HIV treatment has been improved and simplified significantly over the years yet a small fraction of people living with HIV still take complex multi-pill regimens. Spotlight reports on a new combination pill that could make life easier for some in this group. But as two leading experts point out, the development comes against a backdrop where the traditional categorisation of HIV medicines is dissolving.
Twenty years ago, antiretroviral treatment involved taking multiple pills, sometimes multiple times a day. Though these medicines saved many lives, they did cause a variety of side effects, and many people developed resistance to some of the drugs.
Since then, we've seen significant scientific advances. The drugs that cause notable side effects have largely been phased out. In 2013, government introduced a one pill, once a day regimen as the standard first-line treatment.
In 2019, first-line treatment was further strengthened when a breakthrough new antiretroviral drug called dolutegravir was included in a new daily combination pill. Apart from high potency and having very few side effects, the new combination is also remarkably robust against the development of drug-resistance.
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Dolutegravir made it possible for many people who were on second-line regimens to switch away from multiple tablets to a single tablet containing the drug, Professor Francois Venter tells Spotlight. Venter is a clinician researcher at Ezintsha at the University of the Witwatersrand.
This regimen, a combination of the drugs tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD), is still the backbone of South Africa's HIV treatment programme, with over five million people taking it every day. It is also recommended by the World Health Organisation for treatment of almost all people living with HIV.
HIV & KIDS | The potent antiretroviral drug dolutegravir has become the backbone of SA's HIV treatment programme. New estimates suggest that most children aged one to four living with HIV have now been switched to the drug, reports @elri-voigt.bsky.social.
Simplifying complex treatment
There is however a subset of people living with HIV for whom TLD doesn't work and who accordingly may need more complex treatment regimens. Such complex treatment regimens have typically required taking multiple pills, multiple times a day, but new research suggests that might not be the case for much longer.
A phase three study, called ARTISTRY 1, published in the Lancet medical journal in February, looked at the safety and efficacy of a combination pill containing the drugs bictegravir and lenacapavir compared to several more complex HIV regimens. There were nine different complex regimens being taken by participants in the study. The bictegravir and lenacapavir pill was found to be non-inferior (meaning roughly as good as) to the complex regimens, and no drug resistance was seen. People in the study reported an increased treatment satisfaction after switching to bictegravir-lenacapavir (referred to as BIC/LEN) compared to those who stayed on their existing regimens.
Presenting the results at the 2026 Conference on Retroviruses and Opportunistic Infections (CROI) in February, the study's principal investigator, Chloe Orkin, Professor of Infection and Inequities at Queen Mary University of London, said most people living with HIV are taking single-tablet regimens.
"However," she added, "there are still many people who have to take complex, multi-tablet regimens, often due to viral resistance, intolerance, contraindications. And in many cases, these individuals are our elders, diagnosed early on in the [HIV] pandemic."
This can be challenging since they might have a high pill burden, struggle with adherence, and be at risk for drug-drug interactions, Orkin explained. "[T]his is a clear unmet need, and a novel drug such as BIC/LEN could optimise treatment for individuals with viral suppression who are on these complex regimens."
Study design
The study looked at 557 adults who were already taking a complex HIV regimen, which either included older HIV drugs, more than two pills a day, pills taken twice a day or needed an injection in addition to tablets. The participants also had to have been stable on treatment for at least six months.
The study population, drawn from sites across 15 countries, including South Africa, were quite unique in that they had on average been taking treatment for 28 years, in other words since before the turn of the century and almost a decade before South Africa's public sector treatment programme started in earnest. In fact, the study notes that this is the "oldest study population ever enrolled in a registrational programme for HIV treatment".
In the study, 186 people stayed on their existing regimen and 371 were switched to the bictegravir and lenacapavir pill.
At the start of the study, of the 557 people enrolled, Orkin said more than half had at least two comorbidities, and 60% of the participants were taking two or more concomitant medications to treat these comorbidities.
Despite this, Orkin said the side effects reported were similar across the two study groups, with the most common being upper respiratory symptoms or headache.
This essentially means that the researchers didn't observe abnormal side effects due to the study drug. There were five deaths in the group taking the bictegravir and lenacapavir pill, but these were not related to the drug.
