HBV/HIV Coinfection Medical Management
"Hepatitis B Virus Infection in HIV-infected Persons"
Chloe L. Thio, MD
Johns Hopkins University School of Medicine, 1503 E. Jefferson Street, Baltimore, MD 21231-1001, USA.
Current Hepatitis Reports August, 2004, 3:91-97
Natural History and Significance of HIV-HBV Coinfection
• Natural history of HBV in HIV-uninfected persons
• The effect of HIV on hepatitis B
• The effect of HBV on HIV
Management of Chronic Hepatitis B
• Diagnosis and evaluation
• Treatment goals
• Treatment of CHB
References and Recommended Reading
"...Treatment for CHB should be considered in persons with circulating HBeAg or HBV-DNA levels 104 copies/mL and evidence of necroinflammation based on either ALT values or on liver biopsy. However, persons with lower levels of HBV DNA should also be evaluated because the cut-off for treatment in coinfected persons has not been determined. There are many available therapeutic options for CHB in the HIV-HBV-coinfected patient, but HIV complicates these options necessitating individualization of the treatment plan..."
1. Because HIV and hepatitis B virus (HBV) share routes of acquisition, up to 90% of all HIV-infected patients have a serum marker indicative of a prior or present HBV infection . In the United States, up to 10% of HIV-infected individuals are coinfected with HBV
2. Hepatitis B is transmitted more efficiently than HIV through sexual, vertical, and percutaneous routes
3. In an HIV-uninfected adult, 90% to 95% of acute HBV infections result in viral recovery (note from Jules Levin: a high percent with HBV infection appear to spontaneously clear HBV. The development of occult HBV appears to be an interesting phenomena with unclear clinical implications. Evaluation & diagnostic testing, which is complicated, needs to be properly done by knowledgeable medical provider expert in HBV to assess these issues.
4. HIV infection negatively impacts HBV infection by decreasing the rate of HBsAg clearance in acute infection and enhancing the progression of liver disease in those with CHB
5. HIV infection has been associated with higher HBV-DNA levels and increased risk for cirrhosis (relative risk 4.2) from CHB, ...and...mortality from hepatitis B-related liver disease is increased in HIV-infected persons
6. HIV also appears to be a risk factor for reactivation of hepatitis B in persons who have developed anti-HBs...
7. HIV infection is also associated with occult hepatitis B, which is the presence of HBV DNA without HBsAg... In the Swiss Cohort Study... 30% had persistently detectable HBV DNA
8. Coinfected patients are also at increased risk for the rare condition of hepatic steatosis and lactic acidosis from the nucleoside analogues, which can occur after years of therapy
9. Chronic hepatitis B is diagnosed by the presence of HBsAg for a minimum of 6 months. Those with CHB should be tested for HBeAg, anti-HBe, and HBV DNA to determine if they have active or inactive disease; however, none of these predict the rate of liver disease progression
10. The best indicator of the grade and stage of liver disease is the liver biopsy, ALT levels may not accurately reflect the state of liver disease
11. Because anti-HBV therapy does not eradicate viral reservoirs (ie, cccDNA), complete elimination of HBV is not possible with current therapy.. the goal in CHB treatment is suppression of viral replication, which stops or decreases the progression of liver disease and risk for HCC
12. Although published guidelines for the treatment of CHB in HIV-infected individuals do not exist, at the minimum those who have either circulating HBeAg or HBV DNA 104 copies/mL, along with evidence of necroinflammation in the liver, should be considered for treatment of CHB
13. The ideal regimen for the treatment of CHB in HIV-infected persons has not been determined by a clinical trial
14. The three US Food and Drug Administration-approved drugs for the treatment of CHB include interferon alpha, lamivudine, and adefovir dipivoxil. Three other drugs, which are active against HBV and are approved for other indications, include pegylated interferon alpha, tenofovir disoproxil fumarate (DF), and emtricitabine. The choice of which of these to use needs to be individualized based upon the stage of both HIV and HBV infections.
15. Studies of interferon alpha therapy in HIV-HBV-coinfected individuals are limited, but collectively suggest a decreased response compared to those without HIV infection
16. data for pegylated interferon alpha in HIV-infected persons with CHB do not exist, it may be more efficacious than standard interferon alpha for the treatment of CHB in HIV-uninfected individuals . In this study, response rates in HBeAg-positive CHB were 12% and 24% with standard and pegylated interferon
17. the future of treatment is likely combination therapy as is done for HIV therapy; however, the best combination(s) have not been determined. ( note from Jules Levin: a limited number & quality of combination therapy studies have been so far conducted & show limited value to combination therapy).
