PUBLICATIONS
 
Third-line ART Has Potential to Improve Care for People Living with HIV in Lower-to-Middle Income Countries
There is limited information about which HIV drugs can be best used to treat people living with HIV who have multi-drug resistance. To address this gap, A5288 was conducted in 2013-2015 among 545 participants whose secondary treatment with a boosted PI-based regimen was ineffective in suppressing their HIV. The study was conducted at 19 urban sites in 10 low-to-middle income countries. This analysis assessed the use and efficacy of raltegravir, darunavir, and/or etravirine beyond the 48 weeks of the original A5288 among 257 participants who experienced treatment failure from multi-drug resistance (including resistance to lopinavir/ritonavir, which was the most common PI used in this setting during that time period).
 
The study found that the third-line regimens including raltegravir, darunavir, and/or etravirine were able to suppress HIV to a lower limit of detection for more than three years. Apart from good efficacy, this regimen was also well tolerated. These drugs are beneficial in delaying HIV progression and can prevent onward HIV transmission of multi-class drug resistance for a long period of time. The findings from this study provide evidence that these HIV drugs can be used among diverse populations of people living with HIV with multidrug resistance in lower-to-middle income countries and have the potential to improve care for people living with HIV.
 
Editor’s note: One of the important roles for studies like this is demonstrating that newer antiretrovirals can be used in diverse geographic settings, adding data to help countries and the World Health Organization (WHO) update treatment guidelines in a timely manner. A5288 is a part of the WHO Consolidated Guidelines for HIV prevention, testing, treatment, service delivery, and monitoring (https://www.who.int/publications/i/item/9789240031593).
 

Avihingsanon, A.; Hughes, M.D.; Salata, R.; Godfrey, C.; McCarthy, C.; Mugyenyi, P.; Hogg, E.; Gross, R.; Cardoso, S.W.; Bukuru; A.; Makanga, M.; Badal‐aesen, S.; Mave, V.;  Ndege, B.W.; Fontain, S.N.; Samaneka, W.; Secours, R.; Van Schalkwyk, M.; Mngqibisa, R.; Mohapi, L.; Valencia, J.; Sugandhavesa, P.; Montalban, E.; Munyanga, C.;  Chagomerana, M.; Santos, B.R.; Kumarasamy, N.; Kanyama, C.; Schooley, R.T.; Mellors, J.W.; Wallis, C.L.; Collier, A.C.; Grinsztejn, B. and for the A5288 Study team. Third‐line antiretroviral therapy, including raltegravir (RAL), darunavir (DRV/r) and/or etravirine (ETR), is well tolerated and achieves durable virologic suppression over 144 weeks in resource‐limited settings: ACTG A5288 strategy trial. J Int AIDS Soc. 2022 Jun; 25(6): e25905.
 
Geographical Differences in Self-Reported Functional Impairment of People Living with HIV
One of the keys to healthy aging is the maintenance of a high level of physical function. Functional impairments may occur earlier among people living with HIV compared to those without HIV. In a smaller group of U.S.-based REPRIEVE participants, researchers previously found physical function impairment among nearly 50% of participants (measured by time to rise from a chair and four-meter walking speed). The current analysis explored differences across regions in self-reported physical function, and the factors that are associated with physical function in the larger, global REPRIEVE cohort.
 
Among 7,736 REPRIEVE participants, the average age was 50 years old, 30% were female, and 43% were Black. The study found that 64% had no functional impairments, 28% had some impairment, 8% had moderate impairment, and <0.5% had severe impairment. The investigators found that increased functional impairment was associated with the following:

• Living in the South Asia region (and lower impairment in Southeast/East Asia)
• Older age
• Being female
• Being Asian or Black
• Having more obesity
• Having been on ART for a longer period of time, longer thymidine analogue exposure, and lower CD4 T-cells
• Certain ART regimens

The investigators also found that some or moderate/severe functional impairments were associated with small increases (0.3- 0.5 points) in heart disease risk score. Moderate/severe functional impairments were also associated with greater likelihood of metabolic syndrome (a cluster of conditions that occur together and raises one’s risk of heart disease) or a high waist circumference.
 
