That HIV can develop resistance to the drugs used to treat it is nothing new, but results from recent studies reveal the emergence of resistance in subsets of people living with HIV to dolutegravir - an antiretroviral widely used in South Africa. Top HIV experts spoke to Elri Voigt about the new findings and what it means for people living with HIV in the country.
One of the most notable shifts in HIV treatment over the past two decades is that the antiretrovirals used today have much fewer side effects than the older ones and do a better job at suppressing the virus. Following a World Health Organization (WHO) recommendation in 2018, South Africa started providing a new antiretroviral called dolutegravir in 2019. There was much excitement about dolutegravir, given that it has hardly any side effects, is extremely good at suppressing HIV, and the HIV virus does not easily develop resistance to it.
In a span of just four years, over 4.7 million people in South Africa were switched over to dolutegravir-based treatment (it is typically combined into a single pill with the antiretrovirals tenofovir and emtracitabine). Indications are that the switch has been a resounding success. A large study published in the Lancet medical journal found that people in the country 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) indicate that drug resistance to dolutegravir is emerging in certain populations, with the WHO report stating that the levels of resistance are higher than anticipated. CROI took place in Denver, Colorado in March.
In a press release that accompanied the WHO report, it was stated that among the four surveys that provided data to the WHO, levels of resistance to dolutegravir ranged from 3.9% to 8.6%. It reached a high of 19.6% among people with high viral loads (the amount of HIV in a person's blood) who switched from other antiretroviral treatments 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 who had high viral loads. Since people on treatment with high viral loads are at higher risk of resistance, the percentage of people with dolutegravir resistance in these sub-groups will be higher than among people on dolutegravir more generally.
"It's a very small number of cases and the majority of the dolutegravir cases of resistance we're seeing are in a very specific context - patients who failed monotherapy [treatment with a single antiretroviral] so dolutegravir monotherapy clinical trials, dual therapy [treatment with two antiretrovirals] or patients who have been exposed to other integrase inhibitors [a class of antiretroviral drug designed to block a specific step in viral replication]," explains Professor Francois Venter, the head of Ezintsha at Wits University. (Besides dolutegravir, other integrase inhibitors include raltegravir, bictegravir, and cabotegravir.)
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Along similar lines, Professor Graeme Meintjes, an infectious diseases specialist with a research interest in HIV and TB, stresses that the studies presented at CROI looked at specific populations. These were people experiencing high viral loads on dolutegravir and therefore at risk for developing dolutegravir resistance. The rates of resistance observed in these studies are slightly higher than in the clinical trials for dolutegravir and the rates anticipated. However, he says the rates of resistance are still low when one considers it in relation to all people receiving dolutegravir in the settings the studies were conducted, the majority of whom have virological suppression - meaning that the amount of virus in the blood is below a certain threshold (typically 400 or 1 000 copies of HIV per milliliter of blood).
"It was completely predictable that we're eventually going to get resistance," says Venter, adding that resistance was specifically monitored for. While the numbers are currently small, he says they are expected to increase and we should plan for it. "There's never room for complacency, but people should not be panicking at this stage," he says.
Meintjes explains that drug resistance has been seen in every single antiretroviral drug used so far, and that the likelihood of resistance falls on a spectrum. It ranges from fragile, which is to say it is easy to develop resistance to the drugs, to robust meaning its quite difficult to develop resistance to the drug. 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.
What the CROI studies found
A small study conducted in Kenya assessed the frequency of drug resistance in people receiving dolutegravir-based HIV treatment who had viral loads above 200 copies per ml (in other words people in whose bodies there was a detectable level of HIV replication). Of 44 samples genotyped to check for resistance, 32 were from people who switched to dolutegravir after having been on other antiretroviral treatment and 12 were from people who were starting treatment for the first time. In the first group, 22% (of the 32 samples genotyped) had dolutegravir resistance and in the second group 8% (of the 12 samples genotyped) had dolutegravir resistance.
Another study looked specifically at children living with HIV in Malawi. 125 children who were on a dolutegravir-based regimen for nine months or longer, who had a previous high viral load (in this case more than 1 000) were genotyped for drug mutations. 89% had taken other antiretrovirals before they started dolutegravir. High-level dolutegravir resistance was seen in 15.5% of the children. According to the researchers, this is twice as high as the 8.5% resistance found in a parallel study among adults.
