Adefovir Dipivoxil (PREVEON) New Results with Hepatitis B, HIV
On April 6 Gilead Sciences released results of two clinical trials of adefovir dipivoxil (PREVEON (tm)) for the potential treatment of HIV, and another trial of adefovir dipivoxil at a lower dose (30 mg) for hepatitis B. The hepatitis trial (which used HIV-negative volunteers) was clearly a major success, with a reduction of hepatitis B viral load of 4 logs (99.99%) in the 12-week trial, with adefovir dipivoxil once daily as the only treatment.The two trials of adefovir dipivoxil (PREVEON) for HIV both produced positive results; however, the sizes of the viral load and CD4 differences were small. It is possible that adefovir could be more important than the numbers indicate, since it is metabolized differently than nucleoside analogs, and may be effective in cells where those are not. However, the information released recently does not answer this question, which may be crucial for determining the role of the drug in HIV clinical practice.
One trial, called GS 411, assigned 85 treatment-naive patients to one of five regimens, all of which included indinavir (CrixivanŽ):
indinavir + adefovir + AZT, or
indinavir + adefovir + d4T, or
indinavir + adefovir + 3TC, or
indinavir + adefovir + AZT + 3TC, or
indinavir + AZT + 3TC. (The last one is a control regimen, including only standard treatments.) An interim analysis at 20 weeks found all of these groups were equivalent in viral load decline (2.1 to 2.5 logs viral load drops in the adefovir groups, vs. 2.15 logs in the control group), suggesting that adefovir may substitute for some approved nucleoside analogs, while providing an easier regimen (one pill a day), different side effects, and different drug resistance.
The other HIV trial, GS 408, randomly assigned 442 volunteers who were already receiving anti-HIV treatment to add either adefovir or a placebo to their existing regimen. At 24 weeks the average viral load drop was -0.39 logs in the adefovir group vs. -.01 logs in the placebo group, a statistically significant difference--about a 0.4 log benefit from adding adefovir in these pre-treated patients.
Comment
Adefovir dipivoxil has advantages of easy administration, and activity against other viruses besides HIV (including hepatitis B, CMV, HHV6, and Epstein-Barr virus). Also, it could provide a new treatment option, which is important because patients are different and many are not succeeding with the available regimens.
A central question is whether this drug can contribute to long-term control of HIV. Adefovir dipivoxil is active in many cell types, including lymphocytes, monocytes, and macrophages, and it works in both resting and activated T-cells. Even a small viral load drop compared to conventional treatment alone could be important, if this drop is accounted for by viral suppression in a small reservoir of cells not reached effectively by the other treatments, since otherwise these cells would allow HIV replication and therefore development of drug-resistant virus.
HIV drug development is moving too fast to wait several years to see which regimens give the best long-term suppression of HIV; a drug would already be obsolete by the time the answer is found. But a reasonable way to estimate long-term viral control, without waiting for a long time to see it, would be to look at how many patients reach a viral load below 20 copies (or even less, as even more sensitive tests become available). It is known that if viral replication is almost completely shut off, patients are less likely to have a rebound of resistant virus, compared to those who only get slightly below the 400-copy quantification limit of the currently approved viral load test.
Therefore--assuming a regimen can be tolerated indefinitely--the proportion of patients undetectable on the best viral load tests, at perhaps three months to a year, may be the best indicator of long-term antiretroviral activity, and important for determining the place of new treatment regimens in HIV clinical practice.