18. Tenofovir DF, a nucleotide analogue similar to adefovir dipivoxil, is approved for the treatment of HIV but is also efficacious against HBV. The largest study to date consists of 107 coinfected individuals, of whom 90 had detectable HBV DNA while receiving lamivudine . After a median of 10 months of tenofovir, 30 (33%) of them had undetectable HBV DNA (< 200 copies/mL), suggesting that it may be more potent than 10 mg of adefovir dipivoxil
19. Several other agents are in development for CHB treatment and appear promising. Entecavir... is active against lamivudine-resistant HBV and produces equivalent HBV-DNA decline of approximately 4.7 log copies HBV DNA over all ALT levels... Phase III studies are underway. Telbivudine is very potent... clevudine, demonstrated a minimum median log10 decline of 2.5 copies/mL and a 30% HBeAg seroconversion rate in a 28-day trial
Coinfection with HIV and hepatitis B virus (HBV) is common due to shared modes of transmission. The extended life expectancy of HIV-infected persons from effective antiretroviral therapy has led to the emergence of chronic hepatitis B (CHB) as an important problem. HIV adversely affects CHB, leading to accelerated progression of liver disease, as evidenced by an increased incidence of cirrhosis and liver-related mortality in coinfected persons. Furthermore, CHB increases the risk of hepatotoxicity from antiretroviral therapy, potentially jeopardizing the efficacy of HIV treatment. For these reasons, HIV-infected persons must be evaluated for coinfection with HBV and, if present, must be considered for CHB treatment. Management of CHB in HIV-infected persons is particularly complex due to lack of controlled trials, inability for current therapeutics to eradicate HBV, overlap in therapeutic agents for both viruses, and potential for development of drug-resistant HBV and HIV. Thus, treatment of HIV-HBV-coinfected patients requires simultaneous consideration of both viral infections. Further research is needed to determine the optimum management of CHB in HIV-infected persons.
Because HIV and hepatitis B virus (HBV) share routes of acquisition, up to 90% of all HIV-infected patients have a serum marker indicative of a prior or present HBV infection . In the United States, up to 10% of HIV-infected individuals are coinfected with HBV [2, 3], and the burden is likely to be greater in areas of the world with high HBV endemicity. Furthermore, a recent study demonstrates that in HIV-infected persons, the incidence of acute hepatitis B is 12.2 per 1000 person-years, which is considerably higher than the general population incidence of 0.03 per 1000 person-years . Thus, chronic hepatitis B (CHB) in the HIV-infected person is a growing clinical problem, which is highlighted by its inclusion in the forthcoming Department of Health and Human Services Guidelines for Therapy of HIV-associated Opportunistic Infections. Management of such coinfected patients is complex because HBV can exacerbate antiretroviral hepatotoxicity, some antiretrovirals are active against and can lead to drug-resistant mutants in both viruses, and HBV is difficult to eliminate. This article emphasizes the natural history and management of CHB in the HIV-infected person.
NATURAL HISTORY & SIGNIFICANCE of HIV-HBV COINFECTION
Natural history of HBV in HIV-uninfected persons
Hepatitis B is transmitted more efficiently than HIV through sexual, vertical, and percutaneous routes [5, 6]. In an HIV-uninfected adult, 90% to 95% of acute HBV infections result in viral recovery, which is detected by the presence of hepatitis B core antibody (anti-HBc) and hepatitis B surface antibody (anti-HBs) . Of the 5% to 10% of individuals who maintain the hepatitis B surface antigen (HBsAg) (chronic hepatitis B), some eliminate the hepatitis B e antigen (HBeAg), develop antibodies against HBeAg (anti-HBe), and have undetectable levels of HBV DNA (inactive carrier). Those who maintain the HBeAg or develop precore mutant virus (HBeAg negative and detectable HBV DNA) are at risk for developing cirrhosis and hepatocellular carcinoma (HCC) .
The effect of HIV on hepatitis B
HIV infection negatively impacts HBV infection by decreasing the rate of HBsAg clearance in acute infection and enhancing the progression of liver disease in those with CHB. Bodsworth et al.  found that after an acute HBV infection, 23% of HIV-infected persons had circulating HBsAg compared with 4% of HIV-uninfected individuals. In that study, the rate of HBsAg clearance correlated with the CD4+ cell count at the time of HBV infection. In another study, Gilson et al.  demonstrated an approximate 2.5-fold decrease in HBeAg clearance over time in the presence of HIV. HIV infection has also been associated with higher HBV-DNA levels and increased risk for cirrhosis (relative risk 4.2) from CHB, despite decreased necroinflammation in the liver biopsies .
Furthermore, mortality from hepatitis B-related liver disease is increased in HIV-infected persons. Thio et al. [12*] examined mortality from liver disease in 5293 men, of whom 326 had detectable HBsAg. Those subjects who had HIV and CHB had a mortality rate attributable to liver disease of 14.2 per 1000 person-years, compared with rates of 0.8 and 1.7 per 1000 person-years in men with either HBV or HIV alone, respectively. This study also demonstrated a trend toward more severe liver disease in those with lower CD4 cell counts.
Contrary to what may be expected, acute HIV infection is not consistently associated with an increase in HBV-DNA levels in the immediate HIV seroconversion period . The reason for this is unclear but may be due to release of cytokines, leading to noncytolytic elimination of infected hepatocytes during acute HIV infection. However, given cross-sectional studies demonstrating higher HBV-DNA levels in the setting of HIV coinfection , further research is needed to understand the interaction of these two viruses.
HIV also appears to be a risk factor for reactivation of hepatitis B in persons who have developed anti-HBs [14, 15, 16], which may be a consequence of accelerated loss of anti-HBs after HIV infection . It is not known how frequently HIV-infected persons who have developed an effective immune response against HBV lose this immunity and reactivate their HBV infection as they become immunosuppressed. Reactivation is not surprising because HBV DNA can be detected by sensitive polymerase chain reaction methods in immunocompetent hosts who have developed anti-HBs , which suggests the presence of latent reservoirs. The covalently closed circular form of the HBV DNA (cccDNA) in the hepatocytes can serve as a reservoir for HBV, but it is not known whether other latent reservoirs exist. Given that up to 60% to 70% of HIV-infected individuals have anti-HBs, it will be important to determine if reactivation still occurs in persons receiving effective antiretroviral therapy.
