Study indicates NNRTI mutations have little effect upon HIV-1 replicative capacity

9 December 2001. Related: Antiretrovirals.

Brian Boyle, MD for HIVandHepatitis.com

During the past 5 years, highly active antiretroviral therapy (HAART) has improved morbidity and mortality rates in HIV-positive patients. In some patients on HAART, these improvements have been observed and CD4+ T cell increases have been maintained, despite the presence of persistent low-grade virologic replication.

The explanation for this discordance is likely to be multi-factorial and to include, to some extent, viral fitness changes that result from the genetic mutations that cause viral resistance to antiretrovirals.

In a study published in AIDS, Investigators from Italy investigated the role of resistance mutations in the HIV reverse transcriptase (RT) and protease (PR) genes as predictive factors in dissociation of immunological and virological responses to HAART. They studied 354 HIV-infected patients with virological failure – defined as a reduction of the HIV-1-RNA level of less than 1 log10 copies/mL after 2 months of treatment or a viral load > 80 copies/mL after 6 months on HAART or any viral rebound after achieving an undetectable viral load – who maintained or failed to maintain a greater than 100 CD4+ T cell increase from baseline.

The patients’ median CD4+ T cell count and HIV-1-RNA level at genotyping were 275 cells/mm3 and 4.63 log10 copies/mL, respectively, and they were on HAART for a median of 26 months. A mean increase of 129 CD4+ T cells/mm3 and a mean decrease of 0.09 log10 copies/mL of HIV-1 RNA were observed from the time HAART was started to the time the genotype was obtained. Despite virologic failure, A CD4+ T cell count increase of over 100 cells/mm3 was observed in 159 (45%) patients.

The investigators found that the factors associated with immunological recovery of more than 100 CD4+ T cells/mm3 from baseline despite virological failure were a prolonged time on HAART, a history of an ever-undetectable HIV-1-RNA level, the presence of RT M184V and PR L24I and V82A mutations. In contrast, the probability of immunologic recovery in these patients was significantly decreased by a high HIV-1-RNA level at genotype, a high CD4+ T cell count at baseline, nevirapine exposure and the emergence of the RT Y181C mutation.

The multivariate analysis showed that only the HIV-1-RNA level at genotype, CD4+ T cell count at baseline, and RT Y181C mutation were associated with a reduced probability of sustained immunological recovery, whereas overall time on HAART, an ever-undetectable HIV-1-RNA level and the PR L24I mutation were significant predictors of a persistently elevated CD4+ T cell count. Patients with immunological recovery had lower mean values of HIV-1 RNA at genotype (4.52 versus

4.82 log10 copies/mL; P < 0.01). Patients with RT Y181C mutants had higher mean values of HIV-1 (4.86 versus 4.59 log10 copies/mL; P < 0.01), lower absolute values of CD4+ T cell counts at genotyping (231 versus 313 cells/mm3; P < 0.01) and a lower change of CD4 cell count between baseline and genotyping (+68 versus +142 cells/mm3; P < 0.01).

The authors conclude from these data -Our finding of lower HIV-1-RNA levels in patients with CD4 cell recovery confirmed the role of viral fitness. According to these observations most HIV-1 strains in patients with a discordant viro-immunological response harboured primary and secondary mutations in the protease gene. [The] modest impact on the viral fitness of selected NNRTI mutations, such as K103N and Y181C, is in agreement with the higher HIV-1-RNA level in patients carrying Y181C mutants and with the negative predictive value of Y181C on sustained CD4 cell recovery observed in our study…These observations may have several clinical implications.

It has been observed that among patients with persistent viraemia, despite the presence of reduced drug susceptibility, antiretroviral therapy is associated with sustained immunological benefit, with the maintenance of a viral population with reduced replicative capacity. It is conceivable that these viro-immunological discrepancies could be at least partly mediated by the different effects of mutations on viral fitness.

On one hand, this opens the possibility of considering, in situations of remarkable viro-immunological dissociation and in the absence of valid therapeutic alternatives, the maintenance of drugs selecting for mutations strongly affecting virus fitness. On the other hand, the emergence of a single point mutation able to lead rapidly to broad cross-resistance to the entire NNRTI drug class, in the absence of sustained immunological response (as is the case with Y181C), should suggest a rapid discontinuation of NNRTI after a confirmed virological failure. –

Reference:

Antinori A; Liuzzi G; Cingolani A et al. Drug-resistant mutants of HIV-1 in patients exhibiting increasing CD4 cell count despite virological failure of highly active antiretroviral therapy. AIDS 2001; 15:2325-2327.

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