Attendees at a fascinating, but flawed, presentation at the end of the first day of the Fifteenth International AIDS Conference in Bangkok heard that San Franciscans with an AIDS diagnosis at some point between 1980 and 2002, and who initiated HAART with efavirenz and 3TC alongside either AZT or d4T, survived longer than those taking any other possible HAART regimen that was available prior to 2002. Individuals taking nevirapine with either of the nucleoside analogue backbones also had significantly better survival than patients who received PI-containing regimens.
The study from Johns Hopkins Bloomberg School of Public Health and the San Francisco Department of Public Health used citywide AIDS mortality surveillance data for this retrospective, matched, nested case-control study. In other words, 310 San Franciscans who died of AIDS prior to the end of 2002 (cases) were matched with 1,161 San Franciscans still living with an AIDS diagnosis in 2002 (controls) by year of AIDS diagnosis, the level and year of their earliest known CD4 count (within 100 cells/mm3), and controlled for CD4 count nearest to treatment initiation, age, injection drug use, and homelessness.
The aim of their study was to see whether the four World Health Organisation 3x5 drug options (efavirenz/3TC or nevirapine/3TC with either AZT or d4T) were the best initial treatment options in terms of survival. The researchers compared the odds of survival for regimens that were initiated after 1996 by at least ten individuals, comprising 39 different combinations, that included, at a minimum, one protease inhibitor (PI) or one non-nucleoside reverse transcriptase inhibitor (NNRTI).
Three of the four most common first-line regimens were, in fact, PI-based: d4T/3TC/nelfinavir (n = 151), AZT/3TC/nelfinavir (n = 148), AZT/3TC/indinavir (n = 142) and AZT/3TC/efavirenz (n = 122). However, the best survival outcomes were among individuals initiating treatment with d4T/3TC/efavirenz (n = 68, adjusted odds ratio [AOR] 0.35, p = 0.024) or AZT/3TC/efavirenz (n = 122, AOR 0.39, p = 0.013). Individuals initiating treatment with the two other WHO 3x5 regimens still had good survival outcomes (d4T/3TC/nevirapine: n = 68, AOR 0.52, p =0 .12; AZT/3TC/nevirapine: n = 73, AOR 0.68, p = 0.31) and the difference between the four regimens was not statistically significant. Of interest, d4T/3TC/saquinavir had the worst survival outcome of the 39 combinations analysed.
However, the researchers’ conclusion that the survival data could be compared between San Francisco – where people with HIV had a myriad of second- and third-line and salvage therapy options after the failure of their first-line treatment – and resource-limited countries where, currently, few second-line options are available, was found to be flawed in the question and answer session that followed.
Principal investigator, Sanny Chen, did concede that this was not a randomised clinical trial, and no data on adherence, gender, subsequent changes in regimens, side effects or viral loads were included in the analysis, and amended her conclusion that the 3x5 regimens are “well chosen,” with the proviso that this should be “interpreted with caution.”
Nevertheless, the fact that San Franciscans who initiated HAART with NNRTI-based triple therapy did better long-term suggests that initiating antiretroviral therapy with a PI-sparing regimen appears to lead to longer survival in well-resourced settings where resistance testing and a myriad of second- and third-line and salvage treatment options are available. Whether HAART based around the NNRTIs, efavirenz and nevirapine, and 3TC – all of which have a low genetic barrier to resistance – are the best long-term options for the 3x5 programme remains to be seen.
Reference
Chen SY et al. Which antiretroviral regimens yield the best odds of survival in San Francisco? XV International AIDS Conference, Bangkok, abstract MoOrC1082, 2004.