No drug is immune to resistance, but dolutegravir, one of the most widely used HIV drugs, has so far shown an excellent barrier to resistance. Nevertheless, a large study that analysed data from several countries found that resistance was more common in people who took dolutegravir monotherapy or dual therapy with lamivudine, or who had resistance to NRTIs (the backbone drugs usually combined with dolutegravir). In their paper published in The Lancet HIV, an international team of researchers caution that varying degrees of resistance may occur even on dolutegravir-based regimens and resistance should be more carefully monitored.
In clinical and real-world studies, treatment failure on dolutegravir-based regimens is seen usually in fewer than 5% of participants. Even in case of treatment failure, very few people develop resistance to the drug which is why it is said to have a high barrier to resistance. This is important as it means that the drug could be reused with a different combination. It also means that treatment failure on dolutegravir-based therapy does not usually limit future treatment options, as most people will not have resistance that can affect their treatment success on similar drugs in the future.
In this study, 6% had some level of resistance against dolutegravir and the odds of having resistance were influenced by the regimen these people were on. In addition, those with a non-B variant of HIV had an increased risk of resistance to dolutegravir.
The study
Eight cohorts from Canada, France, Germany, Italy, the Netherlands, Switzerland, South Africa, and the UK contributed data on 599 people who had detectable viral load on dolutegravir-based therapy and had resistance testing. Data was collected only on those who had resistance testing done from two weeks after starting up to two months after stopping a dolutegravir-based regimen. With this information, the researchers then tried to detect resistance mutations (changes in the virus that may give it advantage against dolutegravir) and the level of resistance.
In order to analyse the associated risk factors with dolutegravir resistance, they looked at the data only from those who were followed-up for at least a year since starting dolutegravir. This led to the inclusion of 90% (540) of all ‘participants’ in the analysis.
The major characteristics between all participants and the subgroup further analysed for risk factors were similar. Two-thirds were men and most had subtype B, with minor presence of subtypes C, A, and G (each around 10%). Eighty-five per cent were on dolutegravir triple therapy while only 12% were on dual therapy and 3% on monotherapy. Over 80% had switched to the dolutegravir-based regimen from a previous one, while less than 20% started HIV therapy directly on a dolutegravir regimen. A third of the participants had previously been on a regimen containing first-generation integrase inhibitors.
Dolutegravir, being a ‘second generation’ integrase inhibitor has a higher resistance barrier to the virus, however, some resistance mutations acquired on a first generation integrase inhibitor (such as raltegravir in Isentress) may increase the chances of dolutegravir resistance, hence, it was an important variable to account for.
Resistance analysis
Fourteen per cent of all participants had at least one integrase inhibitor resistance mutation and 3% had more than one. Interestingly, being on a first-generation integrase inhibitor regimen did not seem to significantly influence the likelihood of present integrase inhibitor resistance, but still increased the number of total resistance mutations.
It is important to note that the presence of a resistance mutation does not directly translate into treatment failure, hence some mutations may be present without affecting viral suppression. Usually only certain mutations or combinations of mutations lead to treatment failure. The reverse is true too, sometimes undetectable levels may not be reached despite the lack of resistance mutations. With that said, 94% of the participants were fully susceptible (lacked resistance) to dolutegravir.
Of the remaining 6%, 1% had potential low-level resistance, 1% had low-level resistance, 3% had intermediate-level resistance and another 1% had high-level resistance.
Monotherapy
Of all risk factors, being on dolutegravir monotherapy rather than triple therapy had the strongest association with dolutegravir resistance. While it is not surprising that monotherapy contributed to increased resistance, it is certainly surprising that there were 18 people on monotherapy as none of the existing HIV treatment guidelines supports its use.
Dual therapy
Dolutegravir-based dual therapy was also associated with an increased risk of dolutegravir resistance; particularly dual therapies comprising dolutegravir plus lamivudine (available as Dovato). Other dolutegravir dual therapies had a weaker association with resistance.
Despite other data giving reassurance about the efficacy of dolutegravir-based dual therapies, these findings warn that dual therapy, particularly with lamivudine, may still come with some level of increased risk of resistance.
Resistance to accompanying drugs
The presence of dolutegravir resistance was linked to resistance to the accompanying NRTIs, such as lamivudine and abacavir in Triumeq. Fortunately, most participants (82%) were fully susceptible to NRTIs with only 2% having high-level resistance, although lower levels of NRTI resistance seemed to correlate with various levels of dolutegravir resistance too. A similar trend appeared with another class of HIV drugs – NNRTIs (such as rilpivirine in Juluca) too, but only at intermediate and high-level resistance. NNRTIs do the same job as NRTIs but function a bit differently. Again, most people (73%) were fully susceptible to NNRTIs.
If the virus becomes resistant to the drugs that accompany dolutegravir this creates a situation of an unintended monotherapy (often referred to as functional monotherapy as the other drugs are present but no longer work). These drugs are usually NRTIs (or sometimes, NNRTIs) and it makes sense that the risk of resistance to dolutegravir may be heightened as the other drugs are functionally ‘absent’. Their function is essential as they block the conversion of the viral genome into a more compatible form that can then merge with our own genome, otherwise the virus would not survive.
However, the study is limited in that it cannot tell us the direction of this resistance – whether it was dolutegravir resistance that prompted the NRTI and NNRTI resistances or the other way around. In other words, it cannot clearly determine the cause-and-effect relationship.
HIV subtype
Non-B subtypes of the virus seemed to increase the risk of dolutegravir resistance; this was most pronounced for subtype A. However, of all risk factors, this one showed somewhat a weaker association with resistance.
One limitation of the study is that almost all the data came from cohorts in Europe and North America, where subtype B is the major form of HIV. In Africa where the majority of HIV infections are concentrated, there is a greater diversity with subtype C dominating.
Takeaway
It is important to distinguish a few concepts – the presence of resistance does not necessarily mean treatment failure (uncontrollable viral load) but may increase its risk. What is more important is that resistance to one drug in a given combination may create an unintended dual or monotherapy that can increase the risk of resistance to the other drugs in the combination. Further, in people with detectable viral loads, those resistant viruses may be transmitted to other people. This is where the problem grows in scale as these resistant strains may spread to more people and limit their treatment options.
Given that dolutegravir is currently the cornerstone of HIV therapy due to its excellent efficacy, good safety and falling price, the spread of resistant strains would be a major setback in the fight against HIV. This setback would be felt more significantly in lower- and middle-income countries as the availability of alternative and equally effective treatment options is limited and often impeded by politics, logistics, and a country’s budget for these drugs. In order to avoid this scenario, consistent availability of drugs, accessible healthcare, adherence counselling and resistance monitoring are among the first things that should be improved and applied more widely.
Loosli T. et al. HIV-1 drug resistance in people on dolutegravir-based antiretroviral therapy: a collaborative cohort analysis. The Lancet HIV 10: e733-e741, 2023.