Correlation between reduction in plasma HIV1 RNA concentration 1 week after start of antiretroviral treatment and longerterm efficacy
Levels of concentration of HIV1 RNA in plasma are standard markers for AIDS and death during the course of the disease, as well as indicators of the efficacy of antiretroviral treatment. Virological responses to treatment are commonly measured by HIV1 RNA levels 412 weeks after the start of treatment. The kinetics of the treatment in the initial stages is not commonly measured.
According to guidelines produced by the Department of Health and Human Services, decisions to change therapy include less than a 0.500.75 log reduction in plasma HIV1 RNA by 4 weeks. However, viral resistance can develop during these weeks if therapy is suboptimal, and patients could be exposed unnecessarily to ineffective and toxic drugs. Therefore, earlier prediction of drug efficacy could be helpful for optimising therapy.
The investigators assumed that the initial slopes of HIV1 concentration changes during the first week of therapy and is linked to drug efficacy. The authors thus investigated the possibility of using the very early dynamics of HIV1, assessed by measurement of daily samples for different cohorts of patients, including patients on HAART, as a possible predictor of drug efficacy in the longerrun.
Data were obtained from three cohorts of patients. One consisted of 52 children who had never received protease inhibitors, who completed 12 weeks of a phase I trial of indinavir monotherapy in 1996. The second cohort comprised 34 adults, naïve to protease inhibitors and nonnucleoside reverse transcriptase inhibitors, treated with a fourdrug combination regimen during 19972000. The third cohort consisted of 38 children, naïve to protease inhibitors, who completed 12 weeks of a phase I trial of ritonavir monotherapy in 19951996.
The number of CD4 cells was measured by flow cytometry. HIV 1 RNA concentrations in plasma were measured by PCR. The baseline HIV1 RNA concentrations were calculated as an average of two log concentrations from samples taken on day 0 and the previous day or a few days before. The baseline variance was smaller than 0.3 log. Patients with a continuous decline of HIV1 concentrations and in whom HIV1 was either undetectable or declined by more than 1.5 log at 12 weeks were defined as good responders; the rest were poor responders.
There was no significant difference in the baseline plasma HIV1 RNA concentration between groups on monotherapy and on HAART. The mean change in log HIV1 RNA concentration for poor and good responders was 0.82 and 2.10 log, respectively, at week 5, and 0.50 and 2.60 at week 8. According to the authors, -the individual virus decay rate constants (k) at day 6 correlated significantly (r>0.66, p<0.0001) with changes in HIV1 concentrations at 4, 8 and 12 weeks, and correctly predicted 84% of the responses with a cutoff value of k=0.21 per day (in log scale). Reduction in plasma HIV1 less than 0.72 log by day 6 after initiation of therapy predicted poor longterm responses in more than 99% of patients. –
The authors took advantage of what are now judged to be suboptimal regimens of ritonavir and indinavir monotherapy that were given several years ago. For patients on single or combination therapy, the earliest and most important indicator of drug efficacy determining long term (12week) response was the change in plasma HIV1 RNA levels at days 36. This indicates that early measurement will indicate efficacy with HIV1. However, as the authors indicate, this method may not work with all cohorts, was used with naïve patients, and is dependent upon adherence to treatment, a major problem in current HIV1 treatments. The authors recommend further prospective studies with larger homogeneous cohorts and cohorts of drugexperience patients.
Polis MA, Sidorov IA, Yoder C et al. Correlation between reduction in plasma HIV1 RNA concentration 1 week after start of antiretroviral treatment and longerterm efficacy. Lancet 2001 Nov 24;358(9295):17601765.
Source: Centers for Disease Control & Prevention (CDC), HIV/STD/TB Prevention News Update