Dolutegravir resistance very rare after a switch - even with detectable HIV

The emergence of high-level dolutegravir resistance was extremely rare in people switched to first-line dolutegravir-based treatment in Zambia and Malawi, a large prospective study has found.

But the risk of having unsuppressed HIV one and two years after switching was six to seven times higher in people who switched to dolutegravir with detectable HIV. The researchers say their findings emphasise the importance of viral load monitoring before switching.

The study findings are reported in Clinical Infectious Diseases.

Since 2018, many low- and middle-income countries have systematically switched people taking their first antiretroviral regimen to a new combination containing the integrase inhibitor dolutegravir. The switch follows the World Health Organization’s recommendation that all adults should receive dolutegravir-based treatment wherever possible, because it is more potent, better tolerated and has a higher genetic barrier to the development of resistance.

Most people were switched from a regimen containing a non-nucleoside reverse transcriptase inhibitor, usually efavirenz. The World Health Organization recommended that switching to dolutegravir and two nucleoside reverse transcriptase inhibitors (usually tenofovir disoproxil and lamivudine) should only take place in people with viral load below 1000. People with a viral load above 1000 might already have resistance to lamivudine and tenofovir.

A dolutegravir-based regimen containing these drugs might not be potent enough to overcome resistance, leading to further viral replication and the development of dolutegravir resistance. If dolutegravir resistance emerged, it would eliminate the prospect of switching to an effective second-line regimen consisting of dolutegravir.

Although the World Health Organization recommends viral load testing before a switch, this does not happen in many settings due to lack of resources and capacity. To investigate the consequences of switching to dolutegravir with a viral load above 1000 copies/ml, researchers from Zambia, Malawi and the University of Bern in Switzerland carried out DTG SWITCH, a prospective observational study of people who switched from NNRTI-containing first-line treatment to dolutegravir-containing treatment in two large HIV treatment programmes in Zambia and Malawi between 2019 and 2021.

People with HIV were eligible for inclusion in the analysis if they had been taking an NNRTI-based regimen as first-line treatment for at least six months, were switching to dolutegravir-based treatment and had a viral load measurement at the time of switching. A total of 1422 people in Malawi and 1410 in Zambia were eligible for inclusion in the study.

In Malawi, national guidelines recommended switching regardless of viral load. In Zambia, switching was recommended only for those with viral load below 1000.

The outcomes of interest in the study were viral load above 400 copies/ml and integrase inhibitor resistance mutations, measured one and two years after switching.

Most of those switching were women (99% in Malawi and 85% in Zambia), probably due to the deferral of switching for women of childbearing age until it became clear that dolutegravir did not raise the risk of neural tube defects if taken around the time of conception.

Study participants had been taking antiretroviral treatment for a median of six years, almost all in the form of efavirenz, tenofovir and either emtricitabine or lamivudine. In Malawi, 4.5% had viral load above 1000 and 5% had viral load above 400 at the time of switch, compared to 1.8% and 3% respectively in Zambia. In those with detectable viral load, the median viral load was 8952 in Malawi and 1163 in Zambia. A quarter of those who switched to dolutegravir in Malawi with detectable viral load had viral loads above 52,000 at the time of switch.

One year after switching, viral load measurements were available for 1137 participants (80% of switchers) in Malawi and 1320 participants (88% of switchers) in Zambia. In Malawi, 3.8% had detectable viral load compared to 1.9% in Zambia. After two years, 4.7% in Malawi and 1.8% in Zambia had detectable viral loads.

Overall, the risk of having unsuppressed HIV was six times higher after one year, and seven times higher after two years, in people who switched to dolutegravir with a viral load above 400.

But the study found differences in the risk of having unsuppressed HIV between the two countries, reflecting the different national policies regarding switching. The risk of having unsuppressed HIV was 45% lower after one year and 67% lower after two years in Zambia, where switching was only recommended for those with a viral load below 1000. In Malawi, detectable viral load one year and two years after switching was overwhelmingly observed in participants who had had a detectable viral load prior to switching. There was no significant difference in the likelihood of detectable viral load according to viral load prior to switching in Zambian participants.

A total of 112 samples with viral load above 1000 copies taken at year 1 or 2 visits were available for resistance testing. Sequencing was successful in 79 samples from 72 participants. Five participants had drug resistance mutations in the integrase gene; two of these had major integrase resistance mutations conferring high-level resistance to dolutegravir. One of the participants with high-level dolutegravir resistance also had resistance to tenofovir, lamivudine and emtricitabine. In the other case, sequencing of reverse transcriptase was unsuccessful. None of the participants with low- to moderate resistance to dolutegravir had NRTI resistance mutations.

The study authors say that the low prevalence of drug resistance suggests that non-adherence to medication was the most frequent explanation for viremia at the time of switching and at follow-up visits.

Although the findings “highlight the infrequency of viremia postswitch”, the researchers warn that switching with viral load above 1000 heightens the risk of treatment failure. “Our findings emphasize the necessity of viral load monitoring and resistance testing to maintain ART effectiveness.”