Limited implications for South Africa
Promising as these findings are, two local experts told Spotlight this regimen is unlikely to have a large impact on South Africa's HIV treatment programme, as most people living with HIV in the country are not on a complex treatment regimen.
"This is a fantastic breakthrough for an important group of patients, but a fairly small group of patients in South Africa," says Professor Graeme Meintjes. He is an infectious diseases specialist based at the University of Cape Town and Clinical Professor of Infectious Diseases at Queen Mary University of London.
The majority of these patients would be in the private health sector, since they would have had access to the first available antiretroviral therapies that might have predisposed them to complex multi-drug resistance patterns over their treatment journey, he adds.
"I think it's phenomenal to do a trial of people that have been on HIV treatment for 20 to 30 years and provide them with such a breakthrough," Meintjes says. "[This] shows the breadth of innovation that's happening in the HIV field, even if it's not something that's going to impact millions of people".
Venter adds: "It's not something that South Africans need by and large, but it does, as a proof of concept, show that this is going to be possible going forward. It is a remarkable result, and suggests these new drugs are retaining potency in the face of resistance."
Classes of drugs
To understand the evolution of antiretroviral therapy, we need to briefly touch on the science of HIV treatment. In short, HIV invades the body mainly by hijacking an immune cell called a CD4 cell. The drugs used to treat HIV work by targeting and stopping different stages of this process, which is how the treatment keeps the virus under control. These drugs are classified into different drug classes, named after the part of the virus's replication process or life cycle that it targets. (Here is an excellent overview of the HIV lifecycle).
There are several HIV drug classes, but only five of the most common ones will be highlighted here, for a more exhaustive list here is a useful summary.
As noted in the South African Journal of HIV Medicine, the drugs most commonly used to treat HIV inhibit one of three important enzymes HIV uses to replicate. These are: reverse transcriptase, integrase and protease.
The two drug classes Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) work by targeting the virus's reverse transcription process, albeit in different ways. This essentially prevents the virus from turning RNA into DNA, which it needs to do in order to replicate. A well-known NRTI is the drug lamivudine, while a well-known NNRTI is efavirenz.
Integrase Strand Transfer Inhibitors (INSTIs) targets integrase enzymes, which then stops the virus from integrating its DNA into the CD4 cell's DNA. Bictegravir, raltegravir, and dolutegravir fall into this drug class.
Protease Inhibitors (PIs) blocks the protease enzyme, which HIV uses to make new viral proteins functional. In this class, a well-known drug is darunavir.
Finally, Capsid Inhibitors, target several stages of the virus's life cycle, blocking the assembly of the virus's capsid and its uncoating when it enters new CD4 cells. The capsid is like a box inside the virus that encases the virus's RNA. The drug lenacapavir is the best-known member of this drug class.
ICYMI | A world without an HIV cure will mean that many millions of people will still be living with HIV until late in the 21st century. Explore this special briefing from our archives.
www.spotlightnsp.co.za/2024/11/12/i...
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-- Spotlight (@spotlightnsp.bsky.social) May 14, 2026 at 10:42 AM
Very early HIV treatment consisted of pills from only one drug class, known as monotherapy, which made those taking it prone to developing drug resistance. Scientific breakthroughs in the mid-1990s led to the current, highly effective HIV treatments which are a combination of two or more drugs from different classes. By taking drugs from more than one class, more than one of the key enzymes are disrupted, and HIV replication in the body is more effectively crippled.
The regimen most people living with HIV in South Africa are on, TLD, contains two NRTIs (tenofovir disoproxil fumarate and lamivudine) and a INSTI (dolutegravir).
The end of first, second and third line?
Since the introduction of different antiretrovirals and the early roll out of South Africa's HIV treatment programme, the antiretroviral regimens offered have been categorised as first-, second- and third- line.
The basic idea is that if someone is diagnosed with HIV, they are started on a standardised first-line regimen. To monitor whether the drugs are working to bring the virus under control, a series of viral load tests are done at different time points after that person starts treatment. A viral load test shows how much HIV is present in the blood. The ideal result that shows treatment is working, is an "undetectable" result, or a viral load of less than 50 copies per ml.
