Is there a risk of developing HIV resistance to adefovir or other HIV antiretrovirals (such as tenofovir) when using low-dose adefovir (10 mg/day) for the treatment of chronic hepatitis B?
The potential for the development of HIV resistance is always a primary concern when adding a single agent to an antiretroviral regimen. Under these circumstances, the risk of developing HIV resistance to adefovir is presumably greatest in people who have detectable HIV viremia (i.e. a viral load greater than the lower limit of detection either because they are not taking antiretrovirals, or because their medications are unable to effectively suppress HIV replication). There are limited laboratory and clinical data to suggest that low-dose adefovir therapy is not associated with the development of adefovir resistant HIV. First, at the dose used to treat HBV (10 mg daily compared to 120 mg daily that was used to treat HIV), adefovir apparently has no activity against HIV, making it unlikely that the virus would be under a significant selective pressure to develop resistance mutations. Second, in the recent French trial (see article), none of the 11 people evaluated, who all had HIV viral loads of at least 1,000 copies/mL at the time of genotyping, developed mutations associated with adefovir resistance after using low-dose adefovir for 48 weeks. Because adefovir is not FDA approved to treat HIV infection, a greater concern is for the potential development of cross-resistance to other antiretrovirals, most notably tenofovir, a recently approved antiretroviral in the same class as adefovir. Although there are no clinical data examining the development of tenofovir resistance in people treated with low-dose adefovir, a recent study indicated that use of adefovir for up to 48 weeks at 120 mg daily (the dose used during the testing of adefovir for HIV infection) was not associated with the development of decreased susceptibility to tenofovir1. Ongoing studies at the NIH are aimed at examining this important issue of the risk of developing HIV resistance to a variety of antiretrovirals while taking low dose adefovir.
What studies are being done to investigate combinations of antiretrovirals for treating HBV in HIV-infected people?
HBV, like HIV, has a reverse transcriptase enzyme and thus is susceptible to drugs active at this stage of its lifecycle. Based on this similarity, and our experience with treating HIV infection, combination therapy for HBV infection would appear prudent, especially to avoid the development of multi-drug resistant HBV caused by sequential monotherapy treatments. However, because of the substantial differences between HBV and HIV, the HIV paradigm of combination therapy may not be valid for the treatment of chronic HBV, and a single potent HBV agent may be sufficient to treat the infection. Only clinical trials will help to determine the need for a single or multiple agents to treat HBV. Current protocols are examining the combination use of lamivudine and adefovir, in particular in people who have lamivudine-resistant HBV.
What role might tenofovir play in treating HBV?
There are no clinical data available evaluating the efficacy of tenofovir for treating chronic hepatitis B. The agent has activity against HBV in the laboratory, but has not been tested in a clinical trial. However, because tenofovir works against HBV in the laboratory, clinicians should religiously screen people for evidence of chronic HBV by serologies prior to initiating tenofovir (or lamivudine) therapy. If chronic hepatitis B is detected, physicians should carefully evaluate the indications, and necessity, to use an agent(s) that treats both HIV and HBV.
Has HBV resistance to adefovir been detected?
To date, there have been no reports of HBV resistance to adefovir, including analyses of studies in which HIV-negative people received adefovir for over two years. These results are encouraging, especially when compared to the rapid development of HBV resistance to lamivudine seen in most protocols. Ongoing HBV clinical trials continue to carefully monitor for any evidence of emerging HBV adefovir resistance.