In what is possibly one of the largest treatment roll-outs in South African history, more than 4m people with HIV have started taking the antiretroviral dolutegravir since its introduction just four years ago.
The medication – associated with more people staying on treatment and higher rates of viral suppression – is a three-in-one combination of the antiretroviral drugs tenofovir, lamivudine and dolutegravir (TLD for short) and was first recommended by the World Health Organisation (WHO) in 2018.
A year later it was recommended in the South African treatment guidelines as first line treatment for HIV and a three-year tender was awarded. Since then, it has largely replaced the antiretroviral called efavirenz, and become the recommended treatment option, writes Elri Voigt for Spotlight.
The 2023 national antiretroviral (ARV) guidelines also include recommendations for child-friendly formulations of dolutegravir and dolutegravir-containing regimens for children.
Fixed dose
The department’s goal was that 90% of those eligible for it should receive TLD as a first line regimen: and by March 2023, 4 127 427 people were on TLD. Additionally, about 650 000 were on other dolutegravir based regimens. Altogether, there are thus now more than 4.7m South Africans on treatment combinations that include dolutegravir.
Of the total number of people on ART in the public health sector, 75.8% are on TLD.
The transition from efavirenz to dolutegravir-based regimens has not been smooth, however.
A study published in The Lancet earlier this year looked at real-world roll-out data from 2019 to 2022. Conducted in 59 clinics countrywide, it collected data from two cohorts-one involved first time initiators of ART and the other cohort was people transitioning from regimens that did not include dolutegravir to ones that did.
In the initiator cohort, just more than 45 000 people were initiated on ART between December 2019 and February 2022. Of those, 68.9% were initiated on dolutegravir-based regimens, 31.1% on efavirenz-based regimens, and 0.1% on nevirapine-based regimens.
Those on dolutegravir-based regimens were more likely to still be on treatment a year later and were also more likely to be virally suppressed than those who were on the other regimens.
In December 2019, in the transition cohort, just more than 180 000 people were on a non-dolutegravir first line regimen. By February 2022, 67% had transitioned to a dolutegravir-based regimen.
These people were also more likely to be retained in care at 12 months and be virologically suppressed than those who had not switched to a dolutegravir-based regimen.
“It means the treatment’s working, people are less likely to get unwell and also, they can’t transmit the virus,” said Dr Jienchi Dorward, one of the study authors and an academic clinical lecturer at the University of Oxford and honorary associate scientist at the Centre for the Aids Programme of Research in South Africa (CAPRISA).
‘Bumpy transition’
Dr Yukteshwar Sookrajh, a senior medical practitioner at the eThekwini Municipality Health Unit who was also involved in the study, told Spotlight the roll-out quickly gathered momentum.
“But initially there were issues to navigate around drug interactions; concurrent TB infection and the use of dolutegravir in women of childbearing potential,” he said. “Once those concerns were addressed, the ease of switching to dolutegravir was increased and most of our patients have now safely transitioned to dolutegravir-based regimens.”
In many ways South Africa was slower than other African countries in rolling out dolutegravir, said Professor Francois Venter, head of Ezintsha at Wits University. Reasons include an initial concern around the safety of dolutegravir use among pregnant women, and disruption in training due to the pandemic.
He said the South African Clinicians Society was alerted during the Covid-19 pandemic that many patients had still not been transitioned to dolutegravir. An education campaign was then launched to speed this up, and has been a huge success.
Initial safety concerns
One important reason to conduct the study reported in The Lancet, said Dorward, was a safety concern regarding dolutegravir and pregnant women.
An earlier study conducted in Botswana called Tsepamo found a higher prevalence of neural-tube defects associated with dolutegravir exposure at conception than with other types of antiretroviral exposure.
As more data have been gathered since, it has, however, become clear that dolutegravir does not, in fact, increase the risk of neural-tube defects.
But the Tsepamo scare did affect who was initiated and transitioned on to dolutegravir in first two years of the rollout.
The Lancet study found that pregnant women and non-pregnant women were less likely to be initiated on dolutegravir than men early in the rollout, with the biggest difference between women and men aged 15 to 24 years old. This difference decreased with age and by age 55 there was no difference between men and women receiving dolutegravir.
But this changed over time and by September 2021 women were as likely to get initiated on dolutegravir as men.
The rollout was done in two stages. In the first stage men, adolescent boys, women on reliable contraception, and older women were prioritised.
Of those who started treatment during the study period, 46.9% of the pregnant women in the cohort were initiated on dolutegravir-based regimens, while 63.9% of the non-pregnant women and 82.3% of the men in the cohort were initiated on dolutegravir-based regimens.
“In both those groups [cohorts] we found women were less likely than men to get dolutegravir, particularly in younger women,” Dorward said. “As time went on, the difference between men and women became much less…around June to September 2021 was a period where we found women and men began to equally get dolutegravir.”
Dorward says the data showed an uptick in women in the study being given dolutegravir once the South African guidelines changed to reflect that there was no longer a concern around neural-tube defects.
It is thus likely that the safety concern was responsible for the lower initial uptake among young women.
He said messaging around this potential risk was based on the evidence available at the time and clearly outlined in the guideline document and training for dolutegravir use, but these did not appear to adequately allay healthcare workers’ concerns.
