Cross-Sectional Detection of Acute HIV Infection: Timing of Transmission, Inflammation and Antiretroviral Therapy
Cross-sectional screening was employed to detect HIV RNA positive, antibody negative subjects. Date of HIV acquisition was estimated from clinical history and correlated with sequence diversity assessed by single genome amplification (SGA). Twenty-two cytokines/chemokines were measured from enrollment through week 24.
To find subjects immediately after HIV acquisition we employed cross-sectional screening to identify HIV RNA positive, seronegative subjects. Using SGA to estimate infection dates based on number of viral generations, BEAST (Bayesian Evolutionary Analysis by Sampling Trees v.1.5.3) results correlated well with estimated-date-of-infection per symptom report in subjects with single variant transmissions.
To our knowledge, this is the first report of using molecular clock modeling in conjunction with symptom data to estimate date of HIV acquisition. The results validate using molecular clocks to confirm AHI with clinical data, to estimate HIV transmission dates without specific exposure or symptom information, and use of 14 days prior to symptom onset to estimate HIV transmission dates.
We also examined plasma cytokine levels and the effects of antiretroviral therapy (ART) on these markers of inflammation. A cytokine storm was not observed in this prospective study as in prior work among plasma donors, suggesting enrollment occurred after peak levels of viremia and cytokines.
However, differences were observed between the AHI subjects and seronegative controls in some cytokines/chemokines that are elevated for a relatively sustained period during the acute phase (i.e. IL-18, IP-10, IFN-gamma, IL6 and IL-10) and in other analytes that are increased later in AHI (i.e. IL-1beta, IL-2, IL-7 and GM-CSF).
We noted minimal effect of ART on levels of cytokines/chemokines at week 16-24 possibly due to the delay from presentation-to-care, to diagnosis and for referral resulting in ART initiation usually after peak viremia. Over one-third of acutely infected participants were seen at least once prior to diagnosis, reflecting symptom non-specificity and that the clinical suspicion for AHI remains low among practitioners. Notably, the overall delay from symptom onset to the date of testing for AHI was relatively short (median 6 days). The majority of the latter delay results from a median turn-around of 12 days for confirmed NAT pooling results.
Overall, our results provide a clear, prospective picture of patients with AHI, and emphasize the difficulty in recruiting subjects very early in AHI due to missed opportunities for earlier diagnosis and diagnostic delays. Accordingly, wider awareness of the clinical presentation by medical providers as well as more rapid strategies to diagnosis AHI are needed.
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Cynthia Gay, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America
Key words: Acute HIV infection