HIV infection is also associated with occult hepatitis B, which is the presence of HBV DNA without HBsAg. The most common serologic pattern for occult hepatitis B is a positive serologic test only for anti-HBc. In the Swiss Cohort Study, of 195 persons with anti-HBc only followed for a median of 31 months, 90% had at least one sample with detectable HBV DNA and 30% had persistently detectable HBV DNA . Prospective studies are needed to determine the clinical significance of occult hepatitis B in the setting of HIV infection.
The effect of HBV on HIV
Although HIV clearly accelerates the progression of an HBV infection, the influence of HBV on HIV disease progression remains controversial. There is a theoretic possibility that HBV could accelerate the progression of HIV infection because the HBV X protein is capable of upregulating HIV replication in vitro . Most studies find no differences in HIV progression between those with and without CHB [10, 21, 22]; however, these studies are limited by the heterogeneity of the HIV disease at study entry. Solomon et al.  attempted to adjust for this variability by CD4+ count stratification, and they were still unable to detect an association. Other studies suggest that CHB may negatively impact HIV progression. Greenspan et al.  compared rates of progression to AIDS in patients presenting with oral hairy leukoplakia . HBV infection was associated with a four times increased risk for rapid progression to AIDS (< 1000 days). Ockenga et al.  found that of patients with AIDS, those coinfected with HIV and HBV had decreased survival compared to patients without HBV infection, but their analysis did not control for baseline differences between the groups, such as drug use or duration of AIDS prior to the study inception.
Although it is controversial as to whether CHB impacts HIV disease progression, it clearly impacts management of HIV because it increases the risk of toxicity from antiretroviral medications by approximately threefold [25, 26, 27*]. However, only a small minority experience a severe, reversible hepatotoxicity within the first 6 months of starting a regimen (alanine aminotransferase [ALT] > five times the upper limits of normal [ULN]). Coinfected patients are also at increased risk for the rare condition of hepatic steatosis and lactic acidosis from the nucleoside analogues, which can occur after years of therapy. The long-term hepatotoxicity risk from antiretroviral medications in coinfected patients has not been studied. Thus, the available data suggest that antiretroviral therapy can be given safely to HIV-HBV-coinfected persons, but serum liver enzymes must be monitored closely.
MANAGEMENT OF CHRONIC HEPATITIS B
Diagnosis and evaluation
Chronic hepatitis B is diagnosed by the presence of HBsAg for a minimum of 6 months. Those with CHB should be tested for HBeAg, anti-HBe, and HBV DNA to determine if they have active or inactive disease; however, none of these predict the rate of liver disease progression. Those with active disease (HBeAg or detectable HBV DNA) should be evaluated for the presence of chronic liver disease with a history and physical examination for signs and symptoms of liver disease, ALT, albumin, prothrombin time, direct bilirubin, and platelet count. The best indicator of the grade and stage of liver disease is the liver biopsy, especially for HIV-infected persons whose ALT levels may not accurately reflect the state of liver disease [10, 11].
Individuals with CHB should also be counseled regarding ways to prevent liver damage and HBV transmission. Those not immune to hepatitis A virus should receive the hepatitis A vaccine. They should be counseled to avoid alcohol and to minimize risks for acquiring hepatitis C infection. They should also be screened for HCC. Those most at risk for developing HCC have a positive family history, are HBeAg positive, are greater than 45 years old, or have cirrhosis. In Taiwan, individuals with both HBsAg and HBeAg had a 60-fold increased risk for HCC compared with those negative for both markers . The optimal screening methods for HCC have not been determined, but the American Association for the Study of Liver Diseases Practice Guidelines recommends a-fetoprotein and ultrasound every 6 months in HIV-uninfected patients [28**]. Whether HIV alters the risk for HCC is not known, so at present, data do not support more frequent HCC screening in the setting of HIV infection. To prevent transmission of HBV, susceptible partners of HBV-infected persons should be vaccinated against HBV.
Because anti-HBV therapy does not eradicate viral reservoirs (ie, cccDNA), complete elimination of HBV is not possible with current therapy. Thus, the goal in CHB treatment is suppression of viral replication, which stops or decreases the progression of liver disease and risk for HCC. Although sustained loss of HBsAg is considered by some to be a "complete response" [28**], other markers of treatment response include the loss of HBeAg with the development of anti-HBe ("HBeAg seroconversion") , normalization of hepatic transaminases, and substantial diminution in HBV DNA. Although a decline in HBV DNA correlates with response, no threshold HBV-DNA goal has been established; however, lowering it below 105 copies/mL (100,000 c/ml) slows the progression of liver disease . As demonstrated in persons waiting for liver transplant, even a partial response can improve liver histology.
Treatment of CHB
Although published guidelines for the treatment of CHB in HIV-infected individuals do not exist, at the minimum those who have either circulating HBeAg or HBV DNA _ 104 copies/mL, along with evidence of necroinflammation in the liver, should be considered for treatment of CHB [28**, 31**]. Necroinflammation can be determined either by consistently elevated ALT or by a liver biopsy. The HBV-DNA level at which to treat is controversial because fluctuations are common and lower levels can be associated with liver disease progression [31**]. Thus, for individuals with HBV DNA consistently between 200 copies/mL and 104 copies/mL, consideration should be given for a liver biopsy to evaluate the need for treatment.
