HIV This Week

Zolopa A, Andersen J, Powderly W, Sanchez A, Sanne I, Suckow C, Hogg E, Komarow L. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS ONE. 2009;4(5):e5575.

Optimal timing of antiretroviral therapy initiation for individuals presenting with AIDS-related opportunistic infections has not been defined. A5164 was a randomized strategy trial of “ early antiretroviral therapy”—given within 14 days of starting treatment for acute opportunistic infection versus “deferred antiretroviral therapy”—given after treatment for acute opportunistic infection is completed. Randomization was stratified by presenting opportunistic infections and entry CD4 count. The primary week 48 endpoint was 3-level ordered categorical variable: 1. Death/AIDS progression; 2. No progression with incomplete viral suppression (ie HIV viral load (VL) >or=50 copies/ml); 3. No progression with optimal viral suppression (ie HIV VL <50 copies/ml). Secondary endpoints included: AIDS progression/death; plasma HIV RNA and CD4 responses and safety parameters including IRIS. 282 subjects were evaluable; 141 per arm. Entry opportunistic infections included Pneumocytis jirovecii pneumonia 63%, cryptococcal meningitis 12%, and bacterial infections 12%. The early and deferred arms started antiretroviral therapy a median of 12 and 45 days after the start of treatment for opportunistic infections, respectively. AIDS progression/death was seen in 20 (14%) vs. 34 (24%); whereas no progression but with incomplete viral suppression was seen in 54 (38%) vs. 44 (31%); and no progression with optimal viral suppression in 67 (48%) vs 63 (45%) in the early vs. deferred arm, respectively (p = 0.22). However, the early antiretroviral therapy arm had fewer AIDS progression/deaths (OR = 0.51; 95% CI = 0.27-0.94) and a longer time to AIDS progression/death (stratified HR = 0.53; 95% CI = 0.30-0.92). The early antiretroviral therapy had shorter time to achieving a CD4 count above 50 cells/mL (p<0.001) and no increase in adverse events. Early antiretroviral therapy resulted in less AIDS progression/death with no increase in adverse events or loss of virologic response compared to deferred antiretroviral therapy. These results support the early initiation of antiretroviral therapy in patients presenting with acute AIDS-related opportunistic infections, absent major contraindications.

Editors’ note: Waiting to complete treatment for an opportunistic infection before initiating antiretroviral treatment in this USA/South Africa study was associated with a higher risk of HIV disease progression and/or death, with no safety or virological advantage. Concerns about toxicity, drug-drug interactions, immune reconstitution inflammatory syndrome, and adherence have made clinicians cautious about initiating antiretroviral treatment during treatment for opportunistic infections. However, as this study demonstrates, earlier antiretroviral treatment brings earlier improvement in immune responsiveness, which narrows the ‘window of vulnerability’ to additional HIV-related complications, preventing clinical progression.

Demeter LM, Jiang H, Mukherjee AL, Morse GD, Difrancesco R, Dicenzo R, Dykes C, Sista P, Bacheler L, Klingman K, Rinehart A, Albrecht M. A randomized trial of therapeutic drug monitoring of protease inhibitors in antiretroviral-experienced, HIV-1-infected patients. AIDS. 2009;23(3):357-68

Whether therapeutic drug monitoring of protease inhibitors improves outcomes in HIV-infected patients is controversial. Demeter and colleagues evaluated this strategy in a randomized, open-label clinical trial, using a normalized inhibitory quotient (NIQ), which incorporates drug exposure and viral drug resistance. NIQs </= 1 may predict poor outcome and identify patients who could benefit from dose escalation. Eligible patients had a viral load >/=1000 copies/ml on a failing regimen, and began a new protease inhibitor containing regimen at entry. All FDA-approved protease inhibitors available during the study recruitment (June 2002-May 2006) were allowed. One hundred and eighty-three participants with NIQ </= 1, on the basis of their week 2 protease inhibitor trough concentration and pre-entry drug resistance test, were randomized at week  4 to standard of care (SOC) or protease inhibitor dose escalation (therapeutic drug monitoring). The primary endpoint was change in log10 plasma HIV-1 RNA concentration from randomization to 20 weeks later. Ninety-one patients were randomized to standard of care and 92 to therapeutic drug monitoring. NIQs increased more in the therapeutic drug monitoring arm compared to standard of care (+69 versus +25%, P = 0.01). Despite this, therapeutic drug monitoring and standard of care arms showed no difference in outcome (+0.09 versus +0.02 log10, P = 0.17). In retrospective subgroup analyses, patients with less HIV resistance to their protease inhibitors benefited from therapeutic drug monitoring (P = 0.002), as did black and Hispanic patients (P = 0.035 and 0.05, respectively). Differences between black and white patients persisted when accounting for protease inhibitor susceptibility. There was no overall benefit of therapeutic drug monitoring. In post hoc subgroup analyses, therapeutic drug monitoring appeared beneficial in black and Hispanic patients, and in patients whose virus retained some susceptibility to the protease inhibitors in their regimen.

Editors’ note: Although the authors state that they compared differences between the therapeutic drug monitoring group and the standard of care group with respect to the primary endpoint (change in viral load after 20 weeks) in specific sub-groups of patients according to sex, race and ethnicity, number of protease inhibitors in the study regimen, and whether fos-amprenavir was used) no data are provided for women who constituted 13% of the study participants. This is another example of the ‘fugitive data issue’ that the Women and Trials movement has identified as problematic. Authors need to make an extra effort to publish these data, as not enough is known about sex differences in pharmacokinetics and pharmacodynamics.