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Dolutegravir, the current first-line treatment for HIV, may not be as effective as expected in sub-Saharan Africa, new research published on World AIDS Day suggests. The study finds that this so-called “wonder drug” may be less effective in patients resistant to older drugs.
As HIV copies itself and replicates, it can develop errors or “mutations” in its genetic code (its RNA). While a drug may initially suppress or even kill the virus, certain mutations can allow the virus to develop resistance to its effects. If a mutated strain begins to spread within a population, it may mean that drugs that were once effective can no longer treat people.
HIV treatment usually consists of a cocktail of drugs that includes a type of drug known as a non-nucleoside reverse transcriptase inhibitor (NNRTI). However, in recent years, HIV has started to develop resistance to NNRTIs. Between 10% and 15% of patients in much of sub-Saharan Africa are infected with a strain of HIV resistant to these drugs. If a patient is infected with a strain resistant to NNRTIs, they have a two to three times greater risk that the drug regimen will fail.
In 2019, the World Health Organization began recommending dolutegravir as the preferred first-line treatment for HIV in most populations. Dolutegravir was called a “wonder drug” because it was safe, powerful, and cost-effective, and scientists had not seen resistance to the drugs in clinical trials. However, there is little data on the success of dolutegravir against circulating strains of HIV in sub-Saharan Africa.
In a study published today in Communications from nature, an international team of researchers from South Africa, the United Kingdom and the United States examined the genetic code of HIV to determine whether drug resistance mutations in 874 volunteers living with HIV affected the success of their treatment. The individuals were enrolled in a clinical trial for people starting HIV treatment to compare two drug regimens: efavirenz, an NNRTI, and prior first-line therapy in the region, and dolutegravir.
The objective of this study was to determine whether drug resistance to efavirenz before starting treatment affected the success of treatment (virus suppression in the blood) during the first two years of therapy with these two regimens.
As expected, the presence of drug resistance substantially reduced the chances of treatment success in people taking efavirenz, successfully suppressing the virus for 96 weeks in 65% of participants compared to 85% of individuals. not resistant. However, unexpectedly, the same pattern was true for people taking dolutegravir-based treatments: 66% of those with efavirenz resistance mutations remained suppressed for 96 weeks compared to 84% of those without mutations. These relationships held true after taking into account other factors, such as adherence to treatment.
We fully expected that efavirenz would be less effective among patients with NNRTI-resistant strains of HIV. What took us completely by surprise was that dolutegravir, a different class of drug that is generally effective against drug resistance, would also be less effective in people with these resistant strains.
We are now working to determine if this was due to the virus or to participants, for example, whether people with resistance are less likely to take their pills regularly. Either way, if this pattern holds, it could have far-reaching impacts on our predictions of long-term treatment control for millions of people taking dolutegravir in the region. “
Dr. Mark Siedner, Faculty Member, Africa Health Research Institute, KwaZulu-Natal, South Africa and Massachusetts General Hospital in Boston, Massachusetts
Professor Ravi Gupta from the Cambridge University Department of Medicine said: “This is a major concern. Dolutegravir was seen as a ‘wonder drug’, but our study suggests that it may not be as effective in a significant number of patients who they are resistant to another important class of antiretroviral drugs. “
The researchers say that it is not clear why mutations resistant to efavirenz should affect the susceptibility of dolutegravir, although one hypothesis is that integrase inhibitors such as dolutegravir push the virus to replicate and mutate faster, in turn developing resistance to it. new drug in an evolutionary arms race. . Alternatively, it could be due to poor adherence to treatment regimens, although the analysis accounted for adherence using two independent methods. More research is needed to find out why.
Professor Gupta added: “What this shows is that we urgently need to prioritize site-of-care testing to identify people with drug-resistant HIV, particularly against efavirenz, and to more closely and accurately monitor compliance The development of such trials is at an advanced stage, but there is a lack of investment from donors and philanthropic donors, and we urgently need agencies and individuals to step up and help support these programs.
“In addition, we need to provide widespread access to viral load monitoring so that we can find those who are struggling, make them receive more appropriate regimens, and limit the emergence of resistance when patients do not respond to treatment.”
Source:
Magazine reference:
Siedner, MJ, et al. (2020) Efficacy reduction of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase. Nature Communications. doi.org/10.1038/s41467-020-19801-x.