Individuals who have HBsAg and are classified as inactive carriers do not need treatment and can be observed with ALT and aspartate transaminase every 6 months to look for a change in the activity of disease. Those who develop persistently elevated liver enzymes should have a liver biopsy.
The ideal regimen for the treatment of CHB in HIV-infected persons has not been determined by a clinical trial. The three US Food and Drug Administration-approved drugs for the treatment of CHB include interferon alpha, lamivudine, and adefovir dipivoxil. Three other drugs, which are active against HBV and are approved for other indications, include pegylated interferon alpha, tenofovir disoproxil fumarate (DF), and emtricitabine. The choice of which of these to use needs to be individualized based upon the stage of both HIV and HBV infections. Data in HIV-infected persons suggest advantages and disadvantages to each of these drugs, and the future of treatment is likely combination therapy as is done for HIV therapy; however, the best combination(s) have not been determined.
Studies of interferon alpha therapy in HIV-HBV-coinfected individuals are limited, but collectively suggest a decreased response compared to those without HIV infection. In a meta-analysis of interferon alpha trials, the 55 HIV-infected persons showed a 38% decreased response compared with the 780 HIV-uninfected persons (P = 0.02) . Seven small studies (two randomized) involving 98 HIV-HBV-coinfected patients demonstrate a 14.3% HBeAg seroconversion rate to interferon alpha treatment [33, 34, 35, 36, 37, 38, 39], which is lower than the 33% seen in HIV-uninfected persons. None of these studies have been performed in the highly active antiretroviral therapy era; thus, interferon alpha has not been fairly evaluated in HIV-infected individuals with a reconstituted immune system.
The recommended duration of interferon alpha treatment for HBeAg-positive disease in HIV-uninfected persons is 4 to 6 months, but it has not been evaluated in those with HIV infection [28**]. Persons with HBeAg-negative CHB have a high rate of relapse, but a recent study demonstrated that 24 months of therapy resulted in a 30% response rate (normal ALT and undetectable HBV DNA by polymerase chain reaction), which was durable for 1 year . Thus, a longer duration of therapy is beneficial for HBeAg-negative CHB, but similar results may be obtained with greater than 12, but less than 24, months of therapy.
It is not known if the characteristics for a favorable response to interferon alpha in HIV-uninfected persons, including high ALT (> two times ULN), lower HBV DNA (< 2.8 times 107 copies/mL or 100 pg/mL), and circulating HBeAg [41, 42], apply to HIV-infected persons; however, it is reasonable to try interferon alpha in HIV-infected persons with these characteristics. Interferon alpha is attractive in HBeAg-positive patients due to its short treatment duration and the 90% durability of response , but its major limitation is side effects, including flu-like symptoms, alopecia, thyroid abnormalities, psychiatric effects, and bone marrow toxicity. Interferon alpha is also contraindicated in decompensated liver disease due to an increased risk of death from liver failure or sepsis .
Standard interferon alpha has been pegylated, which permits once-weekly dosing and produces more constant interferon alpha levels. There are currently two forms of pegylated interferon alpha approved for the treatment of chronic hepatitis C, peginterferon-alfa 2b (Peg-Intron, Schering-Plough Corp., Kenilworth, NJ) and peginterferon-alfa 2a (Pegasys, Roche Laboratories, Basil, Switzerland). Although data for pegylated interferon alpha in HIV-infected persons with CHB do not exist, it may be more efficacious than standard interferon alpha for the treatment of CHB in HIV-uninfected individuals . In this study, response rates in HBeAg-positive CHB were 12% and 24% with standard and pegylated interferon, respectively. Unlike standard interferon alpha, pegylated interferon alpha performed equally well in those with lower ALT (< five times ULN) levels, which often occurs in HIV-infected persons. Furthermore, it also appears to be effective in HBeAg-negative disease . Given its superior performance, pegylated interferon alpha will likely become the preferred form of interferon alpha for CHB treatment regardless of HIV status.
Lamivudine, a nucleoside analogue, inhibits HBV replication by competing with the natural nucleoside triphosphates for incorporation into viral DNA. In the HIV-HBV-coinfected patient, lamivudine should be used in conjunction with a complete antiretroviral regimen at the dose effective against HIV replication, 150 mg twice daily or 300 mg/d. For HBeAg-positive persons, treatment is for 6 months after HBeAg seroconversion or 1 year, whichever comes later [28**]. For HBeAg-negative persons treatment is longer, but the optimal duration of therapy has not been determined.
The assessment of the efficacy of lamivudine in HIV-HBV-coinfected patients has only been studied retrospectively in cohorts who received lamivudine for HIV treatment. Those studies show rates of HBeAg seroconversion of 22% to 28% [47, 48], which appear comparable to the HIV-uninfected patient.
Although more than a year of lamivudine therapy increases the HBeAg seroconversion rate and may improve outcome in HBeAg-negative patients, long-term lamivudine also increases the risk of developing mutations in the catalytic domain (YMDD motif, M204V/I) of the HBV polymerase gene . In HIV-uninfected persons, the prevalence of lamivudine-resistant HBV mutations increased from 14% at year 1 to 38%, 49%, and 66% at years 2, 3, and 4, respectively [28**]. In HIV-HBV-coinfected individuals, this resistance develops more rapidly and has been documented at a rate of approximately 25% per year . It is not known, but it seems plausible that combination therapy may reduce this rate of development of resistance. Coinfected individuals on long-term lamivudine develop unique mutations, one of which has the potential to act as a vaccine escape mutant [51*]. Development of such mutants is important because transmission of lamivudine-resistant HBV has been documented .
