HIV coinfection with hepatitis b

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 * Ujjwal Rastogi, MBBS [mailto:urastogi@perfuse.org]

Overview
Coinfection with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) is common due to shared routes of transmission. The impact of coinfection is especially important in regions with widespread use of ART. As the use of ART becomes more prevalent in parts of the world with high HBV endemicity and long term survival increases, it is likely that liver disease from chronic hepatitis B in HIV-infected population may emerge as a greater public health problem than before.

Epidemiology
In areas of low endemicity, such as North America, Australia and Europe, HBV and HIV infection are usually acquired in adulthood through sexual or percutaneous transmission. In areas of low endemicity, the prevalence of chronic coinfection is around 5-7% among HIV-infected individuals. In countries with intermediate and high HBV endemicity, the main routes of transmission of HBV are perinatal or in early childhood; in these countries HBV coinfection rates are 10-20%.

Natural History
The rate of progression and complications from viral hepatitis are accelerated in patients with HIV coinfection. After acquiring HBV infection, HIV infected individuals are 6 times more likely to develop chronic hepatitis B than HIV negative individuals. This was more likely to occur in HIV infected men with lower CD4 cells. Decreased rates of clearance of HBeAg and increased HBV replication are also seen, with higher HBV DNA viral load. In addition, HIV infected individuals are more likely to lose previously developed protective anti-HBs antibody and develop acute hepatitis B infection; This risk is also associated with lower CD4 counts.

HIV also hastens the progression of HBV related liver disease. Cirrhosis is more common despite lower ALT levels than in HBV mono-infection and is also more common with lower CD4 counts.

Complications
Following initiation of antiretroviral therapy (ART), immune reconstitution inflammatory syndrome (IRIS) may occur which can lead to worsening liver disease including hepatic decompensation. In addition, after discontinuation of an ART regimen containing anti-HBV agents, reactivation of hepatitis B can occur. ALT elevations occurred in 29% of 147 patients within 6 months of withdrawal. If reactivation occurs, resuming an agent that is active against HBV is required.

HIV-HBV coinfected men are greater than 17 times more likely to die of liver related causes compared to those mono-infected with HBV. For individuals on ART, coinfection with chronic hepatitis B increases the risk of hepatotoxicity from ART three-fold to five-fold.

It is unclear at present if the risk of hepatocellular carcinoma (HCC) is increased, but there is some evidence that HIV infected individuals with lower CD4 counts are at greater risk of developing HCC.

Diagnosis
Accurate assessment of HBV infection in HIV coinfected individuals is necessary in order to base therapeutic decisions.

WHO advocates HBsAg testing especially in areas of high HBV prevalence; but additional testing for HBV markers such as HBeAg and HBV DNA and to assess stage of liver disease (e.g. liver enzymes, liver biopsy) may not be widely available in many resource limited countries.

Liver biopsy remains the gold standard for assessing disease severity in HIV-HBV coinfection. Non-invasive markers are also available but none have been widely studied in coinfected patients.

Hoffman and Thio provided management recommendations for use in areas with limited resources. They recommend that HBsAg and liver enzymes be tested before ART, with liver enzymes being repeated once or twice during the first 3 months after commencing ART. Detection of HBV DNA is helpful but may not be available. Chronic HBV carriers with HBeAg positivity may benefit from starting anti-HBV therapy early.

Screening
For HIV infected individuals with chronic HBV, additional screening for coinfection with HCV is recommended; hepatocellular carcinoma screening with alpha fetoprotein and imaging of liver every 6 months is being suggested by some but the cost benefit of one or both tests as well as the frequency of  monitoring in various health economies remain to be assessed.

Treatment
Treatment is most beneficial for those in the immunoactive phase of chronic hepatitis B (characterized by liver enzyme elevations, fluctuating HBV DNA levels and pronounced hepatic necro-inflammation)

Patient characteristics that favour treatment success are
 * Low HBV DNA levels.
 * HBeAg positivity.
 * Evidence of liver inflammation based on liver biopsy findings.
 * Liver enzyme elevations.

It is unknown, if this applies to HIV coinfected individuals who have higher HBV DNA and lower liver enzyme elevations but more cirrhosis, and therefore the optimum time to commence treatment in HIV-HBV coinfected individuals is unclear at present.