The test is ideally done when treatment starts, three months later and then six months later, according to the Southern African HIV Clinician's Society's 2023 guidelines. This is generally what happens:
If someone's viral load goes down to less than 50 copies per ml while taking treatment, then the treatment is working and they can continue on that regimen. And viral load tests can be reduced to once a year.
If someone's viral load doesn't go down, or if it comes back up again, the guidelines flag three common reasons. The drugs are not being taken by the patient - sometimes due to reasons outside of their control, like stock-outs of the drugs; drug resistance, either acquired or transmitted, to the regimen they are on; the levels of drug needed in the body are not being reached, possibly due to drug-drug interactions or other absorption difficulties.
If someone's viral load has been more than 1 000 copies per ml on two to three consecutive viral load tests, treatment with that regimen has "failed", according to the guidelines, and the person needs to be tested for drug resistance - done through an expensive laboratory test. If they do have drug resistance to the regimen they are on, they are moved to a second-line regimen. If that regimen also fails, then there is a third-line treatment option.
However, dolutegravir, which Venter describes as the "one drug that rules them all", has simplified how people living with HIV are initiated on treatment or switched to different regimens. Four years after dolutegravir was approved for use, the country's 2023 national guidelines cleared the way for most people living with HIV currently on treatment to be switched to TLD, regardless of their treatment history.
Dolutegravir changed the game, and may change the terminology
Most people who take dolutegravir as part of their first antiretroviral therapy will be able to get their viral load suppressed, Venter explains. He adds that for the most part among this group, if someone's viral load isn't coming down, it is because they are not taking their pills. Then it's up to the clinicians to figure out why and counsel the patient.
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Venter also notes that there are some people living with HIV who can't tolerate tenofovir (another drug in the first-line combination pill) because of issues with their kidneys. These people are switched to a regimen of the drugs abacavir (an NRTI), lamivudine and dolutegravir, or simply switched to a simpler version of TLD, combining only lamivudine and dolutegravir, which remains very potent.
Because most people are on a dolutegravir-based regimen and doing well, regardless of whether it was the first regimen they started taking or one they were switched to, Meintjes says that it's time to retire the first-, second- and third-line language.
In an opinion piece in the Lancet journal, Meintjes and several others argue that this terminology was useful in a context where there had to be multiple treatment options, because treatment regimens sequentially and commonly failed. However, the treatment landscape has shifted, with TLD being the current standard of care.
"[The regimen] is highly effective and very well tolerated; substitutions due to side-effects, virological failure, and emergence of clinically relevant drug resistance are very low," they write. "As of December 2023, an estimated 77% of people with HIV worldwide were receiving ART [antiretroviral therapy], with more than 80% of these individuals being treated with tenofovir, lamivudine, and dolutegravir."
They continue: "Referring to a tenofovir, lamivudine, and dolutegravir regimen with first-line or second-line terminology does little to support clinical decision making or drug procurement. When assessing an individual for HIV treatment, the key information needed consists of four essential aspects: previous exposure to antiretroviral drugs, previous exposure to specific drug classes, history of treatment failure, and treatment tolerability."
Instead, the writers make a case for using terminology such as "initial" and "subsequent regimens".
Venter agrees that the language used should change.
"So, I think what it means is that our current first-line therapy is so powerful that, for a very small number of people, we'll need alternatives. That's been the case for the last six, seven years, and will be the case for the next little while until alternatives come," he says.
There have been some cases worldwide of dolutegravir resistance, but some leading experts Spotlight has previously spoken to are not overly concerned. As very few people have developed resistance to dolutegravir if it is the first regimen they've been on.
There will be people, albeit a small portion for now, who if started on dolutegravir after another regimen has failed, will develop drug resistance, Meintjes says. This group has about a 2-3% chance of failing on the regimen due to developing dolutegravir resistance and will need other treatment options.
For those, the ideal regimen is darunavir/ritonavir, a boosted PI regimen, with other drugs. Other PI drugs are Lopinavir/ritonavir as well as Atazanavir/ritonavir, but generally Lopinavir is not used because of its side effects. Meintjes estimates that less than 5% of people living with HIV in the country would need a PI regimen.
