AHI’s contribution to HIV transmission

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Acute HIV infection (AHI) contributes significantly to HIV transmission and may be important for intervention strategies seeking to reduce incidence and achieve a functional cure. Medical Xpress reports that in a study by the US Military HIV Research Programme (MHRP), Walter Reed Army Institute of Research, scientists enrolled and intensively followed a cohort of high-risk individuals, tracking their HIV status and characterising the disease through the acute stages of HIV infection.

This landmark study (RV217) is a prospective cohort of individuals from East Africa and Thailand at high risk for HIV infection, who had blood drawn twice weekly for qualitative plasma HIV RNA nucleic acid testing (NAT), a highly sensitive assay that allows for early detection of the virus. This is the first study to characterize the evolution of symptoms and signs prospectively in a large number of persons with acute infection.

“We were able to capture people with HIV infection before they had symptoms and before they had antibodies, which is how a diagnosis of HIV is usually made, and while their viral loads were actually very low,” said Dr Merlin Robb, the study’s principal investigator and the deputy director of MHRP. “We’re able to define the symptoms and signs during the acute interval, and now we’re working intensively on evaluating the relationship between the virus and the host immune response.”

Early events in HIV infection also appear to impact future course of the disease in individuals. It has been known that the amount of HIV virus in blood increases rapidly during acute infection and then decreases over time. The exact duration and type of human immune responses for controlling the viremia have not been not well defined.

“We find that events that occur in the first 30 days or so of infection are critical, and that is what we refer to as the acute phase,” said Robb. Researchers found a correlation between peak viremia, which is the point during acute infection when the amount of virus in the blood is highest, and set-point viremia, which dictates the risk of transmission and long-term disease course. The study showed that viral load set-point is established at resolution of acute viremia, within 18-42 days after infection.

“This indicates that events during acute infection are abrupt and decisive, meaning they play a role in later disease outcomes over many years of HIV infection in the absence of treatment,” said Robb.

RV217 also demonstrated that clinical presentation of HIV infections was less symptomatic than previously believed. The duration and number of symptoms were briefer, milder and fewer than reported previously. “Our impression from this finding is that most of these people would not have come into a clinic with complaints and would not have been identified as acutely HIV infected,” said Robb. “It changes the way we need to think about identifying people with acute infection.”

Interventions during AHI may influence the long-term course of the disease. The present study demonstrates that identifying infected individuals during the observed brief AHI interval is possible, although not yet feasible on a large scale, as it would require scalable NAT diagnostic approaches.

“This study is now being re-purposed to allow us to test promising new interventions at the very earliest period of HIV infection with a view to develop approaches to HIV cure,” said Col Nelson Michael, the MHRP director and senior author of the paper.

Abstract
Background: Acute human immunodeficiency virus type 1 (HIV-1) infection is a major contributor to transmission of HIV-1. An understanding of acute HIV-1 infection may be important in the development of treatment strategies to eradicate HIV-1 or achieve a functional cure.
Methods: We performed twice-weekly qualitative plasma HIV-1 RNA nucleic acid testing in 2276 volunteers who were at high risk for HIV-1 infection. For participants in whom acute HIV-1 infection was detected, clinical observations, quantitative measurements of plasma HIV-1 RNA levels (to assess viremia) and HIV antibodies, and results of immunophenotyping of lymphocytes were obtained twice weekly.
Results: Fifty of 112 volunteers with acute HIV-1 infection had two or more blood samples collected before HIV-1 antibodies were detected. The median peak viremia (6.7 log10 copies per milliliter) occurred 13 days after the first sample showed reactivity on nucleic acid testing. Reactivity on an enzyme immunoassay occurred at a median of 14 days. The nadir of viremia (4.3 log10 copies per milliliter) occurred at a median of 31 days and was nearly equivalent to the viral-load set point, the steady-state viremia that persists durably after resolution of acute viremia (median plasma HIV-1 RNA level, 4.4 log10 copies per milliliter). The peak viremia and downslope were correlated with the viral-load set point. Clinical manifestations of acute HIV-1 infection were most common just before and at the time of peak viremia. A median of one symptom of acute HIV-1 infection was recorded at a median of two study visits, and a median of one sign of acute HIV-1 infection was recorded at a median of three visits.
Conclusions: The viral-load set point occurred at a median of 31 days after the first detection of plasma viremia and correlated with peak viremia. Few symptoms and signs were observed during acute HIV-1 infection, and they were most common before peak viremia.

Authors
Merlin L. Robb, M.D., Leigh A. Eller, Ph.D., Hannah Kibuuka, M.B., Ch.B., Kathleen Rono, M.B., Ch.B., Lucas Maganga, M.B., Ch.B., Sorachai Nitayaphan, M.D., Eugene Kroon, M.D., Fred K. Sawe, M.B., Ch.B., Samuel Sinei, M.B., Ch.B., Somchai Sriplienchan, M.D., Linda L. Jagodzinski, Ph.D., Jennifer Malia, Dr.Ph., Mark Manak, Ph.D., Mark S. de Souza, Ph.D., Sodsai Tovanabutra, Ph.D., Eric Sanders-Buell, B.S., Morgane Rolland, Ph.D., Julie Dorsey-Spitz, B.S., Michael A. Eller, Ph.D., Mark Milazzo, B.A., Qun Li, M.Sc., Andrew Lewandowski, Ph.D., Hao Wu, Ph.D., Edith Swann, Ph.D., Robert J. O’Connell, M.D., Sheila Peel, Ph.D., Peter Dawson, Ph.D., Jerome H. Kim, M.D., and Nelson L. Michael, M.D., Ph.D., for the RV 217 Study Team

Full Medical Xpress report
New England Journal of Medicine abstract


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