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  International AIDS Conference
Durban, South Africa
July 18-22 2016
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Adding RAL to 3-Drug First Regimen Does Not Cut Mortality in Low-CD4 Group
  21st International AIDS Conference (AIDS 2016), July 18-22, 2016, Durban, South Africa
Mark Mascolini
Adding raltegravir to standard first-line triple therapy in Africans with low CD4 counts trimmed viral loads faster than triple therapy but did not cut mortality in the 1805-person REALITY trial [1]. Nor did the 4-drug raltegravir regimen lower rates of World Health Organization (WHO) grade 3 or 4 events or other clinical outcomes.
Death rates are high in the first months of antiretroviral therapy for sub-Saharan adults and children with advanced HIV infection. Previous research found that mortality in this population declines as viral load drops and CD4 counts rise [2]. Because integrase inhibitors such as raltegravir drive viral loads down faster than antiretrovirals in other classes, the REALITY investigators planned this raltegravir trial in Uganda, Zimbabwe, Malawi, and Kenya.
The researchers randomized 1805 antiretroviral-naive adults and children more than 5 years old to two nucleosides and a nonnucleoside (n = 903) or to that regimen plus raltegravir (n = 902). Everyone had a CD4 count below 100. The primary endpoint was mortality at 24 weeks. The raltegravir-quad group and the standard-therapy group were similar in proportions of males (53% and 53%), median age (36 and 36), proportions 5 to 17 years old (4% and 4%), pretreatment CD4 count (38 and 36), pretreatment viral load (230,660 and 230,000 copies), and proportions starting efavirenz (89% and 90%) and tenofovir/emtricitabine (78% and 80%).
Overall adherence to the randomized strategy was 99%. In the raltegravir and standard-therapy arms, participants spent 98% and 99% of time to 48 weeks taking their assigned regimen or one with only in-class substitutions. Proportions with a viral load below 50 copies were significantly higher in the raltegravir arm at week 4 (P < 0.001) and week 12 (about 80% versus 60%, P < 0.001). About 80% in each arm had a viral load below 50 copies at week 24. Both study groups gained an average 100 CD4 cells through week 12. By week 48 the raltegravir group had added significantly more CD4 cells (just over 150 versus just under 150, P = 0.04), but CD4 counts did not differ significantly between groups over the entire 48 weeks (P = 0.30).
After 24 weeks mortality measured 10.9% in the raltegravir group and 10.2% in the standard-therapy group, a nonsignificant difference (P = 0.54). By week 48 mortality rates were 12.4% in the raltegravir arm and 13.0% in the standard-therapy arm, also a nonsignificant difference (P = 0.86). Hazard ratio analysis found no significant differences between groups in WHO stage 4 events or death, WHO stage 3 or 4 events or death, new tuberculosis, serious adverse events, grade 3 or 4 adverse events, or most other endpoints. The raltegravir group had a significantly lower rate of grade 4 adverse events definitely or probably related to antiretroviral therapy (P = 0.03).
1. Kityo C, Siika A, Szubert AJ, et al. 12-week raltegravir-intensified quadruple therapy versus triple first-line ART reduces viral load more rapidly but does not reduce mortality in severely immunosuppressed African HIV-infected adults and older children: the REALITY trial. 21st International AIDS Conference (AIDS 2016). July 18-22, 2016. Durban, South Africa. Abstract FRAB0102LB.
2. Walker AS, Prendergast AJ, Mugyenyi P, et al. Mortality in the year following antiretroviral therapy initiation in HIV-infected adults and children in Uganda and Zimbabwe. Clin Infect Dis. 2012;55:1707-1718. http://cid.oxfordjournals.org/content/55/12/1707.long