Cleveland Clinic Journal of Medicine

The management of hepatitis B virus (HBV) infection in pregnancy is complex. Because infection with HBV in infancy often leads to chronic disease, prevention of perinatal, or vertical, transmission is a worthy goal; yet, prophylactic therapy during pregnancy is not well studied. This article explores the consequences of HBV infection during pregnancy, the specific risks imposed by high viral load, the evidence to support preemptive antiviral therapy, and the timing of therapy during pregnancy.

PERINATAL TRANSMISSION

Perinatal transmission is the most common mode of HBV transmission worldwide; however, the maternal screening programs and universal vaccination in newborns with active and passive immunoprophylaxis have dramatically reduced HBV transmission rates. According to recent data from the US Centers for Disease Control and Prevention, prenatal screening for hepatitis B surface antigen (HBsAg) in the United States is nearly universal; 97% of pregnant women undergo screening before delivery.¹ Further, among infants at risk of acquiring HBV infection, 92% complete the three-dose vaccination series by the time they are 3 years old. There is some nationwide variation, however, in the appropriate administration of immunoprophylaxis to infants exposed perinatally, ranging from 78% in Louisiana to 99.8% in one California health maintenance organization.²

Perinatal transmission of HBV infection has declined steadily in the United States over the past 2 decades, consistent with the successful implementation of universal screening of pregnant women and vaccination policies.³ Outside the United States, however, many high-prevalence countries lack vaccination coverage and perinatal transmission is common. In 87 countries with a prevalence of HBV infection that exceeds 8%, the infant vaccine coverage was only 36%.⁴

Risk of chronic infection

The risk of progression to chronic HBV infection is inversely proportional to the age at which the infection was acquired. Without immunoprophylaxis, up to 90% of infants born to hepatitis B e antigen (HBeAg)-positive mothers become HBV carriers. In comparison, 20% to 30% of children infected between age 1 year and 5 years, and fewer than 5% of immunocompetent adults, become HBV carriers.^5–7

If the mother is positive for both HBsAg and HBeAg and her baby does not receive immunoprophylaxis, the risk of the baby developing chronic HBV infection by age 6 months is 70% to 90%.^8–10 Of those exposed in early childhood, 28.8% are HBsAg positive by age 4 years.⁵ These data underscore the need for early vaccination.

In a study of 402 HBsAg-positive pregnant women in China, Xu et al¹¹ found that 3.7% of their newborn infants were HBsAg positive within 24 hours of birth. Of the women who were HBeAg positive, the intrauterine infection rate was 9.8%. Analysis of placental tissue for HBsAg, hepatitis B core antigen (HBcAg), and viral load (HBV DNA) uncovered an overall placental infection rate of 44.6%.

Transplacental transmission of HBV has been observed in multiple studies, especially when mothers are positive for HBsAg and HBeAg and have high viral loads. Among mothers positive for HBeAg, Burk et al¹² found an odds ratio of 147 for a persistently infected infant when the maternal HBV DNA level was at least 1.4 ng/mL compared with less than .005 ng/mL. Among the HBeAg-negative mothers, the odds ratio for a persistently infected infant was 19.2 with high versus low maternal HBV DNA levels.

Importance of maternal viremia

Despite successful screening and vaccination programs, high maternal HBV DNA correlates in some studies with perinatal transmission. Wiseman et al¹³ studied 298 chronically HBV-infected women and their infants, who were tested for HBV at age 9 months. Interim analysis showed a transmission rate of 8.5% for infants born to mothers with virus levels greater than 8 log₁₀ copies/mL. These data suggest that perinatal transmission may still be occurring despite the use of effective active and passive immunoprophylaxis. Additional studies are needed to assess the potential risk reduction associated with treatment of high maternal viremia during pregnancy.

Maternal HBV DNA positivity was associated with a high rate of intrauterine transmission of HBV in a program in India in which 11,524 woman were screened for HBV infection.¹⁴ Babies of the 133 women found to be positive at the time of birth were screened for HBsAg, HBeAg, and HBV DNA in serum and cord blood. Of 127 deliveries in which the mothers were positive for HBV DNA, 66% of infants had HBV DNA in their cord blood and 41% had serum markers that were positive at birth. Maternal HBV DNA greater than 1.5 X 10⁵ copies/mL was significantly associated with intrauterine transmission (P = .025), whereas mode of delivery and maternal HBeAg status were not. This study adds to the concern that in some cases, the vaccine and hepatitis B immune globulin (HBIg) given at the time of birth may not prevent infection in those born already infected and further supports the need to assess the treatment of pregnant women with high viral titers.

The use of active and passive immunoprophylaxis to reduce the risk of perinatal transmission of HBV is well accepted in clinical practice. HBIg given at the time of birth in combination with three doses of the recombinant hepatitis B vaccine given over the first 6 months of life has been up to 95% effective in preventing perinatal transmission. As noted above, however, the risk of perinatal transmission of HBV increases as the mother’s viral load increases. In one series of mothers with high viral loads, this risk was as high as 28%.¹⁵

It stands to reason that if the mother’s viral load can be reduced at the time of birth, the risk of perinatal transmission could also be reduced (see “Case: Minimizing risk in a 29-year-old woman”). In fact, lamiv­udine treatment of highly viremic HBsAg-positive women during the final months of pregnancy appears safe and may effectively reduce the risk of perinatal transmission of HBV, even in the setting of HBV vaccination plus HBIg.

Evidence for third-trimester treatment

van Zonneveld et al¹⁵ studied eight HBeAg-positive women with HBV DNA levels of 1.2 X 10⁹ copies/mL or greater who were treated with 150 mg/day of lamiv­udine after the 34th week of pregnancy, and compared the rates of perinatal transmission between them and 24 matched historical controls who did not receive treatment. All children received standard immunoprophylaxis at birth and were followed for 12 months. In five of the eight treated mothers, viral load declined to less than 1.2 X 10⁸ copies/mL. Of the eight infants born to treated mothers, four were HBsAg positive at birth, but only one remained positive at 1 year. This 12.5% rate of perinatal transmission was substantially lower than the 28% rate observed among the controls. No adverse events occurred with lamivudine in this study.

In a multicenter, randomized, double-blind, placebo-controlled study in China and the Philippines, Xu et al¹⁶ assessed outcomes among 114 HBsAg-positive pregnant women who had high viral loads (HBV DNA > 1,000 mEq/mL). The women were randomized to placebo or treatment with lamivudine starting at 32 weeks of gestation and continuing until 4 weeks postpartum. All of the infants received standard vaccine plus HBIg.

The mothers treated with lamivudine were more likely (98%) to have a reduction in their viral loads to less than 1,000 mEq/mL than the controls (31%). This reduction in viral load translated to improved outcomes for the infants of mothers receiving lamivudine. At 1 year, 18% of infants born to mothers treated with lamivudine were HBsAg positive compared with 39% of infants born to mothers randomized to placebo (P = .014). The rate of HBV DNA positivity at 1 year was reduced by more than half among the infants born to actively treated mothers compared with those who received placebo (20% vs 46%, respectively; P = .003). There was no difference in the rate of adverse events between the treatment and control groups in either the mothers or the infants.

The Xu study suggests that the use of lamivudine in the third trimester in mothers with high viral loads may effectively reduce the risk of perinatal transmission beyond what can be achieved with active and passive immunoprophylaxis. As this study has been presented in abstract form only, we await the final analysis of these data. This therapy appears to be relatively safe for both mother and infant, although the optimal timing and duration of therapy is still unclear.

Treatment options during pregnancy

Most human experience with antiviral drug therapy in pregnancy has been with lamivudine. More than 4,600 women have been exposed to the drug during their second or third trimesters.¹⁷ Even though lamiv­udine is classified as FDA pregnancy risk category C, it is associated with a risk of birth defects (2.2% to 2.4%) that is no higher than the baseline birth defect rate.¹⁷

Of the two agents classified as FDA pregnancy risk category B, only tenofovir received this classification based on data collected in human exposure. The experience with tenofovir in pregnant women consists of 606 women in their first trimester and 336 in their second trimester.¹⁷ The rate of birth defects associated with tenofovir ranges from 1.5% (second-trimester use) to 2.3% (first-trimester use), which is similar to the background rate.¹⁷ Telbivudine received its pregnancy risk category B rating based on animal studies; there are few human pregnancy registry data.

Nonpegylated interferon alfa-2b has been shown to have abortifacient effects in rhesus monkeys at 15 and 30 million IU/kg (estimated human equivalent of 5 and 10 million IU/kg, based on body surface area adjustment for a 60-kg adult). Peginterferon alfa-2b should therefore be assumed to also have abortifacient potential, as there are no adequate and well-controlled studies in pregnant women. Peginterferon alfa-2b is to be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is recommended for use in fertile women only when they are using effective contraception during the treatment period. Pegylated interferon alfa-2a is approved for treatment of chronic HBV infection, but is not recommended for use during pregnancy.

Adapted from Current Hepatitis Reports (Tran TT, et al. Management of the pregnant hepatitis B patient. Current Hepatitis Reports 2008; 7:12–17). © 2008 with kind permission from Current Medicine Group LLC .

If the mother is HBsAg positive in the first trimester, history of perinatal transmission and an assessment of viral load at week 28 guide further management decisions. All children of HBsAg-positive mothers receive HBIg in addition to vaccination at birth.

Women with high viral loads can be considered for treatment with antiviral therapy, but a comprehensive discussion of risks and benefits needs to take place before opting for treatment as the data are too limited at this time to advocate therapy. One strategy for therapy is the use of lamivudine, tenofovir, or telbivudine starting at 32 weeks of pregnancy; the HBV DNA level that warrants treatment depends on the presence or absence of a history of perinatal transmission. If a previous child was HBV positive, concerns about the risk of perinatal transmission may be higher, so the threshold for treatment may be lower (HBV DNA > 10⁶ copies/mL) than if the previous child were not positive for HBV. If the previous child was not HBV positive, treatment might be considered with HBV DNA levels greater than 10⁸ copies/mL.

SUMMARY

Although a case can be made for treatment of HBV infection during pregnancy, the risks and benefits must be weighed carefully. The benefits of treatment appear to be most pronounced in cases with high maternal viremia; in such instances, treatment should be considered and discussed with the patient at the start of the third trimester. Viable treatment choices are limited to lamivudine, tenofovir, and telbivudine. Of these, lamivudine and tenofovir appear to be the therapeutic options with reasonable human exposure and safety data in pregnancy.

DISCUSSION

William D. Carey, MD: Referring to your case patient, assume that you treat her with tenofovir and her viral load declines. She delivers her baby and then undergoes a thorough workup, including a liver biopsy, that shows no particular liver damage. What would you do?

Tram T. Tran, MD: There are two separate issues: treating the baby and treating the mother. When you’re treating a mother in her third trimester, your goal is to prevent perinatal transmission of HBV. Once the baby is delivered, treated with HBIg, and vaccinated, then your attention turns to the mother. You can then decide based on treatment guidelines and your clinical judgment whether you want to treat the mom.

The period immediately after birth is a time of treatment uncertainty in mothers who choose to breastfeed, because the nucleoside analogues are likely passed in breast milk to some unknown degree, and it’s probably unwise to expose the child this way. In a mother who chooses to breastfeed, I would stop the medication after the delivery, by which time the baby will have received HBIg and the vaccine. When treatment is stopped, you have to think about the potential for a flare; although clinically significant flares are uncommon, the mother should be monitored after stopping treatment. After she stops breastfeeding, you can decide whether to treat her.

Robert G. Gish, MD: What are the effects of tenofovir on bone? Do you talk to your patients about it, and is it an issue during pregnancy or after the baby is delivered?

Dr. Tran: Some data show a decrease in bone mineral density with tenofovir in the human immunodeficiency virus patient population. I definitely talk to my patients about all the potential risks associated with these medicines as, naturally, pregnant women will be very sensitive to any possible risk to their unborn child. Lamiv­udine probably has the safest profile in pregnancy, given its large body of human experience; however, it is now classified as an FDA pregnancy risk category C drug, whereas tenofovir is classified as category B. This may make a difference to some clinicians.

The management of hepatitis B virus (HBV) infection in pregnancy is complex. Because infection with HBV in infancy often leads to chronic disease, prevention of perinatal, or vertical, transmission is a worthy goal; yet, prophylactic therapy during pregnancy is not well studied. This article explores the consequences of HBV infection during pregnancy, the specific risks imposed by high viral load, the evidence to support preemptive antiviral therapy, and the timing of therapy during pregnancy.

