Journal of Hepatology
Volume 44, Issue 1 , Pages 1-3, January 2006

Treatment of lamivudine-resistant hepatitis B in HIV-infected persons: Is adefovir dipivoxil the answer?

  • Chloe L. Thio

      Affiliations

    • Corresponding Author Information1503 E Jefferson St., Baltimore, MD 21231, USA. Tel.: +1 410 955 0349; fax: +1 410 614 7564.

Johns Hopkins University School of Medicine, Baltimore, MD, USA

published online 08 November 2005.

See Article, pages 62--67

Article Outline

 

Effective therapy against HIV infection has led to a significant decline in the incidence of many opportunistic infections and a corresponding increase in the life expectancy of HIV-infected individuals. This trend has allowed chronic diseases to emerge in this population with liver disease established as a leading cause of morbidity and mortality [1]. Chronic hepatitis B, which shares modes of transmission with HIV, is an important cause of this liver disease affecting an estimated 10% of HIV-infected individuals [2], [3], [4]. As HIV therapy is being actively rolled out into areas of the world with high HBV endemicity, chronic hepatitis B will become an increasingly important cause of morbidity and mortality in HIV-infected persons.

Lamivudine, the first oral drug approved for the treatment of chronic hepatitis B, is limited not only by its inadequate efficacy but also by the development of lamivudine-resistant virus due to mutations in the HBV Pol gene [5], [6]. There are several reasons why lamivudine-resistant hepatitis B is a critical issue in the HIV-HBV co-infected population. First, lamivudine resistance occurs more rapidly in those co-infected with HIV with an estimated 90% of HIV-HBV co-infected individuals having lamivudine-resistant HBV after 4 years of treatment [7]. Second, lamivudine has been used in HIV-infected persons since the early 1990s when it was first studied for its use in HIV infection. Since then it continues to be a cornerstone of many HIV treatment regimens, so the majority of HIV co-infected individuals who have received antiretroviral therapy have been exposed to years of lamivudine. Third, lamivudine-resistant HBV in HIV co-infected persons is associated with significant elevations in serum ALT and HBV DNA [8]. These points coupled with the fact that lamivudine-resistant hepatitis B leads to continued progression of liver disease [9], [10] and cross-resistance to other nucleos(t)ide analogues [11] and that HIV accelerates the development of liver disease [12], data are needed on how best to treat HIV-HBV coinfected persons with lamivudine-resistant hepatitis B.

In this issue of the Journal, Benhamou and colleagues try to shed some light on this problem by studying the addition of adefovir dipivoxil to ongoing lamivudine in 35 HIV-infected patients with hepatitis B e antigen (HBeAg)-positive hepatitis B [13]. Only 29 of the 35 patients were followed for 144 weeks and are reported on in the current study. Results from this cohort were first published after 48 weeks of therapy [14], and the good news is that the participants have maintained their response to adefovir dipivoxil therapy. The authors find that the HBV DNA decline continues through 144 weeks and with an average decline of about 0.6log10copies/ml every 48 weeks since week 48. However, since week 108, the median total decline in HBV DNA has been constant at −5.9log10copies/ml suggesting that these patients may be reaching a plateau in the decline of HBV DNA. It is not known if this decline is enough since the threshold level of HBV DNA needed to stop progression of liver disease has not been determined, but there is mounting evidence from several Taiwanese studies that lower is better. Chen and colleagues studied 3774 persons and found that even the lowest HBV DNA group (≤1000copies/ml) amongst those who were HBeAg+ were 2.6 times more likely to develop cirrhosis than the reference group of persons who were HBeAg- and HBV DNA ≤1000copies/ml [15]. Given such emerging data, it is notable that after 144 weeks of adefovir dipivoxil, only 25% of this cohort achieved a level below the limit of the detection of the assay (200copies/ml), suggesting that adefovir dipivoxil is not potent enough at least in the co-infected population. Using a HBV DNA cut-off of 1000copies/ml, only 45% attained this goal, which is lower than the 56% seen in HBeAg+ HBV-monoinfected individuals after 144 weeks of adefovir dipivoxil [16]. It is not surprising that HIV-infected individuals are less likely to achieve such low levels of HBV DNA since HIV co-infected individuals have higher baseline HBV DNA levels compared to HBV monoinfected persons [17].

In HBV monoinfection, HBeAg seroconversion is an endpoint that appears to be durable since it correlates with sustained response off of therapy and with augmentation of the immune response. In this study, only two patients developed antibodies to HBeAg (anti-HBe), both of which occurred before week 48 and were maintained (one of these patients died at week 88 due to hepatocellular carcinoma). In their earlier paper, the authors stated that these individuals had low levels of HBV DNA [14]; however, they did not state the actual levels. In the current paper, the authors do not state whether the HBV DNA levels increased during follow-up, whether the ALT levels normalized, or whether any basal core promoter/precore mutations were documented in these two patients. All this information is important to determine whether these seroconversions represent a true response to therapy. Assuming these seroconversions represent a true therapeutic response, this rate (2/35) is much lower than is seen in HBeAg+ immunocompetent persons receiving adefovir dipivoxil (43% at 144 weeks) [16]. It is also discouraging that no further HBeAg seroconversions occurred despite well-controlled HIV disease. Taken together, these data on HBeAg seroconversion and HBV DNA decline suggest that unless more potent drugs are found, the majority of HIV-HBV coinfected persons will require indefinite treatment for their chronic hepatitis B.

