Emergence of Resistance-Associated Mutations Over 96 Weeks in Patients Initiating ABC/3TC + d4T, EFV or APV/r

Dr. Lanier and colleagues presented data on the emergence of HIV drug resistance in the ESS40001 study. This was a three-arm study in which drug naive patients (100 patients in each arm) were randomized to receive abacavir (ABC, Ziagen)/3TC (lamivudine, Epivir) twice daily with either d4T (stavudine, Zerit) twice daily, efavirenz (EFV, Sustiva) once daily or amprenavir (APV, Agenerase) 1200 mg and ritonavir (RTV or r, Norvir) 200 mg, both once daily. Fos-amprenavir (GW433908) was substituted at 1400 mg once daily along with ritonavir 200 mg in 86 percent of the patients after about 169 days on regular amprenavir regimens.

There was also a switch strategy built into the study, whereby patients who failed their primary regimen were changed to another previously designated combination. Patients had to have a viral load of > 5,000 copies/mL and a CD4 count > 50 cells/mm3 prior to enrollment. Viral genotype and phenotype were determined at baseline and after virologic failure. Virologic failure was defined as no decrease in viral load to < 400 copies/mL after 24 weeks, or in those who achieved a viral load < 400 copies/mL, when they rebounded to a viral load > 1,265 copies/mL.

Forty-seven patients across the three arms experienced virologic failure, of whom 33 (70 percent) had both baseline and viral failure resistance test information. Of the 33 failures, 14 were in the d4T arm, three in the efavirenz arm and 16 in the amprenavir arm.

Several figures were presented that showed individual patient graphs of viral load and CD4-count responses over time representing each of the three arms. These figures represented patients with virologic failure who were changed to a second treatment combination. The most common mutation found across the three arms was the M184V mutation, which confers resistance to 3TC. This mutation was found more often in the d4T and efavirenz arms compared to the amprenavir arm.

Abacavir-associated mutations, or thymidine-associated mutations (TAMs, seen with both d4T and AZT [zidovudine, Retrovir]) were rarely found. Only one patient developed a protease inhibitor (PI)-associated mutation after the primary regimen, but this did not result in phenotypic resistance to amprenavir.

This poster did not describe the overall comparative efficacy rates of these three primary regimens. The number of patients with resistance was small, and only three out of 10 patients who failed in the efavirenz arm had samples that could be evaluated. The finding of 3TC resistance development as the first sign of virologic failure has been described in many previous studies, including those with an abacavir/3TC combination. This study confirms the observation that the failure of a regimen does not necessarily mean that a patient's virus has developed resistance to all drugs in the combination regimen. In fact, this study suggests that a boosted-PI regimen (in this case amprenavir boosted with low dose ritonavir) may result in less overall resistance mutation development. Resistance, and hence failure, to efavirenz or 3TC only requires the development of a single mutation in the HIV-1 reverse transcriptase gene. This means there is a low genetic barrier to the development of resistance, whereas many mutations in the HIV-1 protease gene, required for the development of high-level PI resistance, mean there is a high genetic barrier to the development of resistance. In addition, boosting a PI with ritonavir to increase blood levels can sometimes overcome low-level PI resistance. So, PIs can overcome low-level resistance and regain some lost activity if concentrations are increased.