Incidence of HIV-1 Drug Resistance Among Antiretroviral Treatment-Naive Individuals Starting Modern Therapy Combinations

• Published in: Clinical infectious diseases 2012-01, Vol.54 (1), p.131-140
• Main Authors: von Wyl, Viktor, Yerly, Sabine, Böni, Jürg, Shah, Cyril, Cellerai, Cristina, Klimkait, Thomas, Battegay, Manuel, Bernasconi, Enos, Cavassini, Matthias, Furrer, Hansjakob, Hirschel, Bernard, Vernazza, Pietro L., Ledergerber, Bruno, Günthard, Huldrych F.
• Format: Article
• Language: English
• Subjects: Adult; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiretroviral drugs; Antiretrovirals; Antiviral agents; Biological and medical sciences; Cohort studies; Drug resistance; Drug Resistance, Viral; Drug therapy; Estimates; Female; Genetic mutation; Genotype; HIV; HIV 1; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - classification; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 - isolation & purification; HIV/AIDS; Human immunodeficiency virus; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Incidence; Infectious diseases; Male; Medical sciences; Middle Aged; Pharmacology; Pharmacology. Drug treatments; RNA; Statistical median; Treatment Outcome; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Viral Load; Virology
• ISSN: 1058-4838; 1537-6591
• DOI: 10.1093/cid/cir728

Background. Estimates of drug resistance incidence to modern first-line combination antiretroviral therapies against human immunodeficiency virus (HIV) type 1 are complicated by limited availability of genotypic drug resistance tests (GRTs) and uncertain timing of resistance emergence. Methods. Five first-line combinations were studied (all paired with lamivudine or emtricitabine): efavirenz (EFV) plus zidovudine (AZT) (n = 524); EFV plus tenofovir (TDF) (n = 615); lopinavir (LPV) plus AZT (n = 573); LPV plus TDF (n = 301); and ritonavir-boosted atazanavir (ATZ/r) plus TDF (n = 250). Virological treatment outcomes were classified into 3 risk strata for emergence of resistance, based on whether undetectable HIV RNA levels were maintained during therapy and, if not, whether viral loads were > 500 copies/mL during treatment. Probabilities for presence of resistance mutations were estimated from GRTs (n = 2876) according to risk stratum and therapy received at time of testing. On the basis of these data, events of resistance emergence were imputed for each individual and were assessed using survival analysis. Imputation was repeated 100 times, and results were summarized by median values (2.5th-97.5th percentile range). Results. Six years after treatment initiation, EFV plus AZT showed the highest cumulative resistance incidence (16%) of all regimens (< 11%). Confounder-adjusted Cox regression confirmed that first-line EFV plus AZT (reference) was associated with a higher median hazard for resistance emergence, compared with other treatments: EFV plus TDF (hazard ratio [HR], 0.57; range, 0.42-0.76), LPV plus AZT (HR, 0.63; range, 0.45-0.89), LPV plus TDF (HR, 0.55; range, 0.33-0.83), ATZ/r plus TDF (HR, 0.43; range, 0.17-0.83). Two-thirds of resistance events were associated with detectable HIV RNA level ≤500 copies/mL during treatment, and only one-third with virological failure (HIV RNA level, >500 copies/mL). Conclusions. The inclusion of TDF instead of AZT and ATZ/r was correlated with lower rates of resistance emergence, most likely because of improved tolerability and pharmacokinetics resulting from a once-daily dosage.