Raymond Allmond
1955-2021
                                   
By Jan Kosmyna
Longtime member of the Case Western/UH CAB and CRS GCAB representative, Ray Allmond, passed away unexpectedly at his Cleveland residence during the weekend of April 10, 2021.

Ray was an alumnus of Case Western Reserve University, majoring in Speech, Communications, Media and Theatre. He used those skills often in his work with the ACTG. He was a former Cleveland Firefighter, voice-over actor, and associate of Karamu House, Cleveland’s premier African-American Theatre and Arts Community, where he had been an actor and director.

We know Ray best for his tireless advocacy for people living with HIV, spanning more than two decades. Among many other activities, Ray served on the Ryan White Planning Council, Cleveland AIDS Task Force, and was one of our Community Partners representatives. However, his passion was being co-chair of the HIV and Aging Working Group.

Ray will be missed, not only for his work, but for being such a gentle, empathetic, remarkable man with a megawatt smile.

Evaluating Ruxolitinib to Decrease Inflammation among People Living with HIV on ART – A5336/3

Inflammation is a serious concern among people living with HIV, as it is associated with increased occurrence of other health conditions and death. Ruxolitinib is an anti-inflammatory medication that has reduced inflammation in people without HIV and lowers indicators of the HIV reservoir (the amount of HIV still within a person even though they may have an “undetectable” viral load) in laboratory studies. A5336 was an open-label, multi-site, randomized-controlled trial that evaluated the addition of ruxolitinib (10mg twice a day) to stable ART for five weeks compared to ART alone, in an effort to determine its safety and efficacy among people living with HIV on ART. Eligible participants had been virally suppressed on ART for more than two years without other health conditions and had >350 CD4+ T-cells. Study endpoints were discontinuation of ruxolitinib, safety events, and changes in measures of inflammation and the HIV reservoir. Ultimately, the study showed that ruxolitinib was well-tolerated by healthy, virologically suppressed people living with HIV on ART. Although there was no significant reduction in IL-6, the primary inflammatory marker endpoint (whose baseline levels were normal), ruxolitinib did significantly decrease other markers of inflammation. Future studies of this class of medications should target people living with HIV who have residual inflammation despite suppressive ART.

Summary and Implications: Ruxolitinib is not ready to be used in people living with HIV to decrease inflammation. It may be more helpful in people who show clear signs of inflammation, but this needs to be tested. We are still searching for the best way to address excess inflammation in people living with HIV.

Marconi, V. C., Moser, C., Gavegnano, C., Deeks, S. G., Lederman, M. M., Overton, E. T., Tsibris, A., Hunt, P. W., Kantor, A., Sekaly, R. P., Tressler, R., Flexner, C., Hurwitz, S. J., Moisi, D., Clagett, B., Hardin, W. R., Del Rio, C., Schinazi, R. F., & Lennox, J. J. (2021). Randomized Trial of Ruxolitinib in Antiretroviral-Treated Adults with HIV. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, ciab212. Advance online publication. https://doi.org/10.1093/cid/ciab212
 
Colorectal Tissue is More Easily Infected in Cisgender Women Compared to MSM Before and During Oral PrEP – A5305/17
 
Study A5305/17 was a mucosal tissue-focused sub-study of HPTN 069/ACTG 5305. The objectives were to compare medication levels in different body tissues (cervix and colorectal tissues) and blood in HIV-negative cisgender women and men who have sex with men (MSM) who are taking oral PrEP. In addition, colon cells were checked to see how susceptible they may be to HIV infection (outside the body, or ex-vivo). Samples were collected at baseline (before receiving PrEP), at week 24 and 48 (on PrEP), and at week 49 (one-week after discontinuing PrEP). The study measured the degree of HIV infectivity in colon tissue biopsies challenged ex vivo with HIV, followed by HIV p24 measurement.
 
The study demonstrated a substantial two- to 16-fold increase in susceptibility of colorectal tissue to HIV infection in cisgender women compared to MSM. Differences in adherence, drug concentration, and colorectal tissue flow cytometry do not explain these findings well. Additional research is necessary to understand this increased susceptibility.
 