The treatment and management of coinfected individuals requires modification in resource poor countries due to limited availability of some HBV tests as well as therapeutic agents for treatment of HIV and HBV. 3TC is widely available and tenofovir and adefovir have limited availability.

Current Regimen
There are several agents presently used for the treatment of HBV and HIV coinfection including interferon and nucleoside or nucleotide analogs. Decisions regarding when to initiate anti-HBV therapy require assessment of HIV status prior to initiation of treatment as several of these agents (tenofovir, lamivudine, emtricitabine, adefovir and entecavir) have activity against both HIV and HBV.

Telbivudine, a newer agent used to treat HBV, has not been shown to have activity against HIV.

Treatment decisions should be based on a combination of these factors:
 * 1) Which virus needs treatment.
 * 2) The type of antiviral agents  used in the concurrent anti-HIV regimen.
 * 3) The presence of 3TC-resistant HBV.
 * 4) The potential effect of drug resistance on the long term management of HIV and HBV infection.

If ART is to be initiated, then first line therapy should include TDF and 3TC/FTC as the nucleoside backbone.

Current WHO criteria for commencing ART in HIV infected individuals are based on a combination of WHO Clinical Stage and CD4 count.

Lamivudine/emtricitabine (3TC/FTC)
Dore et al demonstrated the efficacy of 3TC in persons coinfected with HIV and hepatitis B virus in the CAESAR study, a randomized placebo-controlled trial assessing the addition of 3TC or 3TC (150 mg 2x/day) plus loviride (100 mg 3x/day) to zidovudine-containing background antiretroviral treatment. Baseline HBsAg was positive in 122 (6.8%) of 1790 subjects. At weeks 12 and 52, median log10 HBV DNA change was -2.0 and -2.7, respectively, in the lamivudine arms, compared with no reduction among placebo recipients (P<.001).

A trend to lower ALT level, and delayed progression of HIV disease (relative hazard, 0.26; 95% confidence interval, 0.08-0.80) were also seen in the 3TC arms, compared with the placebo group. 3TC used as monotherapy however, results in the development of resistance at rates of 14-32% annually, exceeding 70% after 49 months of treatment and plateauing at > 90% in HIV-coinfected patients at 4-5 years.

Since 3TC has been widely used as part of ARV regimens in coinfected persons, with HBV Pol mutations observed in 94% of viremic patients who have been on treatment for at least four years.

FTC possesses similar characteristics to 3TC, although FTC has a longer half-life and is more potent in monotherapy in treatment naive patients.

3TC/FTC are interchangeable agents according to current treatment guidelines.

Tenofovir (TDF) with or without 3TC/FTC
There is now significant data supporting the use of TDF in coinfected patients. TDF is highly effective in suppressing HBV replication in HBV mono-infected patients with 3TC resistant HBV. TDF has also demonstrated potent anti-HBV efficacy in the setting of HIV coinfection.