PERINATAL TRANSMISSION

Perinatal transmission is the most common mode of HBV transmission worldwide; however, the maternal screening programs and universal vaccination in newborns with active and passive immunoprophylaxis have dramatically reduced HBV transmission rates. According to recent data from the US Centers for Disease Control and Prevention, prenatal screening for hepatitis B surface antigen (HBsAg) in the United States is nearly universal; 97% of pregnant women undergo screening before delivery.¹ Further, among infants at risk of acquiring HBV infection, 92% complete the three-dose vaccination series by the time they are 3 years old. There is some nationwide variation, however, in the appropriate administration of immunoprophylaxis to infants exposed perinatally, ranging from 78% in Louisiana to 99.8% in one California health maintenance organization.²

Perinatal transmission of HBV infection has declined steadily in the United States over the past 2 decades, consistent with the successful implementation of universal screening of pregnant women and vaccination policies.³ Outside the United States, however, many high-prevalence countries lack vaccination coverage and perinatal transmission is common. In 87 countries with a prevalence of HBV infection that exceeds 8%, the infant vaccine coverage was only 36%.⁴

Risk of chronic infection

The risk of progression to chronic HBV infection is inversely proportional to the age at which the infection was acquired. Without immunoprophylaxis, up to 90% of infants born to hepatitis B e antigen (HBeAg)-positive mothers become HBV carriers. In comparison, 20% to 30% of children infected between age 1 year and 5 years, and fewer than 5% of immunocompetent adults, become HBV carriers.^5–7

If the mother is positive for both HBsAg and HBeAg and her baby does not receive immunoprophylaxis, the risk of the baby developing chronic HBV infection by age 6 months is 70% to 90%.^8–10 Of those exposed in early childhood, 28.8% are HBsAg positive by age 4 years.⁵ These data underscore the need for early vaccination.

In a study of 402 HBsAg-positive pregnant women in China, Xu et al¹¹ found that 3.7% of their newborn infants were HBsAg positive within 24 hours of birth. Of the women who were HBeAg positive, the intrauterine infection rate was 9.8%. Analysis of placental tissue for HBsAg, hepatitis B core antigen (HBcAg), and viral load (HBV DNA) uncovered an overall placental infection rate of 44.6%.

Transplacental transmission of HBV has been observed in multiple studies, especially when mothers are positive for HBsAg and HBeAg and have high viral loads. Among mothers positive for HBeAg, Burk et al¹² found an odds ratio of 147 for a persistently infected infant when the maternal HBV DNA level was at least 1.4 ng/mL compared with less than .005 ng/mL. Among the HBeAg-negative mothers, the odds ratio for a persistently infected infant was 19.2 with high versus low maternal HBV DNA levels.

Importance of maternal viremia

Despite successful screening and vaccination programs, high maternal HBV DNA correlates in some studies with perinatal transmission. Wiseman et al¹³ studied 298 chronically HBV-infected women and their infants, who were tested for HBV at age 9 months. Interim analysis showed a transmission rate of 8.5% for infants born to mothers with virus levels greater than 8 log₁₀ copies/mL. These data suggest that perinatal transmission may still be occurring despite the use of effective active and passive immunoprophylaxis. Additional studies are needed to assess the potential risk reduction associated with treatment of high maternal viremia during pregnancy.

Maternal HBV DNA positivity was associated with a high rate of intrauterine transmission of HBV in a program in India in which 11,524 woman were screened for HBV infection.¹⁴ Babies of the 133 women found to be positive at the time of birth were screened for HBsAg, HBeAg, and HBV DNA in serum and cord blood. Of 127 deliveries in which the mothers were positive for HBV DNA, 66% of infants had HBV DNA in their cord blood and 41% had serum markers that were positive at birth. Maternal HBV DNA greater than 1.5 X 10⁵ copies/mL was significantly associated with intrauterine transmission (P = .025), whereas mode of delivery and maternal HBeAg status were not. This study adds to the concern that in some cases, the vaccine and hepatitis B immune globulin (HBIg) given at the time of birth may not prevent infection in those born already infected and further supports the need to assess the treatment of pregnant women with high viral titers.

The use of active and passive immunoprophylaxis to reduce the risk of perinatal transmission of HBV is well accepted in clinical practice. HBIg given at the time of birth in combination with three doses of the recombinant hepatitis B vaccine given over the first 6 months of life has been up to 95% effective in preventing perinatal transmission. As noted above, however, the risk of perinatal transmission of HBV increases as the mother’s viral load increases. In one series of mothers with high viral loads, this risk was as high as 28%.¹⁵

It stands to reason that if the mother’s viral load can be reduced at the time of birth, the risk of perinatal transmission could also be reduced (see “Case: Minimizing risk in a 29-year-old woman”). In fact, lamiv­udine treatment of highly viremic HBsAg-positive women during the final months of pregnancy appears safe and may effectively reduce the risk of perinatal transmission of HBV, even in the setting of HBV vaccination plus HBIg.

Evidence for third-trimester treatment

van Zonneveld et al¹⁵ studied eight HBeAg-positive women with HBV DNA levels of 1.2 X 10⁹ copies/mL or greater who were treated with 150 mg/day of lamiv­udine after the 34th week of pregnancy, and compared the rates of perinatal transmission between them and 24 matched historical controls who did not receive treatment. All children received standard immunoprophylaxis at birth and were followed for 12 months. In five of the eight treated mothers, viral load declined to less than 1.2 X 10⁸ copies/mL. Of the eight infants born to treated mothers, four were HBsAg positive at birth, but only one remained positive at 1 year. This 12.5% rate of perinatal transmission was substantially lower than the 28% rate observed among the controls. No adverse events occurred with lamivudine in this study.

In a multicenter, randomized, double-blind, placebo-controlled study in China and the Philippines, Xu et al¹⁶ assessed outcomes among 114 HBsAg-positive pregnant women who had high viral loads (HBV DNA > 1,000 mEq/mL). The women were randomized to placebo or treatment with lamivudine starting at 32 weeks of gestation and continuing until 4 weeks postpartum. All of the infants received standard vaccine plus HBIg.

The mothers treated with lamivudine were more likely (98%) to have a reduction in their viral loads to less than 1,000 mEq/mL than the controls (31%). This reduction in viral load translated to improved outcomes for the infants of mothers receiving lamivudine. At 1 year, 18% of infants born to mothers treated with lamivudine were HBsAg positive compared with 39% of infants born to mothers randomized to placebo (P = .014). The rate of HBV DNA positivity at 1 year was reduced by more than half among the infants born to actively treated mothers compared with those who received placebo (20% vs 46%, respectively; P = .003). There was no difference in the rate of adverse events between the treatment and control groups in either the mothers or the infants.

The Xu study suggests that the use of lamivudine in the third trimester in mothers with high viral loads may effectively reduce the risk of perinatal transmission beyond what can be achieved with active and passive immunoprophylaxis. As this study has been presented in abstract form only, we await the final analysis of these data. This therapy appears to be relatively safe for both mother and infant, although the optimal timing and duration of therapy is still unclear.

Treatment options during pregnancy

Most human experience with antiviral drug therapy in pregnancy has been with lamivudine. More than 4,600 women have been exposed to the drug during their second or third trimesters.¹⁷ Even though lamiv­udine is classified as FDA pregnancy risk category C, it is associated with a risk of birth defects (2.2% to 2.4%) that is no higher than the baseline birth defect rate.¹⁷

Of the two agents classified as FDA pregnancy risk category B, only tenofovir received this classification based on data collected in human exposure. The experience with tenofovir in pregnant women consists of 606 women in their first trimester and 336 in their second trimester.¹⁷ The rate of birth defects associated with tenofovir ranges from 1.5% (second-trimester use) to 2.3% (first-trimester use), which is similar to the background rate.¹⁷ Telbivudine received its pregnancy risk category B rating based on animal studies; there are few human pregnancy registry data.

Nonpegylated interferon alfa-2b has been shown to have abortifacient effects in rhesus monkeys at 15 and 30 million IU/kg (estimated human equivalent of 5 and 10 million IU/kg, based on body surface area adjustment for a 60-kg adult). Peginterferon alfa-2b should therefore be assumed to also have abortifacient potential, as there are no adequate and well-controlled studies in pregnant women. Peginterferon alfa-2b is to be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is recommended for use in fertile women only when they are using effective contraception during the treatment period. Pegylated interferon alfa-2a is approved for treatment of chronic HBV infection, but is not recommended for use during pregnancy.

Adapted from Current Hepatitis Reports (Tran TT, et al. Management of the pregnant hepatitis B patient. Current Hepatitis Reports 2008; 7:12–17). © 2008 with kind permission from Current Medicine Group LLC .

If the mother is HBsAg positive in the first trimester, history of perinatal transmission and an assessment of viral load at week 28 guide further management decisions. All children of HBsAg-positive mothers receive HBIg in addition to vaccination at birth.

Women with high viral loads can be considered for treatment with antiviral therapy, but a comprehensive discussion of risks and benefits needs to take place before opting for treatment as the data are too limited at this time to advocate therapy. One strategy for therapy is the use of lamivudine, tenofovir, or telbivudine starting at 32 weeks of pregnancy; the HBV DNA level that warrants treatment depends on the presence or absence of a history of perinatal transmission. If a previous child was HBV positive, concerns about the risk of perinatal transmission may be higher, so the threshold for treatment may be lower (HBV DNA > 10⁶ copies/mL) than if the previous child were not positive for HBV. If the previous child was not HBV positive, treatment might be considered with HBV DNA levels greater than 10⁸ copies/mL.

SUMMARY

Although a case can be made for treatment of HBV infection during pregnancy, the risks and benefits must be weighed carefully. The benefits of treatment appear to be most pronounced in cases with high maternal viremia; in such instances, treatment should be considered and discussed with the patient at the start of the third trimester. Viable treatment choices are limited to lamivudine, tenofovir, and telbivudine. Of these, lamivudine and tenofovir appear to be the therapeutic options with reasonable human exposure and safety data in pregnancy.

DISCUSSION

William D. Carey, MD: Referring to your case patient, assume that you treat her with tenofovir and her viral load declines. She delivers her baby and then undergoes a thorough workup, including a liver biopsy, that shows no particular liver damage. What would you do?

Tram T. Tran, MD: There are two separate issues: treating the baby and treating the mother. When you’re treating a mother in her third trimester, your goal is to prevent perinatal transmission of HBV. Once the baby is delivered, treated with HBIg, and vaccinated, then your attention turns to the mother. You can then decide based on treatment guidelines and your clinical judgment whether you want to treat the mom.

The period immediately after birth is a time of treatment uncertainty in mothers who choose to breastfeed, because the nucleoside analogues are likely passed in breast milk to some unknown degree, and it’s probably unwise to expose the child this way. In a mother who chooses to breastfeed, I would stop the medication after the delivery, by which time the baby will have received HBIg and the vaccine. When treatment is stopped, you have to think about the potential for a flare; although clinically significant flares are uncommon, the mother should be monitored after stopping treatment. After she stops breastfeeding, you can decide whether to treat her.

Robert G. Gish, MD: What are the effects of tenofovir on bone? Do you talk to your patients about it, and is it an issue during pregnancy or after the baby is delivered?

Dr. Tran: Some data show a decrease in bone mineral density with tenofovir in the human immunodeficiency virus patient population. I definitely talk to my patients about all the potential risks associated with these medicines as, naturally, pregnant women will be very sensitive to any possible risk to their unborn child. Lamiv­udine probably has the safest profile in pregnancy, given its large body of human experience; however, it is now classified as an FDA pregnancy risk category C drug, whereas tenofovir is classified as category B. This may make a difference to some clinicians.

The management of hepatitis B virus (HBV) infection in pregnancy is complex. Because infection with HBV in infancy often leads to chronic disease, prevention of perinatal, or vertical, transmission is a worthy goal; yet, prophylactic therapy during pregnancy is not well studied. This article explores the consequences of HBV infection during pregnancy, the specific risks imposed by high viral load, the evidence to support preemptive antiviral therapy, and the timing of therapy during pregnancy.

