First-line antiretroviral regimens are safe, effective and easily administered (one pill taken once daily). Even so, the annual failure rate is around 10-15% of treated patients. Second-line regimens have a number of limitations, disproportionately impacting resource-limited settings. Ideally choice of the second-line regimen is guided by expensive and technically demanding HIV drug resistance testing. Drug resistance, previous treatment and known toxicities means individuals require a tailored regimen of second-line therapy where multiple pills are taken more than once a day. Unaddressed, the challenge of care for patients failing first-line antiretroviral therapy could profoundly and negatively affect the long-term effectiveness of treatment programs for infected individuals and their communities.
The trial was originally deisgned to establish if a simple, novel combination of antiretroviral drugs (dolutegravir and ritonavir boosted darunavir) was safe and effective as the currently recommended World Health Organisation standard of care (SOC) second-line regimens. The benefits of this novel combination included a high barrier to resistance, negating the need for HIV drug resistance testing; the ability to co-formulate the drugs into a single pill requiring once daily dosing; cost savings as the simplified regimen would support task-shifting where prescriptions can be written by clinical nurses or physician assistants; simplification of supply chain and distribution by reducing the number of pills required.
Since the D²EFT study commenced, data has emerged to suggest that use of dolutegravir with pre-determined nucleosides may be an additional useful approach to second line therapy. Dolutegravir with pre-determined nucleosides is now available at a very low cost in low income countries. If effective in second line, this approach would allow substantial reductions in cost and complexity of care. After consultation with the World Health Organisation and other key stakeholders, the D²EFT study has been modified to add a third arm, allowing evaluation of a simplified approached of dolutegravir with pharmaco-enhanced darunavir versus dolutegravir with predetermined nucleosides against recommended standard of care antiretroviral regimens and secondarily against each other.
D²EFT is a randomised, open-label study recruiting participants from sites Argentina, Chile, Colombia, India, Malaysia, Mexico, Brazil, South Africa, Thailand, Zimbabwe, Nigeria, Indonesia, Mali and Guinea. The design is based on the hypothesis that the simplified regimens will be non-inferior to SOC in terms of virologic control, while the primary endpoint is the proportion of participants in each arm whose plasma viral load is <50 copies/mL at 48 weeks. The open label nature of the study allows routine care to be undertaken. A comparison of costs and estimates of cost-effectiveness between the treatment groups will be made utilising drug costs, health-care costs and quality of life measures.
The 48 primary analysis is expected in 2021. Final week 96 analyses would be expected the following year.
The over-arching goal of the project is to provide the highest standard of evidence that will inform applicable treatment guidelines for second-line HIV therapy in resource-limited settings. It will either provide further validation for current recommendations or offer alternate approaches. If the latter, we would anticipate that the resulting recommendations would be implemented through the responsible agencies within defined geographical areas or countries. By incorporating diversity in our trial design we ensure the results are broadly applicable and generalisable to a similarly diverse set of clinical situations, making our findings directly translatable into the treatment of millions of people in resource-limited settings.