The appearance of the lamivudine-resistant virus, which is often heralded by a rise in ALT or rebound in HBV DNA, provides a dilemma in the best strategy for management. Discontinuation of lamivudine should not be the reflex response because it may be important for anti-HIV therapy. Furthermore, discontinuation of lamivudine in those with detectable HBV DNA may lead to a severe, even fatal, rebound hepatitis . Conversely, continuation of lamivudine may lead to compensatory mutations, which either increases replicative capacity or drug resistance [54, 55], and may not provide continued histologic benefit . Furthermore, a report of secondary mutations leading to a virus whose replication is enhanced by lamivudine has been documented in a transplant recipient . If lamivudine is discontinued, careful monitoring of ALT and HBV DNA is mandatory and reinstitution of lamivudine (or perhaps adefovir dipivoxil) could be lifesaving in those with the rebound hepatitis.
Emtricitabine, a fluorinated derivative of lamivudine, is active against hepatitis B in the coinfected patient with 59% of the 24 individuals having HBV DNA less than 4700 copies/mL at 48 weeks . Emtricitabine resistance develops with the same mutation (M204V/I), thus it is not active against lamivudine-resistant hepatitis B.
Adefovir dipivoxil, 10 mg/d, is a nucleotide analogue active against both wild-type and lamivudine-resistant HBV for both HBeAg-negative and -positive disease [59, 60]. Adefovir dipivoxil in HIV-HBV-coinfected persons has only been studied in a cohort of 32 patients, and they appear to respond similarly to HIV-negative patients. After 48 weeks, the decline in HBV DNA was 4 log copies/mL, but only 6% and 19% had HBV DNA less than 1000 copies/mL and ALT normalization, respectively . Continuing adefovir dipivoxil to 144 weeks improved the response with an HBV-DNA decline of 5.5 log10 copies/mL, with 46% achieving levels less than 1000 copies/mL and 64% normalizing ALT . Only two individuals developed anti-HBe and no adefovir-resistant HIV or HBV mutations developed.
Resistance to adefovir dipivoxil in HIV-negative persons occurs but develops slowly. In a study of 989 subjects who received 144 weeks of adefovir dipivoxil, mutations occur at positions N236T and A181V, with a cumulative probability of 3.9% . These mutations were only found in individuals on adefovir dipivoxil monotherapy and not in those also receiving lamivudine.
Tenofovir DF, a nucleotide analogue similar to adefovir dipivoxil, is approved for the treatment of HIV but is also efficacious against HBV [64, 65, 66, 67, 68]. The largest study to date consists of 107 coinfected individuals, of whom 90 had detectable HBV DNA while receiving lamivudine . After a median of 10 months of tenofovir, 30 (33%) of them had undetectable HBV DNA (< 200 copies/mL), suggesting that it may be more potent than 10 mg of adefovir dipivoxil. Further work is needed to understand the efficacy of tenofovir DF and to characterize tenofovir-resistant mutations.
Following lessons learned from HIV, combination therapy for treatment of CHB may lead to increased potency and decreased rates of development of resistance. The combination of interferon alpha and lamivudine has been studied in two randomized trials and does not clearly demonstrate an advantage, but the optimal combination regimen of these two drugs may not have been studied [70, 71]. However, it is logical to study other combinations, including pegylated interferon alpha with lamivudine or emtricitabine, tenofovir DF, or adefovir dipivoxil, and also to study the combination of lamivudine or emtricitabine with tenofovir. Combination therapy for CHB is likely to emerge as the preferred treatment for CHB, and studies in this area are urgently needed.
When considering treatment of CHB in HIV-HBV-coinfected persons, treatment needs to be individualized with consideration given to the state of both viral infections. Although the optimal therapeutic regimen is not known for the treatment of CHB in this population, some general recommendations based on available data are presented (Table 1). It is important to first determine which virus(es) need treatment. For those in whom only HBV needs treatment, adefovir dipivoxil or pegylated interferon alpha is the preferred options because neither one produces HIV resistance. Adefovir dipivoxil could theoretically lead to HIV resistance; however, this has not been demonstrated thus far . Currently, there is no clear advantage of one of these over the other. For those in whom only HIV needs treatment, one could consider sparing lamivudine/emtricitabine and tenofovir until they are also needed for CHB treatment. Alternatively, if either of these is needed for an optimal HIV regimen, one should try to include both of them to minimize the emergence of drug-resistant HBV. If both viruses need treatment and the patient is naive to lamivudine, then emtricitabine and tenofovir in combination are recommended to try and maximize potency and minimize resistance. If the patient is lamivudine experienced, then tenofovir or adefovir dipivoxil is preferred depending on whether one wants to spare tenofovir for future HIV therapy. Pegylated interferon alpha may be an option, but it has not been studied in lamivudine-resistant virus.
