Optimizing Combination Therapy after Treatment Failure Using the Latest Technologies in Resource-Limited Settings

ACTG A5288 was the first large multicontinental clinical trial in low- and middle-income countries (LMICs) for people living with HIV who experienced treatment failure after at least six months of second-line antiretroviral treatment (ART). When this study was being planned, there were no recommendations for which ART to choose when a second-line treatment was unsuccessful – thus, third-line therapy was not available in most LMICs.

A5288 enrolled people whose HIV-1 RNA levels were ≥ 1000 copies/mL after more than 24 weeks of protease inhibitor (PI)-based ART and prior unsuccessful non-nucleoside reverse transcriptase inhibitor-based ART. This analysis, which focused on the 278 participants who had no resistance to the PI they had taken and no or limited resistance to nucleoside reverse transcriptase inhibitors (NRTIs), who continued taking their PI and had the flexibility to change NRTIs, found that poor adherence was likely a major contributor to unsuccessful second-line ART. Proportional hazards models were used to evaluate predictors of virologic failure during follow-up.

The majority of participants (56%) were female, median age was 40 years, time on ART was 7.8 years, median CD4 count was 169 cells/mm3, HIV-1 RNA 20,444 copies/mL; and 37% had NRTI resistance. The estimated proportion of individuals who were not virally suppressed went from 39% at week 24 to 60% at week 96. In multivariable analysis, significant predictors at study entry of treatment failure included:

  • Higher HIV-1 RNA (adjusted hazard ratio: 2.20 for ≥ 10,000 versus < 10,000 copies/mL)
  • Younger 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)
  • Shorter ART duration (1.62 for < 10 versus ≥ 10 years)

Those who were not virally suppressed at week 96 had more of the risk factors listed above (treatment failure was observed in 8% for those with zero risk factors and rose to 31%, 40%, 73%, and 100% for one, two, three, and four/five factors, respectively). Only 13% of participants developed new NRTI or PI resistance mutations during study follow up.

This analysis identified factors that predict future treatment failure when continuing PI-based ART among participants who are not virally suppressed on that current regimen (and have no PI resistance and no/limited NRTI resistance). The simple scoring system based on these factors merits further evaluation to assess whether its use, coupled with novel adherence support strategies and newer ART regimens, might enhance outcomes in this population.


Salata, R. A., Grinsztejn, B., Ritz, J., Collier, A. C., Hogg, E., Gross, R., Godfrey, C., Kumarasamy, N., Kanyama, C., Mellors, J. W., Wallis, C. L., Hughes, M. D., & ACTG A5288 Study Team (2023). 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. AIDS research and therapy, 20(1), 3. https://doi.org/10.1186/s12981-022-00494-9