The Journal of Family Practice

CASE › James G, age 43, recently had blood work performed for a life insurance policy, and his human immunodeficiency virus (HIV) test came back positive. At a follow-up office visit, Mr. G reports having anonymous male sexual partners when traveling to New York on business and rarely using condoms. His last HIV test was “about 4 years ago.” He is otherwise in good health, takes no regular medications, and is not married.

Having recently completed a primary care CME program on HIV disease, you order a CD4/T-cell count, an HIV RNA (viral load) test, and an HIV genotype drug resistance test on Mr. G, along with other baseline lab work, including a complete blood count, chemistry panel, and hepatitis panel. You schedule a follow-up visit with Mr. G in 2 weeks when all of the lab results will be available so that you can discuss his plan of care.

A diagnosis of HIV has moved from being a fatal disease to that of a chronic condition that can be effectively managed with combination antiretroviral therapy (ART) regimens over an almost normal lifespan. As a result, the role of the primary care practitioner in the ongoing care of patients with HIV has grown and will continue to do so, making knowledge of these drug combinations vital.

20 years have changed everything

Combination ART has existed since 1996 when the first protease inhibitors (PIs) were approved by the US Food and Drug Administration (FDA). Prior to this, treatment was limited to mono or dual therapy with nucleoside reverse transcriptase inhibitors (NRTIs). These agents provided some short-term clinical benefit, but didn’t significantly improve patient survival and ultimately failed due to viral resistance.¹

Since the approval of zidovudine (AZT) in 1987, the FDA has approved more than 25 drugs in 6 different classes for the treatment of HIV disease.² These include the NRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs), PIs, a fusion inhibitor (FI), a CCR5 antagonist, and, more recently, integrase strand transfer inhibitors (INSTIs). In addition, 2 drugs, cobicistat and ritonavir, are used solely to improve or “boost” the pharmacokinetic profiles of several antiretroviral drugs.²

Most of these newer agents are more potent, have a higher genetic barrier to resistance, and a longer half-life than their predecessors. Moreover, many are less toxic and thus more tolerable than older drugs. With the progressive development and approval of single-tablet regimens (STRs) that contain 3 or 4 drugs, the majority of patients with HIV in the United States now take just one pill per day to treat their infection, facilitating far greater medication adherence.

The US Department of Health and Human Services (DHHS) guidelines now recommend that all people infected with HIV, regardless of CD4 cell count, begin ART.² The evidence for this recommendation comes largely from the START³ and TEMPRANO⁴ trials, which found that early initiation of ART significantly reduces morbidity and mortality associated with HIV. In addition, the HPTN 052 study concluded that early ART is associated with a 93% lower risk of viral transmission in serodiscordant heterosexual couples.⁵ The DHHS guidelines do note that when initiating ART, it is important to appropriately educate patients on the benefits of treatment and address strategies to optimize adherence.² (For more on factors to consider when selecting an initial HIV regimen, see TABLE 1.²) On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors, but it should never be withheld unless the risks clearly outweigh the benefits. Ideally, ART should be initiated as soon as possible after the initial diagnosis of HIV.

The DHHS guidelines divide treatment options into 3 categories:²

• Recommended regimens are backed by randomized controlled trials that show optimal and durable virologic efficacy, they have favorable tolerability and toxicity profiles, and they are easy to use.
• Alternative regimens have less or lower quality supporting data than recommended regimens. Although they are effective and may be optimal for certain individual patients, they have potential disadvantages and/or limitations in certain populations.
• Other regimens have limited supporting data, reduced virologic activity, a higher pill burden, more drug interactions, and greater toxicity.

Currently recommended first-line therapies

An antiretroviral regimen for a treatment-naive patient should consist of 2 NRTIs in combination with a third active antiretroviral drug from one of 3 drug classes. These include: an INSTI, a boosted PI, or, in some situations, an NNRTI. The DHHS guidelines panel currently recommends 6 different ART combinations as first-line treatment in treatment-naive patients (TABLE 2).²

Dolutegravir/abacavir/lamivudine (Triumeq). Approved by the FDA as a single-tablet regimen in 2014, the combination of dolutegravir/abacavir/lamivudine has proven to be highly effective and well-tolerated in many clinical trials.^6-9 However, before this regimen is started, patients must be screened for the HLA-B*5701 allele, which predicts hypersensitivity to abacavir.¹⁰ Assessing patients’ risk for cardiovascular disease is also advised because some data suggest that abacavir may increase the risk of cardiovascular events, although this remains controversial.²

Most of the newer agents are more potent, less toxic, have a higher genetic barrier to resistance, and a longer half-life than their predecessors.Dolutegravir is generally well-tolerated with minimal adverse effects (≥2% incidence of headache and insomnia) and toxicity.¹¹ Dolutegravir/abacavir/lamivudine should be taken 2 hours before or 6 hours after taking antacids or laxatives, sucralfate, and oral supplements with iron or calcium. However, it may be taken with calcium or iron supplements if it is also taken with food.¹¹ Dolutegravir increases levels of metformin about 2-fold, so patients should not take more than 1000 mg/d of this oral hypoglycemic agent.¹¹

Dolutegravir plus tenofovir disoproxil fumarate/emtricitabine (Tivicay plus Truvada). The combination of dolutegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine is administered as 2 pills per day. Because tenofovir disoproxil fumarate can cause proximal renal tubular dysfunction, phosphate wasting, and decreased bone mineral density (BMD), avoid prescribing it for patients with underlying renal dysfunction (creatinine clearance [CrCl] <50 mL/min) and prescribe it cautiously for patients with hypertension or diabetes who are at increased risk of renal disease. Emtricitabine is generally safe and well tolerated, but the dose should be reduced in patients with renal insufficiency, which would preclude the use of this fixed-dose combination.¹²

Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (Genvoya). The newer 4-drug combination of elvite­gravir/­­cobicistat/tenofovir alafenamide/emtricitabine­­ that was approved by the FDA in November 2015,¹³ contains the more recently approved form of tenofovir, which can be used in patients who have a CrCl as low as 30 mL/min. Compared to formulations containing tenofovir disoproxil fumarate, the newer tenofovir alafenamide formulation achieves higher intracellular levels in CD4 lymphocytes (but not in renal tubular cells). This allows for a lower dose of the drug and a smaller tablet size with co-formulation. It does not appear to cause kidney problems or loss of BMD as can be seen with tenofovir disoproxil fumarate.¹⁴ This newer single-tablet regimen may be best suited for older patients with HIV or those with comorbidities such as hypertension or diabetes.

Elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (Stribild). The FDA approved the combination of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine as a single-tablet regimen in 2012. The integrase inhibitor, elvitegravir, requires boosting with the CYP3A inhibitor, cobicistat, and should be taken with food.¹⁵ Two clinical trials demonstrated the superior efficacy of elvitegravir compared to a boosted PI and NNRTI-based regimen.^16,17 Elvitegravir is generally well tolerated, but sometimes causes dyspepsia, nausea, or diarrhea.¹⁵ Similar to dolutegravir, it should not be taken concurrently with certain supplements—in this case, those containing aluminum, calcium, iron, magnesium, or zinc.¹⁵ Because it contains tenofovir disoproxil fumarate as an active agent, it should not be used in patients with a CrCl of <70 mL/min.¹⁵

Cobicistat inhibits tubular secretion of creatinine, so it may produce an elevation in serum creatinine without actually affecting glomerular function. Cobicistat may also cause drug-drug interactions with certain antiarrhythmics, sedative-hypnotics, and erectile dysfunction agents, and is contraindicated with some statins, anticonvulsants, and ergot derivatives.¹⁸

