Low frequency nonnucleoside reverse-transcriptase inhibitor-resistant variants contribute to failure of efavirenz-containing regimens in treatment- experienced patients.

BACKGROUND: The contribution of low frequency drug-resistant human immunodeficiency virus type 1 (HIV-1) variants to failure of antiretroviral therapy is not well defined in treatment-experienced patients. We sought to detect minor nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistant variants at the initiation of multidrug efavirenz-containing therapy in both NNRTI-naive and NNRTI-experienced patients and to determine their association with virologic response. METHODS: Plasma samples at entry and at time of virologic failure from patients enrolled in the AIDS Clinical Trials Group study 398 were analyzed by standard genotype, single-genome sequencing and allele-specific polymerase chain reaction (K103N and Y181C) to detect and quantify minor NNRTI-resistant variants. RESULTS: Minor populations of NNRTI-resistant variants that were missed by standard genotype were detected more often at study entry in NNRTI-experienced patients than NNRTI-naive patients by both single-genome sequencing (8 of 12 vs 3 of 15; P = .022) and allele-specific polymerase chain reaction (11% Y181C, 5 of 22 vs 3 of 72, respectively; P = .016). K103N variants at frequencies 11% were associated with inferior HIV-1 RNA response to efavirenz-containing therapy between entry and week 24 (change in HIV-1 RNA level, +0.5 vs -1.1 log(10) copies/mL; P < .001). CONCLUSIONS: Minor NNRTI-resistant variants were more prevalent in NNRTI-experienced patients and were associated with reduced virologic response to efavirenz-containing multidrug regimens.

A randomized trial of treatment interruption before optimized antiretroviral therapy for persons with drug-resistant HIV: 48-week virologic results of ACTG A5086.

BACKGROUND: The role of structured treatment interruption (STI) before optimized antiretroviral therapy (ART) in patients with drug-resistant human immunodeficiency virus type 1 (HIV-1) is uncertain. METHODS: AIDS Clinical Trial Group protocol A5086 was a prospective trial of 41 patients with multiple drug class-resistant HIV who were randomized to undergo a 16-week STI followed by optimized ART (STI) or immediate optimized ART (no STI). The primary end point was the proportion of subjects with HIV-1 RNA loads <400 copies/mL 48 weeks after randomization. RESULTS: Of 39 evaluable patients, 4 (19%) in the STI arm and 6 (33%) in the no STI arm had HIV-1 RNA loads <400 copies/mL at 48 weeks (P=.44). Median changes from baseline in CD4+ cell counts and HIV-1 RNA loads were similar for both arms. Standard genotypes at the end of STI showed nearly complete reversion to wild-type virus in a minority of patients (n=5; 28%). Virus with 3-drug class resistance reemerged even when ART included only 1 or 2 drug classes. Single-genome sequencing showed that each genome encoded resistance mutations for 3 drug classes. CONCLUSIONS: A 16-week STI before optimized ART did not improve virologic response. Genetic analyses strongly suggest that virologic failure resulted from the reemergence of virus present before STI that encoded 3-drug class resistance on the same genome.

Detection of drug-resistant minority variants of HIV-1 during virologic failure of indinavir, lamivudine, and zidovudine.

We evaluated zidovudine-experienced patients for whom treatment with indinavir, lamivudine, and zidovudine failed, for indinavir-resistant minority variants. Of 10 patients with plasma human immunodeficiency virus type 1 RNA suppression and subsequent rebound, 6 without primary indinavir-resistance mutations underwent clonal analysis. One had evidence of V82A in 9 of 30 clones at week 24, with no increase at week 40. The dominant week-40 82V-M184V clones had changes at protease codons 62-64, compared with all clones at week 24 and minority clones at week 40. Resistance to indinavir can emerge during treatment failure in nucleoside-experienced patients but may be missed by routine sequence analysis. Selection for indinavir-resistant variants on treatment with indinavir, lamivudine, and zidovudine may occur slowly, depending on the genetic context in which they arise.

Mother-to-child transmission in the United States of subtypes D and A/G human immunodeficiency virus type 1.

In the United States and Western Europe, most human immunodeficiency virus type 1 (HIV-1) infections are caused by subtype B. We analyzed the nucleotide sequence of HIV-1 RNA in plasma samples from 141 children enrolled into PACTG 377, a comparative study of several antiretroviral therapy regimens. Phylogenetic analysis revealed that two children, both born in the United States, were infected with non-B subtypes that are most commonly found in Africa: one with subtype D and the other with circulating recombinant form CRF02, an A/G recombinant lineage. Viral load assays performed to monitor treatment response underestimated the levels of HIV-1 RNA in the child with the A/G recombinant. These cases demonstrate mother-to-child transmission of non-B subtypes of HIV-1 in the United States. Non-B subtypes should be considered in the management of HIV-1-infected pregnant women and children to optimize strategies to prevent and treat pediatric HIV-1 infection.