A recent analysis of people who had undetectable viral load at baseline in the HPTN-052 study found detectable ARV drug levels and most of those randomised to the deferred treatment arm continued to use treatment.
Luckily, these numbers are small enough not to affect the main study results, but this raises an interesting challenge for future researchers.
HPTN 052 randomised HIV positive partners in sero-different couples to either starting treatment while their CD4 count was between 350 and 550 cells/mm3 or to defer treatment until it reached 250 and the study has been widely reported due to the impact that treatment had on reducing sexual HIV transmission. Participants self-reported no use of ART upon enrolling in the trial. However, blood samples at enrolment were subsequently tested in a subset of participants and showed that ART drugs were commonly detected.
The results of this retrospective sub-group analysis were reported by Jessica Fogel from Johns Hopkins University and colleagues in the 1st August 2013 edition of the Journal of Infectious Diseases.1
The large phase 3 HPTN 052 was conducted in Africa, Asia and the Americas. The results were widely publicised for showing a 96% reduction of HIV transmission.2
However, an interim review by the Data and Safety Monitoring Board (DSMB) for the study noticed that some of the HIV positive partners already had an undetectable viral load when they entered the study. This raised concerns that some participants were already taking ART, and others in the delayed treatment arm perhaps continued their treatment. Since then, this post-hoc analysis retrospectively analysed enrolment blood samples from 209 HIV positive partners for 16 most commonly used ARVs, based on viral load at baseline: all those with suppressed <400 copies/mL (n=96); or low 401 and 1,000 copies/mL (n=48); and a random group with high viral load >1,000 copies m/L (n=65). Follow up sampling was also conducted.
Almost half the suppressed group (45/96, 47%) had a least one ARV detected (d4T, AZT, 3TC, nevirapine), with minimal use in the other groups (only 2/48 in the low viral load group and 1/65 with high viral load). These cases were distributed from five different countries. Demographic and clinical factors associated with ART detection were country of origin and lower CD4 count. No association was seen in regards to age, race, gender, reported ART use for pMTCT, or self reported condom use. None of the 48 participants transmitted HIV to their partners. Follow-up testing was performed from enrollment samples to determine whether ART was still used off-study after enrolment.
Roughly half of the people with detectable drug levels were randomised to the deferred treatment arm of the main study, and they appear to have continued using treatment (based on results from the 16 people with follow up samples).
Off-study ART use did not appear to impact the study-administered ART response. In those in the early ART initiated arm of the trial, off-study ART use was not associated with viral suppression or treatment failure. In the delayed ART arm, viral suppression in the first year of the study despite off-study ART was more common among those who had ART detected at enrolment. In most cases those participants continued to use off-study ART after enrolment did this without the knowledge of the research staff.
Self-reporting of prior ART use can therefore be a limitation of similar transmission studies. However, the reasons for not disclosing would be important to know. Some HIV positive people may have wanted to enter a trial in order to have help with disclosure to their partner from counselors.
In addition, 51 of the 96 people with undetectable viral loads are likely to be elite controllers and would presumably be at low risk for transmitting HIV. In addition to the value of monitoring for drug use at baseline, this raises the question of whether a minimum viral load should be an entry criteria for future studies of PrEP, which would also overcome this problem.
- Fogel JM et al. Undisclosed antiretroviral drug use in a multi-national clinical trial (HPTN 052). J Infect Dis (2013) Advanced access online, 1 August 2013. doi: 10.1093/infdis/jit390.
- Cohen MS et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365:493-505, (11 August 2011). DOI: 10.1056/NEJMoa1105243.
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