Enhanced monitoring of a change in HIV first-line treatment: transitioning from Efavirenz to Dolutegravir (EMEDT study)
Dolutegravir (DTG) is a new generation HIV integrase strand transfer inhibitor (INSTI) with high efficacy and excellent tolerability in clinical trials, fewer drug interactions and a high genetic barrier to resistance. Since 2018 WHO has recommended DTG with two nucleoside reverse transcriptase inhibitors (NRTIs) as the preferred 1st-line anti-retroviral therapy (ART). The previous first-line regimen was comprised of one non-nucleoside reverse transcriptase inhibitor (NNRTI) molecule (mainly Efavirenz (EFV)), in combination with two NRTIs, Tenofovir (TDF) and Lamivudine (3TC). The only difference between the previous and the new first-line regimen is that the NNRTI (EFV) component is being replaced with the new drug DTG, while keeping the “NRTI-backbone“ TDF+3TC constant (TDF+3TC+EFV is replaced by TDF+3TC+DTG). Notably, in September 2017, a generic once-per-day fixed-dose combination of tenofovir-lamivudine-dolutegravir (TLD) became available for use in low- and middle-income countries (LMICs), with an annual cost as low as 75 $US per patient per year. Most national HIV treatment guidelines in Sub-Saharan African (SSA) countries have since adopted TLD as the new national first-line ART. Among the first countries in SSA to roll out TLD was Malawi, where nationwide transitioning took place in 2019 and included two groups:
- people living with HIV (PLWH) who were already receiving NNRT-based 1st-line,
- newly diagnosed who initiated ART.
One of the concerns surrounding the wide-scale public health roll-out of the fixed dose combination TLD in resource limited settings is the lack of information on treatment efficacy among patients with pre-existing drug resistance (specifically with resistance to the TDF+3TC “NRTI backbone” of the regimen). Currently no clinical data exist to support switching a large cohort of patients with detectable or unknown VL (and thus inherently an unknown resistance profile) to TLD. While clinical trials are ongoing to address the issue, close monitoring of any public health roll out of TLD is essential in settings where VL monitoring capacity is limited. Since access to HIV viral load (VL) testing (= the gold standard for monitoring treatment effectiveness) is still limited in Malawi, the MoH policy did not consider systematic VL testing of patients on 1st line before transitioning to TLD. The new MoH guideline also recommends genotypic drug resistance testing (DRT) for patients with virological failure on DTG-based regimen, but also access to DRT remains insufficient. Given the limited capacity of MoH Malawi to closely monitor the TLD roll-out policy nationwide, MoH approached MSF for support and take the lead in a collaborative prospective enhanced monitoring on the Efavirenz to Dolutegravir Transitioning (EMEDT study) in Chiradzulu District, Southern Region of Malawi, where MSF has been supporting HIV care since 1996. The EMEDT study accompanied the national roll-out of TLD as a parallel activity. Between January to May 2019, 1928 participants were enrolled and started on TLD first-line: among these 1892 participants who had already been on NNRTI-based ART and 35 who initiated ART with TLD. Study participants are followed up for up to 18 months post TLD treatment start. The main outcome is HIV viral load suppression, specifically among participants who had non-suppressed VL and drug resistance at TLD start. Among secondary objectives, acquired drug resistance to dolutegravir and adherence to treatment (by assessing ARV drug concentration in plasma) among participants with detectable VL is documented.
Tentative End date
MOH Malawi, Queen Elizabeth Hospital Laboratory Blantyre Malawi, Laboratoire de Pharmacocinétique Hôpital Bichat AP-HP France, Hôpital Pitié-Salpêtrière AP-HP France
For more information contact: Birgit Schramm
Mid-term evaluation of models of care for adolescents living with HIV in 3 programs supported by MSF.
Treatment failure is more frequent in adolescents living with HIV than in adults cohorts. In addition, while mortality has declined significantly among children and adults over the past 15 years, it has continued to rise among adolescents until 2015 and has been slowly declining since then.
The reasons for this specificity are multiple: disclosure poorly made or made too late, a long therapeutic history that led to the selection of resistance mutations, the lack of specific management of adolescents by poorly trained teams, etc.