Various studies have been conducted, as listed below:
 * Dore did a substudy analysis of two phase 3 randomized, double-blind, placebo-controlled trials recently examined the safety and efficacy of tenofovir DF among antiretroviral therapy-experienced (.study 907) and -naive (study 903) HIV-1-infected patients. Substudies of study 907 and study 903 were undertaken to examine the safety and efficacy of tenofovir DF among antiretroviral therapy-experienced and -naive HIV-HBV-coinfected individuals.
 * Individuals in study 907 were randomized to receive TDF or placebo, and individuals in study 903 were randomized to receive antiretroviral therapy regimens that included lamivudine plus tenofovir. Among individuals co infected with HIV and HBV in these 2 randomized controlled trials, therapy with TDF demonstrated anti-HBV virologic efficacy.
 * During 48 weeks of therapy with TDF, a mean reduction of 4 -5 log, copies/mL in the HBV DNA level was seen in antiretroviral therapy-experienced HIV-HBV-co infected individuals with or without resistance to lamivudine.
 * During the 48 weeks of the study, a similar reduction in the HBV DNA level was seen in antiretroviral therapy-naive HIV-HBV-co infected individuals who received combination therapy with lamivudine and TDF as a component of their initial 3-drug HAART regimen.
 * A trend toward greater suppression of HBV DNA as well as reduced YMDD resistance in HIV-HBV-co infected individuals who were receiving lamivudine and TDF, compared with lamivudine alone.
 * Van Bommel et al evaluated 52 patients with HBV infection, 21 coinfected with HIV and compared TDF with adefovir (ADV) in 3TC resistant HBV. All TDF treated patients (n=35) showed a strong and early suppression of HBV DNA within a few weeks as compared to ADV. At week 48, TDF treated individuals had a higher reduction in viral load (5.5 log10 copies/ml for TDF vs 2.8 log10 copies/ml with ADV) and 100% TDF were undetectable vs 44% with ADV. There was no resistance in TDF treated patients at 130 weeks.
 * Benhamou evaluated the efficacy and tolerability of TDF in 3TC naïve and 3TC refractory coinfected patients in a retrospective study. Of 65 coinfected patients (54 HBeAg positive and 11 HBeAg negative) with serum HBV DNA > 2.3 copies/ml were started on TDF therapy. 68% were 3TC refractory. Over 12 months, the median reduction in HBV DNA as 4.56 log10 copies/ml in HBeAg positive patients and 2.53 log10 copies/ml in HBeAg negative individuals. At the end of the study (median follow up of 12 months), 30% of HBeAg positive and 82% of HBeAg negative had undetectable HBV DNA. No TDF mutations were detected in this study.
 * Lacombe evaluated 85 HIV-HBV co infected patients in an open label study initiating an ARV regimen including either TDF or ADV. The decline in HBV DNA was more pronounced in patients treated with TDF than with ADV at 12 months (66% versus 53%, p=00001). Patients receiving TDF had a steeper rate of decline and mean time to undetectable HBV DNA was 19 months with TDF compared to 26 months with ADV.

The combination of TDF and 3TC has also been evaluated in a multi centre European study. Schmutz et al compared the efficacy of TDF plus 3TC with that of sequential therapy with TDF in HIV infected individuals with 3TC resistant HBV. In this study, 50 patients received TDF as the only active HBV agent subsequent to 3TC therapy and 25 received ART containing TDF plus 3TC. At 116 weeks, 84% treated with TDF had undetectable HBV DNA < 1000 copies/ml compared to 76% receiving TDF plus 3TC; this was not a statistically significant difference (p=0.53). The rates of loss of HBeAg and HBsAg were similar in both arms. This study indicates that TDF plus 3TC are no more efficacious than TDF alone. Sheldon reported the development of resistance to TDF in 2 of 43 HIV-HBV co infected patients treated for longer than 12 months.
 * Matthews et al evaluated 36 HIV-HBV co-infected patients in Thailand; subjects were randomized to receive either 3TC, TDF or both. At the end of 48 weeks, the average decline in HBV DNA was similar in all three arms, ranging from 4.07-4.73 log10 copies/ml. However, suppression of HBV DNA levels to < 1000 copies/ml was more frequent in subjects receiving TDF (92% and 91% compared to 46% in 3TC arm). Again, adding 3TC to TDF is no more efficacious than TDF alone. Drug resistance developed in 2 subjects both in 3TC only arm.
 * In a study in Australia, Matthews evaluated a cross sectional cohort of 3TC experienced HIV-HBV co infected patients. Individuals receiving TDF plus either 3TC or FTC were more likely to have undetectable HBV DNA (<100IU/ML) than those receiving either TDF or 3TC monotherapy.  The combination group was also less likely to have high HBV DNA levels (>200,000 IU/ML).  Despite the limitations of a cross sectional study, this study does provide some evidence that TDF-3TC/FTC combination therapy is superior to TDF or 3TC monotherapy in HIV-HBV co infected individuals with 3TC resistant HBV. However, confounders were not controlled for.
 * Alvarez-Uria reported on their experience in the UK in a retrospective observational study to investigate the long term efficacy of TDF against HBV in a cohort of HIV co infected patients. Median duration of follow up was 34 months and 41 (79%) were HBeAg positive and 35 had received previous 3TC therapy for a median duration of 32 months.  Nadir CD4 cell count was 110 cells/mm3 in individuals experiencing virologic breakthrough.  At the  end of the follow up period, HBV DNA was < 1000 copies/ml in 42 (81%) patients and < 200 copies/ml in 31 (60%) patients.  In the 3TC experienced group, longer duration of 3TC was associated with failure to achieve HBV DNA < 200 copies/ml (p=0.036).  Adding 3TC or FTC did not improve virologic suppression.  Of 39  patients who achieved HBV DNA of < 200 copies/ml during TDF treatment, virologic breakthrough was seen in 2 (5% patients) after a median follow up of 40 months.