NEW DRUGS IN DEVELOPMENT
Several other agents are in development for CHB treatment and appear promising. Entecavir, a guanine analogue, inhibits priming of HBV polymerase, reverse transcription of HBV DNA, and positive-strand synthesis. It is not active against HIV and in vitro it does not appear to interact with nucleoside analogues specific for HIV infection . It is active against lamivudine-resistant HBV and produces equivalent HBV-DNA decline of approximately 4.7 log copies HBV DNA over all ALT levels . However, in these phase II studies only 14% lost HBeAg. Phase III studies are underway at a dose of 0.5 mg in naive patients and 1.0 mg in lamivudine-refractory patients. Telbivudine is an L-nucleoside analogue that is very potent and appears to show greater efficacy in reducing HBV-DNA levels than lamivudine . A third drug, clevudine, demonstrated a minimum median log10 decline of 2.5 copies/mL and a 30% HBeAg seroconversion rate in a 28-day trial .
Coinfection with HIV and HBV is common and HIV increases the severity of liver disease from CHB. Such coinfected individuals also have an increased risk for hepatotoxicity from antiretroviral therapy. Thus, it is important to screen for CHB in all HIV-infected patients and to vaccinate susceptible persons against HBV infection. Those individuals with HIV-HBV coinfection should have both of the infections completely assessed in order to decide on the best therapeutic option for both viruses. Treatment for CHB should be considered in persons with circulating HBeAg or HBV-DNA levels _ 104 copies/mL and evidence of necroinflammation based on either ALT values or on liver biopsy. However, persons with lower levels of HBV DNA should also be evaluated because the cut-off for treatment in coinfected persons has not been determined.
There are many available therapeutic options for CHB in the HIV-HBV-coinfected patient, but HIV complicates these options necessitating individualization of the treatment plan. As more medications to treat CHB become available, combination therapy will likely be the preferred treatment. Clinical trials are needed to determine which combinations are most efficacious in both HIV-infected and -uninfected persons.
REFERENCES & RECOMMENDED READING
Recently published papers of particular interest have been highlighted as:
* Of importance
** Of major importance
1.Levine OS, et al.: Seroepidemiology of hepatitis B virus in a population of injecting drug user. Association with drug injection patterns. Am J Epidemiol 1995, 142:331-341.
2.Homann C, et al.: High incidence of hepatitis B infection and evolution of chronic hepatitis B infection in patients with advanced HIV infection. J Acquir Immune Defic Syndr 1991, 4:416-420.
3.Rustgi VK, et al.: Hepatitis B virus infection in the acquired immunodeficiency syndrome. Ann Intern Med 1984, 101:795-797.
4.Kellerman SE: Prevalence of chronic hepatitis B and incidence of acute hepatitis B infection in human immunodeficiency virus-infected subjects. J Infect Dis 2003, 188:571-577.
5.Levine OS, et al.: Differences in the incidence of hepatitis B and human immunodeficiency virus infections among injecting drug users. J Infect Dis 1996, 173:579-583.
6.Kingsley LA, et al.: Sexual transmission efficiency of hepatitis B virus and human immunodeficiency virus among homosexual men. JAMA 1990, 264:230-234.
7.Mahoney FJ: Update on diagnosis, management, and prevention of hepatitis B virus infection. Clin Microbiol Rev 1999, 12:351-366.
8.Yang HI, et al.: Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 2002, 347:168-174.
9.Bodsworth NJ: The influence of human immunodeficiency virus type 1 infection on the development of the hepatitis B carrier state. J Infect Dis 1991, 163:1138-1140.
10.Gilson RJC, et al.: Interactions between HIV and hepatitis B virus in homosexual men: effects on the natural history of infection. AIDS 1997, 11:597-606.
11.Colin JF, et al.: Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. Hepatology 1999, 29:1306-1310.
12.* Thio CL, et al.: HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter AIDS Cohort Study (MACS). Lancet 2002, 360:1921-1926.
This analysis demonstrates an increased risk for death from liver disease in men coinfected with both HIV and HBV, providing evidence that HIV accelerates progression of CHB.
13.Thio CL, et al.: Changes in hepatitis B virus DNA levels with acute HIV infection. Clin Infect Dis 2004, 38:1024-1029.
14.Vento S, et al.: Reactivation of hepatitis B in AIDS. Lancet 1989, 2:108-109.
15.Lazizi Y, et al.: Reappearance of hepatitis B virus in immune patients infected with the human immunodeficiency virus type 1. J Infect Dis 1988, 158:666-667.
16.Waite J, et al.: Hepatitis B virus reactivation or reinfection associated with HIV-1 infection. AIDS 1988, 2:443-448.
17.Biggar RJ: Accelerated loss of antibody to hepatitis B surface antigen among immunodeficient homosexual men infected with HIV. N Engl J Med 1987, 316:630-631.
18.Rehermann B: The hepatitis B virus persists for decades after patients" recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat Med 1996, 2:1104-1108.
19.Hofer M, et al.: Frequent chronic hepatitis B virus infection in HIV-infected patients positive for antibody to hepatitis B core antigen only. Swiss HIV Cohort Study. Eur J Clin Microbiol Infect Dis 1998, 17:6-13.
20.Gomez-Gonzalo M, et al.: The hepatitis B virus X protein induces HIV-1 replication and transcription in synergy with T-cell activation signals: functional roles of NF-kappaB/NF-AT and SP1-binding sites in the HIV-1 long terminal repeat promoter. J Biol Chem 2001, 276:35435-35443.
21.Scharschmidt BF, et al.: Hepatitis B in patients with HIV infection: relationship to AIDS and patient survival. Ann Intern Med 1992, 117:837-838.