Key Takeaways: We’ve long known that exercise is important to prevent heart disease. In this study, researchers show that the level of activity and ability to do simple tasks like getting up from a chair or walking faster are related to heart disease risk. This extends our understanding to a global population. In the future, this study will be able to relate an individual’s ability to do simple tasks to the development of heart problems and worsening of blockages in the blood vessels that feed the heart.
 
Erlandson, K.M.; Fitch, K.V.; McCalllum, S.A.; Ribaudo, H.J.; Overton, E.T.; Zannie, M.V.; Bloomfield, G.S.; Brown. T.T.; Fichtenbaum, C.J.; Bares, S.; Aberg, J.A.; Douglas, P.S.; Fulda, E.S.; Santana-Bagur, J.L.; Castro, J.G.; Moran, L.E.; Mave, V.; Supparatpinyo, K.; Ponatshego, P.L.; Schechter, M.; Grinspoon, S.K. Geographical Differences in the Self-Reported Functional Impairment of People With Human Immunodeficiency Virus (HIV) and Associations With Cardiometabolic Risk. Clinical Infectious Diseases, 15 February 2022, https://doi.org/10.1093/cid/ciac098
 
Bedaquiline Is Able to Penetrate the Blood-Cerebrospinal Fluid Barrier, May Hold Potential for Treatment of TB Meningitis
TB meningitis is the deadliest form of TB, killing one in four, with mortality even higher in people living with HIV or those with drug-resistant TB (hard-to-treat TB). Bedaquiline is the first new drug to be developed for TB in decades and has had a significant impact on treatment outcomes when used in a multi-drug regimen for drug-resistant TB.
 
The A5343 DELIBERATE study investigated the effect of bedaquiline and delamanid, alone or in combination, on the QT interval (QT measures the electrical activity of this heart contraction process or the time it takes for the heart muscle to contract and then recover). A pharmacokinetic sub-study aimed to measure the concentrations of bedaquiline and delamanid in cerebrospinal fluid collected from the participants through an opt-in lumbar puncture. This was undertaken because guidelines for the treatment of TB meningitis emphasize the use of drugs with known central nervous system penetration, but the penetration of bedaquiline into the cerebrospinal fluid up until now has been unknown.
 
This sub-study recruited 12 participants, seven of whom received bedaquiline and had bedaquiline levels measured in their cerebrospinal fluid. Bedaquiline was detected in all samples and was found at concentrations similar to the expected unbound (active) fraction in plasma. This suggests that unbound bedaquiline (the portion not bound to proteins in plasma) is able to penetrate across the blood-cerebrospinal fluid barrier. It is possible that bedaquiline may have a role to play in the treatment of TB meningitis. It can be included in multi-drug regimens where drug-resistance is confirmed while additional evidence on its contribution to successful treatment outcomes is explored.
 
Key takeaway: This sets the stage to test whether bedaquiline can be used to help people with TB meningitis.
 
Upton, C.M.; Steele, C.I.; Maartens, G.; Diacon, A.H.; Wiesner, L.; Dooley, K.E.; Pharmacokinetics of bedaquiline in cerebrospinal fluid (CSF) in patients with pulmonary tuberculosis (TB). J Antimicrob Chemother; 2022 May 29;77(6):1720-1724.


PROFILES
 
Community Profiles
In honor of the ACTG’s recently launched clinical trial A5418 or STOMP evaluating a potential new monkeypox treatment, the ACTG is exciting to profile two Global Community Advisory Board members who are providing input into that study.
 
