given data that HCV-infected individuals are at increased risk of fulminant hepatic failure from HAV.^12,13

Active-duty service members have long been considered at higher risk of HAV infections due to deployments in endemic areas and exposure to contaminated food and water.^51,52 Shortly after the FDA approved HAV vaccination in 1995, the Department of Defense (DoD) mandated screening and HAV immunization for all incoming active-duty service members and those deployed to areas of high endemicity.⁵³ However, US veterans who were discharged before the adoption of universal HAV vaccination remain at increased risk for HAV infection, particularly given the high prevalence of CLD, homelessness, and substance use disorder (SUD) in this cohort.^54-56 Given the importance of HAV prevention for high-risk individuals, an analysis was performed to determine rates of HAV vaccination and testing within VA-enrolled individuals with selected risk factors for HAV acquisition or complications.

Methods

A cross-sectional analysis of veterans in VA care from June 1, 2016 to June 1, 2017 was performed to determine national rates of HAV susceptibility among patients with HCV exposure, homelessness, SUD, or HIV infection. The definitions of homelessness, SUD (alcohol, cannabis, opioid, sedatives, hallucinogens, inhalants, stimulants, or tobacco), and HIV infection were based on the presence of appropriate ICD-9 or ICD-10 codes. History of HCV exposure was based on a positive HCV antibody test. Presence of HAV vaccination was determined based on CPT codes for administration of the single-antigen HAV vaccination or combination HAV/HBV vaccination.

While HIV infection is not independently considered an indication for HAV vaccination, the authors included this group given its high proportion of patients with other risk factors, including MSM and IV drug use. All data were obtained from the VA Corporate Data Warehouse (CDW), a comprehensive national repository of all laboratory, diagnosis, and prescription results (including vaccines) within the VHA since 1999.

Hepatitis A virus nonsusceptibility was defined as (1) documented receipt of HAV vaccination within the VHA; (2) anti-HAV IgG antibody testing within the VHA; or (3) active-duty service after October 1997. It was considered likely that patients who received HAV testing either showed evidence of HAV immunity (eg, positive anti-HAV IgG) or were anti-HAV IgG negative and subsequently immunized. Therefore, patients with anti-HAV IgG antibody testing were counted presumptively as nonsusceptible. The DoD implemented a universal HAV vaccination policy in 1995, therefore, 1997 was chosen as a time at which the military’s universal HAV vaccination campaign was likely to have achieved near 100% vaccination coverage of active-duty military.

Results

The cohort included 5,896,451 patients in VA care, including 381,628 (6.5%) who were homeless, 455,344 (7.7%) with SUD, 225,889 (3.8%) with a lifetime history of positive HCV antibody (indicating past HCV exposure), and 29,166 (0.5%) with HIV infection.

There was wide geographic variability in rates of HAV susceptibility (Figure 1). 

Discussion

Widespread HAV vaccination has decreased the incidence of HAV infection in the US dramatically. Nevertheless, recent outbreaks demonstrate that substantial population susceptibility and associated risk for HAV-related morbidity and mortality remains, particularly in high-risk populations. Although the VHA has not experienced a significant increase in acute HAV infections to date, this cross-sectional analysis highlights that a large proportion of VA patients in traditionally high-risk groups remain susceptible to HAV infection.

Strengths

Strengths of this analysis include a current reflection of HAV susceptibility within the national VHA, thus informing HAV testing and vaccination strategies. This study also involves a very large cohort, which is possible because the VHA is the largest integrated healthcare system in the US. Lastly, because the VHA uses electronic medical records, there was nearly complete capture of HAV vaccinations and testing obtained through the VHA.

Limitations

This cross-sectional analysis has several potential limitations. First, findings may not be generalizable outside the VHA. In addition, determination of homelessness, substance abuse, and HIV infection were based on ICD-9 and ICD-10 codes, which have been used in previous studies but may be subject to misclassification. The authors deliberately included all patients with positive HCV antibody testing to include those with current or prior risk factors for HAV acquisition. This population does not reflect patients with HCV viremia who received HAV testing or vaccination. Lastly, misattribution of HAV susceptibility could have occurred if patients with negative HAV IgG results were not vaccinated or if patients previously received HAV vaccination outside the VHA.

Conclusion

To mitigate the risk of future HAV outbreaks, continued efforts should be made to increase vaccination among high-risk groups, improve awareness of additional prevention measures, and address risk factors for HAV acquisition, particularly in areas with active outbreaks. Further study is suggested to identify geographic areas with large caseloads of at-risk patients and to highlight best practices utilized by VHA facilities that achieved high vaccine coverage rates. Recommended approaches likely will need to include efforts to improve hygiene and reduce risks for HAV exposure associated with SUD and homelessness.

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