Raltegravir plus tenofovir disoproxil fumarate/emtricitabine (Isentress plus Truvada). The combination of the integrase inhibitor raltegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine has been recommended by the DHHS as first-line therapy for approximately 5 years. The recommendation is based mainly on data from the STARTMRK trial, a phase III non-inferiority trial that followed more than 500 patients for 5 years and concluded that raltegravir/tenofovir/emtricitabine has superior efficacy with fewer drug-related adverse effects than efavirenz/tenofovir/emtricitabine.¹⁹ The overall pill burden with this regimen is 3 tablets per day. Although highly effective, the main drawbacks of raltegravir are that it must be dosed twice daily (which may be less preferable if adherence is a concern) and the genetic barrier to resistance is lower than that of the other 2 approved integrase inhibitors. There is a once-daily formulation of raltegravir that's expected to be available late in 2017.²⁰

Before starting a regimen with abacavir, screen patients for the HLA-B*5701 allele, which predicts hypersensitivity to the drug.Adverse effects and toxicities (except the renal and bone effects due to tenofovir disoproxil fumarate mentioned earlier) and drug interactions with this regimen are infrequent. Raltegravir can be taken with or without food. Concurrent use of antacids that contain aluminum or magnesium may reduce absorption of raltegravir and so should be avoided.²¹

PI-based regimen

Darunavir (Prezista) and ritonavir (Norvir) plus tenofovir disoproxil fumarate/emtricitabine (Truvada). PIs were once the key component of all ART regimens; however, boosted darunavir is now the only PI-based regimen currently recommended as first-line therapy. It is taken as 3 tablets once daily. If the co-formulation with cobicistat is used, just 2 tablets daily are required. One advantage with darunavir with either of the boosting agents is that it does not appear to cause insulin resistance or dyslipidemia as occurs with older PIs, such as indinavir and lopinavir.² The boosting agents do, however, increase the likelihood of drug-drug interactions. As with all PIs, darunavir has a very high genetic barrier to resistance, which is important in patients for whom adherence is a concern.

Adverse effects of the PIs may include nausea, vomiting, and diarrhea, all of which are typically mild and self-limiting.²² Co-formulation of darunavir with cobicistat, tenofovir alafenamide, and emtricitabine is in phase III studies. Projected to be available in late 2017, it will provide yet another daily STR option.²³

The addition of fixed-dose tenofovir alafenamide/emtricitabine

In July 2016, the DHHS panel made some additions to their guidelines to reflect the FDA approval of 3 fixed-dose combination products that contain tenofovir alafenamide. Specifically, the combination of tenofovir alafenamide and emtricitabine is recommended for use with the integrase inhibitors—dolutegravir or raltegravir. It is also recommended in combination with ritonavir-boosted darunavir.

The DHHS guidelines also include “alternative” (TABLE 3²) and “other” regimens (available at: http://aidsinfo.nih.gov/guidelines) that may be used when first-line regimens may not. These second-line options are very effective, but have some possible clinical disadvantages or limitations. They are also less well supported by data from clinical trials. However, in certain situations, depending on an individual patient’s comorbidities, inability to tolerate one of the preferred regimens, or personal preferences, an alternative regimen may be the optimal choice.

Under the category of alternative regimens, the panel has included tenofovir alafenamide and emtricitabine in combination with the NNRTI efavirenz or with ritonavir- or cobicistat-boosted atazanavir or darunavir.

Consider the new 4-drug, single-tablet formulation for older patients with HIV or those with comorbidities such as hypertension or diabetes.The third group or “other” regimens have reduced virologic activity, increased toxicity, and even more limited data from clinical trials. Generally, medications from the DHHS “alternative” and “other” categories should be prescribed in consultation with an HIV specialist.

The future of ART

The currently available drugs are highly effective in fully suppressing HIV and allowing for immune recovery and clinical stability for most patients. Life expectancy for patients living with HIV is estimated to be approaching that of uninfected adults—provided they remain on ART.²⁴ As a way to further simplify ART, current clinical trials are looking at 2-drug regimens including an integrase inhibitor with an NRTI, an INSTI, or an NNRTI, or a PI with one NRTI.^25,26 This approach could further reduce pill burden and toxicity and substantially decrease the cost of long-term treatment.²⁷ Also on the horizon are long-acting injectable antiretroviral drugs that will likely be available for clinical use in the next 2 to 3 years.^28,29

CASE › At the 2-week follow-up visit, you discuss with Mr. G that his CD4+ count is 390 cells/mm³, his HIV RNA level is 32,450 copies/mL, and his HIV genotype test showed no antiviral drug resistance. Explaining that all patients with HIV should be treated with antiviral therapy regardless of CD4+ count, you recommend that Mr. G begin taking fixed-dose tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat (Stribild), noting that it is one of the regimens recommended by the DHHS national treatment guidelines. You provide a patient handout that discusses dosing and adverse effects, including nausea and headache. The patient’s pharmacy was contacted and it was determined that Mr. G’s co-pay for the drug would be $50, which he found acceptable.

In addition, you discuss the importance of good adherence to this medication, and instruct Mr. G to contact the office via phone or patient portal for any concerns or questions that arise after starting the medication. Lastly, you advise him to return in 4 weeks for follow-up blood testing, including viral load monitoring, and additional care, if needed, and strongly recommend that he begin using condoms regularly.

CORRESPONDENCE
Jeffrey T. Kirchner, DO, FAAFP, AAHIVS, Medical Director, LGHP Comprehensive Care, 554 North Duke St., 3rd Floor, Lancaster, PA 1760; [email protected].

CASE › James G, age 43, recently had blood work performed for a life insurance policy, and his human immunodeficiency virus (HIV) test came back positive. At a follow-up office visit, Mr. G reports having anonymous male sexual partners when traveling to New York on business and rarely using condoms. His last HIV test was “about 4 years ago.” He is otherwise in good health, takes no regular medications, and is not married.

Having recently completed a primary care CME program on HIV disease, you order a CD4/T-cell count, an HIV RNA (viral load) test, and an HIV genotype drug resistance test on Mr. G, along with other baseline lab work, including a complete blood count, chemistry panel, and hepatitis panel. You schedule a follow-up visit with Mr. G in 2 weeks when all of the lab results will be available so that you can discuss his plan of care.

A diagnosis of HIV has moved from being a fatal disease to that of a chronic condition that can be effectively managed with combination antiretroviral therapy (ART) regimens over an almost normal lifespan. As a result, the role of the primary care practitioner in the ongoing care of patients with HIV has grown and will continue to do so, making knowledge of these drug combinations vital.

20 years have changed everything

Combination ART has existed since 1996 when the first protease inhibitors (PIs) were approved by the US Food and Drug Administration (FDA). Prior to this, treatment was limited to mono or dual therapy with nucleoside reverse transcriptase inhibitors (NRTIs). These agents provided some short-term clinical benefit, but didn’t significantly improve patient survival and ultimately failed due to viral resistance.¹

Since the approval of zidovudine (AZT) in 1987, the FDA has approved more than 25 drugs in 6 different classes for the treatment of HIV disease.² These include the NRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs), PIs, a fusion inhibitor (FI), a CCR5 antagonist, and, more recently, integrase strand transfer inhibitors (INSTIs). In addition, 2 drugs, cobicistat and ritonavir, are used solely to improve or “boost” the pharmacokinetic profiles of several antiretroviral drugs.²

Most of these newer agents are more potent, have a higher genetic barrier to resistance, and a longer half-life than their predecessors. Moreover, many are less toxic and thus more tolerable than older drugs. With the progressive development and approval of single-tablet regimens (STRs) that contain 3 or 4 drugs, the majority of patients with HIV in the United States now take just one pill per day to treat their infection, facilitating far greater medication adherence.

