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Dolutegravir resistance: Finding the silver lining

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Dolutegravir (DTG), approved by the US FDA in 2013, is a second-generation HIV integrase strand transfer inhibitor – a relatively novel therapy for the treatment of HIV/Aids  that combined potency and tolerability with minimal resistance compared to previous ART regimens. Its low cost and rising resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) led the WHO to recommend it as a preferred HIV treatment in 2018. Such has been the success of the therapy that, by 2022, 91% of adults in low- and middle-income countries were on a DTG-based ARV regimen.  

We spoke to Dr Jeremy Nel, Head of Division at Wits University’s Infectious Diseases Research Institute, about the scope of the DTG resistance problem and whether we are under- or overreacting.

Recent reports of increased rates of resistance to DTG were highlighted by the WHO in its latest HIV Drug Resistance Heading Report. While it was encouraging to note that populations on DTG-containing ARVs achieved high viral load suppression rates (>90%), the WHO noted that drug resistance to DTG was steadily surpassing levels observed in clinical trials.  

While the WHO reported initial Rresistance to DTG as ranginged from 3.9% to 8.6%, reaching 19.6% in extreme cases, a. A study presented at the Conference of Retroviruses and Opportunistic Infections (CROI) focused on HIV-infected children in Malawi. Of 125 children on dolutegravir for over nine months, with initial high viral loads (over 1,000), 89% had prior antiretroviral use. Genotyping revealed 15.5% had high-level dolutegravir resistance, twice the 8.5% seen in a similar adult study.  

We spoke to Dr Jeremy Nel, Head of Division at Wits University’s Infectious Diseases Research Institute, about the scope of the problem and whether we are under- or overreacting.  

Medical Academic (MA): Hi Dr Nel. Given the rise in resistance cases, should health providers in South Africa be worried about DTG resistance?  

Dr Jeremy Nel: Most patients in South Africa are now on a DTG-containing regimen, so clearly this is the drug to watch when it comes to resistance. The good news is that, for treatment-naïve people who are started on a DTG-based regimen as part of their initial antiretroviral regimen, it remains exceptionally rare to ever develop resistance. 

This is quite an incredible achievement. For treatment-experienced people who live with HIV who are switched to a DTG-containing regimen as second-line therapy, DTG-based regimens remain a very robust option. It has to be noted however that we are slowly seeing an increase in DTG-resistance in this group.  

Levels of DTG drug resistance will only grow over time of course, so it’s something to watch out for, and health providers need to educate themselves about this threat.  

MA: Do we know what the current rate of resistance in SA is?  

Dr Nel: Getting good surveillance data is difficult, but the data that is available indicates that DTG resistance remains reasonably rare overall. However, in the subset of patients who have a high HIV viral load (who are failing therapy) on a DTG, the levels of resistance are obviously quite a bit higher, though again hard to quantify accurately.  

MA: What is the primary reason for the emergence of DTG resistance? Is it more prominent in certain patient populations?  

Dr Nel: Look, the causes of DTG resistance aren’t a mystery. It happens for the same reasons that resistance to antiretroviral therapy has always developed, namely patients who occasionally skip doses, leading to lower drug levels in their bodies, which allows HIV to replicate and therefore mutate.  

Ed’s Note: There are also numerous psychosocial factors that impact adherence. Many studies have found, for example, that paediatric populations have unique challenges such as disclosure, caregiver issues, challenges with understanding and acceptance of the disease, limited drug options and lack of access to child-friendly formulations. 

If it mutates in just the right way, resistance can occur. Resistance has historically been one of the biggest problems in managing patients with HIV, but DTG’s robustness has given the HIV community a few years of breathing space from worrying about it as a big issue. That looks to be slowly changing as resistance accumulates even to DTG, but that’s not unexpected. We’ve been here before with antiretroviral therapy and we know how to approach it! 

MA: How does DTG resistance alter current prophylaxis of mother-to-child transmission, if at all?  

Dr Nel: It hasn’t had a big impact, and isn’t likely to in the near term. Mothers diagnosed for the first time in pregnancy would be put on a DTG-containing regimen usually, but the chances of them having picked up a resistant strain are pretty low. Mothers who are already on antiretroviral therapy in pregnancy but who are failing therapy may have DTG resistance, but they could be switched to non-DTG regimens.  

And the regimens the children get as prophylaxis aren’t affected by DTG resistance. So hopefully it’s not a massive issue, though obviously there will be individual cases where DTG resistance does have an impact.  

MA: New research indicates that most instances of drug resistance are found among patients who have been on treatment for a while and have developed other drug resistances, including NNRTI resistance. How do you explain this, and is it good news?  

Dr Nel: Again, the explanation is probably that the patients who are treatment-experienced often have some resistance present in the antiretroviral drugs that DTG gets partnered with as part of their regimen, and so aren’t capable of protecting DTG from resistance developing as readily. 

MA: Do you foresee any changes to the current recommendations from the WHO regarding the use of DTG?  

Dr Nel: I don’t think it should impact WHO recommendations. Again, I would like to emphasise that DTG is still outstanding as a first-line therapy, In fact, it is the best therapy we have for first-line care, and it is still very, very good as second-line therapy. Instead of staying away from DTG, I think we should rather be looking for resistance more aggressively than we have been in patients who are failing therapy, so that we can switch away from DTG at the first sign of resistance developing. 

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