History of drug resistance or virological failure warrants caution when switching to dolutegravir plus lamivudine

Two recent observational studies support previous clinical trial findings that switching antiretroviral treatments to the dual-therapy dolutegravir plus lamivudine (also known as Dovato) is effective. While virological failure rates in both cohorts were low, a history of failure and certain drug resistant mutations may warrant caution before deciding to switch to this regimen.

Background

Antiretroviral therapies involving a three-drug regimen have existed since the mid 1990s and have saved countless lives of people living with HIV. Regimens with fewer drugs, however, may offer multiple benefits, including reduced cost and fewer adverse drug effects.

Previous clinical trials have demonstrated that a dual-therapy combination of dolutegravir (an integrase inhibitor) plus lamivudine (a nucleoside reverse transcriptase inhibitor) is noninferior to three-drug regimens as a first-line HIV treatment and when switching therapies.

When people living with HIV miss antiretroviral doses, the HIV virus can begin to replicate again. HIV naturally develops mutations as it replicates because it does not copy its own genetic code perfectly. But when it replicates in the presence of inadequate amounts of a particular drug, that favours developing viral mutations with resistance to that drug. Over time, if a resistance mutation becomes the dominant mutation, combinations including this drug will no longer suppress HIV.

While resistance mutations are less common in people taking dolutegravir, two common resistance mutations that develop in those taking either lamivudine or emtricitabine are M184V and M184I. These mutations may develop quite fast in situations of sub-optimal adherence, or people may acquire forms of HIV that have already developed this type of resistance.

A concern, therefore, is that people who have these lamivudine/emtricitabine mutations may be at higher risk of virological failure after switching to dual-therapy regimens that use one of these drugs.

The studies

A July 2021 study by Dr Alberto Borghetti at Agostino Gemelli University Policlinic in Rome investigated risk factors for virological failure in 669 virologically suppressed people who switched to dolutegravir plus lamivudine. The cohort included mostly men (71%) and mostly White people (91%) between the ages of 45 and 49.

This study defined virological failure as either a single viral load over 200 or two consecutive measurements greater than 50. Over three years, 23 people experienced virological failure. The probability of failure within the entire population was 1.6% at year 1, 4.0% at year 2, and 5.4% at year 3.

The researchers modelled predictors of virological failure and found that the presence of M184V/I mutations increased the risk of virological failure about three-fold after switching to dolutegravir plus lamivudine. The M184 mutations exhibited a synergistic effect with thymidine analogue-associated mutations (TAMs), a separate class of resistance mutations associated with other nucleoside reverse transcriptase inhibitors. When people had M184V/I mutations along with at least one other TAM, they were about 4.5 times more likely to experience failure after switching to this dual therapy.

Regardless of the presence or absence of mutations, the researchers found that people who’d maintained virological suppression for less than two years before switching had about 3.5 times the risk of failure.

Also regardless of the presence or absence of mutations, people who had a history of virological failure with integrase inhibitors had about a six-fold higher risk of failure after switching to dolutegravir plus lamivudine. In the absence of genetic resistance data for integrase inhibitors, the authors suggested that virological failure with integrase inhibitors could represent a proxy for poor adherence, but they recommended future studies evaluate this.

A November 2021 study by Dr Arturo Ciccullo at the Catholic University of the Sacred Heart in Milan analysed a cohort of 785 virologically suppressed people after they had switched to dolutegravir plus lamivudine. The group included mostly men (71%) between the ages of 45 and 58.

This study defined virological failure as either a single viral load measured at or above 1000 (higher than the previous study) or two consecutive measurements greater than 50 (equivalent to the previous study). Over five years, 18 people experienced virological failure, but none developed resistance mutations to either nucleoside reverse transcriptase or integrase inhibitors. The probability of virological failure was 1.5% after about one year, 2.3% after almost two years, 3.1% after less than three years, and 3.6% after about four and a half years.

When assessing risk factors of virological failure after switching, the researchers of this study didn’t observe differences in those with M184V/I mutations. They did report that people with these mutations combined with less than about a seven-year history of viral suppression had a higher risk of failure after switching. However, their results contained high levels of uncertainty. In addition, their analysis showed a higher risk of failure after switching to this drug combination when people had a history of previous virological failure.

Both studies excluded people who also have hepatitis B because hepatitis B is more likely to develop resistance to lamivudine in a two-drug regimen.

Conclusion

The U.S. Department of Human Health and Service guidelines recommend against starting dolutegravir plus lamivudine until a baseline genotype test has checked for possible resistance mutations. This type of testing tends to be limited to higher-income countries and may therefore restrict some countries from using this drug combination.

While switching to dolutegravir plus lamivudine has once again been shown to have a low risk of virological failure, the current research indicates caution be used in certain instances. Specifically, people who have M184V/I mutations – especially if they have other thymidine analogue-associated mutations and less time suppressing their viral loads – may be at higher risk of virological failure after switching to this regimen. People with a history of virological failure with other therapies may also be at higher risk of failure after switching to dolutegravir plus lamivudine.