The US Department of Health and Human Services (DHHS) guidelines now recommend that all people infected with HIV, regardless of CD4 cell count, begin ART.² The evidence for this recommendation comes largely from the START³ and TEMPRANO⁴ trials, which found that early initiation of ART significantly reduces morbidity and mortality associated with HIV. In addition, the HPTN 052 study concluded that early ART is associated with a 93% lower risk of viral transmission in serodiscordant heterosexual couples.⁵ The DHHS guidelines do note that when initiating ART, it is important to appropriately educate patients on the benefits of treatment and address strategies to optimize adherence.² (For more on factors to consider when selecting an initial HIV regimen, see TABLE 1.²) On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors, but it should never be withheld unless the risks clearly outweigh the benefits. Ideally, ART should be initiated as soon as possible after the initial diagnosis of HIV.

The DHHS guidelines divide treatment options into 3 categories:²

• Recommended regimens are backed by randomized controlled trials that show optimal and durable virologic efficacy, they have favorable tolerability and toxicity profiles, and they are easy to use.
• Alternative regimens have less or lower quality supporting data than recommended regimens. Although they are effective and may be optimal for certain individual patients, they have potential disadvantages and/or limitations in certain populations.
• Other regimens have limited supporting data, reduced virologic activity, a higher pill burden, more drug interactions, and greater toxicity.

Currently recommended first-line therapies

An antiretroviral regimen for a treatment-naive patient should consist of 2 NRTIs in combination with a third active antiretroviral drug from one of 3 drug classes. These include: an INSTI, a boosted PI, or, in some situations, an NNRTI. The DHHS guidelines panel currently recommends 6 different ART combinations as first-line treatment in treatment-naive patients (TABLE 2).²

Dolutegravir/abacavir/lamivudine (Triumeq). Approved by the FDA as a single-tablet regimen in 2014, the combination of dolutegravir/abacavir/lamivudine has proven to be highly effective and well-tolerated in many clinical trials.^6-9 However, before this regimen is started, patients must be screened for the HLA-B*5701 allele, which predicts hypersensitivity to abacavir.¹⁰ Assessing patients’ risk for cardiovascular disease is also advised because some data suggest that abacavir may increase the risk of cardiovascular events, although this remains controversial.²

Most of the newer agents are more potent, less toxic, have a higher genetic barrier to resistance, and a longer half-life than their predecessors.Dolutegravir is generally well-tolerated with minimal adverse effects (≥2% incidence of headache and insomnia) and toxicity.¹¹ Dolutegravir/abacavir/lamivudine should be taken 2 hours before or 6 hours after taking antacids or laxatives, sucralfate, and oral supplements with iron or calcium. However, it may be taken with calcium or iron supplements if it is also taken with food.¹¹ Dolutegravir increases levels of metformin about 2-fold, so patients should not take more than 1000 mg/d of this oral hypoglycemic agent.¹¹

Dolutegravir plus tenofovir disoproxil fumarate/emtricitabine (Tivicay plus Truvada). The combination of dolutegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine is administered as 2 pills per day. Because tenofovir disoproxil fumarate can cause proximal renal tubular dysfunction, phosphate wasting, and decreased bone mineral density (BMD), avoid prescribing it for patients with underlying renal dysfunction (creatinine clearance [CrCl] <50 mL/min) and prescribe it cautiously for patients with hypertension or diabetes who are at increased risk of renal disease. Emtricitabine is generally safe and well tolerated, but the dose should be reduced in patients with renal insufficiency, which would preclude the use of this fixed-dose combination.¹²

Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (Genvoya). The newer 4-drug combination of elvite­gravir/­­cobicistat/tenofovir alafenamide/emtricitabine­­ that was approved by the FDA in November 2015,¹³ contains the more recently approved form of tenofovir, which can be used in patients who have a CrCl as low as 30 mL/min. Compared to formulations containing tenofovir disoproxil fumarate, the newer tenofovir alafenamide formulation achieves higher intracellular levels in CD4 lymphocytes (but not in renal tubular cells). This allows for a lower dose of the drug and a smaller tablet size with co-formulation. It does not appear to cause kidney problems or loss of BMD as can be seen with tenofovir disoproxil fumarate.¹⁴ This newer single-tablet regimen may be best suited for older patients with HIV or those with comorbidities such as hypertension or diabetes.

Elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (Stribild). The FDA approved the combination of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine as a single-tablet regimen in 2012. The integrase inhibitor, elvitegravir, requires boosting with the CYP3A inhibitor, cobicistat, and should be taken with food.¹⁵ Two clinical trials demonstrated the superior efficacy of elvitegravir compared to a boosted PI and NNRTI-based regimen.^16,17 Elvitegravir is generally well tolerated, but sometimes causes dyspepsia, nausea, or diarrhea.¹⁵ Similar to dolutegravir, it should not be taken concurrently with certain supplements—in this case, those containing aluminum, calcium, iron, magnesium, or zinc.¹⁵ Because it contains tenofovir disoproxil fumarate as an active agent, it should not be used in patients with a CrCl of <70 mL/min.¹⁵

Cobicistat inhibits tubular secretion of creatinine, so it may produce an elevation in serum creatinine without actually affecting glomerular function. Cobicistat may also cause drug-drug interactions with certain antiarrhythmics, sedative-hypnotics, and erectile dysfunction agents, and is contraindicated with some statins, anticonvulsants, and ergot derivatives.¹⁸

Raltegravir plus tenofovir disoproxil fumarate/emtricitabine (Isentress plus Truvada). The combination of the integrase inhibitor raltegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine has been recommended by the DHHS as first-line therapy for approximately 5 years. The recommendation is based mainly on data from the STARTMRK trial, a phase III non-inferiority trial that followed more than 500 patients for 5 years and concluded that raltegravir/tenofovir/emtricitabine has superior efficacy with fewer drug-related adverse effects than efavirenz/tenofovir/emtricitabine.¹⁹ The overall pill burden with this regimen is 3 tablets per day. Although highly effective, the main drawbacks of raltegravir are that it must be dosed twice daily (which may be less preferable if adherence is a concern) and the genetic barrier to resistance is lower than that of the other 2 approved integrase inhibitors. There is a once-daily formulation of raltegravir that's expected to be available late in 2017.²⁰

Before starting a regimen with abacavir, screen patients for the HLA-B*5701 allele, which predicts hypersensitivity to the drug.Adverse effects and toxicities (except the renal and bone effects due to tenofovir disoproxil fumarate mentioned earlier) and drug interactions with this regimen are infrequent. Raltegravir can be taken with or without food. Concurrent use of antacids that contain aluminum or magnesium may reduce absorption of raltegravir and so should be avoided.²¹

PI-based regimen

Darunavir (Prezista) and ritonavir (Norvir) plus tenofovir disoproxil fumarate/emtricitabine (Truvada). PIs were once the key component of all ART regimens; however, boosted darunavir is now the only PI-based regimen currently recommended as first-line therapy. It is taken as 3 tablets once daily. If the co-formulation with cobicistat is used, just 2 tablets daily are required. One advantage with darunavir with either of the boosting agents is that it does not appear to cause insulin resistance or dyslipidemia as occurs with older PIs, such as indinavir and lopinavir.² The boosting agents do, however, increase the likelihood of drug-drug interactions. As with all PIs, darunavir has a very high genetic barrier to resistance, which is important in patients for whom adherence is a concern.

Adverse effects of the PIs may include nausea, vomiting, and diarrhea, all of which are typically mild and self-limiting.²² Co-formulation of darunavir with cobicistat, tenofovir alafenamide, and emtricitabine is in phase III studies. Projected to be available in late 2017, it will provide yet another daily STR option.²³

The addition of fixed-dose tenofovir alafenamide/emtricitabine

In July 2016, the DHHS panel made some additions to their guidelines to reflect the FDA approval of 3 fixed-dose combination products that contain tenofovir alafenamide. Specifically, the combination of tenofovir alafenamide and emtricitabine is recommended for use with the integrase inhibitors—dolutegravir or raltegravir. It is also recommended in combination with ritonavir-boosted darunavir.