22.Solomon RE, et al.: Association of hepatitis B surface antigen and core antibody with acquisition and manifestations of human immunodeficiency virus type 1 (HIV-1) infection. Am J Public Health 1990, 80:1475-1478.
23.Greenspan D, et al.: Risk factors for rapid progression from hairy leukoplakia to AIDS: a nested case-control study. J Acquir Immune Defic Syndr 1991, 4:652-658.
24.Ockenga J, et al.: Hepatitis B and C in HIV-infected patients. Prevalence and prognostic value. J Hepatol 1997, 27:18-24.
25.Saves M, et al.: Severe hepatic cytolysis: incidence and risk factors in patients treated by antiretroviral combinations. Aquitaine Cohort, France, 1996- 1998. Groupe dEpidemiologie Clinique de Sida en Aquitaine (GECSA). AIDS 1999, 13:F115-F121.
26.Sulkowski MS: Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA 2000, 283:74-80.
27.* Law WP, et al.: Risk of severe hepatotoxicity associated with antiretroviral therapy in the HIV-NAT Cohort, Thailand, 1996-2001. AIDS 2003, 17:2191-2199.
This analysis of antiretroviral toxicity in a Thai cohort with a relatively high prevalence of CHB provides further evidence that hepatitis B coinfection increases the risk of medication-related liver injury.
28.** Lok AS: Chronic hepatitis B. Hepatology 2001, 34:1225-1241.
The American Association for the Study of Liver Diseases Practice Guidelines for treating hepatitis B in the HIV-uninfected patient. Portions of these guidelines have been updated (Hepatology 2004, 39:857).
29.Fattovich G, et al.: Long-term outcome of hepatitis B e antigen-positive patients with compensated cirrhosis treated with interferon alfa. Hepatology 1997, 26:1338-1342.
30.Chu CJ: Quantitative serum HBV DNA levels during different stages of chronic hepatitis B infection. Hepatology 2002, 36:1408-1415.
31.** Keeffe EB, et al.: A treatment algorithm for the management of chronic hepatitis B virus infection in the United States. Clin Gastroenterol Hepatol 2004, 2:87-106.
These recommendations from an international panel differ slightly from those of the American Association for the Study of Liver Diseases and they do discuss HIV coinfection.
32.Wong DK, et al.: Effect of alfa-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. Ann Intern Med 1993, 119:312-323.
33.Wong DK, et al.: Interferon alfa treatment of chronic hepatitis B: randomized trial in a predominantly homosexual male population. Gastroenterology 1995, 108:165-171.
34.McDonald JA, et al.: Diminished responsiveness of male homosexual chronic hepatitis B virus carriers with HTLV-III antibodies to recombinant alpha-interferon. Hepatology 1987, 7:719-723.
35.Dimartino V, et al.: Serum alanine transaminase level is a good predictor of response to interferon alfa therapy for chronic hepatitis B in human immunodeficiency virus-infected patients. Hepatology 2000, 31:1030-1031.
36.Di Martino V, et al.: Long-term effects of interferon-alpha in five HIV-positive patients with chronic hepatitis B. J Viral Hepat 1996, 3:253-260.
37.Marcellin P, et al.: Recombinant alpha interferon for chronic hepatitis B in anti-HIV positive patients receiving zidovudine. Gut 1993, 34(2 suppl):S106.
38.Zylberberg H, et al.: Alpha-interferon for chronic active hepatitis B in human immunodeficiency virus-infected patients. Gastroenterol Clin Biol 1996, 20:968-971.
39.Visco G, et al.: Zidovudine plus interferon alfa-2b treatment in patients with HIV and chronic active viral hepatitis. Gut 1993, 34:S107-S108.
40.Lampertico P, et al.: Long-term suppression of hepatitis B e antigen-negative chronic hepatitis B by 24-month interferon therapy. Hepatology 2003, 37:756-763.
41.Brook MG: Which patients with chronic hepatitis B virus infection will respond to alpha-interferon therapy? A statistical analysis of predictive factors. Hepatology 1989, 10:761-763.
42.Perrillo RP, et al.: A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. N Engl J Med 1990, 323:295-301.
43.Krogsgaard K: The long-term effect of treatment with interferon-alpha 2a in chronic hepatitis B. The Long-Term Follow-up Investigator Group. The European Study Group on Viral Hepatitis (EUROHEP). Executive Team on Anti-Viral Treatment. J Viral Hepat 1998, 5:389-397.
44.Perrillo R, et al.: Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus. Gastroenterology 1995, 109:908-916.
45.Cooksley WG, et al.: Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat 2003, 10:298-305.
46.Marcellin P, et al.: Peg-interferon alfa-2a (40KDa) (Pegasys) monotherapy is more effective than lamivudine monotherapy in the treatment of HBeAg negative chronic hepatitis B: 72 week results from a phase III, partially double-blind study of Pegasys alone vs. Pegasys plus lamivduine vs. lamivudine [abstract 95]. Paper presented at the 39th Annual Meeting of the European Association for the Study of Liver Disease. Berlin, Germany; April 14-18, 2004.
47.Benhamou Y, et al.: Effects of lamivudine on replication of hepatitis B virus in HIV-infected men. Ann Intern Med 1996, 125:705-712.
48.Dore GJ, et al.: Dual efficacy of lamivudine treatment in human immunodeficiency virus/hepatitis B virus-coinfected persons in a randomized, controlled study (CAESAR). The CAESAR Coordinating Committee. J Infect Dis 1999, 180:607-613.
