Identifying People During the Acute and Early Phases of HIV

Research suggests many potential benefits to starting antiretroviral therapy (ART) within the first few days or weeks after HIV has been acquired. Studies that enroll participants with early HIV or after early treatment initiation are especially important to test potential strategies to control HIV that don’t depend on lifelong ART. However, it is logistically difficult to diagnose HIV and start ART so soon after acquisition. A5354 attempted to do this at 30 ACTG sites in the Americas, Africa, and Southeast Asia. Sites used any of six criteria to identify people with very early HIV, including combinations of viral load testing, antibody testing, and antigen testing. Researchers utilized new ways of looking at how strongly positive some of these tests were (the signal-to-cutoff ratio) to determine how recently HIV was acquired. The study enrolled 195 participants and started 171 (87.7%) on ART on the day of enrollment and 24 (12.3%) the next day. After enrollment, centralized testing confirmed that 188 (96.4%) participants had acute or early HIV. Four (2.0%) participants had acquired HIV long ago and were now in the chronic phase of HIV while three (1.5%) were found not to have HIV, discontinued ART, and were withdrawn from the study. The signal-to-cutoff ratio correctly identified 99 of 122 (81.2%) participants who were in specific stages of acute or early HIV (Fiebig stages 2-4) with no false-positive results. Because some of the inclusion criteria in A5354 did not require an HIV viral load (which may take several days or more to produce a result), they may be helpful for clinicians and researchers who are trying to accurately diagnose acute or early HIV and start ART quickly.

How quickly one needs to start HIV treatment is still being investigated. There are no data demonstrating differences in clinical outcomes in starting HIV treatment on the same day of diagnosis versus the within 2-4 weeks of diagnosis. There is broad consensus that starting therapy as soon as possible is beneficial for the individual, may prevent further transmission of HIV and waiting too long (more than 8-12 weeks) can result in illness. Some of the barriers to initiating treatment on the same day of diagnosis is ensuring that the individual is confirmed to have HIV and starting therapy that is likely to work (meaning no resistance to treatment). This study helps to begin to identify people early on with HIV and allow for more prompt initiation of treatment.

Trevor A Crowell, Justin Ritz, Robert W Coombs, Lu Zheng, Joseph J Eron, John W Mellors, Joan Dragavon, Gert U van Zyl, Javier R Lama, Kiat Ruxrungtham, Beatriz Grinsztejn, Roberto C Arduino, Lawrence Fox, Jintanat Ananworanich, Eric S Daar, AIDS Clinical Trials Group A5354/EARLIER (Early ART to Limit Infection and Establishment of Reservoir) Study Team, Novel Criteria for Diagnosing Acute and Early Human Immunodeficiency Virus Infection in a Multinational Study of Early Antiretroviral Therapy Initiation, Clinical Infectious Diseases, Volume 73, Issue 3, 1 August 2021, Pages e643–e651

Understanding latency among people living with HIV in low- and middle-income countries

Many studies from high-income countries have shown that HIV can linger in the body during HIV treatment, meaning that it is not completely eliminated from the body. However, there have been few reports from low- and middle-income countries (LMIC) investigating this phenomenon. NWCS425 aimed to determine how often HIV lingers in the body among individuals achieving very low levels of HIV while on treatment in LMIC. Researchers also conducted a comparison of the rate at which very low levels of HIV remains in the body between individuals in LMIC and the United States. The last available sample among participants living with HIV less than 400 copies/mL for at least three years from A5175 and A5208 were tested by using the method known as the HMMCgag single copy assay (SCA). Detectable HIV was defined as having ≥1 copy/mL. The study included 320 participants, including 246 (77%) from LMIC and 74 (23%) from the United States. NWCS425 found that 57 percent of all participants had HIV remaining in their body during HIV treatment. This percentage was similar among participants from LMIC (59%) and the United States (51%). The study also found that the only factor associated with HIV remaining in the body was more copies of HIV before beginning HIV treatment. This important finding indicates that the sooner antiretroviral treatment is initiated, the less HIV will remain in the body as latent reservoir. In addition, this study confirms that HIV reservoirs are similar regardless of where you live in the world. These results may help us design future cure studies that can be conducted throughout the world.

Gatechompol, S., Zheng, L., Bao, Y., Avihingsanon, A., Kerr, S. J., Kumarasamy, N., Hakim, J. G., Maldarelli, F., Gorelick, R. J., Welker, J. L., Lifson, J. D., Hosseinipour, M. C., Eron, J. J., & Ruxrungtham, K. (2021). Prevalence and risk of residual viremia after ART in low- and middle-income countries: A cross-sectional study. Medicine, 100(35), e26817. https://doi.org/10.1097/MD.0000000000026817

Participant perspectives and experiences entering an intensively monitored antiretroviral pause

Analytical treatment interruptions (ATIs) have become a common feature of HIV cure-related trials but there are currently no biomarkers (or signals in the blood) that can accurately predict when HIV will return during an ATI. Co-led by Drs. Jonathan Li (Brigham and Women's Hospital, Boston) and Davey Smith (University of California, San Diego), A5345 study was designed to identify biomarkers that could predict viral rebound. The study included a socio-behavioral research component led by Dr. Karine Dubé of UNC-Chapel Hill, in collaboration with A5345 community representatives Liz Barr and David Palm.

A5345 showed that most participants perceived societal-level benefits of advancing HIV cure research, as well as personal-level benefits, such as the opportunity to learn about the body’s response to the ATI. Further, most participants demonstrated a detailed understanding of the study. However, approximately 20 percent of A5345 study participants did not report any research risks involved despite these being presented during the informed consent process. Common concerns, in about four in five participants, were related to the ATI – including CD4+ cell count decreases, becoming detectable for HIV, and developing acute retroviral syndrome.

These results underscore the importance of considering how research risks are relayed and the perceived benefits of participation (both physical and psychological) from participants’ perspectives. Key messages pertaining to study-related risks may need to be clarified and reiterated periodically throughout follow-up in HIV cure-related studies involving ATIs. The importance of assessing participants’ perceptions and experiences over time in HIV cure-related studies is increasingly recognized (rather than one-time assessments). The investigative team will soon share results from the A5345 follow-up socio-behavioral assessments. Methods and results from the ACTG A5345 socio-behavioral component are informing the design of participant-centered measures as part of extended ATI trials in the ACTG and at UCSF.

This is a very important study confirming that informed consent is a challenging process. It emphasizes the need to continue to explain research studies to participants and obtain ongoing informed consent. Most researchers and study participants agree that consents are hard to understand and too long. The investigators highlight the need to improve our consent process so that participants understand the risks and are able to make informed decisions about study participation.

Diepstra KL, Barr L, Palm D, et al. Participant Perspectives and Experiences Entering an Intensively Monitored Antiretroviral Pause: Results from the AIDS Clinical Trials Group A5345 Biomarker Study. AIDS Res Hum Retroviruses. 2021;37(6):489-501. doi:10.1089/AID.2020.0222