Abstract
SummaryBackgroundStandard-of-care antiretroviral therapy (ART) uses a combination of drugs deemed essential to minimise treatment failure and drug resistance. Protease inhibitors are potent, with a high genetic barrier to resistance, and have potential use as monotherapy after viral load suppression is achieved with combination treatment. We aimed to assess clinical risks and benefits of protease inhibitor monotherapy in long-term clinical use: in particular, the effect on drug resistance and future treatment options.MethodsIn this pragmatic, parallel-group, randomised, controlled, open-label, non-inferiority trial, we enrolled adults (≥18 years of age) positive for HIV attending 43 public sector treatment centres in the UK who had suppressed viral load (<50 copies per mL) for at least 24 weeks on combination ART with no change in the previous 12 weeks and a CD4 count of more than 100 cells per μL. Participants were randomly allocated (1:1) to maintain ongoing triple therapy (OT) or to switch to a strategy of physician-selected ritonavir-boosted protease inhibitor monotherapy (PI-mono); we recommended ritonavir (100 mg)-boosted darunavir (800 mg) once daily or ritonavir (100 mg)-boosted lopinavir (400 mg) twice daily, with prompt return to combination treatment if viral load rebounded. All treatments were oral. Randomisation was with permuted blocks of varying size and stratified by centre and baseline ART; we used a computer-generated, sequentially numbered randomisation list. The primary outcome was loss of future drug options, defined as new intermediate-level or high-level resistance to one or more drugs to which the patient's virus was deemed sensitive at trial entry (assessed at 3 years; non-inferiority margin of 10%). We estimated probability of rebound and resistance with Kaplan-Meier analysis. Analyses were by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISRCTN04857074.FindingsBetween Nov 4, 2008, and July 28, 2010, we randomly allocated 587 participants to OT (291) or PI-mono (296). At 3 years, one or more future drug options had been lost in two participants (Kaplan-Meier estimate 0·7%) in the OT group and six (2·1%) in the PI-mono group: difference 1·4% (−0·4 to 3·4); non-inferiority shown. 49 (16·8%) participants in the OT group and 65 (22·0%) in the PI-mono group had grade 3 or 4 clinical adverse events (difference 5·1% [95% CI −1·3 to 11·5]; p=0·12); 45 (six treatment related) and 56 (three treatment related) had serious adverse events.InterpretationProtease inhibitor monotherapy, with regular viral load monitoring and prompt reintroduction of combination treatment for rebound, preserved future treatment options and did not change overall clinical outcomes or frequency of toxic effects. Protease inhibitor monotherapy is an acceptable alternative for long-term clinical management of HIV infection.FundingNational Institute for Health Research.
Highlights
Current HIV treatment guidelines recommend a combination of two drug classes for initiation and maintenance of antiretroviral therapy (ART).[1,2] The principle of combining drugs with different mechanisms of action to increase potency and reduce selection of drug-resistant mutants is common to the treatment of many infectious diseases
All investigating lopinavir monotherapy, and, overall, these trials supported the hypothesis of virological non-inferiority of monotherapy to triple therapy
Whereas previous trials compared predefined regimens with short-term viral load endpoints, this trial compared treatment strategies with a primary efficacy endpoint relevant to long-term clinical management. In this trial we noted an increase of about 32% in absolute risk of virological failure with protease inhibitor monotherapy, but all patients with rebound resuppressed spontaneously or with reintroduction of combination ART
Summary
Current HIV treatment guidelines recommend a combination of two drug classes for initiation and maintenance of antiretroviral therapy (ART).[1,2] The principle of combining drugs with different mechanisms of action to increase potency and reduce selection of drug-resistant mutants is common to the treatment of many infectious diseases. In HIV, the need for combination treatment might decrease once viral load has been suppressed. With a high genetic barrier to resistance, and are the only drugs that act at many steps of the HIV lifecycle, having potential for use alone as monotherapy.[3] Protease inhibitor monotherapy could be an attractive therapeutic option because of its potential to reduce renal, CNS, and other toxic effects associated with drugs widely used in standard ART combinations. The high genetic barrier to resistance might reduce the risk of resistance during periods of suboptimum treatment adherence.
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