Resistance history does not affect response to dolutegravir / lamivudine

A history of virologic failure on antiretroviral treatment does not affect the response when people who are virally suppressed switch to a two-drug regimen of dolutegravir and lamivudine (Dovato), even if they have resistance to lamivudine, results of the SOLAR-3D study show.

Presenting SOLAR-3D last month at the 12th International AIDS Society Conference on HIV Science (IAS 2023) in Brisbane, Dr Gary Blick said the findings had the potential to reduce drug costs and drug exposure for people who are not currently eligible for treatment with a two-drug regimen of dolutegravir and lamivudine.

A two-drug regimen of dolutegravir and lamivudine (Dovato) is currently recommended as a switch option for treatment-experienced people with HIV who are virologically suppressed, but only if they have no history of treatment failure and no prior or current resistance to either dolutegravir or lamivudine.

“This applies to perhaps 20% of my practice,” Dr Blick told the conference. “The reason I designed SOLAR-3D was to look at the other 80%.”

To date, the most substantial evidence on this question came from a meta-analysis of studies of dolutegravir / lamivudine which included people with lamivudine resistance. This showed a low incidence of virological failure in those with lamivudine resistance when they switched to the two-drug regimen.

These findings suggest that the M184V mutation, which causes resistance to lamivudine, may not persist in the HIV reservoir, or may survive at such low levels that it cannot cause viral rebound as long as dolutegravir treatment is maintained.

To test the effectiveness of a two-drug regimen in people with a history of virological rebound, Health Care Advocates International in Stratford, Connecticut, carried out a 96-week open-label study in people who had taken at least two antiretroviral regimens. People with HIV were eligible to join the study if they had experienced rebound above 200 copies/ml or never achieved a viral load below 50 copies/ml or had genotypic resistance to lamivudine.

The study recruited 50 people with a history of the M184V resistance mutation and 50 without any history of M184V resistance. Participants were followed for 96 weeks, and the primary outcome of the study was the proportions with viral load above 50 copies/ml at weeks 48 and 96.

The study population had a median age of 58 years, 15% were female and participants were highly treatment experienced. They had taken a median of seven antiretroviral regimens over a median of 22 years on treatment. The study population had been virally suppressed for a median of 11 years. Participants with the M184V mutation were significantly older, had been living longer with HIV, had taken more antiretroviral regimens and had longer durations of both antiretroviral treatment and viral suppression.

Approximately three-quarters (73%) of participants were taking lamivudine or emtricitabine at the time of switching. Most often, participants switched from dolutegravir / abacavir / lamivudine (Triumeq) (51%) or dolutegravir / rilpivirine (Juluca) (21%).

Sequencing of proviral DNA was carried out to perform genotypic resistance testing. The use of next-generation sequencing enabled detection of resistance mutations that were present in at least 10% of the viral population. Next-generation sequencing is more sensitive to minority variants than standard genotyping, which can only detect minority drug-resistant variants when they form at least 20% of the viral population in a sample. Proviral DNA sequencing was successful in samples from 70 participants and showed that the M184V mutation was detectable in 15 out of 50 participants with a history of M184V resistance.

At week 96, 4% of those with a prior M184V mutation and 2% of those without had viral load above 50 copies/ml. Eleven participants had missing data at week 96, including five participants who died from non-study-drug-related causes, two lost to follow-up and two incarcerated. A per-protocol analysis of participants on treatment at week 96 showed no significant difference in viral suppression below 50 copies/ml, a planned secondary outcome of the study (84% vs 88% in the non-M184V group).

There were no discontinuations due to confirmed virologic failure (a viral load above 50 copies/ml followed by a viral load above 200 copies/ml) by week 96. The incidence of viral load blips above 50 copies/ml but below 200 copies/ml, with subsequent resuppression below 50 copies/ml, did not differ between study arms.

Dr Blick said that knowing it was safe to switch virologically suppressed, treatment-experienced people to two-drug treatment had the potential to generate substantial savings in drug costs for treatment programmes in lower- and middle-income countries and for Medicaid in the United States.

“As a general interrnist who’s been treating HIV since the beginning of time, I’ve always believed less is better,” Dr Blick told the conference. “And if less is significantly less expensive, these are important points to make.”

The study findings leave one question unanswered. When is it safe to assume that the M184V mutation will no longer be present at sufficient levels in the viral reservoir to risk viral rebound if people switch to dolutegravir / lamivudine?

“We did have patients do switches with as little as two years of undetectability, but we really need much larger studies to tell us what that cut off is going to be, is it going to be five years,” said Dr Blick. “The data we have suggests five, six, seven years, but we don’t really know what that cut off is. […] This should be done at the ACTG and the ANRS with larger studies, to look at this.”