Drug Resistance in Subjects with Advanced HIV Infection in Whom Antiretroviral Combination Therapy Is Failing

In the current study, researchers evaluated phenotypic and genotypic markers of drug resistance in human immunodeficiency virus type 1 (HIV-1) at the time of virologic failure (VF) in subjects in the AIDS Clinical Trials Group Protocol 388 (ACTG 388) who received lamivudine-zidovudine (Epivir/Retrovir) or lamivudine-stavudine (Epivir/Zerit) and either indinavir (Crixivan), efavirenz-indinavir (Sustiva-Crixivan), or nelfinavir-indinavir (Viracept-Crixivan).

Results of this study were presented in part at the 9th Conference on Retroviruses and Opportunistic Infections, February 2002, Seattle, WA (abstract 564-T).

At VF, phenotypically susceptible HIV-1 was found in 55% of subjects in the nelfinavir-indinavir arm, compared with 22% in the indinavir arm (P = .006).

Phenotypic resistance to lamivudine was less common in the efavirenz-indinavir arm (33% of subjects; P = .002) and the nelfinavir-indinavir arm (43%; P = .003), compared with the indinavir arm (78%).

Isolated phenotypic resistance to efavirenz at VF occurred in HIV-1 recovered from 33% of subjects in the efavirenz-indinavir arm; 24% of the subjects had HIV-1 with both efavirenz and lamivudine resistance.

Results of genotypic tests were similar. The lower frequency of resistance in the nelfinavir-indinavir arm likely reflects decreased drug exposure that is due to intolerance, which is consistent with the lower potency and tolerability of this combination in ACTG 388.

The lower frequency of lamivudine resistance in the efavirenz-indinavir arm is consistent with reports in other studies of potent regimens.

Thus, although dual resistance to efavirenz and lamivudine occurred at VF in the efavirenz-indinavir arm, this risk was relatively low when evaluated in the context of the potency and tolerability of this regimen.

Commentary

In summary, HIV-1 resistant to lamivudine was the most common drug-resistant virus variant found across all study arms, but the frequency of this finding varied among treatment arms.

 Drug-susceptible HIV-1 was common at VF in the indinavir-nelfinavir arm, which is consistent with the hypothesis that reduced drug exposure due to intolerance or toxicity was the cause of VF in this arm.

Although there was a risk of developing dual lamivudine-NNRTI resistance in the indinavir-efavirenz arm, this arm had lower rates of lamivudine resistance overall and lower rates of VF.

University of Rochester and Columbia University College of Physicians and Surgeons, New York, New York; Harvard School of Public Health, Boston, Massachusetts; University of Minnesota Medical School, Minneapolis; Johns Hopkins Medical Institutions, Baltimore, Maryland; ViroLogic, San Francisco, California; and University of Miami School of Medicine, Florida.

08/16/04

Reference
L M Demeter and others. HIV-1 Drug Resistance in Subjects with Advanced HIV-1 Infection in Whom Antiretroviral Combination Therapy Is Failing: A Substudy of AIDS Clinical Trials Group Protocol 388. Clinical Infectious Diseases 39(4): 552-558. August 15, 2004.