These findings complement behavioral and prior pharmacokinetic data in cisgender women. The data may also provide additional explanations for the high level of population risk of receptive anal sex for HIV acquisition among cisgender women, and the differences in oral tenofovir/emtricitabine adherence required to achieve the highest levels of PrEP protection.
 
Summary and Clinical Implications: A number of studies suggest that oral PrEP does not work as well for cisgender women as for other populations. This study shows us that specific tissues are more likely to be infected with HIV in cisgender women, meaning that oral PrEP may not protect them as well as MSM. We need to know why and develop better PrEP options for cisgender women.
 
Sekabira, R., Mcgowan, I., Yuhas, K., Brand, R. M., Marzinke, M. A., Manabe, Y. C., Frank, I., Eron, J., Landovitz, R. J., Anton, P., Cranston, R. D., Anderson, P., Mayer, K. H., Amico, K. R., Wilkin, T. J., Chege, W., Kekitiinwa, R., Mccauley, M., Gulick, R. M., & Hendrix, C. W. (2021). Higher colorectal tissue HIV infectivity in cisgender women compared with MSM before and during oral preexposure prophylaxis. AIDS (London, England), 10.1097/QAD.0000000000002907. Advance online publication. https://doi.org/10.1097/QAD.0000000000002907
 
Novel Methods for Real-Time Central Monitoring Enable Rapid, Prioritized Quality Assurance in a Phase 3 Clinical Trial for Pulmonary Tuberculosis Treatment – A5349/4
 
The Tuberculosis Trials Consortium Study 31/study A5349 is a large (n=2500) international, multi-site (n=34), randomized, open-label, controlled, three-arm, non-inferiority phase 3 clinical trial comparing two four-month regimens to a standard six-month regimen for treatment of drug-susceptible tuberculosis among adolescents and adults. Due to the number of study sites worldwide, complexities inherent in TB diagnosis and treatment, and the major potential impact of this trial, a strong and timely quality assurance program was critical. In response to these demands, the study team developed interventions to improve study conduct and strengthen study quality. Our central monitoring processes included quality control, quality assurance, and monitoring of real-time data. Specifically, we created a novel, five-tiered methodology for quality management at the central level:

1. Performance of “real-time” data checks on submitted data, and development of topic-specific intervention reports
2. Production of site-specific missing forms reports based on the expected study schedule for each participant at the site
3. Evaluation of protocol compliance according to study-specific quality assurance metrics
4. Production of critical data reports
5. Identification and notification of protocol deviations

The use of primary study data to identify data issues promptly allowed CDC, as the study sponsor, to focus quality assurance and data cleaning activities on prioritized data related to protocol compliance and accurate determination of study endpoints. Our approach enabled us to inform sites about protocol deviations, resolve missing or inconsistent data, and gain a deeper understanding of challenges experienced at clinical trial sites. We anticipate the utility of this method will be seen beyond the world of TB, for any clinical trial sponsor with access to their data in real time. We will continue to build upon the central monitoring process in future studies, with a focus on these approaches.
 
Summary and Implications: It is very important to have the best science in every study so that we can trust the results. One of the key challenges in multi-site studies is ensuring that each site performs well. The lessons from this study’s team management plan may help future studies be more successful.
 
Bryant, K. E., Yuan, Y., Engle, M., Kurbatova, E. V., Allen-Blige, C., Batra, K., Brown, N. E., Chiu, K. W., Davis, H., Elskamp, M., Fagley, M., Fedrick, P., Hedges, K., Narunsky, K., Nassali, J., Phan, M., Phan, H., Purfield, A. E., Ricaldi, J. N., Robergeau-Hunt, K., ACTG; Tuberculosis Trials Consortium (2021). Central monitoring in a randomized, open-label, controlled phase 3 clinical trial for a treatment-shortening regimen for pulmonary tuberculosis. Contemporary clinical trials, 104, 106355. Advance online publication. https://doi.org/10.1016/j.cct.2021.106355