The DHHS guidelines also include “alternative” (TABLE 3²) and “other” regimens (available at: http://aidsinfo.nih.gov/guidelines) that may be used when first-line regimens may not. These second-line options are very effective, but have some possible clinical disadvantages or limitations. They are also less well supported by data from clinical trials. However, in certain situations, depending on an individual patient’s comorbidities, inability to tolerate one of the preferred regimens, or personal preferences, an alternative regimen may be the optimal choice.

Under the category of alternative regimens, the panel has included tenofovir alafenamide and emtricitabine in combination with the NNRTI efavirenz or with ritonavir- or cobicistat-boosted atazanavir or darunavir.

Consider the new 4-drug, single-tablet formulation for older patients with HIV or those with comorbidities such as hypertension or diabetes.The third group or “other” regimens have reduced virologic activity, increased toxicity, and even more limited data from clinical trials. Generally, medications from the DHHS “alternative” and “other” categories should be prescribed in consultation with an HIV specialist.

The future of ART

The currently available drugs are highly effective in fully suppressing HIV and allowing for immune recovery and clinical stability for most patients. Life expectancy for patients living with HIV is estimated to be approaching that of uninfected adults—provided they remain on ART.²⁴ As a way to further simplify ART, current clinical trials are looking at 2-drug regimens including an integrase inhibitor with an NRTI, an INSTI, or an NNRTI, or a PI with one NRTI.^25,26 This approach could further reduce pill burden and toxicity and substantially decrease the cost of long-term treatment.²⁷ Also on the horizon are long-acting injectable antiretroviral drugs that will likely be available for clinical use in the next 2 to 3 years.^28,29

CASE › At the 2-week follow-up visit, you discuss with Mr. G that his CD4+ count is 390 cells/mm³, his HIV RNA level is 32,450 copies/mL, and his HIV genotype test showed no antiviral drug resistance. Explaining that all patients with HIV should be treated with antiviral therapy regardless of CD4+ count, you recommend that Mr. G begin taking fixed-dose tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat (Stribild), noting that it is one of the regimens recommended by the DHHS national treatment guidelines. You provide a patient handout that discusses dosing and adverse effects, including nausea and headache. The patient’s pharmacy was contacted and it was determined that Mr. G’s co-pay for the drug would be $50, which he found acceptable.

In addition, you discuss the importance of good adherence to this medication, and instruct Mr. G to contact the office via phone or patient portal for any concerns or questions that arise after starting the medication. Lastly, you advise him to return in 4 weeks for follow-up blood testing, including viral load monitoring, and additional care, if needed, and strongly recommend that he begin using condoms regularly.

CORRESPONDENCE
Jeffrey T. Kirchner, DO, FAAFP, AAHIVS, Medical Director, LGHP Comprehensive Care, 554 North Duke St., 3rd Floor, Lancaster, PA 1760; [email protected].

CASE › James G, age 43, recently had blood work performed for a life insurance policy, and his human immunodeficiency virus (HIV) test came back positive. At a follow-up office visit, Mr. G reports having anonymous male sexual partners when traveling to New York on business and rarely using condoms. His last HIV test was “about 4 years ago.” He is otherwise in good health, takes no regular medications, and is not married.

Having recently completed a primary care CME program on HIV disease, you order a CD4/T-cell count, an HIV RNA (viral load) test, and an HIV genotype drug resistance test on Mr. G, along with other baseline lab work, including a complete blood count, chemistry panel, and hepatitis panel. You schedule a follow-up visit with Mr. G in 2 weeks when all of the lab results will be available so that you can discuss his plan of care.

A diagnosis of HIV has moved from being a fatal disease to that of a chronic condition that can be effectively managed with combination antiretroviral therapy (ART) regimens over an almost normal lifespan. As a result, the role of the primary care practitioner in the ongoing care of patients with HIV has grown and will continue to do so, making knowledge of these drug combinations vital.

20 years have changed everything

Combination ART has existed since 1996 when the first protease inhibitors (PIs) were approved by the US Food and Drug Administration (FDA). Prior to this, treatment was limited to mono or dual therapy with nucleoside reverse transcriptase inhibitors (NRTIs). These agents provided some short-term clinical benefit, but didn’t significantly improve patient survival and ultimately failed due to viral resistance.¹

Since the approval of zidovudine (AZT) in 1987, the FDA has approved more than 25 drugs in 6 different classes for the treatment of HIV disease.² These include the NRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs), PIs, a fusion inhibitor (FI), a CCR5 antagonist, and, more recently, integrase strand transfer inhibitors (INSTIs). In addition, 2 drugs, cobicistat and ritonavir, are used solely to improve or “boost” the pharmacokinetic profiles of several antiretroviral drugs.²

Most of these newer agents are more potent, have a higher genetic barrier to resistance, and a longer half-life than their predecessors. Moreover, many are less toxic and thus more tolerable than older drugs. With the progressive development and approval of single-tablet regimens (STRs) that contain 3 or 4 drugs, the majority of patients with HIV in the United States now take just one pill per day to treat their infection, facilitating far greater medication adherence.

The US Department of Health and Human Services (DHHS) guidelines now recommend that all people infected with HIV, regardless of CD4 cell count, begin ART.² The evidence for this recommendation comes largely from the START³ and TEMPRANO⁴ trials, which found that early initiation of ART significantly reduces morbidity and mortality associated with HIV. In addition, the HPTN 052 study concluded that early ART is associated with a 93% lower risk of viral transmission in serodiscordant heterosexual couples.⁵ The DHHS guidelines do note that when initiating ART, it is important to appropriately educate patients on the benefits of treatment and address strategies to optimize adherence.² (For more on factors to consider when selecting an initial HIV regimen, see TABLE 1.²) On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors, but it should never be withheld unless the risks clearly outweigh the benefits. Ideally, ART should be initiated as soon as possible after the initial diagnosis of HIV.

The DHHS guidelines divide treatment options into 3 categories:²

• Recommended regimens are backed by randomized controlled trials that show optimal and durable virologic efficacy, they have favorable tolerability and toxicity profiles, and they are easy to use.
• Alternative regimens have less or lower quality supporting data than recommended regimens. Although they are effective and may be optimal for certain individual patients, they have potential disadvantages and/or limitations in certain populations.
• Other regimens have limited supporting data, reduced virologic activity, a higher pill burden, more drug interactions, and greater toxicity.

Currently recommended first-line therapies

An antiretroviral regimen for a treatment-naive patient should consist of 2 NRTIs in combination with a third active antiretroviral drug from one of 3 drug classes. These include: an INSTI, a boosted PI, or, in some situations, an NNRTI. The DHHS guidelines panel currently recommends 6 different ART combinations as first-line treatment in treatment-naive patients (TABLE 2).²

Dolutegravir/abacavir/lamivudine (Triumeq). Approved by the FDA as a single-tablet regimen in 2014, the combination of dolutegravir/abacavir/lamivudine has proven to be highly effective and well-tolerated in many clinical trials.^6-9 However, before this regimen is started, patients must be screened for the HLA-B*5701 allele, which predicts hypersensitivity to abacavir.¹⁰ Assessing patients’ risk for cardiovascular disease is also advised because some data suggest that abacavir may increase the risk of cardiovascular events, although this remains controversial.²

Most of the newer agents are more potent, less toxic, have a higher genetic barrier to resistance, and a longer half-life than their predecessors.Dolutegravir is generally well-tolerated with minimal adverse effects (≥2% incidence of headache and insomnia) and toxicity.¹¹ Dolutegravir/abacavir/lamivudine should be taken 2 hours before or 6 hours after taking antacids or laxatives, sucralfate, and oral supplements with iron or calcium. However, it may be taken with calcium or iron supplements if it is also taken with food.¹¹ Dolutegravir increases levels of metformin about 2-fold, so patients should not take more than 1000 mg/d of this oral hypoglycemic agent.¹¹