PERINATAL TRANSMISSION

Perinatal transmission is the most common mode of HBV transmission worldwide; however, the maternal screening programs and universal vaccination in newborns with active and passive immunoprophylaxis have dramatically reduced HBV transmission rates. According to recent data from the US Centers for Disease Control and Prevention, prenatal screening for hepatitis B surface antigen (HBsAg) in the United States is nearly universal; 97% of pregnant women undergo screening before delivery.¹ Further, among infants at risk of acquiring HBV infection, 92% complete the three-dose vaccination series by the time they are 3 years old. There is some nationwide variation, however, in the appropriate administration of immunoprophylaxis to infants exposed perinatally, ranging from 78% in Louisiana to 99.8% in one California health maintenance organization.²

Perinatal transmission of HBV infection has declined steadily in the United States over the past 2 decades, consistent with the successful implementation of universal screening of pregnant women and vaccination policies.³ Outside the United States, however, many high-prevalence countries lack vaccination coverage and perinatal transmission is common. In 87 countries with a prevalence of HBV infection that exceeds 8%, the infant vaccine coverage was only 36%.⁴

Risk of chronic infection

The risk of progression to chronic HBV infection is inversely proportional to the age at which the infection was acquired. Without immunoprophylaxis, up to 90% of infants born to hepatitis B e antigen (HBeAg)-positive mothers become HBV carriers. In comparison, 20% to 30% of children infected between age 1 year and 5 years, and fewer than 5% of immunocompetent adults, become HBV carriers.^5–7

If the mother is positive for both HBsAg and HBeAg and her baby does not receive immunoprophylaxis, the risk of the baby developing chronic HBV infection by age 6 months is 70% to 90%.^8–10 Of those exposed in early childhood, 28.8% are HBsAg positive by age 4 years.⁵ These data underscore the need for early vaccination.

In a study of 402 HBsAg-positive pregnant women in China, Xu et al¹¹ found that 3.7% of their newborn infants were HBsAg positive within 24 hours of birth. Of the women who were HBeAg positive, the intrauterine infection rate was 9.8%. Analysis of placental tissue for HBsAg, hepatitis B core antigen (HBcAg), and viral load (HBV DNA) uncovered an overall placental infection rate of 44.6%.

Transplacental transmission of HBV has been observed in multiple studies, especially when mothers are positive for HBsAg and HBeAg and have high viral loads. Among mothers positive for HBeAg, Burk et al¹² found an odds ratio of 147 for a persistently infected infant when the maternal HBV DNA level was at least 1.4 ng/mL compared with less than .005 ng/mL. Among the HBeAg-negative mothers, the odds ratio for a persistently infected infant was 19.2 with high versus low maternal HBV DNA levels.

Importance of maternal viremia

Despite successful screening and vaccination programs, high maternal HBV DNA correlates in some studies with perinatal transmission. Wiseman et al¹³ studied 298 chronically HBV-infected women and their infants, who were tested for HBV at age 9 months. Interim analysis showed a transmission rate of 8.5% for infants born to mothers with virus levels greater than 8 log₁₀ copies/mL. These data suggest that perinatal transmission may still be occurring despite the use of effective active and passive immunoprophylaxis. Additional studies are needed to assess the potential risk reduction associated with treatment of high maternal viremia during pregnancy.

Maternal HBV DNA positivity was associated with a high rate of intrauterine transmission of HBV in a program in India in which 11,524 woman were screened for HBV infection.¹⁴ Babies of the 133 women found to be positive at the time of birth were screened for HBsAg, HBeAg, and HBV DNA in serum and cord blood. Of 127 deliveries in which the mothers were positive for HBV DNA, 66% of infants had HBV DNA in their cord blood and 41% had serum markers that were positive at birth. Maternal HBV DNA greater than 1.5 X 10⁵ copies/mL was significantly associated with intrauterine transmission (P = .025), whereas mode of delivery and maternal HBeAg status were not. This study adds to the concern that in some cases, the vaccine and hepatitis B immune globulin (HBIg) given at the time of birth may not prevent infection in those born already infected and further supports the need to assess the treatment of pregnant women with high viral titers.

The use of active and passive immunoprophylaxis to reduce the risk of perinatal transmission of HBV is well accepted in clinical practice. HBIg given at the time of birth in combination with three doses of the recombinant hepatitis B vaccine given over the first 6 months of life has been up to 95% effective in preventing perinatal transmission. As noted above, however, the risk of perinatal transmission of HBV increases as the mother’s viral load increases. In one series of mothers with high viral loads, this risk was as high as 28%.¹⁵

It stands to reason that if the mother’s viral load can be reduced at the time of birth, the risk of perinatal transmission could also be reduced (see “Case: Minimizing risk in a 29-year-old woman”). In fact, lamiv­udine treatment of highly viremic HBsAg-positive women during the final months of pregnancy appears safe and may effectively reduce the risk of perinatal transmission of HBV, even in the setting of HBV vaccination plus HBIg.

Evidence for third-trimester treatment

van Zonneveld et al¹⁵ studied eight HBeAg-positive women with HBV DNA levels of 1.2 X 10⁹ copies/mL or greater who were treated with 150 mg/day of lamiv­udine after the 34th week of pregnancy, and compared the rates of perinatal transmission between them and 24 matched historical controls who did not receive treatment. All children received standard immunoprophylaxis at birth and were followed for 12 months. In five of the eight treated mothers, viral load declined to less than 1.2 X 10⁸ copies/mL. Of the eight infants born to treated mothers, four were HBsAg positive at birth, but only one remained positive at 1 year. This 12.5% rate of perinatal transmission was substantially lower than the 28% rate observed among the controls. No adverse events occurred with lamivudine in this study.

In a multicenter, randomized, double-blind, placebo-controlled study in China and the Philippines, Xu et al¹⁶ assessed outcomes among 114 HBsAg-positive pregnant women who had high viral loads (HBV DNA > 1,000 mEq/mL). The women were randomized to placebo or treatment with lamivudine starting at 32 weeks of gestation and continuing until 4 weeks postpartum. All of the infants received standard vaccine plus HBIg.

The mothers treated with lamivudine were more likely (98%) to have a reduction in their viral loads to less than 1,000 mEq/mL than the controls (31%). This reduction in viral load translated to improved outcomes for the infants of mothers receiving lamivudine. At 1 year, 18% of infants born to mothers treated with lamivudine were HBsAg positive compared with 39% of infants born to mothers randomized to placebo (P = .014). The rate of HBV DNA positivity at 1 year was reduced by more than half among the infants born to actively treated mothers compared with those who received placebo (20% vs 46%, respectively; P = .003). There was no difference in the rate of adverse events between the treatment and control groups in either the mothers or the infants.

The Xu study suggests that the use of lamivudine in the third trimester in mothers with high viral loads may effectively reduce the risk of perinatal transmission beyond what can be achieved with active and passive immunoprophylaxis. As this study has been presented in abstract form only, we await the final analysis of these data. This therapy appears to be relatively safe for both mother and infant, although the optimal timing and duration of therapy is still unclear.

Treatment options during pregnancy

Most human experience with antiviral drug therapy in pregnancy has been with lamivudine. More than 4,600 women have been exposed to the drug during their second or third trimesters.¹⁷ Even though lamiv­udine is classified as FDA pregnancy risk category C, it is associated with a risk of birth defects (2.2% to 2.4%) that is no higher than the baseline birth defect rate.¹⁷

Of the two agents classified as FDA pregnancy risk category B, only tenofovir received this classification based on data collected in human exposure. The experience with tenofovir in pregnant women consists of 606 women in their first trimester and 336 in their second trimester.¹⁷ The rate of birth defects associated with tenofovir ranges from 1.5% (second-trimester use) to 2.3% (first-trimester use), which is similar to the background rate.¹⁷ Telbivudine received its pregnancy risk category B rating based on animal studies; there are few human pregnancy registry data.

Nonpegylated interferon alfa-2b has been shown to have abortifacient effects in rhesus monkeys at 15 and 30 million IU/kg (estimated human equivalent of 5 and 10 million IU/kg, based on body surface area adjustment for a 60-kg adult). Peginterferon alfa-2b should therefore be assumed to also have abortifacient potential, as there are no adequate and well-controlled studies in pregnant women. Peginterferon alfa-2b is to be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is recommended for use in fertile women only when they are using effective contraception during the treatment period. Pegylated interferon alfa-2a is approved for treatment of chronic HBV infection, but is not recommended for use during pregnancy.

Adapted from Current Hepatitis Reports (Tran TT, et al. Management of the pregnant hepatitis B patient. Current Hepatitis Reports 2008; 7:12–17). © 2008 with kind permission from Current Medicine Group LLC .

If the mother is HBsAg positive in the first trimester, history of perinatal transmission and an assessment of viral load at week 28 guide further management decisions. All children of HBsAg-positive mothers receive HBIg in addition to vaccination at birth.

Women with high viral loads can be considered for treatment with antiviral therapy, but a comprehensive discussion of risks and benefits needs to take place before opting for treatment as the data are too limited at this time to advocate therapy. One strategy for therapy is the use of lamivudine, tenofovir, or telbivudine starting at 32 weeks of pregnancy; the HBV DNA level that warrants treatment depends on the presence or absence of a history of perinatal transmission. If a previous child was HBV positive, concerns about the risk of perinatal transmission may be higher, so the threshold for treatment may be lower (HBV DNA > 10⁶ copies/mL) than if the previous child were not positive for HBV. If the previous child was not HBV positive, treatment might be considered with HBV DNA levels greater than 10⁸ copies/mL.

SUMMARY

Although a case can be made for treatment of HBV infection during pregnancy, the risks and benefits must be weighed carefully. The benefits of treatment appear to be most pronounced in cases with high maternal viremia; in such instances, treatment should be considered and discussed with the patient at the start of the third trimester. Viable treatment choices are limited to lamivudine, tenofovir, and telbivudine. Of these, lamivudine and tenofovir appear to be the therapeutic options with reasonable human exposure and safety data in pregnancy.

DISCUSSION

William D. Carey, MD: Referring to your case patient, assume that you treat her with tenofovir and her viral load declines. She delivers her baby and then undergoes a thorough workup, including a liver biopsy, that shows no particular liver damage. What would you do?

Tram T. Tran, MD: There are two separate issues: treating the baby and treating the mother. When you’re treating a mother in her third trimester, your goal is to prevent perinatal transmission of HBV. Once the baby is delivered, treated with HBIg, and vaccinated, then your attention turns to the mother. You can then decide based on treatment guidelines and your clinical judgment whether you want to treat the mom.

The period immediately after birth is a time of treatment uncertainty in mothers who choose to breastfeed, because the nucleoside analogues are likely passed in breast milk to some unknown degree, and it’s probably unwise to expose the child this way. In a mother who chooses to breastfeed, I would stop the medication after the delivery, by which time the baby will have received HBIg and the vaccine. When treatment is stopped, you have to think about the potential for a flare; although clinically significant flares are uncommon, the mother should be monitored after stopping treatment. After she stops breastfeeding, you can decide whether to treat her.

Robert G. Gish, MD: What are the effects of tenofovir on bone? Do you talk to your patients about it, and is it an issue during pregnancy or after the baby is delivered?

Dr. Tran: Some data show a decrease in bone mineral density with tenofovir in the human immunodeficiency virus patient population. I definitely talk to my patients about all the potential risks associated with these medicines as, naturally, pregnant women will be very sensitive to any possible risk to their unborn child. Lamiv­udine probably has the safest profile in pregnancy, given its large body of human experience; however, it is now classified as an FDA pregnancy risk category C drug, whereas tenofovir is classified as category B. This may make a difference to some clinicians.

Worldwide, 40 million people are infected with the human immunodeficiency virus (HIV). As many as 4 million of them are coinfected with hepatitis B virus (HBV).¹ In North America and Europe, the highest prevalence of HBV/HIV coinfection is in men who have sex with men. Approximately half of HIV-positive men who have sex with men have evidence of prior or active HBV infection, and 5% to 10% have chronic HBV infection. Among those who acquire HIV through injected drug use or through heterosexual transmission, the coinfection rate is much lower.^2,3

Coinfection with HBV and HIV follows a different course elsewhere in the world. For example, in Africa and Asia, HBV is usually acquired first through neonatal or childhood infection, with either vertical or horizontal transmission after birth.^4,5 In parts of Africa, ritual scarification is likely a major player in the adolescent transmission of HBV. (Ritual scarification is the practice of creating small incisions in the skin of adolescents and rubbing black ash in the wounds to form scars; the cutting instruments are not sterilized between rituals.)

