Results from recent studies reveal the emergence of resistance in subsets of HIV patients to dolutegravir – an antiretroviral commonly used in South Africa – but experts say there is no need to panic.
Elri Voigt writes in Spotlight that after a World Health Organisation (WHO) recommendation, South Africa started providing dolutegravir in 2019: it has hardly any side effects, is extremely good at suppressing HIV, and the HIV virus does not easily develop resistance to it.
In just four years, more than 4.7m people in this country were switched over to dolutegravir-based treatment (typically combined into a single pill with the antiretrovirals tenofovir and emtracitabine), and so far, this has been a resounding success.
A large study published in The Lancet early last year found that South Africans who switched to such dolutegravir-based treatment combinations were more likely to stay on treatment and to have viral suppression.
‘Higher than expected’
Though experts remain overwhelmingly positive about dolutegravir-based HIV treatment, some concerns about drug resistance have emerged. Both a new WHO report on HIV drug resistance and several studies presented at the Conference of Retroviruses and Opportunistic Infections (CROI) in Denver, Colorado, last month, indicated that drug resistance to the treatment is emerging in certain populations, and that levels are higher than anticipated.
Among the four surveys providing data to the WHO, resistance levels ranged from 3.9% to 8.6%. It reached a high of 19.6% among people with high viral loads who switched from other ARVs to a dolutegravir-based regimen.
The WHO report was released a day before a session dedicated to dolutegravir resistance at CROI, which featured findings from five studies. A sixth study was presented at another session at the conference.
Critically, these studies, as with some of the WHO data, didn’t measure dolutegravir resistance in everyone taking the drug, but only in subsets of people with high viral loads.
“It’s a small number of cases and most are in a very specific context,” said Professor Francois Venter, the head of Ezintsha at Wits University.
He added that “it was predictable that we would eventually get resistance”, and that resistance was specifically monitored for. “There’s never room for complacency, but people should not be panicking at this stage.”
Similarly, Professor Graeme Meintjes, an infectious diseases specialist with a research interest in HIV and TB, said the studies presented at CROI looked at specific populations; that drug resistance has been seen in every single antiretroviral drug used so far, and that the likelihood of resistance falls on a spectrum.
This ranges from fragile – when it’s easy to develop resistance to the drugs – to robust, meaning quite difficult to develop resistance.
On the one end of the spectrum is a fragile drug like efavirenz or nevirapine, while on the other end is a robust drug like darunavir. Dolutegravir falls on the robust end of the spectrum.
Findings
A small study conducted in Kenya assessed the frequency of drug resistance in people receiving dolutegravir-based treatment, with viral loads above 200 copies per ml.
Of 44 samples genotyped to check for resistance, 32 were from people who switched to dolutegravir after having been on other ARVs, and 12 were from people starting treatment for the first time. In the first group, 22% had dolutegravir resistance and in the second group, just 8% had resistance.
Another study looked at children with HIV in Malawi: 125 children who were on a dolutegravir-based regimen for nine months or longer and who had a previous high viral load (more than 1 000), were genotyped for drug mutations. A total of 89% had taken other ARVs before starting dolutegravir.
High-level dolutegravir resistance was seen in 15.5% of them, which was twice as high as the 8.5% resistance found in a parallel study among adults.
A Lesotho study did genotypic resistance testing in 54 adults who had changed from a regimen based on Non-Nucleoside Reverse Transcriptase Inhibitor (a class of antiretroviral) to a dolutegravir-based regimen, and had at least one viral load count of 500 or higher.
Six of them had resistance, one had high-level dolutegravir resistance, and five had low-level dolutegravir resistance.
Notably, of the 14 881 potential participants in the area of Lesotho where the study was conducted, only 0.5% met the inclusion criteria for this study. The study thus does not provide a picture of dolutegravir resistance in the area in general, but only for a very limited sub-group.
Most importantly, at CROI, researchers also reported two-year follow-up data for a large study called DTG SWITCH, conducted in Malawi and Zambia. This looked at progress of people who switched to dolutegravir. Among the 1 149 study participants in Malawi and 1 248 from Zambia, assessed two years after switching, 62 had a viral load of 1 000 or more (the threshold for doing resistance testing in the study).
A total of 45 samples were successfully genotyped with only two cases of major dolutegravir resistance – one in Malawi and one in Zambia.
Results in context
The studies presented in Denver should be placed in the right context, Meintjes told Spotlight.
“We need to be cautious in interpreting the data … the big picture involves looking at similar denominators when comparing studies. There does seem to be more dolutegravir resistance emerging than initially expected, but it’s seen in only a minority of patients.”
Within the trial setting, dolutegravir resistance rates were relatively low. However, it was important to distinguish between two groups of study participants and how resistance rates differed.
Some participants were antiretroviral therapy naïve – on their first treatment or had never failed a regimen. Then there are participants who had been on ARVs before, failed on another regimen, and switched to dolutegravir – so dolutegravir would be their second line drug.
Meintjes said four major studies, called NADIA, VISEND, ARTIST and D2EFT, found that those on dolutegravir as a second line regimen had higher resistance rates than those receiving it as a first line regimen.
Resistance rates looking at dolutegravir as a second line regimen ranged between 1% and 4%. Resistance to dolutegravir in first line regimens found that fewer than one in every 1 000 participants developed resistance.
Meintjies said resistance rates were possibly higher in real-world HIV treatment programmes compared with clinical trial data because the trials follow participants closely and have more adherence support.
So in clinical trials, participants on the drug and with elevated viral loads are often identified earlier than in a programme setting, and given more adherence support or switched to another regimen, decreasing their chances of developing resistance.
The study data presented at CROI, he added, confirm a small proportion of people on dolutegravir develop resistance.
HIV programmes and researchers will need to calculate how best to monitor and switch those patients to alternative regimens – and that a darunavir-based regimen was the best alternative.
“The message is still consistent. When used in first line, dolutegravir resistance is extremely rare. When it’s used in second line with companion drugs that are potentially compromised and have resistance, then most people do well. But a small minority will develop dolutegravir resistance, and we need to have algorithms and guidelines in place to detect them.”
Potential implications
Both Meintjes and Venter said that while South Africa needs to be proactive, for now, no big changes were necessary, that higher rates of dolutegravir resistance would emerge over time. This was because the clinical trials and studies have a limited follow-up time of a few years and there might be accumulating resistance as the drug is used for longer durations.
There was a need for continued surveillance for dolutegravir resistance to inform any changes to the treatment programme.
“That’s the value of surveillance, we can then react to the data in real time, on the accumulating data on resistance,” Meintjes said.
There is also a need for more research into better, more cost-effective ways to do resistance testing or triaging for resistance testing, he added.
“In South Africa, a resistance test costs about R3 000 – so we can’t afford to do unnecessary tests.”
Dolutegravir resistance is being monitored through the National Health Laboratory Service, which is “filtering the results to the research fraternity”.
While this was something to keep a “beady eye on”, Venter said there were more pressing issues, like how to meaningfully support the patients to adhere to treatment as this was the best way to reduce or stop dolutegravir resistance.
“We need support for everyone who is battling to swallow their medicines. It really is long past time that we start talking about how we support adherence in general, not just for people with HIV.”
Drug resistance report
See more from MedicalBrief archives:
WHO elaborates on resistance to ARV medicine
Once-daily Dolutegravir-based regimen safe and effective for people taking rifampicin for TB
Dolutegravir-based second-line ART outcomes