Treatment Outcomes with Dolutegravir (DTG)
Over the past four decades, antiretroviral therapy (ART) has transformed HIV from a fatal disease into a manageable chronic condition. Among the most impactful developments is the widespread adoption of DTG-based ART, now used by over 25 million people globally. As such, it has largely replaced non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART previously used in first-line regimens for most people initiating ART, and ritonavir-boosted lopinavir (LPV/r)-based ART previously used in second-line regimens, or as first-line ART for children initiating ART below three years of age. During this programmatic rollout of DTG, the VICONEL cohort offered an opportunity to assess how DTG outcomes from clinical trials translate to real-world outcomes, monitor the programmatic rollout of DTG, and gain further information on participant-reported outcomes including side effects and tolerability.
The DO-REAL cohort nested within VICONEL showed high short-term viral suppression[JB1] and possible improvements in certain neuropsychiatric symptoms[JB2] upon transition from former NNRTI- to DTG-based ART. Subsequent longer-term analyses in VICONEL showed high two-year viral suppression in children and adolescents[JB3] and adults[JB4] changing from an NNRTI to DTG. Even with DTG, low-level viraemia was associated with subsequent treatment failure[JB5] as had previously been shown for other regimens, supporting the lowering of the viral load threshold from 1000 copies/mL to 50 copies/mL in World Health Organisation guidelines since 2021. Finally, the LoDoCA[JB6] cohort assessed changes in treatment satisfaction and tolerability – including gastrointestinal symptoms commonly associated with LPV/r, and sleep and other neuropsychiatric symptoms previously reported with DTG – among children and adolescents transitioning from LPV/r- to DTG-based ART.
[JB1]https://doi.org/10.1111/hiv.13189
[JB2]https://pubmed.ncbi.nlm.nih.gov/35730213/
[JB3]https://doi.org/10.1097/qad.0000000000003835
[JB4]https://doi.org/10.1093/cid/ciad390
DTG Resistance
As shown above, DTG offers high efficacy, good tolerability, and a strong genetic barrier to resistance, making it a cornerstone of current first-line treatment strategies, especially in high-prevalence regions like southern Africa.
However, while resistance to DTG remains relatively rare, emerging cases of DTG resistance pose a significant threat to recent progress in HIV control. In Lesotho, to assess the prevalence of DTG resistance, we analysed samples from VICONEL participants experiencing persistent or recurrent viremia while on DTG-based regimens. Among this subgroup, 9% were found to have intermediate to high-level resistance to DTG (21), underscoring the urgency of addressing this growing challenge.
In response, the VICONEL-resistance[JB1] project aims to deepen understanding and improve the clinical management of DTG resistance. Specifically, we are:
Identifying predictors of DTG resistance and developing validated eligibility criteria for genotypic resistance testing (GRT).
Assessing the impact of GRT-informed care on treatment outcomes among individuals at risk of DTG resistance:
a. In the overall at-risk population.
b. Among those with confirmed DTG resistance.
Quantifying the evolutionary dynamics of DTG resistance, including the accumulation of resistance-associated and compensatory mutations, and evaluating their phenotypic, clinical, and epidemiological relevance.
This research will inform HIV programs in high-burden settings on the value of targeted GRT in line with the World Health Organisation’s public health approach and address critical knowledge gaps around the emergence, progression, and clinical significance of DTG resistance. (https://data.snf.ch/grants/grant/10003309).
Implementation Network
To complement this scientific work, we are establishing an Implementation Network focused on HIV drug resistance in Lesotho. This initiative aims to:
Improve the accessibility and application of resistance data for healthcare providers, patients, and policymakers.
Develop a national HIV resistance database to support surveillance and case management.
Create training materials and deliver nationwide capacity-building for healthcare workers on the management of HIV drug resistance.
Launch a civil society information campaign to raise public awareness of HIV drug resistance.
Through these activities, we aim to strengthen local healthcare systems and empower communities to respond effectively to the challenges posed by emerging resistance, thereby improving long-term outcomes in HIV care. (https://data.snf.ch/grants/grant/229223)
[JB1]This is just a placeholder - but I think we do need a name
Ndovu study
Additionally, we are participating in the Ndovu study, a multi-country initiative investigating the optimal management strategies for individuals with DTG resistance. This collaboration allows us to contribute to a broader evidence base on how best to detect, monitor, and manage DTG resistance across diverse settings. Insights from the Ndovu study will be pivotal in shaping future guidelines and treatment policies to ensure sustained virologic suppression and preserve the long-term efficacy of DTG-based regimens. (https://clinicaltrials.gov/study/NCT06747507).
Funding: Gates Foundation
Leads: Dr Loice Achieng (…)
Lesotho leads: Irene Ayakaka (SolidarMed), Blaise Lukau (SolidarMed)
Collaborators: Dr. Tapiwa Tarumbiswa (Ministry of Health, Lesotho), Mosa Mabataung Monyake (National Reference Laboratory)
DO-REAL (DOlutegravir in REAL‐Life in Lesotho
The DO-REAL prospective cohort study assessed virological outcomes as well as self-reported symptoms and side effects after the programmatic roll-out of dolutegravir-based antiretroviral therapy. The World Health Organization first recommended dolutegravir as the preferred treatment option for most people with HIV in 2018. At the time, there was good evidence from randomised trials on its high efficacy and tolerability, though little data was available from routine care settings. DO-REAL provided some of the first insights into short-term treatment outcomes upon programmatic transition to dolutegravir, which has now largely replaced prior first- and second-line treatment regimens across Africa and is currently taken by well over 20 million people worldwide. Results were reassuring, showing high viral suppression and slight reductions in side effects. As the study period coincided with the COVID-19 pandemic, secondary serological analyses allowed assessments of SARS-CoV-2 seropositivity over time and of correlates of the strength of antibody response. DO-REAL was conducted in one hospital and was operationally nested within VICONEL. After its completion, larger analyses on longer-term treatment outcomes with dolutegravir were conducted throughout the broader VICONEL cohort.