Dolutegravir plus tenofovir disoproxil fumarate/emtricitabine (Tivicay plus Truvada). The combination of dolutegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine is administered as 2 pills per day. Because tenofovir disoproxil fumarate can cause proximal renal tubular dysfunction, phosphate wasting, and decreased bone mineral density (BMD), avoid prescribing it for patients with underlying renal dysfunction (creatinine clearance [CrCl] <50 mL/min) and prescribe it cautiously for patients with hypertension or diabetes who are at increased risk of renal disease. Emtricitabine is generally safe and well tolerated, but the dose should be reduced in patients with renal insufficiency, which would preclude the use of this fixed-dose combination.¹²

Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (Genvoya). The newer 4-drug combination of elvite­gravir/­­cobicistat/tenofovir alafenamide/emtricitabine­­ that was approved by the FDA in November 2015,¹³ contains the more recently approved form of tenofovir, which can be used in patients who have a CrCl as low as 30 mL/min. Compared to formulations containing tenofovir disoproxil fumarate, the newer tenofovir alafenamide formulation achieves higher intracellular levels in CD4 lymphocytes (but not in renal tubular cells). This allows for a lower dose of the drug and a smaller tablet size with co-formulation. It does not appear to cause kidney problems or loss of BMD as can be seen with tenofovir disoproxil fumarate.¹⁴ This newer single-tablet regimen may be best suited for older patients with HIV or those with comorbidities such as hypertension or diabetes.

Elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (Stribild). The FDA approved the combination of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine as a single-tablet regimen in 2012. The integrase inhibitor, elvitegravir, requires boosting with the CYP3A inhibitor, cobicistat, and should be taken with food.¹⁵ Two clinical trials demonstrated the superior efficacy of elvitegravir compared to a boosted PI and NNRTI-based regimen.^16,17 Elvitegravir is generally well tolerated, but sometimes causes dyspepsia, nausea, or diarrhea.¹⁵ Similar to dolutegravir, it should not be taken concurrently with certain supplements—in this case, those containing aluminum, calcium, iron, magnesium, or zinc.¹⁵ Because it contains tenofovir disoproxil fumarate as an active agent, it should not be used in patients with a CrCl of <70 mL/min.¹⁵

Cobicistat inhibits tubular secretion of creatinine, so it may produce an elevation in serum creatinine without actually affecting glomerular function. Cobicistat may also cause drug-drug interactions with certain antiarrhythmics, sedative-hypnotics, and erectile dysfunction agents, and is contraindicated with some statins, anticonvulsants, and ergot derivatives.¹⁸

Raltegravir plus tenofovir disoproxil fumarate/emtricitabine (Isentress plus Truvada). The combination of the integrase inhibitor raltegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine has been recommended by the DHHS as first-line therapy for approximately 5 years. The recommendation is based mainly on data from the STARTMRK trial, a phase III non-inferiority trial that followed more than 500 patients for 5 years and concluded that raltegravir/tenofovir/emtricitabine has superior efficacy with fewer drug-related adverse effects than efavirenz/tenofovir/emtricitabine.¹⁹ The overall pill burden with this regimen is 3 tablets per day. Although highly effective, the main drawbacks of raltegravir are that it must be dosed twice daily (which may be less preferable if adherence is a concern) and the genetic barrier to resistance is lower than that of the other 2 approved integrase inhibitors. There is a once-daily formulation of raltegravir that's expected to be available late in 2017.²⁰

Before starting a regimen with abacavir, screen patients for the HLA-B*5701 allele, which predicts hypersensitivity to the drug.Adverse effects and toxicities (except the renal and bone effects due to tenofovir disoproxil fumarate mentioned earlier) and drug interactions with this regimen are infrequent. Raltegravir can be taken with or without food. Concurrent use of antacids that contain aluminum or magnesium may reduce absorption of raltegravir and so should be avoided.²¹

PI-based regimen

Darunavir (Prezista) and ritonavir (Norvir) plus tenofovir disoproxil fumarate/emtricitabine (Truvada). PIs were once the key component of all ART regimens; however, boosted darunavir is now the only PI-based regimen currently recommended as first-line therapy. It is taken as 3 tablets once daily. If the co-formulation with cobicistat is used, just 2 tablets daily are required. One advantage with darunavir with either of the boosting agents is that it does not appear to cause insulin resistance or dyslipidemia as occurs with older PIs, such as indinavir and lopinavir.² The boosting agents do, however, increase the likelihood of drug-drug interactions. As with all PIs, darunavir has a very high genetic barrier to resistance, which is important in patients for whom adherence is a concern.

Adverse effects of the PIs may include nausea, vomiting, and diarrhea, all of which are typically mild and self-limiting.²² Co-formulation of darunavir with cobicistat, tenofovir alafenamide, and emtricitabine is in phase III studies. Projected to be available in late 2017, it will provide yet another daily STR option.²³

The addition of fixed-dose tenofovir alafenamide/emtricitabine

In July 2016, the DHHS panel made some additions to their guidelines to reflect the FDA approval of 3 fixed-dose combination products that contain tenofovir alafenamide. Specifically, the combination of tenofovir alafenamide and emtricitabine is recommended for use with the integrase inhibitors—dolutegravir or raltegravir. It is also recommended in combination with ritonavir-boosted darunavir.

The DHHS guidelines also include “alternative” (TABLE 3²) and “other” regimens (available at: http://aidsinfo.nih.gov/guidelines) that may be used when first-line regimens may not. These second-line options are very effective, but have some possible clinical disadvantages or limitations. They are also less well supported by data from clinical trials. However, in certain situations, depending on an individual patient’s comorbidities, inability to tolerate one of the preferred regimens, or personal preferences, an alternative regimen may be the optimal choice.

Under the category of alternative regimens, the panel has included tenofovir alafenamide and emtricitabine in combination with the NNRTI efavirenz or with ritonavir- or cobicistat-boosted atazanavir or darunavir.

Consider the new 4-drug, single-tablet formulation for older patients with HIV or those with comorbidities such as hypertension or diabetes.The third group or “other” regimens have reduced virologic activity, increased toxicity, and even more limited data from clinical trials. Generally, medications from the DHHS “alternative” and “other” categories should be prescribed in consultation with an HIV specialist.

The future of ART

The currently available drugs are highly effective in fully suppressing HIV and allowing for immune recovery and clinical stability for most patients. Life expectancy for patients living with HIV is estimated to be approaching that of uninfected adults—provided they remain on ART.²⁴ As a way to further simplify ART, current clinical trials are looking at 2-drug regimens including an integrase inhibitor with an NRTI, an INSTI, or an NNRTI, or a PI with one NRTI.^25,26 This approach could further reduce pill burden and toxicity and substantially decrease the cost of long-term treatment.²⁷ Also on the horizon are long-acting injectable antiretroviral drugs that will likely be available for clinical use in the next 2 to 3 years.^28,29

CASE › At the 2-week follow-up visit, you discuss with Mr. G that his CD4+ count is 390 cells/mm³, his HIV RNA level is 32,450 copies/mL, and his HIV genotype test showed no antiviral drug resistance. Explaining that all patients with HIV should be treated with antiviral therapy regardless of CD4+ count, you recommend that Mr. G begin taking fixed-dose tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat (Stribild), noting that it is one of the regimens recommended by the DHHS national treatment guidelines. You provide a patient handout that discusses dosing and adverse effects, including nausea and headache. The patient’s pharmacy was contacted and it was determined that Mr. G’s co-pay for the drug would be $50, which he found acceptable.

In addition, you discuss the importance of good adherence to this medication, and instruct Mr. G to contact the office via phone or patient portal for any concerns or questions that arise after starting the medication. Lastly, you advise him to return in 4 weeks for follow-up blood testing, including viral load monitoring, and additional care, if needed, and strongly recommend that he begin using condoms regularly.

CORRESPONDENCE
Jeffrey T. Kirchner, DO, FAAFP, AAHIVS, Medical Director, LGHP Comprehensive Care, 554 North Duke St., 3rd Floor, Lancaster, PA 1760; [email protected].

