HIV/AIDS - Uncommon Resistance Mutations Can Cause First-Line Treatment Failure

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HIV/AIDS - Uncommon Resistance Mutations Can Cause First-Line Treatment Failure

SUMMARY: Low-frequency drug-resistance mutations, especially those related to NNRTIs, can lead to virological failure among HIV patients starting antiretroviral therapy (ART) for the first time.

By Liz Highleyman

It is well known that highly treatment-experienced people may not achieve sustained HIV suppression due to drug resistance, which in many cases emerged due to sequential monotherapy or dual therapy in the pre-ART era. Less than optimal adherence can also contribute to development of resistance. But the effects of pre-existing low-frequency or minority resistance mutations are not as well understand.

As described in the April 6, 2011, Journal of the American Medical Association, Li and Kuritzkes from Harvard Medical School and colleagues performed a systematic review to assess the association between pre-existing drug-resistant HIV minority variants and risk of virological failure while on first-line non-nucleoside reverse transcriptase inhibitor (NNRTI) antiretroviral regimens.Using traditional polymerase chain reaction (PCR) amplification and population sequencing techniques, the prevalence of transmitted drug-resistance mutations in North America and Europe is estimated to be between 8% and 16%, the researchers noted as background. Standard tests detect mutations present in about 15% to 25% of an individual's viral strains or quasi-species. But these tests may not detect the

presence of less common minority resistance mutations.

The investigators reviewed published and unpublished studies of ART-naive participants initiating NNRTI-based regimens. They searched PubMed (1966 through 2010), EMBASE (1974 through 2010), conference abstracts, and article references. Authors of all studies were contacted to obtain detailed laboratory, ART, and adherence data.

Out of a total of 1263 study participants, the researchers include those with all drugs in their ART regimen fully active according to standard HIV drug-resistance testing. This left individual data from 10 studies and 985 participants available for analysis, including 808 patients in 6 cohort studies. Most (about 80%) were men and the average age was 38 years.

The investigators correlated presence of mutations with treatment failure defined as HIV RNA >200 copies/mL on 2 consecutive measurements 16 weeks or more after starting therapy.

Results

Low-frequency drug-resistance mutations were detected in 187 of 985 participants (19%) overall, including 117 of 808 patients (14%) in cohort studies.

All had minority reverse transcriptase gene mutations, including K103N and Y181C (which confer resistance to NNRTIs) and M184V and K65R (which confer resistance to nucleoside/nucleoside reverse transcriptase inhibitors [NRTIs]).

In a pooled analysis, low-frequency resistance mutations were associated with a significantly increased risk of virological failure after controlling for adherence, race/ethnicity, baseline CD4 cell count, and plasma viral load (hazard ratio 2.3, or more than twice the risk; P < 0.001).

Increased risk of virological failure was most strongly associated with minority variants resistant to NNRTIs (hazard ratio 2.6; P < 0.001).

The increased risk associated with NRTI-resistance minority variants did not reach statistical significance (hazard ratio 1.6).

Among cohort participants with NNRTI-resistant minority variants, the overall failure rate was 37%, compared with 15% for those without rare variants (hazard ratio 3.8; P < 0.001).

Among people in the cohort studies, 35% of participants with detectable minority resistance mutations experienced virological failure, compared with 15% of those without minority variants.

Presence of minority resistance variants increased the risk of virological failure by 2.5 to 3.0 times, both at >95% and < 95% adherence.

Presence of minority variants at a proportion of >1% conferred a significantly higher risk of virological failure compared with variants present at < 1%.

Study participants with a higher proportion or quantity of drug-resistant variants had a "dose-dependent" increase in the risk of virological failure.

In addition to drug-resistance mutations, other independent predictors of virological failure were medication adherence (hazard ratio 0.86 per 5% better adherence) and race/ethnicity.

White participants had a lower risk of virological failure compared with blacks, Hispanics/Latinos, and people of other races/ethnicities.

Based on these findings, the study authors concluded, "In a pooled analysis, low-frequency HIV-1 drug-resistance mutations, particularly involving NNRTI resistance, were significantly associated with a dose-dependent increased risk of virologic failure with first-line ART.""While we found a dose-dependent effect of drug-resistant minority variants on risk of virologic failure, an increased risk was detected even at very low minority variant frequencies (< 0.5% and 10-99 copies/mL)," they elaborated in their discussion.

They noted, however, that not all of the included studies tested for the most common NRTI and NNRTI mutations (though all did check for K103N), so the prevalence of minority resistant variations might actually be higher.

"The relationship between race/ethnicity and virologic failure may be mediated by factors such as socioeconomic status, drug and alcohol use, or other factors not accounted for here that may correlate with adherence and could contribute to residual confounding," the authors suggested.More sensitive tests for drug resistance mutations (e.g., deep sequencing) are available, but are not yet widely used. The researchers calculated that approximately 11 patients would have to be screened with the most sensitive NNRTI resistance test prior to ART initiation in order to avoid 1 case of virological failure.

"These data provide a rationale for developing standardized clinical assays for the detection of NNRTI-resistant minority variants," they recommended. "Because NNRTI-based regimens are the most commonly prescribed first-line antiretroviral therapy, the clinical use of ultrasensitive screening for drug-resistant HIV could help identify individuals at greatest risk of virologic failure and allow ART to be tailored appropriately."

Investigator Affiliations: Section of Retroviral Therapeutics, Brigham and Women's Hospital, Harvard Medical School and Center for Biostatistics in AIDS Research, Harvard School of Public Health, Harvard University, Boston, MA; IrsiCaixa AIDS Research Institute and Lluita Contra la SIDA Foundation, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Gilead Sciences Inc, City, CA; Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Yale University School of Medicine AIDS Program and VA Connecticut Healthcare System, New Haven, CT; Division of Biostatistics, University of Minnesota, Minneapolis, MN; Institute of Virology, University of Cologne, Cologne, Germany; Departments of Medical Microbiology and Immunology, Aarhus University, and Infectious Diseases, Aarhus University Hospital, Skejby,

Denmark; Department of Virology, University College London Medical School, London, UK; INSERM, U897 Epidemiology and Biostatistics, Bordeaux School of Public Health, Bordeaux, France; Laboratoire de Virologie, CHU de Bordeaux, and Université de Bordeaux, Microbiologie fondamentale et Pathogénicité, Bordeaux; Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA.

4/8/11

Reference

JZ Li, R Paredes, HJ Ribaudo, et al. Low-Frequency HIV-1 Drug Resistance Mutations and Risk of NNRTI-Based Antiretroviral Treatment Failure: A Systematic Review and Pooled Analysis. Journal of the American Medical Association 305(13): 1327-1335 (abstract). April 6, 2011.Other SourceJAMA. HIV-1 Drug Resistance Mutations Associated With Increased Risk of Antiretroviral Treatment Failure. Press release. April 5, 2011. April 1, 2011.

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