NATURAL HISTORY

In general, HBV tends to be more aggressive in HIV-positive individuals than in monoinfected individuals,^2,6 with higher HBV carrier rates, higher levels of HBV viremia, more frequent episodes of activation, and faster progression to cirrhosis.

Hepatocellular carcinoma occurs more often, its onset is earlier, and its course is more aggressive in coinfected individuals than in monoinfected individuals.^7,8 Using data from a prospective cohort study, Thio et al⁹ found that among men coinfected with HIV and HBV, liver-related mortality was almost 19 times greater compared with men infected with HBV only and more than seven times greater compared with those infected with HIV only.

In an observational longitudinal cohort study,¹⁰ the risk of death from liver disease in HIV-positive persons was nearly three times greater among those also infected with HBV (P < .0001).

ASSESSING WHEN TO TREAT

The objectives of HBV therapy in individuals coinfected with HIV are similar to those in the population infected with HBV alone. Suppression of viral replication is the major goal. Ideally, the viral load should be reduced to an undetectable level, which will result in normalization of alanine aminotransferase (ALT) level, improved liver histology, reduced risk of progression to cirrhosis and liver failure (although supportive evidence from controlled clinical trials is lacking), and likely reduced incidence of hepatocellular carcinoma.

For those who are hepatitis B e antigen (HBeAg) positive, seroconversion may be a convenient end point for treatment, although for many patients seroconversion is not associated with remission of disease activity or viral replication.

Treatment decisions depend on whether or not the patient requires highly active antiretroviral therapy (HAART) for HIV infection. If HAART is indicated, then HIV agents that have HBV activity are incorporated into the regimen. If the patient does not yet require HAART for HIV but requires treatment for hepatitis B, this is itself an indication for HAART, since monotherapy for HBV is associated with the development of HIV resistance.

Viral load and ALT

Liver biopsy

If the ALT is normal in the presence of a high HBV DNA level, a liver biopsy is recommended, partly because the ALT level is an inadequate indicator of the severity of liver disease. If significant fibrosis is present, treatment is recommended. No treatment is required if fibrosis is mild, but liver biopsies should be repeated every 3 to 5 years in this group because a hallmark of HBV infection is its variability in time to progression. The extent of fibrosis may influence the choice of therapy.

Often in the coinfected patient, HBV-related liver injury must be distinguished from other forms of liver injury. For instance, some of the drugs used to treat HIV infection can induce non­alcoholic fatty liver disease and lipodystrophy. Because the risk of advanced fibrosis is higher in the coinfected patient than in the patient infected only with HBV, the threshold for biopsy in the coinfected patient should be lower.

At present, noninvasive tools to assess the extent of liver injury have not been validated in chronic HBV infection, unlike in hepatitis C virus infection.

The potential therapies for HBV in the coinfected patient are the same as those for the patient infected with HBV alone (see “Hepatitis B treatment: Current best practices, avoiding resistance”), with the addition of tenofovir and emtricitabine in combination.

Interferon

Early studies of interferon for the treatment of chronic HBV infection included many patients who were also HIV positive. These early studies revealed a lower rate of HBeAg seroconversion in HIV-positive patients compared with HIV-negative patients. Di Martino et al¹¹ found that approximately half (26 of 50) of HIV-negative patients treated with interferon seroconverted at 6 years, compared with only 4 of 26 interferon-treated patients with chronic HBV who were coinfected with HIV. Based on results such as these, interferon therapy in the HBV/HIV-coinfected patient should be limited to patients who are likely to seroconvert: ie, those who are female and younger than 40 years with high ALT levels, low serum HBV DNA levels, and active liver histology (a subgroup that is more likely to undergo spontaneous seroconversion than other HBV-infected groups).

Standard or pegylated interferon is a treatment option for coinfected patients who do not yet require HAART, especially patients who have high ALT levels, low viral loads, and positive HBeAg status without liver decompensation.¹²

Nucleoside and nucleotide analogues

The nucleoside and nucleotide analogues used for HBV therapy have different degrees of effectiveness against HIV polymerase, but none can be used as monotherapy because of the risk of inducing HIV resistance. Lamivudine and tenofovir are used as part of the standard cocktail for the treatment of HIV (see “Case: HIV/HBV with resistance to tenofovir”). Entecavir is now recognized as a partial inhibitor of HIV replication. Both lamivudine and entecavir induce the YMDD mutation, an indication of resistance to therapy, in HIV polymerase. Tenofovir also may select for resistance mutations in HIV polymerase.

At dosages used for the treatment of HBV infection, adefovir has weak activity against HIV, and therefore HIV would not be under significant selective pressure to develop resistance mutations. In HIV polymerase, the mutations that confer resistance to adefovir also confer resistance to tenofovir, and therefore use of adefovir may induce tenofovir resistance.

Telbivudine has not been studied in HIV-infected patients, but its resistance profile is similar to that of lamivudine.

Treating both infections

When both HBV and HIV infections require treatment, HAART is necessary for HIV.¹² The treatment strategy for coinfection is to use standard therapy for HIV, selecting two agents that are effective against HBV infection.

The need to avoid antiviral resistance complicates the selection of active agents. Resistance to HIV therapy limits the choices for treatment of HBV infection. The immediate aim of therapy, an undetectable level of HBV DNA, eliminates the use of less potent agents. The best choice for therapy is the most potent agent that can be used, such as tenofovir plus lamivudine or tenofovir plus emtricitabine.

Antiviral resistance

For the coinfected patient who develops resistance to lamivudine, the recommendation is to treat with tenofovir plus entecavir (the preferable choice because of absence of cross-reactivity between the two agents) or tenofovir plus lamivudine or emtricitabine. There is some evidence that lamivudine resistance predisposes to entecavir resistance, but the studies that generated these results were conducted in patients who had very high baseline viral loads¹³; the effectiveness of entecavir in patients with low baseline viral loads is unknown. Presumably, when entecavir is used in combination with another potent nucleoside analogue in coinfected patients, the sensitivity of HBV will be more durable than when entecavir is used as monotherapy.

Long-term monitoring

Long-term monitoring for the coinfected patient is similar to that for the patient infected with HBV only. HBV DNA levels should be monitored every 3 months for signs of resistance until levels have plateaued or become undetectable. Once the HBV DNA level is stable or undetectable, the monitoring interval can be extended. Ultrasonographic screening for hepatocellular carcinoma should be conducted every 6 months. Patients with cirrhosis should be screened for esophageal varices.

SUMMARY

HBV in the setting of HIV is more aggressive than in a patient infected with HBV only, and treatment must be comparably aggressive and carefully selected. The primary goal of HBV treatment in a coinfected patient is the same as in a patient with HBV infection only: reduction of viral load to undetectable levels. Treatment decisions are based on viral load, ALT level, findings on liver biopsy, the need for HAART, and the drug’s resistance profile. None of the nucleoside or nucleotide analogues can be used as monotherapy in the coinfected patient because of the risk of inducing resistance to HIV therapy. When the patient requires HAART, then the general recommendation is to select a combination of two drugs that have activity against HIV. If resistance develops, the preferred strategy is treatment with tenofovir plus entecavir. Monitoring includes measurement of HBV DNA levels every 3 months and ultrasonographic screening for hepatocellular carcinoma every 6 months.

Worldwide, 40 million people are infected with the human immunodeficiency virus (HIV). As many as 4 million of them are coinfected with hepatitis B virus (HBV).¹ In North America and Europe, the highest prevalence of HBV/HIV coinfection is in men who have sex with men. Approximately half of HIV-positive men who have sex with men have evidence of prior or active HBV infection, and 5% to 10% have chronic HBV infection. Among those who acquire HIV through injected drug use or through heterosexual transmission, the coinfection rate is much lower.^2,3

Coinfection with HBV and HIV follows a different course elsewhere in the world. For example, in Africa and Asia, HBV is usually acquired first through neonatal or childhood infection, with either vertical or horizontal transmission after birth.^4,5 In parts of Africa, ritual scarification is likely a major player in the adolescent transmission of HBV. (Ritual scarification is the practice of creating small incisions in the skin of adolescents and rubbing black ash in the wounds to form scars; the cutting instruments are not sterilized between rituals.)

NATURAL HISTORY

In general, HBV tends to be more aggressive in HIV-positive individuals than in monoinfected individuals,^2,6 with higher HBV carrier rates, higher levels of HBV viremia, more frequent episodes of activation, and faster progression to cirrhosis.

Hepatocellular carcinoma occurs more often, its onset is earlier, and its course is more aggressive in coinfected individuals than in monoinfected individuals.^7,8 Using data from a prospective cohort study, Thio et al⁹ found that among men coinfected with HIV and HBV, liver-related mortality was almost 19 times greater compared with men infected with HBV only and more than seven times greater compared with those infected with HIV only.

In an observational longitudinal cohort study,¹⁰ the risk of death from liver disease in HIV-positive persons was nearly three times greater among those also infected with HBV (P < .0001).

ASSESSING WHEN TO TREAT

The objectives of HBV therapy in individuals coinfected with HIV are similar to those in the population infected with HBV alone. Suppression of viral replication is the major goal. Ideally, the viral load should be reduced to an undetectable level, which will result in normalization of alanine aminotransferase (ALT) level, improved liver histology, reduced risk of progression to cirrhosis and liver failure (although supportive evidence from controlled clinical trials is lacking), and likely reduced incidence of hepatocellular carcinoma.

For those who are hepatitis B e antigen (HBeAg) positive, seroconversion may be a convenient end point for treatment, although for many patients seroconversion is not associated with remission of disease activity or viral replication.

Treatment decisions depend on whether or not the patient requires highly active antiretroviral therapy (HAART) for HIV infection. If HAART is indicated, then HIV agents that have HBV activity are incorporated into the regimen. If the patient does not yet require HAART for HIV but requires treatment for hepatitis B, this is itself an indication for HAART, since monotherapy for HBV is associated with the development of HIV resistance.

Viral load and ALT

Liver biopsy

If the ALT is normal in the presence of a high HBV DNA level, a liver biopsy is recommended, partly because the ALT level is an inadequate indicator of the severity of liver disease. If significant fibrosis is present, treatment is recommended. No treatment is required if fibrosis is mild, but liver biopsies should be repeated every 3 to 5 years in this group because a hallmark of HBV infection is its variability in time to progression. The extent of fibrosis may influence the choice of therapy.

Often in the coinfected patient, HBV-related liver injury must be distinguished from other forms of liver injury. For instance, some of the drugs used to treat HIV infection can induce non­alcoholic fatty liver disease and lipodystrophy. Because the risk of advanced fibrosis is higher in the coinfected patient than in the patient infected only with HBV, the threshold for biopsy in the coinfected patient should be lower.

At present, noninvasive tools to assess the extent of liver injury have not been validated in chronic HBV infection, unlike in hepatitis C virus infection.

The potential therapies for HBV in the coinfected patient are the same as those for the patient infected with HBV alone (see “Hepatitis B treatment: Current best practices, avoiding resistance”), with the addition of tenofovir and emtricitabine in combination.

Interferon

Early studies of interferon for the treatment of chronic HBV infection included many patients who were also HIV positive. These early studies revealed a lower rate of HBeAg seroconversion in HIV-positive patients compared with HIV-negative patients. Di Martino et al¹¹ found that approximately half (26 of 50) of HIV-negative patients treated with interferon seroconverted at 6 years, compared with only 4 of 26 interferon-treated patients with chronic HBV who were coinfected with HIV. Based on results such as these, interferon therapy in the HBV/HIV-coinfected patient should be limited to patients who are likely to seroconvert: ie, those who are female and younger than 40 years with high ALT levels, low serum HBV DNA levels, and active liver histology (a subgroup that is more likely to undergo spontaneous seroconversion than other HBV-infected groups).

Standard or pegylated interferon is a treatment option for coinfected patients who do not yet require HAART, especially patients who have high ALT levels, low viral loads, and positive HBeAg status without liver decompensation.¹²

Nucleoside and nucleotide analogues

The nucleoside and nucleotide analogues used for HBV therapy have different degrees of effectiveness against HIV polymerase, but none can be used as monotherapy because of the risk of inducing HIV resistance. Lamivudine and tenofovir are used as part of the standard cocktail for the treatment of HIV (see “Case: HIV/HBV with resistance to tenofovir”). Entecavir is now recognized as a partial inhibitor of HIV replication. Both lamivudine and entecavir induce the YMDD mutation, an indication of resistance to therapy, in HIV polymerase. Tenofovir also may select for resistance mutations in HIV polymerase.