One of my brothers has adult onset bipolar disorder. As luck would have it, he also has type 2 diabetes mellitus. He struggles constantly with blood sugar control since he needs to take 2 psychotropic medications, both of which cause weight gain.

I mistakenly told a patient that her beta-blocker wasn't interfering with her weight loss.His situation has prompted me to think about the responsibility we have as we care, and advocate, for our patients with major mental illness who require these effective medications. At a minimum, we must be knowledgeable about the adverse metabolic effects of these drugs, avoid prescribing them when possible, and advocate for dose reductions when feasible. Knowing, for example, that these drugs fall on a spectrum, with haloperidol causing the least weight gain and olanzapine causing the most, is important.¹

An eye-opener. The article by Saunders in this issue provides advice on avoiding medications that commonly cause weight gain when prescribing for overweight or obese patients with diabetes, hypertension, and/or depression. I was unaware that some of the drugs on the list contribute to the problem. For example, I saw a new patient last week who has hypertension and is obese; she has been taking the beta-blocker metoprolol for the past 8 years. She has tried unsuccessfully to lose weight. She asked me if the metoprolol could be interfering with weight loss, and I mistakenly told her “No.” Thankfully, we decided to discontinue it anyway. I will admit to her my knowledge gap when I see her next month for follow-up. Errors are great teachers, especially when no harm is done.

The scope of the Saunders article is not meant to be comprehensive, since it focuses on medications for diabetes, hypertension, and depression. I think all of us are aware of the weight gain associated with other commonly prescribed drugs, such as systemic corticosteroids and long-acting progesterone for contraception. Thankfully, combination oral contraceptives do not appear to be associated with weight gain²—answering one of the more common questions I receive from patients about weight and medications.

The bottom line. Avoid prescribing medications that can cause weight gain in overweight and obese patients when possible, use the lowest effective dose when such agents are necessary, and warn patients of this adverse effect so that they can take precautions, such as walking an extra mile a day or giving up that high-calorie latte in the morning.

1. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382:951-962.

2. Gallo MF, Lopez LM, Grimes DA, et al. Combination contraceptives: effects on weight. Cochrane Database Syst Rev. 2011;CD003987.

One of my brothers has adult onset bipolar disorder. As luck would have it, he also has type 2 diabetes mellitus. He struggles constantly with blood sugar control since he needs to take 2 psychotropic medications, both of which cause weight gain.

I mistakenly told a patient that her beta-blocker wasn't interfering with her weight loss.His situation has prompted me to think about the responsibility we have as we care, and advocate, for our patients with major mental illness who require these effective medications. At a minimum, we must be knowledgeable about the adverse metabolic effects of these drugs, avoid prescribing them when possible, and advocate for dose reductions when feasible. Knowing, for example, that these drugs fall on a spectrum, with haloperidol causing the least weight gain and olanzapine causing the most, is important.¹

An eye-opener. The article by Saunders in this issue provides advice on avoiding medications that commonly cause weight gain when prescribing for overweight or obese patients with diabetes, hypertension, and/or depression. I was unaware that some of the drugs on the list contribute to the problem. For example, I saw a new patient last week who has hypertension and is obese; she has been taking the beta-blocker metoprolol for the past 8 years. She has tried unsuccessfully to lose weight. She asked me if the metoprolol could be interfering with weight loss, and I mistakenly told her “No.” Thankfully, we decided to discontinue it anyway. I will admit to her my knowledge gap when I see her next month for follow-up. Errors are great teachers, especially when no harm is done.

The scope of the Saunders article is not meant to be comprehensive, since it focuses on medications for diabetes, hypertension, and depression. I think all of us are aware of the weight gain associated with other commonly prescribed drugs, such as systemic corticosteroids and long-acting progesterone for contraception. Thankfully, combination oral contraceptives do not appear to be associated with weight gain²—answering one of the more common questions I receive from patients about weight and medications.

The bottom line. Avoid prescribing medications that can cause weight gain in overweight and obese patients when possible, use the lowest effective dose when such agents are necessary, and warn patients of this adverse effect so that they can take precautions, such as walking an extra mile a day or giving up that high-calorie latte in the morning.

1. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382:951-962.

2. Gallo MF, Lopez LM, Grimes DA, et al. Combination contraceptives: effects on weight. Cochrane Database Syst Rev. 2011;CD003987.

One of my brothers has adult onset bipolar disorder. As luck would have it, he also has type 2 diabetes mellitus. He struggles constantly with blood sugar control since he needs to take 2 psychotropic medications, both of which cause weight gain.

I mistakenly told a patient that her beta-blocker wasn't interfering with her weight loss.His situation has prompted me to think about the responsibility we have as we care, and advocate, for our patients with major mental illness who require these effective medications. At a minimum, we must be knowledgeable about the adverse metabolic effects of these drugs, avoid prescribing them when possible, and advocate for dose reductions when feasible. Knowing, for example, that these drugs fall on a spectrum, with haloperidol causing the least weight gain and olanzapine causing the most, is important.¹

An eye-opener. The article by Saunders in this issue provides advice on avoiding medications that commonly cause weight gain when prescribing for overweight or obese patients with diabetes, hypertension, and/or depression. I was unaware that some of the drugs on the list contribute to the problem. For example, I saw a new patient last week who has hypertension and is obese; she has been taking the beta-blocker metoprolol for the past 8 years. She has tried unsuccessfully to lose weight. She asked me if the metoprolol could be interfering with weight loss, and I mistakenly told her “No.” Thankfully, we decided to discontinue it anyway. I will admit to her my knowledge gap when I see her next month for follow-up. Errors are great teachers, especially when no harm is done.

The scope of the Saunders article is not meant to be comprehensive, since it focuses on medications for diabetes, hypertension, and depression. I think all of us are aware of the weight gain associated with other commonly prescribed drugs, such as systemic corticosteroids and long-acting progesterone for contraception. Thankfully, combination oral contraceptives do not appear to be associated with weight gain²—answering one of the more common questions I receive from patients about weight and medications.

The bottom line. Avoid prescribing medications that can cause weight gain in overweight and obese patients when possible, use the lowest effective dose when such agents are necessary, and warn patients of this adverse effect so that they can take precautions, such as walking an extra mile a day or giving up that high-calorie latte in the morning.

1. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382:951-962.

2. Gallo MF, Lopez LM, Grimes DA, et al. Combination contraceptives: effects on weight. Cochrane Database Syst Rev. 2011;CD003987.

Are you in search of materials that can reinforce what you’ve told patients about how to get a good night’s sleep? Then download this handout, which includes 8 tips that cover the wake-promoting agents to avoid, the proper environment in which to go to sleep, and the dos and don’ts of before-bedtime activities. It also discusses when patients should seek professional help for a possible sleep disorder. This PDF from Neurology Reviews is available at: http://www.mdedge.com/neurologyreviews/article/115138/sleep-medicine/tips-sleep-hygiene/pdf.

Are you in search of materials that can reinforce what you’ve told patients about how to get a good night’s sleep? Then download this handout, which includes 8 tips that cover the wake-promoting agents to avoid, the proper environment in which to go to sleep, and the dos and don’ts of before-bedtime activities. It also discusses when patients should seek professional help for a possible sleep disorder. This PDF from Neurology Reviews is available at: http://www.mdedge.com/neurologyreviews/article/115138/sleep-medicine/tips-sleep-hygiene/pdf.

Are you in search of materials that can reinforce what you’ve told patients about how to get a good night’s sleep? Then download this handout, which includes 8 tips that cover the wake-promoting agents to avoid, the proper environment in which to go to sleep, and the dos and don’ts of before-bedtime activities. It also discusses when patients should seek professional help for a possible sleep disorder. This PDF from Neurology Reviews is available at: http://www.mdedge.com/neurologyreviews/article/115138/sleep-medicine/tips-sleep-hygiene/pdf.

