Download Article PDF/SlidesOver the past 18 months, significant amounts of data presented at scientific conferences have shed additional light on the mechanisms and clinical significance of antiretroviral drug resistance. These include new reports from studies evaluating the incidence and lingering consequences of transmitted drug-resistant HIV, the significance of the K65R mutation in reverse transcriptase, the persistence of minor HIV variants harboring drug-resistance mutations, the selection of TAM pathways, as well as some heartening data indicating that lamivudine retains some activity against HIV carrying the M184V mutation. To discuss these and other emerging data, Dr. Daniel Kuritzkes graciously accepted PRN’s offer to speak at the May 2004 meeting, the proceedings from which are reviewed here.
| I. Drug-Resistant HIV Transmission | Top of page |
Drug-resistance testing has come to be recognized as an important tool in tracking the growing and troublesome prevalence of transmitted drug-resistant HIV—a problem that appears to be here to stay. To provide PRN members with an update, Dr. Kuritzkes highlighted recent epidemiological data from around the world, looking at different patterns of resistance in both newly infected and chronically infected individuals.
Some of the most intriguing epidemiological data come from the CATCH study, which involved 17 European countries, evaluating the incidence of genotypic resistance in more than 1,600 newly infected HIV-positive individuals (Wensing, 2003). The overall prevalence of HIV strains resistant to at least one antiretroviral agent was 9.6%. “What was interesting about this study was that it was able to divide patients into two groups: those who had been infected for a year or less and those who had been infected for longer than a year, based on the physician’s assessment of infection time,” Dr. Kuritzkes said. According to the data presented at the 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment, held in July 2003 in Paris, the prevalence of drug-resistant HIV among patients infected for a year or less was 10.9%, compared to a prevalence rate of 7.5% among patients infected for more than a year.
Also presented at the 2nd IAS conference were data from the United States, demonstrating similar results. In this study, the prevalence of drug-resistant HIV was assessed among 949 newly infected, antiretroviral-naïve individuals in 10 cities (Bennett, 2003). Using the STAHRS testing algorithm, the investigators determined that 182 patients had been infected within four to six months (primary HIV infection), whereas the remaining 767 patients had been infected for at least six months (chronic HIV infection). Among the patients with primary HIV infection, approximately 11.5% had evidence of resistance to at least one antiretroviral agent. As for patients with chronic HIV infection, approximately 7.5% had evidence of resistance to at least one antiretroviral agent—results similar to the CATCH study. In both studies, resistance to nucleoside reverse transcriptase inhibitors was the most common, followed by resistance to the non-nucleoside reverse transcriptase inhibitors and then the protease inhibitors.
“Not only do the CATCH study and the U.S. study indicate a trend toward increasing prevalence of drug resistance in newly infected individuals,” Dr. Kuritzkes commented, “they also illustrated that drug-resistant HIV persists in plasma for an extended period of time, after transmission has occurred.”
In conflict with the CATCH and U.S.-based studies are data reported at the 11th Conference on Retroviruses and Opportunistic Infections (CROI) suggesting that the prevalence of drug-resistant HIV transmission is actually stabilizing or decreasing. In one study, reporting on new HIV infections at the Academic Medical Center of the University of Amsterdam and the Amsterdam Cohort Studies, the prevalence of transmitted HIV resistant to at least one antiretroviral agent decreased from 20% between the years of 1994 and 1997 to 6% between the years 1998 and 2002 (Bezemer, 2004). And in North Carolina, among the 12 individuals diagnosed with primary HIV infection between January 1998 and June 2000, approximately one-quarter of them had evidence of phenotypic resistance to at least one antiretroviral agent (Hicks, 2004). However, since June 2000, there have been no cases of phenotypic resistance in 18 individuals diagnosed with primary HIV infection.
An explanation for the North Carolina data is not readily available,” Dr. Kuritzkes confessed. “However, it’s important to note that a lot of HIV transmission that has been occurring in recent years is among people of color with limited access to care. And in North Carolina, where the ADAP waiting list is growing longer and longer, it’s possible that the limited care available in the state may be playing a hand in the reduction of transmitted drug-resistant HIV.” As such, differences in the prevalence of resistance, whether between regions or among specific populations, are likely to be important in determining patterns of transmission of resistant HIV.
| III. The Role of Minor Variants | Top of page |
Moving on to resistance issues in heavily pre-treated HIV-positive patients, Dr. Kuritzkes reviewed data stemming from ACTG 398, a clinical trial designed to determine whether the addition of a second protease inhibitor to a regimen containing amprenavir (Agenerase) improved the 24-week response to salvage therapy (Mellors, 2003). The study enrolled 481 heavily pretreated HIV-positive patients: 21% had been on one protease inhibitor in the past, 53% had been on two prior protease inhibitors in the past, and 26% had been on three protease inhibitors in the past. Approximately 44% of the patients had also been on an NNRTI in the past.
All of the patients received efavirenz, adefovir dipivoxil, abacavir, and amprenavir. In addition, subjects were randomized to receive either placebo, nelfinavir (Viracept), saquinavir (Fortovase), or indinavir (Crixivan). There were no statistically significant differences between the three active drug arms. There was, however, a significant difference between the combined active arms and the placebo arm, demonstrating that dual protease inhibitor regimens are superior to single protease inhibitor regimens in heavily pretreated patients.
Not surprisingly, the ACTG 398 investigators reported that NNRTI-naive patients had significantly better responses than NNRTI-experienced patients: 84% of NNRTI-experienced patients, compared to 57% of the NNRTI-naive patients, failed to achieve an undetectable viral load after 24 weeks of follow-up. Of interest, though, is an analysis of the NNRTI-experienced patients. “When we break down the NNRTI-experienced patients into those who did or did not have evidence of NNRTI resistance at baseline, we see that patients who didn’t have evidence of NNRTI resistance seemed to do well during the first 24 weeks of the study,” Dr. Kuritzkes illustrated. After 24 weeks, however, the difference in response rates between these two groups became insignificant and eventually converged. “Why might this be?” Dr. Kuritzkes asked. “There must be something about the prior NNRTI exposure that predisposes this group of patients to fail the NNRTI regimen, compared to patients who have never been exposed to an NNRTI. And whatever that is, it is not being captured using standard resistance assays.”
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