A randomised controlled trial of a protease inhibitor monotherapy versus continuing combination antiretroviral therapy for HIV-1 infected patients previously established on a dual nucleoside and non-nucleoside combination regimen

The current standard-of-care treatment for people living with HIV is combination antiretroviral therapy (ART), usually consisting of 3 drugs: 2 nucleoside reverse transcriptase inhibitors (NRTIs) with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). Although triple ART has a relatively high long-term success rate, a proportion of patients (about 4% per year) continues to experience virological failure, and this is often associated with complete resistance to one or more drugs (especially NRTI and NNRTI classes). Furthermore, long-term drug toxicity remains a concern. Additional strategies for long-term management are needed that preserve future drug options and minimise toxicity. This trial aims to determine whether a strategy of switching to PI monotherapy is non-inferior to continuing triple-therapy, in terms of the proportion of patients who maintain all their future drug treatment options, and to compare clinical events, safety, toxicity and health economic parameters between the two strategies. 400 patients will be randomised (1:1) to PI monotherapy or to continue triple therapy. Patients randomised to the PI monotherapy group will stop other ART drugs and start or continue only on a ritonavir-boosted PI (selection of drug at discretion of physician and patient). Those who do not maintain complete virological suppression or who are unable to tolerate the PI (substitution for toxicity is allowed), will promptly switch back to their previous triple-therapy. Patients randomised to the control group will continue their current regimen. The trial will be conducted over 5 years, including an initial recruitment period estimated to last 12 to 18 months. All patients will continue on treatment and follow-up until close of the trial. Analyses will compare the 2 groups by intention to treat (ITT). Loss of future drug options defined as the occurrence of intermediate to high level resistance to any one or more of the standard antiretroviral drugs (limited to licensed drugs in contemporary use) to which the patients virus was considered to be sensitive at trial entry. Secondary outcome measures are serious drug or disease-related complications; adverse events; virological rebound; CD4+ count change; health-related Quality of Life change; Neurocognitive function change; Cardiovascular risk change; Health care costs report forms (CRFs). The trial will be coordinated by the MRC Clinical Trials Unit and conducted at 40 sites in the UK and Ireland.