Emergence of acquired dolutegravir resistance in treatment-experienced people with HIV in Lesotho
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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 study participants in the part 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 of people.
Maybe most importantly, at CROI researchers also reported two year follow-up data for a large study called DTG SWITCH, conducted in Malawi and Zambia. As the name suggests, DTG SWITCH looked at how it went with people who switched to dolutegravir-based treatment. Among the 1 149 study participants in Malawi and 1 248 participants from Zambia who were assessed two years after switching, 62 had a viral load of 1 000 or more (the threshold for doing resistance testing in the study). 45 samples were successfully genotyped with only two cases of major dolutegravir resistance being found - one in Malawi and one in Zambia.
Placing the results in context
The studies presented in Denver should be interpreted cautiously and placed into the right context, Meintjes tells Spotlight.
"I think one needs to be very cautious in interpreting the data from these studies. Because one...needs to look at it in the big picture and that involves looking at similar denominators when one is comparing across studies," he says. "There does seem to be more dolutegravir resistance emerging than was initially expected, but still, it's a minority of patients who are developing resistance."
Within the clinical trial setting, he explains, dolutegravir resistance rates were relatively low. However, it is important to distinguish between two groups of study participants and how resistance rates differed.
There are those participants who were antiretroviral therapy naïve, meaning this was their first-time receiving treatment or had never failed a regimen-referred to as those who are starting on as their first line drug. Then there are participants who had been on antiretroviral therapy before, failed on another regimen and had been switched to dolutegravir-referred to as those who starting on dolutegravir as their second line drug.
When looking at the clinical data, Meintjes explains that four major studies - called NADIA, VISEND, ARTIST, and D2EFT - found that those on dolutegravir as a second line regimen had higher rates of resistance than those receiving it as a first line regimen. Resistance rates in the studies that looked at dolutegravir as a second line regimen ranged between 1-4%. While the studies that looked at resistance to dolutegravir in first line regimens found that fewer than one in every 1 000 participants developed resistance.
Another important thing to note, he says, is that resistance rates for dolutegravir are likely to be a bit higher in real-world HIV treatment programmes compared to clinical trial data because the trials follow participants closely and have more adherence support. This means that in clinical trials, participants who have elevated viral loads while on dolutegravir are often identified a lot earlier than in a programme setting and given more adherence support or switched to another regimen, which decreases their chances of developing dolutegravir resistance.
The study data presented at CROI, according to Meintjes, confirms that a small proportion of people on dolutegravir develop resistance and this is something HIV programmes and researchers will need to figure out how best to monitor for and switch those patients to alternative regimens. He mentions that a darunavir-based regimen is the best alternative regimen for those who develop dolutegravir resistance.
"For me 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 the majority of people do well. But there's a small minority that will develop dolutegravir resistance and we need to have algorithms and guidelines in place to detect those people," he says.
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Potential implications
In response to the emerging dolutegravir resistance data, Meintjes and Venter highlight that South Africa needs to be proactive - but for now no big changes are necessary.
Meintjes cautions that there is a possibility that higher rates of dolutegravir resistance will emerge over time. This is because the clinical trials and current 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.
He emphasises the need for continued surveillance for dolutegravir resistance to inform any changes to the country's 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 says. "We do need to continue to monitor carefully and see."
There's also a need for more research into better, more cost-effective ways to do resistance testing or triaging for resistance testing, says Meintjes. In South Africa, a resistance test will cost about R3 000 per test so we can't afford to do unnecessary tests.
"I think that there's still work to be done on what the optimum monitoring strategies is that balances out issues around cost and around feasibility with optimum patient care," he says.
Venter explains that dolutegravir resistance is being monitored in South Africa through the National Health Laboratory Service. They are "filtering the results to the research fraternity and at this stage they just need to keep telling us what's going on and we'll need to work out based on their data what we need to do going forward".
While dolutegravir resistance is something to keep a "beady eye on", Venter says there are more pressing issues to focus on in the healthcare system. For instance, how to meaningfully support people living with HIV so they can better take their treatment as this will be the best way to reduce or stop dolutegravir resistance.
It is therefore essential, he says, to find innovative ways to support people living with HIV and ensure treatment adherence as well as "reconvening regularly" to think about ways to "make the systems better and smarter".
"We need support for everyone who is battling to swallow their medicines," Venter adds. "It really is long past time that we talk about how we support adherence in general, not just for people [living] with HIV."
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