Long-lasting protection of activity of nucleoside reverse transcriptase inhibitors and protease inhibitors (PIs) by boosted PI containing regimens

PLoS One. 2012;7(11):e50307. doi: 10.1371/journal.pone.0050307. Epub 2012 Nov 26.

Abstract

Background: The accumulation of mutations after long-lasting exposure to a failing combination antiretroviral therapy (cART) is problematic and severely reduces the options for further successful treatments.

Methods: We studied patients from the Swiss HIV Cohort Study who failed cART with nucleoside reverse transcriptase inhibitors (NRTIs) and either a ritonavir-boosted PI (PI/r) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). The loss of genotypic activity <3, 3-6, >6 months after virological failure was analyzed with Stanford algorithm. Risk factors associated with early emergence of drug resistance mutations (<6 months after failure) were identified with multivariable logistic regression.

Results: Ninety-nine genotypic resistance tests from PI/r-treated and 129 from NNRTI-treated patients were analyzed. The risk of losing the activity of ≥1 NRTIs was lower among PI/r- compared to NNRTI-treated individuals <3, 3-6, and >6 months after failure: 8.8% vs. 38.2% (p = 0.009), 7.1% vs. 46.9% (p<0.001) and 18.9% vs. 60.9% (p<0.001). The percentages of patients who have lost PI/r activity were 2.9%, 3.6% and 5.4% <3, 3-6, >6 months after failure compared to 41.2%, 49.0% and 63.0% of those who have lost NNRTI activity (all p<0.001). The risk to accumulate an early NRTI mutation was strongly associated with NNRTI-containing cART (adjusted odds ratio: 13.3 (95% CI: 4.1-42.8), p<0.001).

Conclusions: The loss of activity of PIs and NRTIs was low among patients treated with PI/r, even after long-lasting exposure to a failing cART. Thus, more options remain for second-line therapy. This finding is potentially of high relevance, in particular for settings with poor or lacking virological monitoring.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-HIV Agents / administration & dosage
  • Anti-HIV Agents / therapeutic use*
  • Antiretroviral Therapy, Highly Active
  • Cohort Studies
  • Drug Resistance, Viral / genetics
  • Female
  • Genotype
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • HIV-1* / drug effects
  • HIV-1* / genetics
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Protease Inhibitors / administration & dosage
  • Protease Inhibitors / therapeutic use*
  • Reverse Transcriptase Inhibitors / administration & dosage
  • Reverse Transcriptase Inhibitors / therapeutic use*
  • Risk Factors
  • Time Factors
  • Treatment Failure
  • Viral Load

Substances

  • Anti-HIV Agents
  • Protease Inhibitors
  • Reverse Transcriptase Inhibitors

Grants and funding

This work was supported in the framework of the Swiss HIV Cohort Study, by the Swiss National Science Foundation (SNF grant #33CS30-134277). Further support was provided by SNF grant # 3247B0-112594 (to HFG, SY and BL), SNF grant # 324730-130865 and the SHCS projects # 470, 528, 569, 683, the SHCS Research Foundation, the European Community's Seventh Framework Programme (grant FP7/2007–2013), under the Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN; grant 223131), and by a further research grant of the Union Bank of Switzerland, in the name of a donor to HFG, and an unrestricted research grant from Tibotec, Switzerland, to HFG and from Gilead, Switzerland, to HFG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.