Entecavir (ETV)
Entecavir (ETV) has been shown to be superior to 3TC with superior histological improvement, greater mean reduction in HBV DNA and normalization of serum ALT levels and large RCT have demonstrated efficacy up to 96 weeks. Entecavir is associated with lower rates of development of resistance as compared with 3TC. Entecavir is associated with lower rates of development of resistance as compared with 3TC. Entecavir monotherapy is now considered contra-indicated as anti-HIV activity has been described and monotherapy has led to the development of HIV resistance mutation (M184V0) which are relevant for HIV therapy. There is one RCT of ETV in 68 HIV/HBV coinfected patients comparing ETV to placebo while continuing 3TC containing ART for 24 weeks followed by ETV open-label. ETV was given at 1.0mg dose. At 24 weeks, 6% of 51 patients had HBV DNA < 300 copies/ml and at 48 weeks, 8% had HBV DNA < 300 copies/ml. Mean decline in HBV DNA was 3.65 log10 copies/ml.

Telbivudine
Telbivudine is not known to be active against HIV but one drawback is that HBV resistance may develop if this drug is used a single agent; in the GLOBE trial comparing 3TC vs telbivudine for mono-infected patients, resistance developed in 25% patients receiving telbivudine vs 40% those treated with 3TC.

Adefovir (ADV)
Of agents with activity against HBV, adefovir is the least potent. In addition, adefovir at low doses (10mg) does not have activity against HIV but higher doses do have activity against HIV. Adefovir has been studied in 35 co-infected patients continuing on 3TC and after 144 weeks of therapy, 45% achieved HBV DNA < 1000 copies/ml (vs 56% in HBV mono-infection). Resistance also develops less frequently than with 3TC in HBV mono-infected patients with HBeAg negative CHB: 2% after 2 years, 11% after 3 years, 18% after 4 years and 29% after 5 years.

Interferon
Pegylated interferon-alpha has not been studied as HBV treatment in HIV co infected individuals and as such its efficacy in this setting is unknown. However, in HIV-uninfected individuals, it has been demonstrated to be more effective than short acting interferon. One small study of 18 coinfected patients who were HBeAg positive, with documented 3TC resistance to HBV and on ART containing 3TC evaluated the use of ADV and pegylated interferon alpha2a for 48 weeks and achieved a median decline in HBV DNA of 3.6 log10 copies/ml at 48 weeks and 1.4 log10 copies./ml at 72 weeks. None of the patients became HBeAg negative. On treatment response was not maintained off therapy.

Goals of treatment
HIV: Treatment for HIV has resulted in a marked reduction in AIDS-related mortality. As a result, liver disease from HBV and HCV is now becoming a major cause of morbidity and mortality in HIV infected patients. Therefore the goal of treatment is to optimize anti-HIV therapy in HIV/HBV coinfected patients to improve and/or preserve immune function and reduce HIV associated morbidity and mortality.

HBV: In mono-infected patients, HBV therapy can reduce the risk of developing complications of liver disease. Natural history studies of chronically infected individuals have linked the risk of progression to cirrhosis and HCC to ongoing HBV replication. In addition, treatment for HBV has been directed at reducing replicating virus. It has been demonstrated that the degree of HBV viral suppression achieved during treatment appears to be the most important determinant of treatment outcomes, but HBV DNA levels as low as 2000 IU/mL is still associated with  disease progression. Recent recommendations have advocated for undetectable HBV DNA as the therapeutic goal with the overall goal of therapy being to reduce 5 progression to cirrhosis, liver  failure, HCC and need for liver transplantation.

Related Chapters

 * Coinfection
 * AIDS
 * HIV disease
 * Hepatitis C with HIV coinfection
 * Tuberculosis and HIV coinfection
 * HIV and tuberculosis coinfection : drug interaction