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Higher Pre-ART Viral Load Predicts Death in 12,000-Person Italian Analysis
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16th European AIDS Conference, October 25-27, 2017. Milan
Mark Mascolini
Higher viral load before starting antiretroviral therapy (ART) predicted all-cause mortality and AIDS mortality in a large contemporary Italian study [1]. The researchers believe that in this integrase inhibitor age their findings "suggest that viral-induced damage does not completely regress even with potent therapies."
Researchers at Milan's San Raffaele Scientific Institute and other centers noted that work focused on the late 1990s linked high pre-ART viral loads to a worse prognosis or marginally higher death risk [2,3], but little research addresses this issue in the current ART era. To fill that gap, they combined the San Raffaele and ICONA cohorts to chart mortality trends in people who started 3 or more antiretrovirals after 1998 and had a pre-ART viral load and CD4 count. They divided pre-ART loads into 100,000 copies or less, 100,000 to 500,000, 500,000 to 1 million, and more than 1 million. They used Cox regression analysis to explore associations between pre-ART viral load and all-cause mortality, AIDS-related mortality, and non-AIDS mortality.
The analysis included 11,877 people whose median year starting ART was 2011 (interquartile range [IQR] 2005-2014. While 7313 people started ART with a viral load below 100,000 copies, 3334 started between 100,000 and 500,000 copies, 652 between 500,000 and 1 million copies, and 578 above 1 million copies. The group had a median age of 38, 78% were men, 82% Italian, 41% infected during sex between men, 35.5% infected during sex between men and women, and 13% infected while injecting drugs. Almost half (49%) started ART within 6 months of their HIV diagnosis. Median viral load and CD4 count when ART began were 62,228 copies and 309 CD4s.
Through a median follow-up of 3.8 years (IQR 1.6 to 7.2) after ART began, 494 people died, including 171 (35%) from AIDS, 272 (55%) from non-AIDS causes, and 51 (10%) from unknown causes. Crude incidence of all-cause mortality was 0.637 per 100 person-years with a pre-ART viral load below 100,000 copies, 0.937 per 100 with a pre-ART load of 100,000 to 500,000 (P = 0.0007 compared with under 100,000), 1.265 per 100 with a pre-ART viral load of 500,000 to 1 million (P = 0.0004), and 1.861 with a pre-ART load above 1 million (P < 0.0001).
Pre-ART viral load predicted all-cause mortality, AIDS mortality, and non-AIDS mortality in a single-factor analysis. In multivariate analysis, pre-ART viral load still strongly predicted all-cause mortality and AIDS mortality, but the association with non-AIDS mortality weakened. The following list gives adjusted hazard ratios (aHR) (and 95% confidence intervals) for death according to pre-ART viral load:
For death from any cause (vs less than 100,000 copies):
-- 100,000 to 500,000: aHR 1.220 (0.979 to 1.520), P = 0.076
-- 500,000 to 1 million: aHR 1.477 (1.003 to 2.174), P = 0.048
-- Over 1 million: aHR 2.229 (1.530 to 3.249), P < 0.001
For AIDS-related death (vs less than 100,000 copies):
-- 100,000 to 500,000: aHR 1.455 (0.990 to 2.140), P = 0.057
-- 500,000 to 1 million: aHR 1.979 (1.129 to 3.469), P = 0.017
-- Over 1 million: aHR: aHR 2.156 (1.178 to 3.944), P = 0.013
For non-AIDS-related death (vs less than 100,000 copies):
-- Over 1 million: aHR 2.619 (1.564 to 4.386), P = 0.0003
Gender did not predict all-cause mortality, AIDS mortality, or non-AIDS mortality. HCV positivity independently predicted all-cause mortality and non-AIDS mortality. An AIDS diagnosis independently predicted all three types of mortality. Each more recent year of testing positive for HIV independently lowered the risk of all-cause mortality (aHR 0.975, 0.960 to 0.991, P = 0.003) and AIDS mortality (aHR 0.949, 0.924 to 0.975, P = 0.0001) but not non-AIDS mortality.
The researchers noted that the modest impact of pre-ART viral load on non-AIDS death risk needs further study. They concluded that the independent impact of pre-ART load on all-cause mortality and AIDS mortality should sustain concern that exposure to high levels of HIV RNA could have an irreversible negative impact. But the declining death risk with each more recent year of HIV diagnosis suggests stronger ART and better overall care are trimming mortality.
References
1. Galli L, Castagna A, Vergori A, et al. High pre-ART viral load and risk of death in HIV-1 infected subjects: an Italian inter-cohort study. 16th European AIDS Conference. October 25-27, 2017. Milan. Abstract PE21/17.
2. Egger M, May M, Chene G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. 2002;360:119-129.
3. Hogg RS, Yip B, Chan KJ, et al. Rates of disease progression by baseline CD4 cell count and viral load after initiating triple-drug therapy. JAMA. 2001;286:2568-2577.
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