Lamivudine resistance mutation may persist for many years in some people with HIV

A mutation that can undermine two-drug treatment with dolutegravir and lamivudine persists for at least 12 years in the ‘archive’ of HIV locked up in the DNA of blood cells in one in three people, French researchers report. Their study tracked disappearance of the mutation in people with suppressed viral load on antiretroviral treatment.

They used ultra-deep sequencing, a research technique designed to locate HIV sequences that are hidden in DNA in cells, not currently producing virus. Ultra-deep sequencing can detect small quantities of HIV containing sequences of interest, enabling the detection of drug resistance in a small proportion of viruses.

The M184V mutation causes resistance to lamivudine and emtricitabine, which form part of many antiretroviral regimens. Virus with the M184V mutation is archived in DNA, where it will lie latent until reactivated. The reactivation of virus with this mutation may lead to a burst of viral replication that undermines a two-drug regimen containing lamivudine, particularly if there are lapses in adherence.

Knowing how long the M184V resistance mutation can affect response to treatment with the two-drug combination of dolutegravir / lamivudine (Dovato) is important, as current US guidance does not recommend the use of dolutegravir / lamivudine in people with a history of drug resistance. The British HIV Association says the combination is not suitable for anyone with a history of the M184V mutation. And the European AIDS Clinical Society says that the combination is unsuitable as a switch option for anyone with a history of resistance, even if they are virally suppressed.

These guidelines currently exclude a large proportion of previously treated people with HIV from using dolutegravir / lamivudine. Studies of the impact of a history of M184V resistance on the response to dolutegravir / lamivudine have produced contradictory findings.

A systematic review and meta-analysis of five intervention studies and five cohort studies concluded that a history of the M184V mutation did not affect the response to dolutegravir / lamivudine.

But one study included in that analysis, LAMRES, found that in people with the M184V mutation and a suppressed viral load who switched to dolutegravir / lamivudine, the risk of viral rebound was greater in people with a shorter duration of viral suppression. Although this association ceased to be significant after controlling for demographic factors and peak viral load level, the researchers expressed concern that anyone who had been virally suppressed for less than three-and-a-half years before switching to dolutegravir / lamivudine is potentially at higher risk of rebound if they have the M184V mutation.

Knowing how long the mutation remains in the HIV reservoir in people with suppressed HIV could help in determining when it is safe to use dolutegravir / lamivudine. Over time, virus in the HIV reservoir disappears, either through random bursts of activation or because the cells storing the virus are eliminated.

To investigate further the persistence of the M184V mutation, French researchers investigated how long the M184V mutation persists in the HIV reservoir and what factors are associated with the clearance of the mutation.

They looked at changes in the detection of the M184V mutation in proviral DNA over time in 22 people with HIV. They looked for provirus containing the M184V mutation in stored blood samples. Samples came from 18 men and four women who had been virally suppressed for at least five years (median 7.7 years) and who had the M184V mutation detectable in at least 2% of proviral DNA at baseline. Participants had a median CD4 count of 564 at first sample, the median lowest-ever CD4 count (or nadir) was 164, and the median peak viral load was 4.99 log (just under 100,000 copies/ml).

Samples covering five years were sequenced to analyse the loss of the M184 mutation over time. After five years, 14 out of 22 had cleared the M18V mutation. Half of participants had cleared the mutation within 2.5 years.

Multivariate analysis of the factors associated with M184V detectability at a cut-off of 2% or 5% of proviral DNA found that the presence of emtricitabine or lamivudine in the current regimen did not affect detectability. Nor did sex or CD4 nadir. The only factor showing an association, at a cut-off of 5%, was viral load peak. The higher the peak viral load ever recorded, the less likely a participant was to clear the M184V mutation after five years of follow-up. A univariate analysis found that in addition to viral load peak, a lower nadir CD4 count was also associated with persistence of the mutation.

The association between peak viral load and persistence of the M184V mutation may indicate that M184V persistence is influenced by the size of the HIV reservoir. A higher peak in viral load influences the amount of virus that is stored in the reservoir.

“Altogether, these results indicate that a longer delay after the last RAM [resistance associated mutations] detection is needed to minimize the risk of virological failure,” the study authors conclude.

They found that despite prolonged viral suppression before joining the study, almost one in three participants did not clear the M184V mutation despite a further five years of follow-up.