“The risks versus benefits needed to be messaged more effectively so that they are more confident in offering dolutegravir to women,” he said.
Sookrajh said the National Department of Health’s ARV 2023 guidelines will further improve uptake of dolutegravir.
Surveillance
Venter said proper resistance surveillance was necessary to detect potential dolutegravir resistance.
“We can’t take for granted we’ll never have resistance …eventually there will be the occasional patient who has resistance, but we need proper surveillance. There are still patients getting HIV…lots of new infections…we need to stop that…we’ve got amazing PrEP and too few people getting it. So, we do need to start addressing that.”
Venter said while successful in the public health sector, dolutegravir use in the private sector has been extremely slow, for unknown reasons.
Study details
Implementation and outcomes of dolutegravir-based first-line antiretroviral therapy for people with HIV in South Africa: a retrospective cohort study
Jienchi Dorward, Yukteshwar Sookrajh, Thokozani Khubone, Johan van der Molen, Riona Govender, Sifiso Phakathi, et al.
Published in The Lancet on 28 March 2023
Summary
Background
There are few data assessing the uptake of first-line dolutegravir among men and women living with HIV in low-income and middle-income countries, and subsequent clinical outcomes in non-trial settings. We aimed to determine dolutegravir uptake in women, and the effect of dolutegravir on clinical outcomes in routine care in South Africa.
Methods
In this cohort study, we analysed deidentified data from adults receiving first-line antiretroviral therapy (ART) at 59 South African clinics from Dec 1, 2019, to Feb 28, 2022, using two distinct cohorts. In the initiator cohort, we used Poisson regression models to assess the outcome of initiation with dolutegravir-based ART by gender, and associations between dolutegravir use and the outcomes of 12-month retention in care and viral suppression at less than 50 copies per mL. In the transition cohort, comprising adults who received non-dolutegravir-based first-line ART in December, 2019, we used Cox proportional hazards models to assess the outcome of transition to first-line dolutegravir by gender. We then used time-dependent propensity score matching to compare the outcomes of subsequent 12-month retention in care and viral suppression between people who transitioned to dolutegravir and those who had not yet transitioned at the same timepoint. In both the initiation and transition cohort, the primary viral load analysis was an intention-to-treat analysis, with a secondary as-treated analysis that excluded people who changed their ART regimen after baseline.
Findings
In the initiator cohort, between Dec 1, 2019, and Feb 28, 2022, 45 392 people were initiated on ART. 23 945 (52·8%) of 45 392 were non-pregnant women, 4780 (10·5%) were pregnant women, and 16 667 (36·7%) were men. The median participant age was 31·0 years (IQR 26·0–38·0) and 2401 (5·3%) were receiving tuberculosis treatment at time of ART initiation. 31 264 (68·9%) of 45 392 people were initiated on dolutegravir, 14 102 (31·1%) on efavirenz, and 26 (0·1%) on nevirapine. In a univariable Poisson regression model, pregnant women (risk ratio [RR] 0·57, 95% CI 0·49 to 0·66; risk difference –35·4%, 95% CI –42·3 to –28·5) and non-pregnant women (RR 0·78, 0·74 to 0·82; risk difference –18·4%, –21·6 to –15·2) were less likely to be initiated on dolutegravir than were men. In Poisson models adjusted for age, gender (including pregnancy), time, tuberculosis status, and initiation CD4 count, people initiated on dolutegravir were more likely to be retained in care at 12 months (adjusted RR 1·09, 95% CI 1·04 to 1·14; adjusted risk difference 5·2%, 2·2 to 8·4) and virally suppressed (adjusted RR 1·04, 95% CI 1·01 to 1·06; adjusted risk difference 3·1%, 1·2 to 5·1) compared with those initiated on non-dolutegravir-based regimens. For the transition cohort, on Dec 1, 2019, 180 956 people were receiving non-dolutegravir-based first-line ART at the study clinics, of whom 124 168 (68·6%) were women. The median age was 38 years (IQR 32–45), and the median time on ART was 3·9 years (2·0–6·4) years, with most people receiving efavirenz (178 624 [98·7%] people) and tenofovir (178 148 [98·4%]). By Feb 28, 2022, 121 174 (67·0%) of 180 956 people had transitioned to first-line dolutegravir at a median of 283 days (IQR 203–526). In a univariable Cox regression model the hazard of being transitioned to dolutegravir was lower in women than in men (hazard ratio 0·56, 95% CI 0·56 to 0·57). Among 92 318 propensity score matched people, the likelihood of retention in care was higher among the dolutegravir group compared with matched controls (adjusted RR 1·03, 95% CI 1·02 to 1·03; risk difference 2·5%, 95% CI 2·1 to 2·9). In the dolutegravir group, 33 423 (90·5%) of 36 920 people were suppressed at less than 50 copies per mL compared with 31 648 (89·7%) of 35 299 matched controls (adjusted RR 1·01, 95% CI 1·00 to 1·02; risk difference 0·8%, 95% CI 0·3 to 1·4).
Interpretation
Women were less likely to receive dolutegravir than men. As dolutegravir was associated with improved outcomes, roll-out should continue, with a particular emphasis on inclusion of women.
National ART Clinical Guideline 2023_06_06 version 3 Web
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