Boosted protease inhibitor monotherapy as second-line ART: a strategy for resource-limited settings?

Lopinavir/ritonavir monotherapy as second-line antiretroviral treatment in resource-limited settings - week 104 analysis of ACTG A5230.

Kumarasamy N, Aga E, Ribaudo HJ, Wallis CL, Katzenstein DA, Stevens WS, Norton MR, Klingman KL, Hosseinipour MC, Crump JA, Supparatpinyo K, Badal-Faesen S, Bartlett JA. Clin Infect Dis. 2015 Feb 18. pii: civ109. [Epub ahead of print]

Objective: ACTG A5230 evaluated lopinavir/ritonavir (LPV/r) monotherapy following virologic failure on first-line regimens in Africa and Asia.

Methods: Eligible subjects had received first-line regimens for at least 6 months and had plasma HIV-1 RNA levels 1000-200 000copies/mL. All subjects received LPV/r 400/100mg twice daily. Virologic failure (VF) was defined as failure to suppress to <400 copies/mL by week 24, or confirmed rebound to >400 copies/mL at or after week 16 following confirmed suppression. Subjects with VF added emtricitabine 200mg/tenofovir 300mg (FTC/TDF) once daily. The probability of continued HIV-1 RNA <400 copies/mL on LPV/r-monotherapy through week 104 was estimated with a 95% confidence interval (CI); predictors of treatment success were evaluated with Cox proportional hazards models.

Results: 123 subjects were enrolled. Four subjects died and 2 discontinued prematurely; 117 /123 (95%) completed 104 weeks. Through week 104, 49 subjects met the primary endpoint; 47 had VF, and 2 intensified treatment without VF. Of the 47 subjects with VF, 41 (33%) intensified treatment, and 39/41 subsequently achieved levels <400 copies/mL. The probability of continued suppression <400copies/mL over 104 weeks on LPV/r-monotherapy was 60% [95% CI 50%, 68%]; 80-85% maintained levels <400 copies/mL with FTC/TDF intensification as needed. Ultrasensitive assays on specimens with HIV-1 RNA level<400 copies/mL at weeks 24, 48 and 104 revealed that 61%, 62% and 65% were suppressed to <40 copies/mL, respectively.

Conclusion: LPV/r monotherapy after first-line virologic failure with FTC/TDF intensification when needed provides durable suppression of HIV-1 RNA over 104 weeks.

Abstract access  [1]

Editor’s notes: First-line antiretroviral therapy failure is increasingly encountered in resource-limited settings. However limited access to viral load monitoring means that treatment failure is often not recognised until immunological or clinical failure occurs. Late switching can lead to the accumulation of resistance mutations. Resistance to nucleoside reverse transcriptase inhibitors (NRTI) is of particular concern as this class remains a component of second-line, boosted protease inhibitor (bPI)-based regimens. Several studies have now looked at boosted protease inhibitor monotherapy as an alternative strategy. A strategy which aims to limit the toxicity and additional cost associated with NRTIs. In general boosted protease inhibitor monotherapy has been found to have inferior virologic outcomes when compared to bPI plus two NRTIs or bPI plus raltegravir.

In this study, while short term virologic outcomes were favourable (87% probability of continued virologic suppression over 24 weeks); longer term outcomes with bPI monotherapy were less good. However, with frequent viral load monitoring, 4-12 weekly, early detection of virologic failure and intensification with two NRTIs, outcomes in the bPI monotherapy arm improved substantially. This strategy warrants further investigation. But without markedly increasing access to viral load monitoring and lowering the cost to allow frequent testing, it is difficult to see how this strategy could be implemented in practice in resource-constrained settings. 

HIV Treatment [4]
Africa [5], Asia [6]
India [7], Malawi [8], South Africa [9], Thailand [10], United Republic of Tanzania [11]
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