title: Resistance at virological failure using boosted protease inhibitors versus nonnucleoside reverse transcriptase inhibitors as first-line antiretroviral therapy--implications for sustained efficacy of ART in resource-limited settings.
abstract: BACKGROUND
  Increases in the prevalence of resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs) have been observed among previously untreated individuals in all areas of sub-Saharan Africa. We aimed to examine whether first-line use of 2 NRTIs plus a boosted protease inhibitor (bPI) could protect against emergence of NRTI resistance mutations, compared to the use of 2 NRTIs plus 1 NNRTI.
  
  
  METHODS
  We carried out a weighted meta-analysis of randomized clinical trials comparing bPI- with NNRTI-based first-line antiretroviral therapy regimens using random effects modeling.
  
  
  RESULTS
  In intention to treat analyses, there was no difference in the risk of viral failure at week 48 between NNRTI and bPI (P = .19). At week 48, the overall difference between NNRTI- and PI-based regimens in selection of any major NRTI resistance mutation (crude unweighted prevalence 3.3% vs 1.6%) was 1.7% (95% confidence interval [CI], .4-3.0; P = .00927). There was a statistically significant difference in prevalence of K65R when comparing NNRTI (1.3%) with PI (0.67%); absolute weighted difference 1.0% (95% CI, .3-1.7; P = .00447). There was also a significant difference in prevalence of M184V/I between NNRTI and PI (crude unweighted prevalence 3.2% vs 1.4%); difference 1.6% (95% CI 0.1-3.1; P = .0368).
  
  
  CONCLUSIONS
  Despite the equivalent efficacy and more favorable resistance implications of PI- versus NNRTI-based first line therapy, widespread use of PI-based first-line therapy is not warranted at this time, due to resource limitations and predicted increased risk of resistance-related failure of NNRTI/NRTI second-line regimens. PI-based first-line therapy could be reconsidered when antiretroviral agents from other classes become available for second-line regimens in resource-limited settings.
authors.affiliation: Pharmacology Research Laboratories, Liverpool University, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hill
authors.forename: Angela
authors.initials: A
authors.lastname: McBride
authors.forename: A William
authors.initials: AW
authors.lastname: Sawyer
authors.forename: Nathan
authors.initials: N
authors.lastname: Clumeck
authors.forename: Ravindra K
authors.initials: RK
authors.lastname: Gupta
mesh_terms: D044966:Anti-Retroviral Agents / Q000008:administration & dosage*; D003906:Developing Countries; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D011203:Poverty; D015995:Prevalence; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics; D012044:Regression Analysis; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D044966:Anti-Retroviral Agents; D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors
keywords: ART; HIV; NNRTI; PI; antiretroviral therapy; protease; resistance; reverse transcriptase