July 13, 2024

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Lamivudine Resistance May Persist for Years in People with HIV

Lamivudine Resistance May Persist for Years in People with HIV



Lamivudine Resistance May Persist for Years in People with HIV

French researchers have reported that a mutation capable of compromising dual therapy with dolutegravir and lamivudine can persist in the HIV “reservoir” within the DNA of blood cells for at least 12 years in about one-third of patients. Their study tracked the disappearance of mutations in people whose viral load was suppressed by antiretroviral therapy.

The researchers employed ultra-deep sequencing, a technique designed to detect HIV sequences hidden in the DNA of cells that are not currently producing the virus. This method can identify small amounts of HIV containing the target sequence, thereby detecting drug resistance in a minor fraction of the virus.

Lamivudine Resistance May Persist for Years in People with HIV

The M184V mutation confers resistance to lamivudine and emtricitabine, both integral parts of many antiretroviral therapy regimens. Viruses harboring the M184V mutation are archived in DNA and can remain dormant until reactivated. Reactivation of viruses with this mutation may lead to viral replication bursts, potentially disrupting lamivudine-containing dual therapy, especially if adherence lapses.

Understanding how long the M184V resistant mutation impacts response to the dolutegravir/lamivudine (Dovato) dual therapy is crucial. Current US guidelines do not recommend dolutegravir/lamivudine for patients with a history of resistance. Similarly, the British HIV Association advises against using this combination for anyone with a history of the M184V mutation. The European AIDS Clinical Society also deems this combination unsuitable for switching treatments in any patient with a history of resistance, even if they are virally suppressed.

These guidelines currently exclude a significant portion of previously treated HIV-infected individuals from using dolutegravir/lamivudine. Research on the impact of M184V resistance history on dolutegravir/lamivudine response has yielded conflicting results.

A systematic review and meta-analysis of five intervention studies and five cohort studies concluded that an M184V mutation history does not affect the response to dolutegravir/lamivudine. However, one study included in the analysis, LAMRES, found that people with the M184V mutation and suppressed viral load who switched to dolutegravir/lamivudine had a higher risk of viral rebound if their viral suppression duration was shorter. This association was no longer significant after controlling for demographic factors and peak viral load levels. Nonetheless, researchers expressed concern that anyone with M184V mutations who had been virally suppressed for less than three and a half years might face a higher rebound risk when switching to dolutegravir/lamivudine.

Understanding how long mutations persist in the HIV reservoir of suppressed patients may help determine when it is safe to use dolutegravir/lamivudine. Over time, viruses in the HIV reservoir may disappear either through random activation bursts or because the cells harboring the virus are eliminated.

To further study the persistence of the M184V mutation, French researchers examined its duration in the HIV reservoir and the factors associated with its clearance. They studied changes in the detection of the M184V mutation in the proviral DNA of 22 HIV-infected individuals. They looked for proviruses with the M184V mutation in stored blood samples from 18 men and 4 women who had been virally suppressed for at least five years (median 7.7 years) and had at least 2% of their proviral DNA containing the M184V mutation at baseline. The median CD4 count at the first sample was 564, with a median historical lowest CD4 count (nadir) of 164, and a median peak viral load of 4.99 log (just below 100,000 copies/mL).

Sequencing of samples over five years analyzed the loss of the M184V mutation over time. After five years, 14 of the 22 participants had cleared the M184V mutation. Half of the participants cleared the mutation within 2.5 years.

At detection thresholds of 2% or 5% of proviral DNA, multivariable analysis of factors associated with M184V detectability found that the presence of emtricitabine or lamivudine in the current regimen did not affect detectability. Neither gender nor nadir CD4 count showed an effect. At the 5% threshold, the only factor associated with M184V persistence was peak viral load. Higher recorded peak viral loads decreased the likelihood of clearing the M184V mutation after five years of follow-up. A univariable analysis found that, besides peak viral load, lower nadir CD4 counts were also associated with mutation persistence.

The association between peak viral load and M184V persistence might indicate that the size of the HIV reservoir influences M184V persistence. Higher peak viral loads correspond to larger viral reservoirs.

“In summary, these results suggest a longer delay after the last RAM (resistance-associated mutation) detection to minimize the risk of virological failure,” the study’s authors concluded. They found that despite prolonged viral suppression before entering the study, nearly one-third of participants had not cleared the M184V mutation after five years of follow-up.

Lamivudine Resistance May Persist for Years in People with HIV

References:

Teyssou E et al. The RT M184V resistance mutation clearance in the reservoir is mainly related to CD4 nadir and viral load zenith independently of therapeutic regimen type. Journal of Antimicrobial Chemotherapy, published online 28 May 2024.

(source:internet, reference only)


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