Title: 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
Funder: Department of Health and Social Care

Abstract: 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.

Lay abstract: The standard treatment for HIV infection involves use of three drugs simultaneously that work together to block HIV multiplying in the body and thereby prevent death and disability from the disease. The treatment needs to be taken life-long and is expensive, costing the NHS in excess of £175 million per year. Some newer drugs, protease inhibitors (PI), appear sufficiently potent to be able to maintain the block on HIV replication when used as monotherapy. This has the potential to dramatically reduce HIV drug costs to the NHS and simplified regimens may prove more tolerable to patients. We propose to randomise patients taking standard of care triple therapy to continue this or to switch to PI monotherapy with careful monitoring of viral replication and a prompt switch back to triple therapy for those in whom viral replication is not adequately controlled. The main question is whether patients on PI monotherapy will lose more future drug options by developing resistance mutations at a faster rate than do the control patients, or do they do just as well. The study will also look at the cost savings, as well as comparing side effects between the two treatment groups. There are no major ethical concerns with the study. The intervention arm has careful monitoring and a plan for a prompt switch back to standard of care if the PI monotherapy does not appear sufficiently potent. The drugs used in this study will all be licensed drugs, and the toxicity risks are known to be small. The study will be conducted by the MRC Clinical Trials Unit using an established network of clinical research sites located in HIV treatment clinics throughout the UK. The study team comprises recognised national experts in HIV clinical care, HIV randomised controlled trials, HIV virology and in health economics. The sample size of 400 patients is feasible based on the broad applicability of the study entry criteria and the capacity of the research network. The costs are realistic, and the study represents excellent value to the NHS given that the savings in drug costs in the study almost cover the research costs.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION