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Early Antiretrovirals in People Diagnosed
With AIDS May Quell Inflammation Faster
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17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010, San Francisco
Mark Mascolini
Starting antiretroviral therapy during treatment for opportunistic diseases in people diagnosed with advanced HIV infection lowered several inflammation markers more than treating only the opportunist, according to further analysis of ACTG study A5164 [1]. But only pretreatment lactate dehydrogenase (LDH) levels independently predicted a CD4 count above 200 after 24 weeks of antiretroviral therapy.
ACTG A5164 found that starting antiretrovirals within 14 days of beginning treatment for opportunistic diseases or bacterial infection (except TB) slowed HIV disease progression more than delaying antiretroviral therapy until acute treatment of opportunists ended [2]. The new analysis arose from the hypothesis that starting antiretrovirals during treatment of opportunists would quiet inflammation more than only treating opportunists by defusing HIV-related mediators of inflammation.
To test that hypothesis, the ACTG team measured plasma levels of a panoply of inflammatory cytokines: tumor necrosis factor (TNF)-alpha, soluble TNF receptor (sTNFr), interferon, and the interleukins IL-1, IL-2, IL-6, IL-8, IL-10, IL-15, and IL-17. The ACTG team defined favorable outcomes as a CD4 count above 200 and a viral load below 50 copies 24 weeks after antiretrovirals began and at study week 48.
The trial included 141 people who started antiretrovirals quickly and 141 who delayed treatment. Median age measured 39 years in the early-antiretroviral group and 38 in the deferred group, and median CD4 counts stood at 31 and 28. About three quarters of each study group had an LDH level below 400 IU/L when the study began. LDH can be elevated in people with HIV infection, especially those with Pneumocystis pneumonia, which was the most frequent opportunist in ACTG A5164.
Cytokine levels were equivalent in the two treatment arms when the study began. By study week 4, sTNFr and IL-7 concentrations had dropped in the immediate-antiretroviral group. By antiretroviral week 12, TNF-alpha, IL-2, and IL-17 levels had also declined in the immediate-treatment group.
At study week 4 average CD4 count had dropped in the deferred-antiretroviral group while rising in the immediate group. By antiretroviral week 12 CD4 changes were equivalent in the two groups. Viral load fell from 5.07 log to 3.11 log at study week 4 in the immediate-antiretroviral group while remaining at 5.00 log in the deferred group. By antiretroviral week 12, viral loads were equivalent in the immediate group (2.08 log) and the deferred group (2.01 log).
Starting cytokine levels did not predict CD4 or virologic outcomes at weeks 24 and 48, even after statistical adjustment for assignment to immediate or deferred antiretrovirals. But in statistical models unadjusted for changes in viral load or CD4 count, improvements in TNF-alpha, sTNFr, IL-2, IL-6, IL-8, and IL-17 in the first 12 weeks predicted better 24- and 48-week CD4 and virologic outcomes. In a statistical model adjusting for all variables, only an initial LDH below 400 IU/L significantly predicted a CD4 count above 200 at week 24 (P < 0.05), regardless of whether cytokine levels predicted a CD4 count above 200 at week 24.
The ACTG team concluded that assignment to immediate versus deferred antiretroviral therapy did not affect CD4 or viral load response at week 24 or 48. But they proposed that inflammation in the first 12 weeks of treatment for opportunistic diseases and bacterial infection affects 24- and 48-week CD4 and viral load--regardless of treatment assignment.
A cohort study presented at this meeting by European and Canadian researchers confirmed slower progression to AIDS or death with prompt antiretroviral therapy upon AIDS diagnosis compared with delayed antiretroviral intervention [3].
References
1. Sanchez A, Komarow L, Andersen J, et al. Early ART compared to deferred ART during acute opportunistic infection leads to a reduction in the systemic inflammatory response resulting in improved immunologic outcomes. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 509. http://www.retroconference.org/2010/PDFs/509.pdf.
2. Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One. 2009;4(5):e5575. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0005575.
3. Miro J, Manzardo C, Mussini C, et al. Survival outcomes and effect of early vs deferred cART among HIV-1-infected patients diagnosed at the time of an AIDS-defining event in Europe and Canada: A Collaborative Cohort Analysis (1997 to 2004). 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 529. http://www.retroconference.org/2010/PDFs/529.pdf.
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