In recent years, MSF France has developed programs in three East African countries with a focus on improving the quality of care for adolescents (10-19 years) living with HIV and on ART. Three different approaches have been developed: in Uganda, MSF supports Arua regional reference hospital’s AERT clinic; in Kenya and Malawi, interventions have been developed in rural districts, mainly at the health center level, but with a different approach. In Chiradzulu, MSF teams directly take care of the patients, while in Kenya's Ndiwa district, teams work in mentoring the Ministry of Health teams.
After about three years of adolescent-centered interventions, quantitative results show an improvement in indicators. It therefore makes it interesting to capitalize on these interventions in order to analyze the strengths and weaknesses of each approach, in order to guide other programs concerned with the problem of HIV-infected adolescents in other contexts.
The purpose of the analysis is to
- Provide a description of the differentiated service delivery models (DSD) model implemented in the 3 HIV programs supported by MSF (Malawi-Chiradzulu, Kenya-Ndhiwa and Uganda-Arua) and the achieved coverage of the different services offered under the DSD model and
- Determine the effectiveness of the models-of-care in improving treatment outcomes of adolescents aged 10 to 19 years living with HIV and enrolled in the 3 programs.
Kenya, Malawi, Ouganda
Tentative End date
Quantitative Analysis of the achieved service coverage and the effectiveness of the model-of-care.
For more information contact: Sarala Nicholas
Evaluation of two strategies part of the Differentiated Services Delivery Models (DSDM) in Fishermen’s landing sites.
An HIV population sero-prevalence survey conducted in 2016 by Epicentre in fishing communities surrounding Lake George and Lake Edward, in western Uganda showed a high awareness of HIV and Anti-retroviral Treatment (ART) initiation, at 86% and 78% respectively. However, viral suppression rate was at 67% among HIV-infected individuals on ART. It has been suggested that the mobile nature of the fishermen and limited access to ART sites are two major barriers to achieve viral suppression.
The main objective of the study is to evaluate the acceptability and describe outcomes (Viral Load suppression and retention) of two different ART delivery strategies for the target populations in MSF Landing sites, to reorient project activities and document best practices.
MSF replaced the former routine clinical follow-up at health center independently of individual HIV characteristics and implemented part of the MOH DSDM (Differentiated Services Delivery Models):
- the Fast Track Refill at Health Center level where stable clients pick their drugs from the pharmacy without going through the normal clinic flow, including a doctor’s review.
- the CCLAD at community level: the delivery of ART drugs at community level to a community ART group by one of the community ART group members on a rotational basis.
The purpose is to assess the MSF activities and patients’ outcomes in the landing sites in order to document best practices and generate recommendations for readjustment of MSF activities.
Tentative End date
For more information contact: Jihane Ben-Farhat
In partnership with DNDi, Cipla developed a fully taste masked ABC/3TC/LPV/r/ “4-in-1” granule formulation with good bioavailability in healthy adult volunteers.
This was a direct request from MSF to the DnDi Board. The active components of The combination of various formulations of lopinavir boosted with ritonavir and abacavir plus lamivudine constitutes one of the first line regimen recommended by WHO since 2013. This study,"Lopinavir/r/Lamivudine/ Abacavir as an easy to use Pediatric Formulation in a Phase I/II Study" is the first study of the 4-in-1 in HIV-infected children. The study is carried out in Uganda in HIV-infected children weighing ≥3 to <25 kg and unable to swallow tablets. It aims to provide supportive clinical data on the pharmacokinetics, safety, tolerability and acceptability of the 4-in1. The Lopinavir/Ritonavir pellets plus dual Abacavir/Lamivudine tablets regimen which is current standard of care for young children (<3 years old) in Uganda was chosen to provide elements of comparison. The cross-over design is intended to minimize the impact of intra-subject variations, in particular pharmacokinetics.
The primary objective is to estimate the population average exposure to LPV, ABC and 3TC in the 4-in-1 formulation in HIV infected children dosed per WHO weight bands.
A phase I/II, open label, randomized crossover pharmacokinetic, safety and acceptability study of the Abacavir/ Lamivudine / Lopinavir / Ritonavir Fixed-Dose Combination vs. Lopinavir / Ritonavir plus dual Abacavir / Lamivudine in HIV infected Children.
Tentative End date
Who's Involved Besides MSF?
DNDi, Joint Clinical Research Centre, Uganda, AMS‐PHPT, Research Platform
For more information contact: Juliet Mwanga