At dosages used for the treatment of HBV infection, adefovir has weak activity against HIV, and therefore HIV would not be under significant selective pressure to develop resistance mutations. In HIV polymerase, the mutations that confer resistance to adefovir also confer resistance to tenofovir, and therefore use of adefovir may induce tenofovir resistance.

Telbivudine has not been studied in HIV-infected patients, but its resistance profile is similar to that of lamivudine.

Treating both infections

When both HBV and HIV infections require treatment, HAART is necessary for HIV.¹² The treatment strategy for coinfection is to use standard therapy for HIV, selecting two agents that are effective against HBV infection.

The need to avoid antiviral resistance complicates the selection of active agents. Resistance to HIV therapy limits the choices for treatment of HBV infection. The immediate aim of therapy, an undetectable level of HBV DNA, eliminates the use of less potent agents. The best choice for therapy is the most potent agent that can be used, such as tenofovir plus lamivudine or tenofovir plus emtricitabine.

Antiviral resistance

For the coinfected patient who develops resistance to lamivudine, the recommendation is to treat with tenofovir plus entecavir (the preferable choice because of absence of cross-reactivity between the two agents) or tenofovir plus lamivudine or emtricitabine. There is some evidence that lamivudine resistance predisposes to entecavir resistance, but the studies that generated these results were conducted in patients who had very high baseline viral loads¹³; the effectiveness of entecavir in patients with low baseline viral loads is unknown. Presumably, when entecavir is used in combination with another potent nucleoside analogue in coinfected patients, the sensitivity of HBV will be more durable than when entecavir is used as monotherapy.

Long-term monitoring

Long-term monitoring for the coinfected patient is similar to that for the patient infected with HBV only. HBV DNA levels should be monitored every 3 months for signs of resistance until levels have plateaued or become undetectable. Once the HBV DNA level is stable or undetectable, the monitoring interval can be extended. Ultrasonographic screening for hepatocellular carcinoma should be conducted every 6 months. Patients with cirrhosis should be screened for esophageal varices.

SUMMARY

HBV in the setting of HIV is more aggressive than in a patient infected with HBV only, and treatment must be comparably aggressive and carefully selected. The primary goal of HBV treatment in a coinfected patient is the same as in a patient with HBV infection only: reduction of viral load to undetectable levels. Treatment decisions are based on viral load, ALT level, findings on liver biopsy, the need for HAART, and the drug’s resistance profile. None of the nucleoside or nucleotide analogues can be used as monotherapy in the coinfected patient because of the risk of inducing resistance to HIV therapy. When the patient requires HAART, then the general recommendation is to select a combination of two drugs that have activity against HIV. If resistance develops, the preferred strategy is treatment with tenofovir plus entecavir. Monitoring includes measurement of HBV DNA levels every 3 months and ultrasonographic screening for hepatocellular carcinoma every 6 months.

Worldwide, 40 million people are infected with the human immunodeficiency virus (HIV). As many as 4 million of them are coinfected with hepatitis B virus (HBV).¹ In North America and Europe, the highest prevalence of HBV/HIV coinfection is in men who have sex with men. Approximately half of HIV-positive men who have sex with men have evidence of prior or active HBV infection, and 5% to 10% have chronic HBV infection. Among those who acquire HIV through injected drug use or through heterosexual transmission, the coinfection rate is much lower.^2,3

Coinfection with HBV and HIV follows a different course elsewhere in the world. For example, in Africa and Asia, HBV is usually acquired first through neonatal or childhood infection, with either vertical or horizontal transmission after birth.^4,5 In parts of Africa, ritual scarification is likely a major player in the adolescent transmission of HBV. (Ritual scarification is the practice of creating small incisions in the skin of adolescents and rubbing black ash in the wounds to form scars; the cutting instruments are not sterilized between rituals.)

NATURAL HISTORY

In general, HBV tends to be more aggressive in HIV-positive individuals than in monoinfected individuals,^2,6 with higher HBV carrier rates, higher levels of HBV viremia, more frequent episodes of activation, and faster progression to cirrhosis.

Hepatocellular carcinoma occurs more often, its onset is earlier, and its course is more aggressive in coinfected individuals than in monoinfected individuals.^7,8 Using data from a prospective cohort study, Thio et al⁹ found that among men coinfected with HIV and HBV, liver-related mortality was almost 19 times greater compared with men infected with HBV only and more than seven times greater compared with those infected with HIV only.

In an observational longitudinal cohort study,¹⁰ the risk of death from liver disease in HIV-positive persons was nearly three times greater among those also infected with HBV (P < .0001).

ASSESSING WHEN TO TREAT

The objectives of HBV therapy in individuals coinfected with HIV are similar to those in the population infected with HBV alone. Suppression of viral replication is the major goal. Ideally, the viral load should be reduced to an undetectable level, which will result in normalization of alanine aminotransferase (ALT) level, improved liver histology, reduced risk of progression to cirrhosis and liver failure (although supportive evidence from controlled clinical trials is lacking), and likely reduced incidence of hepatocellular carcinoma.

For those who are hepatitis B e antigen (HBeAg) positive, seroconversion may be a convenient end point for treatment, although for many patients seroconversion is not associated with remission of disease activity or viral replication.

Treatment decisions depend on whether or not the patient requires highly active antiretroviral therapy (HAART) for HIV infection. If HAART is indicated, then HIV agents that have HBV activity are incorporated into the regimen. If the patient does not yet require HAART for HIV but requires treatment for hepatitis B, this is itself an indication for HAART, since monotherapy for HBV is associated with the development of HIV resistance.

Viral load and ALT

Liver biopsy

If the ALT is normal in the presence of a high HBV DNA level, a liver biopsy is recommended, partly because the ALT level is an inadequate indicator of the severity of liver disease. If significant fibrosis is present, treatment is recommended. No treatment is required if fibrosis is mild, but liver biopsies should be repeated every 3 to 5 years in this group because a hallmark of HBV infection is its variability in time to progression. The extent of fibrosis may influence the choice of therapy.

Often in the coinfected patient, HBV-related liver injury must be distinguished from other forms of liver injury. For instance, some of the drugs used to treat HIV infection can induce non­alcoholic fatty liver disease and lipodystrophy. Because the risk of advanced fibrosis is higher in the coinfected patient than in the patient infected only with HBV, the threshold for biopsy in the coinfected patient should be lower.

At present, noninvasive tools to assess the extent of liver injury have not been validated in chronic HBV infection, unlike in hepatitis C virus infection.

The potential therapies for HBV in the coinfected patient are the same as those for the patient infected with HBV alone (see “Hepatitis B treatment: Current best practices, avoiding resistance”), with the addition of tenofovir and emtricitabine in combination.

Interferon

Early studies of interferon for the treatment of chronic HBV infection included many patients who were also HIV positive. These early studies revealed a lower rate of HBeAg seroconversion in HIV-positive patients compared with HIV-negative patients. Di Martino et al¹¹ found that approximately half (26 of 50) of HIV-negative patients treated with interferon seroconverted at 6 years, compared with only 4 of 26 interferon-treated patients with chronic HBV who were coinfected with HIV. Based on results such as these, interferon therapy in the HBV/HIV-coinfected patient should be limited to patients who are likely to seroconvert: ie, those who are female and younger than 40 years with high ALT levels, low serum HBV DNA levels, and active liver histology (a subgroup that is more likely to undergo spontaneous seroconversion than other HBV-infected groups).

Standard or pegylated interferon is a treatment option for coinfected patients who do not yet require HAART, especially patients who have high ALT levels, low viral loads, and positive HBeAg status without liver decompensation.¹²

Nucleoside and nucleotide analogues

The nucleoside and nucleotide analogues used for HBV therapy have different degrees of effectiveness against HIV polymerase, but none can be used as monotherapy because of the risk of inducing HIV resistance. Lamivudine and tenofovir are used as part of the standard cocktail for the treatment of HIV (see “Case: HIV/HBV with resistance to tenofovir”). Entecavir is now recognized as a partial inhibitor of HIV replication. Both lamivudine and entecavir induce the YMDD mutation, an indication of resistance to therapy, in HIV polymerase. Tenofovir also may select for resistance mutations in HIV polymerase.

At dosages used for the treatment of HBV infection, adefovir has weak activity against HIV, and therefore HIV would not be under significant selective pressure to develop resistance mutations. In HIV polymerase, the mutations that confer resistance to adefovir also confer resistance to tenofovir, and therefore use of adefovir may induce tenofovir resistance.

Telbivudine has not been studied in HIV-infected patients, but its resistance profile is similar to that of lamivudine.

Treating both infections

When both HBV and HIV infections require treatment, HAART is necessary for HIV.¹² The treatment strategy for coinfection is to use standard therapy for HIV, selecting two agents that are effective against HBV infection.

The need to avoid antiviral resistance complicates the selection of active agents. Resistance to HIV therapy limits the choices for treatment of HBV infection. The immediate aim of therapy, an undetectable level of HBV DNA, eliminates the use of less potent agents. The best choice for therapy is the most potent agent that can be used, such as tenofovir plus lamivudine or tenofovir plus emtricitabine.

Antiviral resistance

For the coinfected patient who develops resistance to lamivudine, the recommendation is to treat with tenofovir plus entecavir (the preferable choice because of absence of cross-reactivity between the two agents) or tenofovir plus lamivudine or emtricitabine. There is some evidence that lamivudine resistance predisposes to entecavir resistance, but the studies that generated these results were conducted in patients who had very high baseline viral loads¹³; the effectiveness of entecavir in patients with low baseline viral loads is unknown. Presumably, when entecavir is used in combination with another potent nucleoside analogue in coinfected patients, the sensitivity of HBV will be more durable than when entecavir is used as monotherapy.

Long-term monitoring

Long-term monitoring for the coinfected patient is similar to that for the patient infected with HBV only. HBV DNA levels should be monitored every 3 months for signs of resistance until levels have plateaued or become undetectable. Once the HBV DNA level is stable or undetectable, the monitoring interval can be extended. Ultrasonographic screening for hepatocellular carcinoma should be conducted every 6 months. Patients with cirrhosis should be screened for esophageal varices.

SUMMARY

HBV in the setting of HIV is more aggressive than in a patient infected with HBV only, and treatment must be comparably aggressive and carefully selected. The primary goal of HBV treatment in a coinfected patient is the same as in a patient with HBV infection only: reduction of viral load to undetectable levels. Treatment decisions are based on viral load, ALT level, findings on liver biopsy, the need for HAART, and the drug’s resistance profile. None of the nucleoside or nucleotide analogues can be used as monotherapy in the coinfected patient because of the risk of inducing resistance to HIV therapy. When the patient requires HAART, then the general recommendation is to select a combination of two drugs that have activity against HIV. If resistance develops, the preferred strategy is treatment with tenofovir plus entecavir. Monitoring includes measurement of HBV DNA levels every 3 months and ultrasonographic screening for hepatocellular carcinoma every 6 months.

A 74-year-old man is admitted to the hospital with a 7-day history of fever, rigors, chest pain, and general weakness. He underwent coronary artery bypass surgery 10 years ago.

After 2 weeks of intravenous ceftriaxone 2 g/day, the patient undergoes excision of the mycotic pseudoaneurysm of the descending aorta, with placement of an aortic homograft. Biopsy of the excised aortic segment shows calcified fibroatheromatous plaques with no evidence of cystic medial degeneration or granulomas.

DISCUSSION

Mycotic aneurysm is a localized and irreversible dilatation of an artery due to destruction of the vessel wall by an infection. The dilatation is at least one and one-half times the normal diameter of the affected artery. It may be a true aneurysm or a pseudoaneurysm, involving all or some layers of the arterial wall. It is a rare but life-threatening condition.

A mycotic aneurysm can develop from septic embolization to the vasa vasorum, hematogenous seeding of an existing aneurysm, or extension from a contiguous site of infection.^1,2 Mycotic infections of the aorta show a preference for male patients already infected with S enteritidis or S typhimurium. ³ Predisposing factors include rheumatic deformity of the valves, a bicuspid valve, impaired immunity,⁴ self-induced or iatrogenic arterial trauma,^5,6 atherosclerotic deposits and calcification of the endovascular structure,⁷ and, in elderly patients, Salmonella septicemia.^8,9 Computed tomography is the most useful imaging modality.^10,11 Surgical interventions, in addition to parenteral antibiotic therapy for at least 6 weeks,^11,12 are required to:

• Confirm the diagnosis
• Reconstruct the arterial vasculature
• Manage the complications of sepsis
• Start preventive measures (ie, cholecystectomy).²

A 74-year-old man is admitted to the hospital with a 7-day history of fever, rigors, chest pain, and general weakness. He underwent coronary artery bypass surgery 10 years ago.

