ADVANCE Trial – A rigorous clinical trial that could yield better first-line HIV treatment

A rigorous clinical trial that could yield better first-line HIV treatment.

Challenges

Current first-line regimens recommended in low- and middle-income countries have successfully treated over 15 million people. However, the regimens are highly susceptible to drug resistance, even in the event of a slight decrease in adherence. This results in rapid transition to more expensive and more complex second-line regimens. First-line regimens also prove toxic for a significant number of patients, compromising adherence.

The need for better regimens in resource-limited settings remains unmet. Experience has shown that transition to new antiretroviral combinations can be very challenging in low- and middle-income countries. Lack of effective planning and implementation often leads to delays in adopting new WHO recommendations.

Solutions

The ADVANCE project includes a rigorous clinical trial that is providing evidence on optimal first-line regimens with the potential to transform healthcare for HIV-positive people in resource-constrained settings.

A large community-, clinician- and regulatory-engagement programme has been running in tandem with the clinical trial to prepare South Africa and the region for this regimen.

This trial evaluates a new first-line regimen that is cheaper, more tolerable for patients, and require a smaller dose than existing first-line regimens.  It also aims to provide a far higher barrier to resistance.

“If we get this right, patients will benefit from safer, better tolerated, more forgiving and smaller tablets, while governments will save money. It is not often in medicine we get such a win-win.”
François Venter, Principal investigator, ADVANCE trial

Progress so far

The ADVANCE trial started screening in mid-January 2017, with enrolment completed in May 2018. A total of 1,053 participants were enrolled.Interim (48-week) results contributed to the revision of the WHO HIV treatment guidelines in June 2019 and were presented at the IAS conference in Mexico City and published in the New England Journal of Medicine in July 2019. The grant also contributed to changing the national treatment guidelines in South Africa, with the rollout of the updated guidelines in November 2019 and the launch of an ARV tender in Q2 2019.  Additionally, the grant has been instrumental in improving treatment literacy and generating demand for dolutegravir (DTG) -based regimens among communities, through the work of Treatment Action Campaign, and training clinicians through the Southern African HIV Clinicians Society (SAHCS).

96-week findings, which were presented at AIDS 2020 showed that viral suppression did not differ between the three study arms in intention-to-treat analysis, while people taking EFV/TDF/FTC had slightly more treatment-emergent resistance. People randomized to DTG+TAF/FTC gained more weight than those randomized to other arms. The 96-week findings will be published in the Lancet HIV in Q3 2020.

In addition to the 96-week outcomes data being presented at AIDS 2020, predicted risk of adverse pregnancy outcomes from treatment induced obesity in the ADVANCE study, and meta-analysis of DTG use in pregnant women, were also presented. Finally, a manuscript on dolutegravir and folate metabolism was published by the journal AIDS. https://www.nejm.org/doi/10.1056/NEJMoa1902824

In response to weight gain and hyperglycaemia safety signals associated with DTG use in some populations, the ADVANCE trial was extended to reach 192-week outcomes along with Unitaid supported NAMSAL and DoLPHIN-2 trials (collectively known as TRIO) to allow for a longer monitoring period in addition to an opportunity to coordinate and pool data.  Final analysis of TRIO data will be published in Q2 2022.

Two COVID-19 sub-studies were included in the ADVANCE trial:

  1. COHIVE was included in the ADVANCE (and also NAMSAL, DolPHIN-2 and D2EFT trials) to assess the impact of COVID-19 in people living with HIV, clarify risks for people living with HIV (comorbidities, slower clearance and longer transmissibility). Results should be published in Q3/4 2021. https://kirby.unsw.edu.au/project/cohive-coronavirus-outcomes-hiv-evaluation-resource-limited-settings
  1. COVER Health Care Workers (HCW) was included in the ADVANCE trial, aiming to identify oral drugs which could prevent SARS-CoV-2 infection, especially in frontline HCW in resource limited settings both by preventing infections (vis a vis pre-exposure and post-exposure prophylaxis) and in suppressing the viral load for those already infected, lessening the reliance on diagnostics to make decisions on starting treatment. Results should be published in Q3/4 2021.

The impact we are seeking

The ultimate objective of this grant is to generate evidence that supports the wider adoption of optimal ARV regimens that are cheaper, more tolerable for patients, and have a smaller dosage than existing first-line regimens.

The significantly lower price of new therapies has enabled the South African government to provide ART to several million more people with HIV.

Link to related article: Cutting the cost of South African antiretroviral therapy using newer, safer drugs” – South African Medical Journal

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