September 16, 2003
In the past several months, clinicians have been confronted by a series of studies documenting the comparative efficacy of triple-NRTI regimens versus starting patients on NRTIs with the addition of either NNRTIs or protease inhibitors (PIs). There was some hope that if we combined three of our most potent nucleosides -- and three of the safest in terms of the lowest rates of lipodystrophy -- we should be able to create a highly successful combination. These NRTIs -- tenofovir (TDF, Viread), 3TC (lamivudine, Epivir) and abacavir (ABC, Ziagen) -- were tested in this randomized study, and compared to a more standard approach of combining efavirenz (EFV, Sustiva) with 3TC and abacavir. Both regimens were given just once daily.
In all, 345 treatment-naive patients were randomized to one of these two regimens. All had a viral load >5,000 copies/mL at baseline. This study used the new tablet still in development that combines the daily dose of both abacavir and 3TC into one tablet. Because of some concerns voiced by investigators, this study had an unplanned early look at the results. This was done in July 2003 and has already received significant publicity to inform the community about these results. At that point, 194 people were at or beyond week eight.
What was noted was striking: 49 percent of those on the 3TC/abacavir/tenofovir arm did not achieve viral suppression, in contrast to only 5.4 percent of patients on the 3TC/abacavir/efavirenz arm who did not have viral control. Various measures of a lack of response to the 3TC/abacavir/tenofovir were done, and each confirmed the global finding documenting the lack of success in this triple-NRTI approach. Of concern is that all of the patients with rebound who could have a genotype done had the M184V mutation, and 64 percent also had the K65R mutation as well.
It remains a subject of both concern and confusion that this triple NRTI performed as poorly as it did. There are several reasons that have been proposed to explain these results, but it remains uncertain which of these are truly involved. What data we have shows no evidence of a drug-drug interaction between tenofovir and abacavir, and currently among the favored explanations is that it is just "too easy" for HIV to find resistance mutations that interfere with the potency of several of these drugs at the same time.
Indeed, the K65R mutation does confer some degree of resistance to all three drugs in this combination even though this mutation does not occur in all of those with viral rebound. Given these and other results, it remains clear that a triple-NRTI based approach is not as potent as other more recommended regimens. Other research is ongoing, however, including work on four NRTI-based combinations to explore ways to maximize the options we have to reliably and safely suppress HIV.
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