There are a few hopeful aspects worth noting in this study. The number of persons with ALT normalization continues to increase over time with 68% achieving normal ALT at 144 weeks compared to 48% at week 96. It is also encouraging that no adefovir dipivoxil resistance mutations were detected in HBV Pol suggesting that combination therapy, despite the presence of resistance to lamivudine, may be helpful in delaying and perhaps preventing the emergence of resistance to adefovir dipivoxil. However, given the small number of people in this study and adefovir dipivoxil's high genetic barrier to resistance, it is a little too early to use this data to firmly make that conclusion. The rate of resistance in adefovir dipivoxil monotherapy trials for HBeAg negative chronic hepatitis B is about 4–6% at 3 years [18] and 18 and 28% at 4 and 5 years, respectively [19]. If we apply this 3 year rate (144 weeks) to the 29 people in this study, only one person would be expected to develop resistance. However, it is not known if this rate can be applied to HBeAg+ hepatitis B since lamivudine-resistant HBV replicate better in HBeAg negative than HBeAg positive patients in vitro [20]. Thus, continued follow-up of this cohort is needed to determine if mutants resistant to adefovir dipivoxil are selected in this cohort. It is difficult to imagine that resistance will not be selected given significant HBV replication is still occurring since the HBV DNA decline after week 48 is slow.

A theoretical concern with the use of adefovir dipivoxil in HIV-HBV co-infected persons is development of HIV resistance mutations since this drug is active against the HIV reverse transcriptase at higher doses. This would be problematic since cross-resistance to one of the most potent nucleotide analogues against HIV, tenofovir disoproxil fumarate (tenofovir), could occur as the two drugs are chemically similar. It is encouraging that no HIV resistance mutations to adefovir dipivoxil were detected after 144 weeks of therapy, but these data are limited since only nine people had detectable HIV RNA. This paper certainly does not close the book on this topic because the number of patients is small and all patients were on a concomitant highly active antiretroviral regimen (HAART) with very low and stable levels of HIV RNA. Thus, development of HIV resistance to tenofovir is expected to be uncommon in this scenario. Whether adefovir dipivoxil would lead to development of tenofovir-resistant HIV in individuals with higher levels of HIV RNA replication, such as in individuals who are not on HAART, is not known.

What have we learned from this study about treatment of lamivudine-resistant HBeAg positive hepatitis B in the HIV co-infected patient? Adefovir dipivoxil can lead to substantial reductions in HBV DNA in this situation, and it appears to be safe long-term. However, achieving an undetectable HBV DNA is uncommon and HBeAg seroconversion is a rare event. Thus, indefinite therapy is the rule with adefovir dipivoxil, so more potent drugs or drug combinations are needed. Tenofovir is a drug approved for the treatment of HIV with in vitro and limited in vivo data suggesting that it may be more potent than adefovir dipivoxil [21], [22]. Its dual activity against HIV makes it an ideal drug in situations where both infections need treatment, but studies are needed to determine its long-term efficacy and ability to achieve HBeAg seroconversion. With pre-existing lamivudine-resistant hepatitis B, tenofovir-resistant HBV (rtA194T) occurs after more than 12 months of therapy [23], but the rate of developing the mutants is not known. In addition, it cannot be used as monotherapy in situations where HIV treatment is not indicated since tenofovir-resistant HIV will develop. The recently approved drug entecavir is potent even in the presence of lamivudine resistance, however, it is limited by the fact that lamivudine-resistant HBV can develop further mutations that lead to entecavir resistance. The other L-nucleosides in trials (telbivudine and clevudine) will not be active against lamivudine-resistant HBV [11]. Thus, the current panoply of drugs is not adequate for the treatment of lamivudine-resistant HBV in the HIV co-infected person.

In conclusion, lamivudine-resistant hepatitis B is an important problem in the HIV coinfected population that has received antiretroviral therapy. As antiretroviral therapy is introduced into the developing world, lamivudine-resistant HBV will be a growing problem, so more potent drugs with a short duration of therapy are needed for HIV-infected patients with both lamivudine-resistant and wild type hepatitis B. In lamivudine-naïve individuals, I believe it is important to consider limiting the emergence of lamivudine-resistant hepatitis B since lamivudine resistance limits future treatment options. Combination therapy may be a means to prevent the development of drug-resistant hepatitis B in the treatment naïve, HIV co-infected patient since the resistance mutations of the nucleoside/tide analogues do not all overlap. However, trials are needed to test the successful HIV treatment paradigm that combination therapy increases the potency of HBV treatment while decreasing the development of drug resistance.

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Acknowledgements 

CT is supported by NIH grant R01 AI060449. I would like to thank Stephen Locarnini, MD, PhD for the critical reading of this manuscript.

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References 

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PII: S0168-8278(05)00682-3

doi:10.1016/j.jhep.2005.10.012

Journal of Hepatology
Volume 44, Issue 1 , Pages 1-3, January 2006

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