Can the public health threat posed by the hepatitis C virus (HCV) be eliminated by 2030? Researchers in Italy say it can be done. Important elements of success will include the use of oral direct-acting antivirals and a global commitment to prevention. Earlier this year, the World Health Organization (WHO) announced plans to wipe out HCV worldwide by 2030 using the time between now and 2021 to reduce the number of annual new infections by 70%, and to slash the fatality rate by 60%. Find out what success in meeting the WHO challenge will hinge on by going to Family Practice News: http://www.mdedge.com/familypracticenews/article/114780/gastroenterology/direct-acting-antivirals-one-several-keys-hcv.

Can the public health threat posed by the hepatitis C virus (HCV) be eliminated by 2030? Researchers in Italy say it can be done. Important elements of success will include the use of oral direct-acting antivirals and a global commitment to prevention. Earlier this year, the World Health Organization (WHO) announced plans to wipe out HCV worldwide by 2030 using the time between now and 2021 to reduce the number of annual new infections by 70%, and to slash the fatality rate by 60%. Find out what success in meeting the WHO challenge will hinge on by going to Family Practice News: http://www.mdedge.com/familypracticenews/article/114780/gastroenterology/direct-acting-antivirals-one-several-keys-hcv.

Can the public health threat posed by the hepatitis C virus (HCV) be eliminated by 2030? Researchers in Italy say it can be done. Important elements of success will include the use of oral direct-acting antivirals and a global commitment to prevention. Earlier this year, the World Health Organization (WHO) announced plans to wipe out HCV worldwide by 2030 using the time between now and 2021 to reduce the number of annual new infections by 70%, and to slash the fatality rate by 60%. Find out what success in meeting the WHO challenge will hinge on by going to Family Practice News: http://www.mdedge.com/familypracticenews/article/114780/gastroenterology/direct-acting-antivirals-one-several-keys-hcv.

Systematic introduction of palliative care interventions for patients with advanced heart failure improved patients’ quality of life and spurred their development of advanced-care preferences in a pair of independently performed, controlled pilot studies. But, despite demonstrating the ability of palliative-care interventions to help heart failure patients during their final months of life, the findings raised questions about the generalizability and reproducibility of palliative-care interventions that may depend upon the skills and experience of the individual specialists who deliver the care. To learn more about these 2 studies, go to Family Practice News: http://www.mdedge.com/familypracticenews/article/115737/cardiology/palliative-care-boosts-heart-failure-patient-outcomes.

Systematic introduction of palliative care interventions for patients with advanced heart failure improved patients’ quality of life and spurred their development of advanced-care preferences in a pair of independently performed, controlled pilot studies. But, despite demonstrating the ability of palliative-care interventions to help heart failure patients during their final months of life, the findings raised questions about the generalizability and reproducibility of palliative-care interventions that may depend upon the skills and experience of the individual specialists who deliver the care. To learn more about these 2 studies, go to Family Practice News: http://www.mdedge.com/familypracticenews/article/115737/cardiology/palliative-care-boosts-heart-failure-patient-outcomes.

Systematic introduction of palliative care interventions for patients with advanced heart failure improved patients’ quality of life and spurred their development of advanced-care preferences in a pair of independently performed, controlled pilot studies. But, despite demonstrating the ability of palliative-care interventions to help heart failure patients during their final months of life, the findings raised questions about the generalizability and reproducibility of palliative-care interventions that may depend upon the skills and experience of the individual specialists who deliver the care. To learn more about these 2 studies, go to Family Practice News: http://www.mdedge.com/familypracticenews/article/115737/cardiology/palliative-care-boosts-heart-failure-patient-outcomes.

Early age at menopause was associated with the incidence of type 2 diabetes, independent of obesity and a host of other potentially confounding factors, according to a prospect cohort study. “This association is independent of potential intermediate risk factors: obesity, insulin, glucose, inflammation, but also  estradiol and other endogenous sex hormone levels,” said Taulant Muka, MD, PhD, a postdoctoral fellow at Erasmus Medical College, Rotterdam, the Netherlands. Among the 3210 participants in the study, 319 incident cases were identified over the median 10.9-year follow-up period, with a relative risk for incident diabetes of 2.29 for women undergoing menopause before age 40, and 1.49 for those experiencing menopause between the ages of 40 and 44. Read more at Family Practice News: http://www.mdedge.com/familypracticenews/article/115648/diabetes/early-menopause-risk-factor-type-2-diabetes.

Early age at menopause was associated with the incidence of type 2 diabetes, independent of obesity and a host of other potentially confounding factors, according to a prospect cohort study. “This association is independent of potential intermediate risk factors: obesity, insulin, glucose, inflammation, but also  estradiol and other endogenous sex hormone levels,” said Taulant Muka, MD, PhD, a postdoctoral fellow at Erasmus Medical College, Rotterdam, the Netherlands. Among the 3210 participants in the study, 319 incident cases were identified over the median 10.9-year follow-up period, with a relative risk for incident diabetes of 2.29 for women undergoing menopause before age 40, and 1.49 for those experiencing menopause between the ages of 40 and 44. Read more at Family Practice News: http://www.mdedge.com/familypracticenews/article/115648/diabetes/early-menopause-risk-factor-type-2-diabetes.

Early age at menopause was associated with the incidence of type 2 diabetes, independent of obesity and a host of other potentially confounding factors, according to a prospect cohort study. “This association is independent of potential intermediate risk factors: obesity, insulin, glucose, inflammation, but also  estradiol and other endogenous sex hormone levels,” said Taulant Muka, MD, PhD, a postdoctoral fellow at Erasmus Medical College, Rotterdam, the Netherlands. Among the 3210 participants in the study, 319 incident cases were identified over the median 10.9-year follow-up period, with a relative risk for incident diabetes of 2.29 for women undergoing menopause before age 40, and 1.49 for those experiencing menopause between the ages of 40 and 44. Read more at Family Practice News: http://www.mdedge.com/familypracticenews/article/115648/diabetes/early-menopause-risk-factor-type-2-diabetes.

Patients with chronic obstructive pulmonary disease (COPD) who also suffer from depression are less likely to take their COPD maintenance medications, according to a review of Medicare claims by researchers at the University of Maryland, Baltimore. Researchers found that patients with newly diagnosed depression were about 7% less likely to have good adherence to their medications. For more on this research, see the article in CHEST Physician, available at http://www.mdedge.com/chestphysician/article/115659/depression/depression-drops-copd-medication-adherence.

Patients with chronic obstructive pulmonary disease (COPD) who also suffer from depression are less likely to take their COPD maintenance medications, according to a review of Medicare claims by researchers at the University of Maryland, Baltimore. Researchers found that patients with newly diagnosed depression were about 7% less likely to have good adherence to their medications. For more on this research, see the article in CHEST Physician, available at http://www.mdedge.com/chestphysician/article/115659/depression/depression-drops-copd-medication-adherence.

Patients with chronic obstructive pulmonary disease (COPD) who also suffer from depression are less likely to take their COPD maintenance medications, according to a review of Medicare claims by researchers at the University of Maryland, Baltimore. Researchers found that patients with newly diagnosed depression were about 7% less likely to have good adherence to their medications. For more on this research, see the article in CHEST Physician, available at http://www.mdedge.com/chestphysician/article/115659/depression/depression-drops-copd-medication-adherence.

Rivaroxaban is associated with significantly more intra- and extracranial bleeding than dabigatran in patients ages 75 and older with nonvalvular atrial fibrillation (AF), according to a recent report published online in JAMA Internal Medicine. During the study period, rivaroxaban was used 2 to 3 times more often than dabigatran in AF patients in the United States. According to David J. Graham, MD, Center for Drug Evaluation and Research, FDA, that may be “partly because of prescriber misperceptions about bleeding risks with dabigatran, arising from FDA receipt of a large number of post-marketing case reports following its approval.” That’s ironic, according to Graham, since “we [now find] substantially higher bleeding risks with the use of rivaroxaban than dabigatran.” Further analysis on the data can be found in the article from Family Practice News: http://www.mdedge.com/familypracticenews/article/115021/acquired-cardiovascular-disease/rivaroxaban-linked-more-bleeding.

