Replicative capacity of HIV: an emerging diagnostic tool?

Replicative capacity emerged further into the limelight as a diagnostic tool in its own right at this year's 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, which took place last week in San Diego.

Researchers also reported on the speed at which further resistance mutations develop in individuals with viral rebound, and how this pattern of emergence relates to changes in replicative capacity.

Viral rebound and replicative capacity

One group reported on the extent to which drug resistance evolved over an average of 30 weeks on failing therapy.

Sixty four patients with two consecutive genotypic resistance tests and persistent viremia on an unchanged regimen were identified. Only 14.5% of patients who stayed on failing therapy for an average of 30 weeks after their first resistance test developed further reductions in drug susceptibility.

Individuals were tested for genotypic resistance when they had a median viral load of 7, 221 copies/ml; by the time of the second resistance test, the median viral load had risen by just over 0.3 log, to 16,795 copies/ml. 37% developed new resistance mutations, but only 14.5% developed mutations associated with further reductions in drug susceptibility. These mutations were associated with tenofovir resistance.

12.5% developed renewed sensitivity to at least one drug during the period of failing therapy: seven patients cleared the reverse transcriptase mutation 184V, six cleared the NNRTI mutation K103N and two the NNRTI mutation Y108I. Two patients cleared the protease mutation 54V.

Protease inhibitor sensitivity was partially restored despite an ongoing decline in replicative capacity, suggesting that measurement of replicative capacity may provide useful additional information for determining treatment choices in individuals experiencing treatment failure, especially where extensive drug resistance is present.

A smaller study, in 17 patients who remained on the same regimen despite virological failure, looked at mutation rates over a median period of 17 months, albeit using only 42 samples to track changes. The group found that changes in reverse transcriptase slowed during the second half of the study period, regardless of the level of viral load. However, protease mutation rates did not change.

Phenotypic resistance and replicative capacity

In a third study, Virologic researchers took seven patients with good adherence to a virologically failing HAART regimen and measured phenotypic sensitivity over 27 months of follow-up (Goetz).

At the time of treatment failure the CD4 count and viral load were 299 cells/mm³ and 9,010 copies/ml respectively. Phenotypic sensitivity scores for nucleoside analogues, NNRTIs and protease inhibitors were 5.1, 2.7, and 5.3 (where 0 equals sensitivity to a drug and 1 equals reduced at least fourfold reduction in sensitivity to a drug). Replicative capacity was 35% (p

During a mean 27-month follow-up after failure, the time-averaged CD4 count and viral load were 317 cells/mm³ and 16,247 copies/ml (this measure defines the average viremia that prevailed for each individual during the period of failure, and is an indicator of the volume of replication taking place).

The mean final CD4 count and viral load on failing treatment were 332 cells/mm³ and 56,149 copies/ml, and phenotypic sensitivity scores for nucleoside analogues, NNRTIs and protease inhibitors were 5.9, 1.9, and 2.9, and replicative capacity was 15%. The mean changes from initial failure were +33 CD4 cells and +47,139 copies/ml for viral load, whilst phenotypic sensitivity scores changed by +0.7 (NRTIs), -0.9 (NNRTIs) and –2.4 (p

The authors suggest that the modest reductions in CD4 cell count despite failing treatment are associated with reduced replicative capacity despite rising viral load, and that it may not be necessary to alter failing treatment in patients with impaired replicative capacity.

For further information on viral fitness, drug resistance and the immune system, click here.