49.Stuyver LJ, et al.: Nomenclature for antiviral-resistant human hepatitis B virus mutations in the polymerase region. Hepatology 2001, 33:751-757.
50.Benhamou Y, et al.: Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients. Hepatology 1999, 30:1302-1306.
51.* Cooley L, et al.: Prevalence and characterization of lamivudine-resistant hepatitis B virus mutations in HIV-HBV co-infected individuals. AIDS 2003, 17:1649-1657.
This study characterizes mutations in an HIV-HBV-coinfected cohort and highlights the fact that important unique mutations may develop in this population.
52.Thibault V: Primary infection with a lamivudine-resistant hepatitis B virus. AIDS 2002, 16:131-133.
53.Lim SG, et al.: Fatal hepatitis B reactivation following discontinuation of nucleoside analogues for chronic hepatitis B. Gut 2002, 51:597-599.
54.Torresi J, et al.: Restoration of replication phenotype of lamivudine-resistant hepatitis B virus mutants by compensatory changes in the "fingers" subdomain of the viral polymerase selected as a consequence of mutations in the overlapping S gene. Virology 2002, 299:88-99.
55.Allen MI, et al.: Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Hepatology 1998, 27:1670-1677.
56.Dienstag JL, et al.: Histological outcome during long-term lamivudine therapy. Gastroenterology 2003, 124:105-117.
57.Bock CT, et al.: Selection of hepatitis B virus polymerase mutants with enhanced replication by lamivudine treatment after liver transplantation. Gastroenterology 2002, 122:264-273.
58.Harris J, et al.: Emtricitabine therapy for hepatitis infection in HIV-1 patients co-infected with hepatitis B: antiviral response and genotypic findings in antiretroviral treatment naive patients [abstract 836]. Paper presented at the 39th Annual Meeting of the European Association for the Study of Liver Disease. Berlin, Germany; April 14-18, 2004.
59.Marcellin P, et al.: Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003, 348:808-816.
60.Hadziyannis SJ, et al.: Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003, 348:800-807.
61.Benhamou Y, et al.: Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study. Lancet 2001, 358:718-723.
62.Benhamou Y, et al.: Three-year treatment with adefovir dipivoxil in chronic hepatitis B patients with lamivudine-resistant HBV and HIV co-infection results in significant and sustained clinical improvement [abstract 835]. Paper presented at the 39th Annual Meeting of the European Association for the Study of Liver Disease. Berlin, Germany; April 14-18, 2004.
63.Qi X, et al.: Long-term incidence of adefovir dipivoxil resistance in chronic hepatitis B patients after 144 weeks of therapy [abstract 57]. Paper presented at the 39th Annual Meeting of the European Association for the Study of Liver Disease. Berlin, Germany; April 14-18, 2004.
64.Benhamou Y: Tenofovir disoproxil fumarate in patients with HIV and lamivudine-resistant hepatitis B virus. N Engl J Med 2003, 348:177-178.
65.Nelson M, et al.: An open-label study of tenofovir in HIV-1 and hepatitis B virus co-infected individuals. AIDS 2003, 17:F7-F10.
66.Nunez M, et al.: Activity of tenofovir on hepatitis B virus replication in HIV-co-infected patients failing or partially responding to lamivudine. AIDS 2002, 16:2352-2354.
67.Ristig MB, et al.: Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-alpha and lamivudine therapy have failed. J Infect Dis 2002, 186:1844-1847.
68.Dore GJ, et al.: Efficacy of tenofovir disoproxil fumarate in antiretroviral therapy-naive and -experienced patients coinfected with HIV-1 and hepatitis B virus. J Infect Dis 2004, 189:1185-1192.
69.Trimoulet P, et al.: Anti-hepatitis B virus activity of tenofovir disoproxil fumarate in human immunodeficiency virus co-infected subjects [abstract 2467]. Paper presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL; September 14-17, 2003.
70.Schalm SW, et al.: Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial. Gut 2000, 46:562-568.
71.Barbaro G, et al.: Long-term efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. An Italian multicenter, randomized trial. J Hepatol 2001, 35:406-411.
72.Delaugerre C, et al.: Human immunodeficiency virus (HIV) type 1 reverse transcriptase resistance mutations in hepatitis B virus (HBV)-HIV-coinfected patients treated for HBV chronic infection once daily with 10 milligrams of adefovir dipivoxil combined with lamivudine. Antimicrob Agents Chemother 2002, 46:1586-1588.
73.Colonno RJ, et al.: Combination studies involving entecavir and nucleoside reverse transcriptase inhibitors showed no antagonistic effects on HBV or HIV activity in vitro [abstract 366]. Paper presented at the 39th Annual Meeting of the European Association for the Study of Liver Disease. Berlin, Germany; April 14-18, 2004.
74.Lai CL, et al.: Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection. Gastroenterology 2002, 123:1831-1838.
75.Lai CL, et al.: International multicenter trial of LdT (Telbividine) alone and in combination with lamivudine for chronic hepatitis B: an interim analysis. Hepatology 2002, 46(Pt 2):301A.
76.Marcellin P, et al.: A dose escalating trial evaluating the safety and antiviral activity of clevudine in patients with chronic HBV infection [abstract 337]. Paper presented at the Digestive Disease Week Meeting. Orlando, FL; May 18-21, 2003.