Rivaroxaban is associated with significantly more intra- and extracranial bleeding than dabigatran in patients ages 75 and older with nonvalvular atrial fibrillation (AF), according to a recent report published online in JAMA Internal Medicine. During the study period, rivaroxaban was used 2 to 3 times more often than dabigatran in AF patients in the United States. According to David J. Graham, MD, Center for Drug Evaluation and Research, FDA, that may be “partly because of prescriber misperceptions about bleeding risks with dabigatran, arising from FDA receipt of a large number of post-marketing case reports following its approval.” That’s ironic, according to Graham, since “we [now find] substantially higher bleeding risks with the use of rivaroxaban than dabigatran.” Further analysis on the data can be found in the article from Family Practice News: http://www.mdedge.com/familypracticenews/article/115021/acquired-cardiovascular-disease/rivaroxaban-linked-more-bleeding.

Rivaroxaban is associated with significantly more intra- and extracranial bleeding than dabigatran in patients ages 75 and older with nonvalvular atrial fibrillation (AF), according to a recent report published online in JAMA Internal Medicine. During the study period, rivaroxaban was used 2 to 3 times more often than dabigatran in AF patients in the United States. According to David J. Graham, MD, Center for Drug Evaluation and Research, FDA, that may be “partly because of prescriber misperceptions about bleeding risks with dabigatran, arising from FDA receipt of a large number of post-marketing case reports following its approval.” That’s ironic, according to Graham, since “we [now find] substantially higher bleeding risks with the use of rivaroxaban than dabigatran.” Further analysis on the data can be found in the article from Family Practice News: http://www.mdedge.com/familypracticenews/article/115021/acquired-cardiovascular-disease/rivaroxaban-linked-more-bleeding.

The FP suspected tinea cruris and asked the patient if he had athlete’s foot. The patient stated that his feet were fine, but the FP asked to examine them anyway and found signs of tinea pedis between the toes (especially in the interspace between toes 4 and 5). While this supported the diagnosis of tinea cruris, the FP decided to confirm his diagnosis with a potassium hydroxide (KOH) preparation. (See video on how to perform a KOH preparation here.) The KOH preparation showed branching hyphae with septate and visible nuclei, confirming the tinea infection.

Tinea cruris is an intensely pruritic superficial fungal infection of the groin and adjacent skin that is more common in men than women and rarely affects children. It is most commonly caused by the dermatophytes Trichophyton rubrum, Epidermophyton floccosum, Trichophyton mentagrophytes, and Trichophyton verrucosum. T rubrum is the most common organism and can be spread by fomites, such as contaminated towels. Autoinoculation can occur from fungus on the feet or hands. Risk factors include obesity and diabetes.

Most topical antifungals can be used to treat tinea cruris, except for nystatin, which only works for Candida. The fungicidal allylamines (naftifine and terbinafine) and butenafine (allylamine derivative) are more convenient, as they allow for a shorter duration of treatment compared with fungistatic azoles (clotrimazole, econazole, ketoconazole, oxiconazole, miconazole, and sulconazole). Topical azoles should be continued for 4 weeks and topical allylamines for 2 weeks or until clinical cure. Fluconazole 150 mg once weekly for 2 to 4 weeks can effectively treat tinea cruris when topical agents are failing. If there are multiple sites infected with fungus, such as the groin and feet, it helps to treat all active areas of infection simultaneously to prevent reinfection of the groin from other body sites.

For this patient, the FP suggested that he buy over-the-counter topical terbinafine to treat the groin and feet twice daily for a minimum of 2 weeks until the fungal infection was no longer visible and symptomatic. At a follow-up visit 4 weeks later, the tinea had resolved and the patient was very happy with the results.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Smith M. Tinea cruris. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:795-798.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP suspected tinea cruris and asked the patient if he had athlete’s foot. The patient stated that his feet were fine, but the FP asked to examine them anyway and found signs of tinea pedis between the toes (especially in the interspace between toes 4 and 5). While this supported the diagnosis of tinea cruris, the FP decided to confirm his diagnosis with a potassium hydroxide (KOH) preparation. (See video on how to perform a KOH preparation here.) The KOH preparation showed branching hyphae with septate and visible nuclei, confirming the tinea infection.

Tinea cruris is an intensely pruritic superficial fungal infection of the groin and adjacent skin that is more common in men than women and rarely affects children. It is most commonly caused by the dermatophytes Trichophyton rubrum, Epidermophyton floccosum, Trichophyton mentagrophytes, and Trichophyton verrucosum. T rubrum is the most common organism and can be spread by fomites, such as contaminated towels. Autoinoculation can occur from fungus on the feet or hands. Risk factors include obesity and diabetes.

Most topical antifungals can be used to treat tinea cruris, except for nystatin, which only works for Candida. The fungicidal allylamines (naftifine and terbinafine) and butenafine (allylamine derivative) are more convenient, as they allow for a shorter duration of treatment compared with fungistatic azoles (clotrimazole, econazole, ketoconazole, oxiconazole, miconazole, and sulconazole). Topical azoles should be continued for 4 weeks and topical allylamines for 2 weeks or until clinical cure. Fluconazole 150 mg once weekly for 2 to 4 weeks can effectively treat tinea cruris when topical agents are failing. If there are multiple sites infected with fungus, such as the groin and feet, it helps to treat all active areas of infection simultaneously to prevent reinfection of the groin from other body sites.

For this patient, the FP suggested that he buy over-the-counter topical terbinafine to treat the groin and feet twice daily for a minimum of 2 weeks until the fungal infection was no longer visible and symptomatic. At a follow-up visit 4 weeks later, the tinea had resolved and the patient was very happy with the results.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Smith M. Tinea cruris. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:795-798.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP suspected tinea cruris and asked the patient if he had athlete’s foot. The patient stated that his feet were fine, but the FP asked to examine them anyway and found signs of tinea pedis between the toes (especially in the interspace between toes 4 and 5). While this supported the diagnosis of tinea cruris, the FP decided to confirm his diagnosis with a potassium hydroxide (KOH) preparation. (See video on how to perform a KOH preparation here.) The KOH preparation showed branching hyphae with septate and visible nuclei, confirming the tinea infection.

Tinea cruris is an intensely pruritic superficial fungal infection of the groin and adjacent skin that is more common in men than women and rarely affects children. It is most commonly caused by the dermatophytes Trichophyton rubrum, Epidermophyton floccosum, Trichophyton mentagrophytes, and Trichophyton verrucosum. T rubrum is the most common organism and can be spread by fomites, such as contaminated towels. Autoinoculation can occur from fungus on the feet or hands. Risk factors include obesity and diabetes.

Most topical antifungals can be used to treat tinea cruris, except for nystatin, which only works for Candida. The fungicidal allylamines (naftifine and terbinafine) and butenafine (allylamine derivative) are more convenient, as they allow for a shorter duration of treatment compared with fungistatic azoles (clotrimazole, econazole, ketoconazole, oxiconazole, miconazole, and sulconazole). Topical azoles should be continued for 4 weeks and topical allylamines for 2 weeks or until clinical cure. Fluconazole 150 mg once weekly for 2 to 4 weeks can effectively treat tinea cruris when topical agents are failing. If there are multiple sites infected with fungus, such as the groin and feet, it helps to treat all active areas of infection simultaneously to prevent reinfection of the groin from other body sites.

For this patient, the FP suggested that he buy over-the-counter topical terbinafine to treat the groin and feet twice daily for a minimum of 2 weeks until the fungal infection was no longer visible and symptomatic. At a follow-up visit 4 weeks later, the tinea had resolved and the patient was very happy with the results.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Smith M. Tinea cruris. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:795-798.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com