After 2 weeks of intravenous ceftriaxone 2 g/day, the patient undergoes excision of the mycotic pseudoaneurysm of the descending aorta, with placement of an aortic homograft. Biopsy of the excised aortic segment shows calcified fibroatheromatous plaques with no evidence of cystic medial degeneration or granulomas.

DISCUSSION

Mycotic aneurysm is a localized and irreversible dilatation of an artery due to destruction of the vessel wall by an infection. The dilatation is at least one and one-half times the normal diameter of the affected artery. It may be a true aneurysm or a pseudoaneurysm, involving all or some layers of the arterial wall. It is a rare but life-threatening condition.

A mycotic aneurysm can develop from septic embolization to the vasa vasorum, hematogenous seeding of an existing aneurysm, or extension from a contiguous site of infection.^1,2 Mycotic infections of the aorta show a preference for male patients already infected with S enteritidis or S typhimurium. ³ Predisposing factors include rheumatic deformity of the valves, a bicuspid valve, impaired immunity,⁴ self-induced or iatrogenic arterial trauma,^5,6 atherosclerotic deposits and calcification of the endovascular structure,⁷ and, in elderly patients, Salmonella septicemia.^8,9 Computed tomography is the most useful imaging modality.^10,11 Surgical interventions, in addition to parenteral antibiotic therapy for at least 6 weeks,^11,12 are required to:

• Confirm the diagnosis
• Reconstruct the arterial vasculature
• Manage the complications of sepsis
• Start preventive measures (ie, cholecystectomy).²

A 74-year-old man is admitted to the hospital with a 7-day history of fever, rigors, chest pain, and general weakness. He underwent coronary artery bypass surgery 10 years ago.

After 2 weeks of intravenous ceftriaxone 2 g/day, the patient undergoes excision of the mycotic pseudoaneurysm of the descending aorta, with placement of an aortic homograft. Biopsy of the excised aortic segment shows calcified fibroatheromatous plaques with no evidence of cystic medial degeneration or granulomas.

DISCUSSION

Mycotic aneurysm is a localized and irreversible dilatation of an artery due to destruction of the vessel wall by an infection. The dilatation is at least one and one-half times the normal diameter of the affected artery. It may be a true aneurysm or a pseudoaneurysm, involving all or some layers of the arterial wall. It is a rare but life-threatening condition.

A mycotic aneurysm can develop from septic embolization to the vasa vasorum, hematogenous seeding of an existing aneurysm, or extension from a contiguous site of infection.^1,2 Mycotic infections of the aorta show a preference for male patients already infected with S enteritidis or S typhimurium. ³ Predisposing factors include rheumatic deformity of the valves, a bicuspid valve, impaired immunity,⁴ self-induced or iatrogenic arterial trauma,^5,6 atherosclerotic deposits and calcification of the endovascular structure,⁷ and, in elderly patients, Salmonella septicemia.^8,9 Computed tomography is the most useful imaging modality.^10,11 Surgical interventions, in addition to parenteral antibiotic therapy for at least 6 weeks,^11,12 are required to:

• Confirm the diagnosis
• Reconstruct the arterial vasculature
• Manage the complications of sepsis
• Start preventive measures (ie, cholecystectomy).²

A 70-year-old man falls in his bathroom and subsequently presents to an urgent care clinic. Among his complaints is right-sided chest pain. On physical examination he has point tenderness over the lateral right thorax with some superficial swelling and bruising. The chest is normal on auscultation.

Should this patient undergo imaging to determine if he has a rib fracture? And which imaging study would be appropriate?

This article outlines the use of various imaging tests in the evaluation of suspected rib fractures and recommends an approach to management. This article does not address fractures in children.

MANY CAUSES OF RIB FRACTURES

Trauma, the most common cause of rib fractures, includes penetrating injuries and blunt injury to the chest wall. Between 10% and 66% of traumatic injuries result in rib fractures. ¹ Traumatic injury can result from motor vehicle accidents, assault, sports, cardiopulmonary resuscitation, physical abuse (“nonaccidental” trauma), and, rarely, severe paroxysms of coughing.²

Cancer can cause pathologic fractures of the rib.

Stress fractures of the ribs are more likely to occur in high-level athletes whose activity involves repetitive musculoskeletal loading, although they can also occur in people with repetitive coughing paroxysms.³ Sports and activities that result in stress fractures include rowing, pitching or throwing, basketball, weight-lifting, ballet, golf, gymnastics, and swimming.⁴

WHICH RIB IS BROKEN?

The fourth through 10th ribs are the most often fractured. Fractures of the first through the third ribs can be associated with underlying nerve and vascular injuries, and fractures of the 10th through 12th ribs are associated with damage to abdominal organs,⁵ most commonly the liver, spleen, kidneys, and diaphragm.³

Fractures of the costal cartilage can occur by any of the mechanisms described above. The true incidence of costal cartilage fractures is not known because plain radiography, the traditional method of evaluation, does not reliably detect them.

WHY CONFIRM A RIB FRACTURE?

For many rib fractures without associated injury, a radiographic diagnosis has little impact on patient management, which consists mainly of pain control. But knowing whether a patient has a broken rib can often be important.

To detect associated injury. The rate of associated injury in patients with rib fractures is high.⁶ Potentially severe complications include:

• Pneumothorax
• Hemothorax
• Pulmonary contusion
• Flail chest
• Pneumonia
• Vascular and nerve damage (especially with trauma to the upper chest or the first through third ribs)
• Abdominal organ injury (particularly with trauma to the lower thorax or lower ribs).

The absence of a rib fracture does not preclude these conditions, however.

To prevent complications. Even in the absence of associated injuries, radiographic confirmation of a rib fracture can help prevent complications such as atelectasis and is particularly important in patients with comorbidities such as chronic obstructive pulmonary disease, cardiac disease, hepatic disease, renal disease, dementia, and coagulopathy.¹

To document the injury. Radiographic documentation of a rib fracture may be required for medical-legal issues in cases of assault, motor vehicle accident, occupational injury, and abuse.

To help manage pain. Confirmation of rib fracture can facilitate pain management, particularly in patients with undiagnosed fractures with long-standing refractory pain. For example, conservative pain control with nonsteroidal anti-inflammatory drugs may be sufficient for a soft-tissue injury but may not be enough for a rib fracture. Intravenous narcotics or nerve blocks might be preferable.^3,7 Controlling pain helps limit the incidence of associated complications.

To count how many ribs are broken. The more ribs broken, the greater the likelihood of illness and death in certain populations, such as the elderly. One study⁸ found that patients over age 45 with more than four broken ribs are at a significantly higher risk of prolonged stay in the intensive care unit, prolonged ventilator support, and prolonged overall hospital stay.

Knowing the number of ribs fractured may also influence other treatment decisions, such as whether to transfer the patient to a trauma center: a study showed that the more ribs broken, the greater the death rate, and that more than three rib fractures may indicate the need to transfer to a trauma center.⁶

HOW TO DIAGNOSE A BROKEN RIB

Signs and symptoms are unreliable but important

Clinical symptoms do not reliably tell us if a rib is broken.^9,10 Nevertheless, the history and physical examination can uncover possible complications or associated injuries,^10,11 such as flail chest, pneumothorax, or vascular injury.

Classic clinical signs and symptoms of rib fracture include point tenderness, focally referred pain with general chest compression, splinting, bony crepitus, and ecchymosis.⁹ A history of a motor vehicle accident (especially on a motorcycle) or other injury due to rapid deceleration, a fall from higher than 20 feet, a gunshot wound, assault, or a crushing injury would indicate a greater risk of complications.

Signs of complications may include decreased oxygen saturation, decreased or absent breath sounds, dullness or hyperresonance to percussion, tracheal deviation, hypotension, arrythmia, subcutaneous emphysema, neck vein distension, neck hematoma, a focal neurologic deficit below the clavicles or in the upper extremities, and flail chest.¹¹ Flail chest results from multiple fractures in the same rib, so that a segment of chest wall does not contribute to breathing.

Further research is needed into the correlation of clinical symptoms with rib fractures. Much of the evidence that clinical symptoms correlate poorly with fractures comes from studies that used plain radiography to detect the fractures. However, ultrasonography and computed tomography (CT) can detect fractures that plain radiography cannot, and studies using these newer imaging tests may reveal a better correlation between clinical symptoms and rib fracture than previously thought.⁶

Chest radiography may miss 50% of rib fractures, but is still useful

Plain radiography of the chest with or without oblique views and optimized by the technologist for bony detail (“bone technique”) has historically been the imaging test of choice. However, it may miss up to 50% of fractures.¹⁰ Furthermore, it is not sensitive for costal cartilage³ or stress fractures.

Despite these limitations, plain radiography is vitally important in diagnosing complications and associated injuries such as a pneumothorax, hemothorax, pulmonary contusion, pneumomediastinum, or pneumoperitoneum. Also, a widened mediastinum could indicate aortic injury.

Currently, a standard chest x-ray is often the initial study of choice in the evaluation of chest pain and in cases of minor blunt trauma. If rib fractures are suspected clinically, a rib series can be of benefit. A rib series consists of a marker placed over the region of interest, oblique views, and optimization of the radiograph by the technologist to highlight bony detail. The decision to image a rib fracture in the absence of other underlying abnormalities or associated injuries depends on the clinical scenario.

Computed tomography provides more detail

While CT appears to be the best imaging test for evaluating for rib fractures and associated injuries, it is relatively costly, is time-consuming, is not always available, and exposes the patient to a significant amount of radiation.

Also, while CT plays a vital role in major and penetrating trauma of the chest or abdomen, its use in other situations is more limited. Again, the issue of clinical impact of a diagnosis of rib fracture comes into play, and in this setting CT competes with plain radiography and ultrasonography, which are less costly and involve less or no radiation exposure.

Ultrasonography has advantages but is not widely used

Ultrasonography can be used to look for broken ribs and costal cartilage fractures. Associated injuries such as pneumothorax, hemothorax, and abdominal organ injury can also be evaluated. Studies have found it to be much more sensitive than plain radiography in detecting rib fractures,^3,15 whereas other studies have suggested it is only equally sensitive or slightly better.⁷ It also has the advantage of not using radiation.

Because of a number of disadvantages, ultrasonography is rarely used in the evaluation of rib fracture. It is time-consuming and more costly than plain radiography. It is often not readily available. It can be painful, making it impractical for trauma patients. Its results depend greatly on the skill of the technician, and it is unable to adequately assess certain portions of the thorax (eg, the first rib under the clavicle, and the upper ribs under the scapula).^7,15 Although able to detect some associated injuries, ultrasonography is not as sensitive and comprehensive as plain radiography and CT. Its role is therefore limited to situations in which the diagnosis of a rib fracture alone, in an accessible rib, is important.

Technetium Tc 99m methylene diphosphonate bone scanning can be used to look for bone pathology, including rib fractures. Bone scans are sensitive but not specific, and abnormal uptake generates an extensive differential diagnosis.¹⁶ Single-photon emission CT, or SPECT, can help localize the abnormality. ⁴ Because a hot spot on a bone scan can represent a number of conditions besides rib fractures, including cancer, focal sclerosis, and focal osteosclerosis, bone scanning is not routinely used for evaluating rib fractures, although it is very sensitive for stress fractures.

Occasionally, in a patient undergoing a bone scan as part of a workup for cancer, a scan shows a lesion that might be a rib fracture. In this case, one should correlate the results with those of plain radiography or CT.¹⁶

Magnetic resonance imaging: no role yet in rib fracture evaluation

MRI is not considered appropriate for evaluating rib fractures. It may be useful if there is concern about soft-tissue or vascular abnormalities. Beyond this, further research is needed to elucidate its role in rib fracture.

THE CHOICE OF TEST DEPENDS ON THE SITUATION

In patients with penetrating or major chest or abdominal trauma, CT is the study of choice. It provides the most information about associated injuries, and it accurately detects rib fractures. This helps target treatment of associated injuries, and helps identify patients at higher risk, such as those with significant vascular, pulmonary, or abdominal injuries and those with a greater number of fractures. An unstable, critically injured patient would not be a candidate for CT because of the risk of transport to the scanner; chest radiography would have to suffice in these cases.

