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Low-Frequency HIV-1 Drug Resistance Mutations and Risk of NNRTI-Based Antiretroviral Treatment Failure A Systematic Review and Pooled Analysis

Jonathan Z. Li, MD; Roger Paredes, MD, PhD; Heather J. Ribaudo, PhD; Evguenia S. Svarovskaia, PhD; Karin J. Metzner, MD; Michael J. Kozal, MD; Kathy Huppler Hullsiek, PhD; Melanie Balduin, PhD; Martin R. Jakobsen, PhD, Msc; Anna Maria Geretti, MD, PhD; Rodolphe Thiebaut, MD, PhD; Lars Ostergaard, MD, PhD; Bernard Masquelier, PharmD, PhD; Jeffrey A. Johnson, PhD; Michael D. Miller, PhD; Daniel R. Kuritzkes, MD
JAMA. 2011;305(13):1327-1335. doi:10.1001/jama.2011.375.
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Context Presence of low-frequency, or minority, human immunodeficiency virus type 1 (HIV-1) drug resistance mutations may adversely affect response to antiretroviral treatment (ART), but evidence regarding the effects of such mutations on the effectiveness of first-line ART is conflicting.

Objective To evaluate the association of preexisting drug-resistant HIV-1 minority variants with risk of first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)–based antiretroviral virologic failure.

Data Sources Systematic review of published and unpublished studies in PubMed (1966 through December 2010), EMBASE (1974 through December 2010), conference abstracts, and article references. Authors of all studies were contacted for detailed laboratory, ART, and adherence data.

Study Selection and Data Abstraction Studies involving ART-naive participants initiating NNRTI-based regimens were included. Participants were included if all drugs in their ART regimen were fully active by standard HIV drug resistance testing. Cox proportional hazard models using pooled patient-level data were used to estimate the risk of virologic failure based on a Prentice weighted case-cohort analysis stratified by study.

Data Synthesis Individual data from 10 studies and 985 participants were available for the primary analysis. Low-frequency drug resistance mutations were detected in 187 participants, including 117 of 808 patients in the cohort studies. Low-frequency HIV-1 drug resistance mutations were associated with an increased risk of virologic failure (hazard ratio (HR], 2.3 [95% confidence interval {CI}, 1.7-3.3]; P < .001) after controlling for medication adherence, race/ethnicity, baseline CD4 cell count, and plasma HIV-1 RNA levels. Increased risk of virologic failure was most strongly associated with minority variants resistant to NNRTIs (HR, 2.6 [95% CI, 1.9-3.5]; P < .001). Among participants from the cohort studies, 35% of those with detectable minority variants experienced virologic failure compared with 15% of those without minority variants. The presence of minority variants was associated with 2.5 to 3 times the risk of virologic failure at either 95% or greater or less than 95% overall medication adherence. A dose-dependent increased risk of virologic failure was found in participants with a higher proportion or quantity of drug-resistant variants.

Conclusion 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.

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Figure 1. Study Selection
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NNRTI indicates nonnucleoside reverse transcriptase inhibitor.
aInternational HIV Drug Resistance Workshop and Conference on Retroviruses and Opportunistic Infections (2007-2010).
bCommon reasons for exclusion include: does not involve low-frequency resistance variants, review article, epidemiologic study, and treatment-experienced population only.

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Figure 2. Kaplan-Meier Curves for Proportion of Patients Without Virologic Failure by Presence of Drug-Resistant HIV-1 Minority Variants
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Both nonnucleoside reverse transcriptase inhibitor–and nucleoside reverse transcriptase inhibitor–resistant minority variants (MVs) are included in this analysis. To avoid bias induced by targeted sampling in case-control studies, Kaplan-Meier failure time distributions were estimated using only data from cohort studies.1521 Curves only shown to 1250 days because of small sample sizes thereafter. P value comparison by Cox proportional hazard analysis. Median follow-up time, 31 (interquartile range, 13-34) months. HIV indicates human immunodeficiency virus.

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Figure 3. Effect of Minority Variants and Antiretroviral Therapy Adherence on Virologic Failure
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NNRTI indicates nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor.
aParticipant numbers include additional virologic failure cases from the case-control and case-cohort studies.2124
bCox proportional hazard ratios shown are in comparison to those without minority variants unless otherwise noted.
c Three studies contributed to the adherence analysis.15,20,21 One study was excluded from the minority variant 1% threshold analysis because of a limit of detection of 2% for the assay,18 and only NNRTI-resistant minority variants were evaluated for 2 studies because of incompatible limits of detection for NRTI-resistant minority variants.22,23 Four studies were excluded from the 0.5% threshold analysis because of higher limits of minority variant detection.15,18,22,23 Analysis of minority variant copy numbers excluded 3 studies using assays that could not provide a percentage.18,22,23
dMultivariate Cox regression analysis included adherence, race/ethnicity, baseline CD4 cell count, and HIV-1 RNA levels.

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Figure 4. Time to HIV-1 RNA Level Less Than 200 Copies/mL in Patients Achieving Virologic Suppression
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Two studies with frequent human immunodeficiency virus 1 (HIV-1) RNA monitoring20,21 were used to determine the time to HIV-1 RNA less than 200 copies/mL among individuals who experienced virologic suppression. P value comparison by Cox proportional hazard analysis. Median time to virologic suppression was 57 (interquartile range, 28-112) days for those with minority variants and 57 (interquartile range, 27-111) days for those without.



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