HIV - Low-Level NNRTI Resistance Linked to Treatment Failure

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HIV - Low-Level NNRTI Resistance Linked to Treatment Failure

SUMMARY Nearly 20% of HIV positive people on first-line antiretroviral therapy have low-frequency or minority NNRTI resistance mutations, which increase the likelihood of virological treatment failure.

Antiretroviral therapy (ART) regimens containing non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the most widely used for first-line HIV treatment in the U.S. and worldwide. However, resistance to NNRTIs is somewhat common and is known to lead to increased risk of treatment failure and disease progression. Resistance may emerge due to incomplete HIV suppression (for example, due to less than optimal adherence), but people can also become infected with virus that is already resistant to certain drugs.

Commercially available drug-resistance tests can detect resistance mutations present in 15% or more of an individual's viral population. Lower concentrations of drug-resistance mutations can be detected by tests used in research settings. The effect of such low-level, or minority variant drug resistance on risk of treatment failure is not well understood.

As described in the April 6, 2011, Journal of the American Medical Association, Li and colleagues performed a review of 10 studies to analyze the effect of minority variant drug resistance on the risk of first-line treatment failure.

The researchers searched medical publication databases for relevant work, and interviewed investigators from 10 selected studies. Altogether, these studies included 985 people, 83% of whom were men, with a median CD4 T-cell count of 229 cells/mm3 and median HIV viral load of 5 logs.

Results

Overall, drug resistant minority variants were found in 187 of 985 study participants (19%).

People with any minority resistance variants were 2.6 times more likely to experience treatment failure.

NNRTI resistance was associated with treatment failure, while resistance to only nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) was not -- although only 3 people in this study had only NRTI resistance.

People with minority resistance variants had lower average CD4 counts (208 vs 234 cells/mm3).

No difference in treatment failure rates was seen between people with NNRTI resistance taking efavirenz (Sustiva) vs nevirapine (Viramune).

There was also no difference between people with the K103N vs Y181C mutations, which are the most common NNRTI-associated resistance mutations.

People with minority resistance variants and < 95% treatment adherence were 5.1 times more likely to experience treatment failure compared to those with no detectable resistance and > 95% adherence.

The effect of minor variant drug resistance was dose-dependant, with higher levels of resistance mutations (> 1% vs < 1%) increasing the risk of treatment failure.

People without any detectable drug resistance were 9 times more likely to achieve undetectable viral load than those with detectable resistance.

"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," the researchers concluded.

Because NNRTI-based regimens are so common and single mutations can lead to treatment failure, this study is important in further understanding the role of drug resistance in treatment failure. Commercially available tests with a greater sensitivity to detect low concentrations of NNRTI drug-resistance mutations could reduce the likelihood of treatment failure and extend the duration of effective antiretroviral treatment. This study also highlights the importance of high-level adherence to treatment.

Previous research looking at the presence of minority variant mutations conferring resistance to protease inhibitors (PI) and integrase inhibitors has not found that they significantly increase the risk of treatment failure. While NNRTI-based regimens are most widely used as part of first-line therapy, this research suggests that until more sensitive drug-resistance testing is commercially available, PI-based regimens may offer some advantages in terms of resistance-associated treatment failure.

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.

5/3/11

ReferenceJZ 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.

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