In cases of minor blunt trauma when there is little suspicion of associated injuries or complications, plain radiography is likely sufficient. If there is suspicion of a rib fracture alone and confirmation is of clinical importance (eg, in the elderly or those with long-standing refractory pain, or when certain pain management treatments are being considered), then oblique radiographic views, bone technique, and marker placement over the concerning region are recommended. The role of ultrasonography in this setting is still up for debate.

In cases of suspected rib fracture with longstanding pain refractory to conservative pain management, plain radiography with oblique views, bone technique, and marker placement is useful. If the radiograph is negative or if there is a high suspicion of cartilage fracture, CT or ultrasonography may be of benefit only if the diagnosis will alter clinical management.

If stress fracture is suspected, a nuclear bone scan may be helpful to first detect an abnormality, and CT may then be used for correlation if needed.

CASE CONCLUDED: LIVING WITH UNCERTAINTY

As for the 70-year-old man presented at the beginning of this article, the first question is whether we suspect an associated injury on the basis of clinical features. If we had clinical findings suspicious for pneumothorax or hemothorax, plain radiography of the chest would be indicated. Since the patient was not involved in major trauma, a CT scan is not indicated as the first study.

Our patient has clinical findings suggesting a rib fracture without associated injury. In this setting, routine posteroanterior and lateral chest radiography would be useful to rule out major associated injuries and, perhaps, to find a rib fracture. If the chest film is normal and rib fracture is still suspected, we must decide whether the diagnosis would alter our clinical management. Our patient would likely be treated the same regardless of whether or not he has a fracture; therefore, we would prescribe pain management.

Chest radiography was performed to rule out associated injuries, especially since the patient was elderly, but the chest x-ray did not reveal anything. On follow-up approximately 1 month later, he appeared improved, with less pain and tenderness. This may be due to healing of a rib fracture or healing of his soft-tissue injury. We will never know whether he truly had a fracture, but it is irrelevant to his care.

A 70-year-old man falls in his bathroom and subsequently presents to an urgent care clinic. Among his complaints is right-sided chest pain. On physical examination he has point tenderness over the lateral right thorax with some superficial swelling and bruising. The chest is normal on auscultation.

Should this patient undergo imaging to determine if he has a rib fracture? And which imaging study would be appropriate?

This article outlines the use of various imaging tests in the evaluation of suspected rib fractures and recommends an approach to management. This article does not address fractures in children.

MANY CAUSES OF RIB FRACTURES

Trauma, the most common cause of rib fractures, includes penetrating injuries and blunt injury to the chest wall. Between 10% and 66% of traumatic injuries result in rib fractures. ¹ Traumatic injury can result from motor vehicle accidents, assault, sports, cardiopulmonary resuscitation, physical abuse (“nonaccidental” trauma), and, rarely, severe paroxysms of coughing.²

Cancer can cause pathologic fractures of the rib.

Stress fractures of the ribs are more likely to occur in high-level athletes whose activity involves repetitive musculoskeletal loading, although they can also occur in people with repetitive coughing paroxysms.³ Sports and activities that result in stress fractures include rowing, pitching or throwing, basketball, weight-lifting, ballet, golf, gymnastics, and swimming.⁴

WHICH RIB IS BROKEN?

The fourth through 10th ribs are the most often fractured. Fractures of the first through the third ribs can be associated with underlying nerve and vascular injuries, and fractures of the 10th through 12th ribs are associated with damage to abdominal organs,⁵ most commonly the liver, spleen, kidneys, and diaphragm.³

Fractures of the costal cartilage can occur by any of the mechanisms described above. The true incidence of costal cartilage fractures is not known because plain radiography, the traditional method of evaluation, does not reliably detect them.

WHY CONFIRM A RIB FRACTURE?

For many rib fractures without associated injury, a radiographic diagnosis has little impact on patient management, which consists mainly of pain control. But knowing whether a patient has a broken rib can often be important.

To detect associated injury. The rate of associated injury in patients with rib fractures is high.⁶ Potentially severe complications include:

• Pneumothorax
• Hemothorax
• Pulmonary contusion
• Flail chest
• Pneumonia
• Vascular and nerve damage (especially with trauma to the upper chest or the first through third ribs)
• Abdominal organ injury (particularly with trauma to the lower thorax or lower ribs).

The absence of a rib fracture does not preclude these conditions, however.

To prevent complications. Even in the absence of associated injuries, radiographic confirmation of a rib fracture can help prevent complications such as atelectasis and is particularly important in patients with comorbidities such as chronic obstructive pulmonary disease, cardiac disease, hepatic disease, renal disease, dementia, and coagulopathy.¹

To document the injury. Radiographic documentation of a rib fracture may be required for medical-legal issues in cases of assault, motor vehicle accident, occupational injury, and abuse.

To help manage pain. Confirmation of rib fracture can facilitate pain management, particularly in patients with undiagnosed fractures with long-standing refractory pain. For example, conservative pain control with nonsteroidal anti-inflammatory drugs may be sufficient for a soft-tissue injury but may not be enough for a rib fracture. Intravenous narcotics or nerve blocks might be preferable.^3,7 Controlling pain helps limit the incidence of associated complications.

To count how many ribs are broken. The more ribs broken, the greater the likelihood of illness and death in certain populations, such as the elderly. One study⁸ found that patients over age 45 with more than four broken ribs are at a significantly higher risk of prolonged stay in the intensive care unit, prolonged ventilator support, and prolonged overall hospital stay.

Knowing the number of ribs fractured may also influence other treatment decisions, such as whether to transfer the patient to a trauma center: a study showed that the more ribs broken, the greater the death rate, and that more than three rib fractures may indicate the need to transfer to a trauma center.⁶

HOW TO DIAGNOSE A BROKEN RIB

Signs and symptoms are unreliable but important

Clinical symptoms do not reliably tell us if a rib is broken.^9,10 Nevertheless, the history and physical examination can uncover possible complications or associated injuries,^10,11 such as flail chest, pneumothorax, or vascular injury.

Classic clinical signs and symptoms of rib fracture include point tenderness, focally referred pain with general chest compression, splinting, bony crepitus, and ecchymosis.⁹ A history of a motor vehicle accident (especially on a motorcycle) or other injury due to rapid deceleration, a fall from higher than 20 feet, a gunshot wound, assault, or a crushing injury would indicate a greater risk of complications.

Signs of complications may include decreased oxygen saturation, decreased or absent breath sounds, dullness or hyperresonance to percussion, tracheal deviation, hypotension, arrythmia, subcutaneous emphysema, neck vein distension, neck hematoma, a focal neurologic deficit below the clavicles or in the upper extremities, and flail chest.¹¹ Flail chest results from multiple fractures in the same rib, so that a segment of chest wall does not contribute to breathing.

Further research is needed into the correlation of clinical symptoms with rib fractures. Much of the evidence that clinical symptoms correlate poorly with fractures comes from studies that used plain radiography to detect the fractures. However, ultrasonography and computed tomography (CT) can detect fractures that plain radiography cannot, and studies using these newer imaging tests may reveal a better correlation between clinical symptoms and rib fracture than previously thought.⁶

Chest radiography may miss 50% of rib fractures, but is still useful

Plain radiography of the chest with or without oblique views and optimized by the technologist for bony detail (“bone technique”) has historically been the imaging test of choice. However, it may miss up to 50% of fractures.¹⁰ Furthermore, it is not sensitive for costal cartilage³ or stress fractures.

Despite these limitations, plain radiography is vitally important in diagnosing complications and associated injuries such as a pneumothorax, hemothorax, pulmonary contusion, pneumomediastinum, or pneumoperitoneum. Also, a widened mediastinum could indicate aortic injury.

Currently, a standard chest x-ray is often the initial study of choice in the evaluation of chest pain and in cases of minor blunt trauma. If rib fractures are suspected clinically, a rib series can be of benefit. A rib series consists of a marker placed over the region of interest, oblique views, and optimization of the radiograph by the technologist to highlight bony detail. The decision to image a rib fracture in the absence of other underlying abnormalities or associated injuries depends on the clinical scenario.

Computed tomography provides more detail

While CT appears to be the best imaging test for evaluating for rib fractures and associated injuries, it is relatively costly, is time-consuming, is not always available, and exposes the patient to a significant amount of radiation.

Also, while CT plays a vital role in major and penetrating trauma of the chest or abdomen, its use in other situations is more limited. Again, the issue of clinical impact of a diagnosis of rib fracture comes into play, and in this setting CT competes with plain radiography and ultrasonography, which are less costly and involve less or no radiation exposure.

Ultrasonography has advantages but is not widely used

Ultrasonography can be used to look for broken ribs and costal cartilage fractures. Associated injuries such as pneumothorax, hemothorax, and abdominal organ injury can also be evaluated. Studies have found it to be much more sensitive than plain radiography in detecting rib fractures,^3,15 whereas other studies have suggested it is only equally sensitive or slightly better.⁷ It also has the advantage of not using radiation.

Because of a number of disadvantages, ultrasonography is rarely used in the evaluation of rib fracture. It is time-consuming and more costly than plain radiography. It is often not readily available. It can be painful, making it impractical for trauma patients. Its results depend greatly on the skill of the technician, and it is unable to adequately assess certain portions of the thorax (eg, the first rib under the clavicle, and the upper ribs under the scapula).^7,15 Although able to detect some associated injuries, ultrasonography is not as sensitive and comprehensive as plain radiography and CT. Its role is therefore limited to situations in which the diagnosis of a rib fracture alone, in an accessible rib, is important.

Technetium Tc 99m methylene diphosphonate bone scanning can be used to look for bone pathology, including rib fractures. Bone scans are sensitive but not specific, and abnormal uptake generates an extensive differential diagnosis.¹⁶ Single-photon emission CT, or SPECT, can help localize the abnormality. ⁴ Because a hot spot on a bone scan can represent a number of conditions besides rib fractures, including cancer, focal sclerosis, and focal osteosclerosis, bone scanning is not routinely used for evaluating rib fractures, although it is very sensitive for stress fractures.

Occasionally, in a patient undergoing a bone scan as part of a workup for cancer, a scan shows a lesion that might be a rib fracture. In this case, one should correlate the results with those of plain radiography or CT.¹⁶

Magnetic resonance imaging: no role yet in rib fracture evaluation

MRI is not considered appropriate for evaluating rib fractures. It may be useful if there is concern about soft-tissue or vascular abnormalities. Beyond this, further research is needed to elucidate its role in rib fracture.

THE CHOICE OF TEST DEPENDS ON THE SITUATION

In patients with penetrating or major chest or abdominal trauma, CT is the study of choice. It provides the most information about associated injuries, and it accurately detects rib fractures. This helps target treatment of associated injuries, and helps identify patients at higher risk, such as those with significant vascular, pulmonary, or abdominal injuries and those with a greater number of fractures. An unstable, critically injured patient would not be a candidate for CT because of the risk of transport to the scanner; chest radiography would have to suffice in these cases.

In cases of minor blunt trauma when there is little suspicion of associated injuries or complications, plain radiography is likely sufficient. If there is suspicion of a rib fracture alone and confirmation is of clinical importance (eg, in the elderly or those with long-standing refractory pain, or when certain pain management treatments are being considered), then oblique radiographic views, bone technique, and marker placement over the concerning region are recommended. The role of ultrasonography in this setting is still up for debate.

In cases of suspected rib fracture with longstanding pain refractory to conservative pain management, plain radiography with oblique views, bone technique, and marker placement is useful. If the radiograph is negative or if there is a high suspicion of cartilage fracture, CT or ultrasonography may be of benefit only if the diagnosis will alter clinical management.

If stress fracture is suspected, a nuclear bone scan may be helpful to first detect an abnormality, and CT may then be used for correlation if needed.

CASE CONCLUDED: LIVING WITH UNCERTAINTY

As for the 70-year-old man presented at the beginning of this article, the first question is whether we suspect an associated injury on the basis of clinical features. If we had clinical findings suspicious for pneumothorax or hemothorax, plain radiography of the chest would be indicated. Since the patient was not involved in major trauma, a CT scan is not indicated as the first study.

Our patient has clinical findings suggesting a rib fracture without associated injury. In this setting, routine posteroanterior and lateral chest radiography would be useful to rule out major associated injuries and, perhaps, to find a rib fracture. If the chest film is normal and rib fracture is still suspected, we must decide whether the diagnosis would alter our clinical management. Our patient would likely be treated the same regardless of whether or not he has a fracture; therefore, we would prescribe pain management.

