Predictors of virologic outcome among people living with HIV who continue a protease inhibitor-based antiretroviral regimen following virologic failure with no or limited resistance

Abstract

Background: Treatment management after repeated failure of antiretroviral therapy (ART) is difficult due to resistance and adherence challenges. For people who have failed non-nucleoside reverse transcriptase inhibitor-(NNRTI-) and protease inhibitor-(PI-) based regimens with no or limited resistance, remaining on PI-based ART is an option. Using data from an ART strategy trial (A5288) in low/middle-income countries which included this option, we explored whether predictors can be identified distinguishing those who experienced further virologic failure from those who achieved and maintained virologic suppression.

Methods: A5288 enrolled people with confirmed HIV-1 RNA ≥ 1000 copies/mL after ≥ 24 weeks of PI-based ART and prior failure on NNRTI-based ART. This analysis focused on the 278 participants with no resistance to the PI being taken and no or limited nucleoside reverse transcriptase inhibitor (NRTI) resistance, who continued their PI with flexibility to change NRTIs. Proportional hazards models were used to evaluate predictors of virologic failure during follow-up (VF: confirmed HIV-1 RNA ≥ 1000 copies/mL at ≥ 24 weeks of follow-up).

Results: 56% of participants were female. At study entry, median age was 40 years, time on ART 7.8 years, CD4 count 169 cells/mm³, HIV-1 RNA 20,444 copies/mL; and 37% had NRTI resistance. The estimated proportion experiencing VF increased from 39% at week 24 to 60% at week 96. In multivariable analysis, significant predictors at study entry of VF were higher HIV-1 RNA (adjusted hazard ratio: 2.20 for ≥ 10,000 versus < 10,000 copies/mL), lower age (1.96 for < 30 versus ≥ 30 years), NRTI resistance (1.74 for present versus absent), lower CD4 count (1.73 for < 200 versus ≥ 200 cells/mm³), and shorter ART duration (1.62 for < 10 versus ≥ 10 years). There was a strong trend in proportion with VF at week 96 with the number of these five risk factors that a participant had, varying from 8% for zero, to 31%, 40%, 73%, and 100% for one, two, three, and four/five. Only 13% of participants developed new NRTI or PI resistance mutations.

Conclusion: A simple count of five predictors might have value for identifying risk of continued VF. Novel antiretroviral and adherence support interventions are needed to improve virologic outcomes for higher risk individuals.

Fig. 1

Estimated Cumulative proportion of participants with virologic failure (confirmed HIV-1 RNA ≥ 1000 Copies/mL at or after 24 weeks) over time, in the overall study population and by selected characteristics of participants at study entry

Fig. 2

Estimated Cumulative proportion of participants with virologic failure (confirmed HIV-1 RNA ≥ 1000 Copies/mL At or after 24 weeks) at Weeks 24 and 96 by Number of Risk Factors for Virologic Failure a Participant Had. Bars Show Breakdown of Those With Versus Without New NRTI and/or PI Mutations. Risk Factors Were Age at Study Entry < 30 Years, HIV-1 RNA at Study Entry ≥ 10,000 Copies/mL, CD4 Count at Study Entry < 2000 Cells/mm³, Any NRTI Resistance Identified at Study Screening, and Duration of Prior ART at Study Entry < 10 Years