Stanford Chimutimunzeve, Milton Park CRS, Harare, Zimbabwe
Stanford Chimutimunzeve has been with the ACTG since he joined the Harare Parirenyatwa CRS (which is now the Milton Park CRS) in 2007. At that time, he was working for one of the leading local HIV/AIDS service organizations as a community educator/facilitator (and had been since 2004). He was also a youth representative for Harare West Southwest District AIDS Action Committee, a decentralized arm of the National AIDS Council in Zimbabwe. His work focused on HIV prevention, treatment, and care for people living with HIV and he held internationally recognizable HIV/AIDS-specific trainings. The City of Harare Department of Social Services recommended him to be part of the CAB, based on this expertise.
 
His role in A5418, the monkeypox study, is to provide community input and ensure that community insights are incorporated into the study. He does so by collating input from members of the GCAB, participating in all protocol meetings, and meaningfully contributing a community perspective to ensure the safety of study participants and making sure extra cognizance is given to research ethics. He also works to educate members of the community about monkeypox and to ensure that the study is designed to best answer the research question.
 
“It was important for me to be part of the study as community scientific sub-committee representative because I represent Africa and other non-U.S. sites and people from resource-constrained settings in particular,” said Stanford. “There is scant knowledge about monkeypox in Africa and I also suspect limited capacity to diagnose. My involvement has a double dividend of awareness raising and advocacy on monkeypox. Africa needs to be prepared and be involved in trials on monkeypox. I also believe that advocacy around post-trial drug access will be a key component if tecovirimat proves to be effective.”
 
Stanford wants people, especially those from Africa, to know that monkeypox is real and that governments and communities need to be prepared to combat the disease. “I hope the study will be conducted in Africa and also that regulatory authorities will approve studies of this nature so that we continue to save lives across the globe,” he concluded.
 
Danielle Campbell, UCLA CARE Center, Los Angeles, CA
Danielle Campbell has been part of the ACTG for nearly 10 years; her earliest experiences of HIV activism began with her becoming a member of the UCLA CARE Center Community Advisory Board.

Throughout her tenure with the ACTG, Danielle has served in several leadership capacities, including Chair of the Community Women’s Working Group also known as “Team Women,” Community Scientific Subcommittee (CSS) representative to the Network Scientific Steering Agenda Committee (SASC), and member of the Community Steering Committee. Her work within the ACTG has centered around the meaningful inclusion, enrollment, and retention of women, a global population disproportionally affected by HIV, in network studies.
 
“As community, we work in partnership with Network leadership and member scientists to ensure that the perspective of communities living with HIV are centrally considered and incorporated within the science endeavors of the ACTG,” said Danielle. “This is accomplished by community members’ participation on research protocol teams, collaborative and transformative science groups, and other committees within the network.”
 
Working with Stanford, Danielle reports that they continue their duties on the monkeypox study as community scientific subcommittee members involved in all study development activities, reviewing and providing feedback on study documents, flyers, websites, protocol, and other scientific activities. “It is important for me to work on the STOMP study to help do my part in representing communities affected by monkeypox,” she said. “It is REALLY important to share the information I learn to raise awareness about monkeypox virus with those in my community who are at highest risk. It is my hope that people with monkeypox have an effective treatment and that our efforts as part of STOMP will bring us one step closer to developing that treatment.”
 
STOMP is investigating the safety and efficacy of tecrovirimat for the treatment of human monkeypox virus. For more information, please visit the study website or contact the call center at 1-855-876-9997.
 
Introducing the New ACTG Specialty Lab Directors
Nilu Goonetilleke, Ph.D., University of North Carolina CRS, Raleigh-Durham, NC
The Immunology Specialty Laboratory at UNC is directed by Nilu Goonetilleke, whose area of research is human T cell immunology and vaccinology. Her group is focused on understanding how T cells, specifically CD8 T cells, could be harnessed in HIV cure strategies. Working alongside many UNC and ACTG colleagues, they are conducting phase I studies evaluating immunotherapies, including vaccines, in people living with HIV who are taking ART. “I am especially looking forward, indeed it's already happening, to brainstorming with ACTG colleagues to identify the best ways to bring new investigators into the network,” said Nilu.