Chest radiography was performed to rule out associated injuries, especially since the patient was elderly, but the chest x-ray did not reveal anything. On follow-up approximately 1 month later, he appeared improved, with less pain and tenderness. This may be due to healing of a rib fracture or healing of his soft-tissue injury. We will never know whether he truly had a fracture, but it is irrelevant to his care.

A 70-year-old man falls in his bathroom and subsequently presents to an urgent care clinic. Among his complaints is right-sided chest pain. On physical examination he has point tenderness over the lateral right thorax with some superficial swelling and bruising. The chest is normal on auscultation.

Should this patient undergo imaging to determine if he has a rib fracture? And which imaging study would be appropriate?

This article outlines the use of various imaging tests in the evaluation of suspected rib fractures and recommends an approach to management. This article does not address fractures in children.

MANY CAUSES OF RIB FRACTURES

Trauma, the most common cause of rib fractures, includes penetrating injuries and blunt injury to the chest wall. Between 10% and 66% of traumatic injuries result in rib fractures. ¹ Traumatic injury can result from motor vehicle accidents, assault, sports, cardiopulmonary resuscitation, physical abuse (“nonaccidental” trauma), and, rarely, severe paroxysms of coughing.²

Cancer can cause pathologic fractures of the rib.

Stress fractures of the ribs are more likely to occur in high-level athletes whose activity involves repetitive musculoskeletal loading, although they can also occur in people with repetitive coughing paroxysms.³ Sports and activities that result in stress fractures include rowing, pitching or throwing, basketball, weight-lifting, ballet, golf, gymnastics, and swimming.⁴

WHICH RIB IS BROKEN?

The fourth through 10th ribs are the most often fractured. Fractures of the first through the third ribs can be associated with underlying nerve and vascular injuries, and fractures of the 10th through 12th ribs are associated with damage to abdominal organs,⁵ most commonly the liver, spleen, kidneys, and diaphragm.³

Fractures of the costal cartilage can occur by any of the mechanisms described above. The true incidence of costal cartilage fractures is not known because plain radiography, the traditional method of evaluation, does not reliably detect them.

WHY CONFIRM A RIB FRACTURE?

For many rib fractures without associated injury, a radiographic diagnosis has little impact on patient management, which consists mainly of pain control. But knowing whether a patient has a broken rib can often be important.

To detect associated injury. The rate of associated injury in patients with rib fractures is high.⁶ Potentially severe complications include:

• Pneumothorax
• Hemothorax
• Pulmonary contusion
• Flail chest
• Pneumonia
• Vascular and nerve damage (especially with trauma to the upper chest or the first through third ribs)
• Abdominal organ injury (particularly with trauma to the lower thorax or lower ribs).

The absence of a rib fracture does not preclude these conditions, however.

To prevent complications. Even in the absence of associated injuries, radiographic confirmation of a rib fracture can help prevent complications such as atelectasis and is particularly important in patients with comorbidities such as chronic obstructive pulmonary disease, cardiac disease, hepatic disease, renal disease, dementia, and coagulopathy.¹

To document the injury. Radiographic documentation of a rib fracture may be required for medical-legal issues in cases of assault, motor vehicle accident, occupational injury, and abuse.

To help manage pain. Confirmation of rib fracture can facilitate pain management, particularly in patients with undiagnosed fractures with long-standing refractory pain. For example, conservative pain control with nonsteroidal anti-inflammatory drugs may be sufficient for a soft-tissue injury but may not be enough for a rib fracture. Intravenous narcotics or nerve blocks might be preferable.^3,7 Controlling pain helps limit the incidence of associated complications.

To count how many ribs are broken. The more ribs broken, the greater the likelihood of illness and death in certain populations, such as the elderly. One study⁸ found that patients over age 45 with more than four broken ribs are at a significantly higher risk of prolonged stay in the intensive care unit, prolonged ventilator support, and prolonged overall hospital stay.

Knowing the number of ribs fractured may also influence other treatment decisions, such as whether to transfer the patient to a trauma center: a study showed that the more ribs broken, the greater the death rate, and that more than three rib fractures may indicate the need to transfer to a trauma center.⁶

HOW TO DIAGNOSE A BROKEN RIB

Signs and symptoms are unreliable but important

Clinical symptoms do not reliably tell us if a rib is broken.^9,10 Nevertheless, the history and physical examination can uncover possible complications or associated injuries,^10,11 such as flail chest, pneumothorax, or vascular injury.

Classic clinical signs and symptoms of rib fracture include point tenderness, focally referred pain with general chest compression, splinting, bony crepitus, and ecchymosis.⁹ A history of a motor vehicle accident (especially on a motorcycle) or other injury due to rapid deceleration, a fall from higher than 20 feet, a gunshot wound, assault, or a crushing injury would indicate a greater risk of complications.

Signs of complications may include decreased oxygen saturation, decreased or absent breath sounds, dullness or hyperresonance to percussion, tracheal deviation, hypotension, arrythmia, subcutaneous emphysema, neck vein distension, neck hematoma, a focal neurologic deficit below the clavicles or in the upper extremities, and flail chest.¹¹ Flail chest results from multiple fractures in the same rib, so that a segment of chest wall does not contribute to breathing.

Further research is needed into the correlation of clinical symptoms with rib fractures. Much of the evidence that clinical symptoms correlate poorly with fractures comes from studies that used plain radiography to detect the fractures. However, ultrasonography and computed tomography (CT) can detect fractures that plain radiography cannot, and studies using these newer imaging tests may reveal a better correlation between clinical symptoms and rib fracture than previously thought.⁶

Chest radiography may miss 50% of rib fractures, but is still useful

Plain radiography of the chest with or without oblique views and optimized by the technologist for bony detail (“bone technique”) has historically been the imaging test of choice. However, it may miss up to 50% of fractures.¹⁰ Furthermore, it is not sensitive for costal cartilage³ or stress fractures.

Despite these limitations, plain radiography is vitally important in diagnosing complications and associated injuries such as a pneumothorax, hemothorax, pulmonary contusion, pneumomediastinum, or pneumoperitoneum. Also, a widened mediastinum could indicate aortic injury.

Currently, a standard chest x-ray is often the initial study of choice in the evaluation of chest pain and in cases of minor blunt trauma. If rib fractures are suspected clinically, a rib series can be of benefit. A rib series consists of a marker placed over the region of interest, oblique views, and optimization of the radiograph by the technologist to highlight bony detail. The decision to image a rib fracture in the absence of other underlying abnormalities or associated injuries depends on the clinical scenario.

Computed tomography provides more detail

While CT appears to be the best imaging test for evaluating for rib fractures and associated injuries, it is relatively costly, is time-consuming, is not always available, and exposes the patient to a significant amount of radiation.

Also, while CT plays a vital role in major and penetrating trauma of the chest or abdomen, its use in other situations is more limited. Again, the issue of clinical impact of a diagnosis of rib fracture comes into play, and in this setting CT competes with plain radiography and ultrasonography, which are less costly and involve less or no radiation exposure.

Ultrasonography has advantages but is not widely used

Ultrasonography can be used to look for broken ribs and costal cartilage fractures. Associated injuries such as pneumothorax, hemothorax, and abdominal organ injury can also be evaluated. Studies have found it to be much more sensitive than plain radiography in detecting rib fractures,^3,15 whereas other studies have suggested it is only equally sensitive or slightly better.⁷ It also has the advantage of not using radiation.

Because of a number of disadvantages, ultrasonography is rarely used in the evaluation of rib fracture. It is time-consuming and more costly than plain radiography. It is often not readily available. It can be painful, making it impractical for trauma patients. Its results depend greatly on the skill of the technician, and it is unable to adequately assess certain portions of the thorax (eg, the first rib under the clavicle, and the upper ribs under the scapula).^7,15 Although able to detect some associated injuries, ultrasonography is not as sensitive and comprehensive as plain radiography and CT. Its role is therefore limited to situations in which the diagnosis of a rib fracture alone, in an accessible rib, is important.

Technetium Tc 99m methylene diphosphonate bone scanning can be used to look for bone pathology, including rib fractures. Bone scans are sensitive but not specific, and abnormal uptake generates an extensive differential diagnosis.¹⁶ Single-photon emission CT, or SPECT, can help localize the abnormality. ⁴ Because a hot spot on a bone scan can represent a number of conditions besides rib fractures, including cancer, focal sclerosis, and focal osteosclerosis, bone scanning is not routinely used for evaluating rib fractures, although it is very sensitive for stress fractures.

Occasionally, in a patient undergoing a bone scan as part of a workup for cancer, a scan shows a lesion that might be a rib fracture. In this case, one should correlate the results with those of plain radiography or CT.¹⁶

Magnetic resonance imaging: no role yet in rib fracture evaluation

MRI is not considered appropriate for evaluating rib fractures. It may be useful if there is concern about soft-tissue or vascular abnormalities. Beyond this, further research is needed to elucidate its role in rib fracture.

THE CHOICE OF TEST DEPENDS ON THE SITUATION

In patients with penetrating or major chest or abdominal trauma, CT is the study of choice. It provides the most information about associated injuries, and it accurately detects rib fractures. This helps target treatment of associated injuries, and helps identify patients at higher risk, such as those with significant vascular, pulmonary, or abdominal injuries and those with a greater number of fractures. An unstable, critically injured patient would not be a candidate for CT because of the risk of transport to the scanner; chest radiography would have to suffice in these cases.

In cases of minor blunt trauma when there is little suspicion of associated injuries or complications, plain radiography is likely sufficient. If there is suspicion of a rib fracture alone and confirmation is of clinical importance (eg, in the elderly or those with long-standing refractory pain, or when certain pain management treatments are being considered), then oblique radiographic views, bone technique, and marker placement over the concerning region are recommended. The role of ultrasonography in this setting is still up for debate.

In cases of suspected rib fracture with longstanding pain refractory to conservative pain management, plain radiography with oblique views, bone technique, and marker placement is useful. If the radiograph is negative or if there is a high suspicion of cartilage fracture, CT or ultrasonography may be of benefit only if the diagnosis will alter clinical management.

If stress fracture is suspected, a nuclear bone scan may be helpful to first detect an abnormality, and CT may then be used for correlation if needed.

CASE CONCLUDED: LIVING WITH UNCERTAINTY

As for the 70-year-old man presented at the beginning of this article, the first question is whether we suspect an associated injury on the basis of clinical features. If we had clinical findings suspicious for pneumothorax or hemothorax, plain radiography of the chest would be indicated. Since the patient was not involved in major trauma, a CT scan is not indicated as the first study.

Our patient has clinical findings suggesting a rib fracture without associated injury. In this setting, routine posteroanterior and lateral chest radiography would be useful to rule out major associated injuries and, perhaps, to find a rib fracture. If the chest film is normal and rib fracture is still suspected, we must decide whether the diagnosis would alter our clinical management. Our patient would likely be treated the same regardless of whether or not he has a fracture; therefore, we would prescribe pain management.

Chest radiography was performed to rule out associated injuries, especially since the patient was elderly, but the chest x-ray did not reveal anything. On follow-up approximately 1 month later, he appeared improved, with less pain and tenderness. This may be due to healing of a rib fracture or healing of his soft-tissue injury. We will never know whether he truly had a fracture, but it is irrelevant to his care.

With prolonged cellular telephone use, people may note the onset of aching, burning, numbness, or tingling in the ulnar forearm and hand. This constellation of symptoms, termed “cell phone elbow” by the lay press, is known medically as cubital tunnel syndrome—the second most common nerve compression syndrome in the upper extremities after carpal tunnel syndrome.

In most cases, treatment consists simply of modifying the activity and avoiding activities that aggravate the symptoms. Switching hands frequently while talking on the phone or using a hands-free headset can help. Other daily activities that produce cubital tunnel syndrome include leaning on an elbow while driving or working, and sitting at a computer workstation that requires elbow flexion greater than 90 degrees. Making ergonomic adjustments to these activities is beneficial.

For patients who have nocturnal symptoms, a simple elbow pad worn anteriorly or a towel wrapped around the elbow to prevent flexion while sleeping can be very efficacious. Occasionally, anti-inflammatory injections can be given to quiet an inflamed ulnar nerve and reduce symptoms.¹ Surgical interventions, discussed below, are available for patients with severe, persistent symptoms.