Drug-resistant strains of HIV can remain archived in the reservoir of latently infected cells for five years or more after a successfully suppressive HAART regime, according to research published in the April 15th issue of the Journal of Acquired Immune Deficiency Syndrome. This confirms previous findings that drug-resistant strains prior to suppressive HAART can re-emerge when HAART is stopped, and has important clinical implications, particularly for highly treatment-experienced people on salvage therapy.
To study how long resistant HIV strains persist, researchers from Ghent University in Belgium examined the DNA of HIV that was archived in the peripheral blood mononuclear cells (PBMCs) of eleven individuals attending their HIV clinic. All had received suboptimal antiretroviral treatment prior to HAART, most of which was mono- and/or dual therapy with nucleoside reverse transcriptase inhibitors (NRTIs: AZT, ddC, ddI, 3TC) for between eleven and 96 months (over an average of 46 months). One individual also had prior experience with the experimental non-nucleoside (NNRTI), loviride. All had been on suppressive HAART for more than four years, and their viral loads had remained below 50 copies/ml with the exception of one ‘blip’ of 206 copies/ml in one individual.
At the time the PBMC samples were taken, the participants had been on HAART for an average of 59 months (range 54-68) with a combination of two NRTIs and one ritonavir boosted or unboosted protease inhibitor (PI). All had experienced a rapid decline in viral load after starting HAART, and an average rise in CD4 cells of 575 (range 203-837).
In nine out of eleven cases, the investigators noted that the HIV DNA found inside the PBMCs consisted of a mixture of wild-type (drug sensitive) and drug-resistant viruses. The individual with only wild-type virus found in their PBMCs had been on suboptimal therapy for the shortest period, eleven months. The individual with only drug-resistant virus found in their PBMCs had been on suboptimal therapy for five years, which, the researchers suggest, indicates that there may be an association between time on suboptimal therapy and the amount of archived resistant HIV. In fact, the researchers observed a significant correlation between the time on suboptimal therapy and the relative amount of different archived viruses (P = 0.004). On the other hand, since no pre-treatment plasma samples were available for this individual, it is possible that this person had been originally infected with HIV-resistant virus.
When the researchers tested the plasma samples of the eleven individuals, which had been stored when they were on their suboptimal regimens, they found (almost without exception) that the same resistant variants (between three and eight NRTI-associated mutations) were still archived. One individual had extra mutations in their PBMCs (additional M184I and T69N variants) although no PI-associated mutations were seen in any of the individuals.
The researchers suggest that their study supports the theory that the maintenance of the viral reservoir is a dynamic process: new drug-resistant HIV variants that are able to replicate for a certain period of time enter the reservoir to be archived for longer periods. Additionally, since they were unable to find clear evidence that resistant virus evolves further under HAART, this suggests that a full treatment history may indicate to which drugs an individual may be more or less sensitive.
Interestingly, however, the individuals studied here (who began their HAART regimes prior to resistance testing, and who were on regimens that might be considered suboptimal when looking at their archived resistant virus) still had long-term, successful responses to their HAART regimen.
This bodes well for the recycling of drugs in salvage regimens, the researchers conclude, since even drugs to which HIV has previously built up resistance “can still add to the overall activity of the combination by preventing the replication of this latent wild-type, drug-sensitive, virus pool.”
Further information on this website
Resistance in tissue and other compartments - treatments
Resistance - booklet (pdf)
Resistance - factsheet
Verhofstede C et al. Drug-resistant variants that evolve during nonsuppressive therapy persist in HIV-1–infected peripheral blood mononuclear cells after long-term highly active antiretroviral therapy. J Acquir Immune Defic Syndr 35 (5), 473-483, 2004.