• Poorer Muscle Quality and Quantity With ART Initiation Is Associated With Greater Inflammation and Immune Activation

    JAIDS, December 2021.

    Research has demonstrated that starting antiretroviral therapy (ART) is associated with an increase in skeletal muscle, though it tends to be quite fatty. A5260s explored whether the gains in skeletal muscle area or the amount of fattiness were associated with markers of inflammation and immune activation. Individuals living with HIV were randomized to start treatment with raltegravir, ritonavir-boosted atazanavir, or darunavir, in combination with tenofovir disoproxil fumarate/emtricitabine. This substudy included 222 participants, analyzed abdominal computed tomography scans at baseline and week 96 for muscle amount and fattiness, and reviewed previously measured markers of inflammation and immune activation.

    At baseline, greater muscle fat and lower muscle area were associated with higher inflammation and immune activation. From baseline to week 96, a greater increase in muscle fat and decrease in muscle area were associated with greater increases in inflammation and immune activation. Whether these muscle characteristics are the cause or the consequence of inflammation cannot be determined within this study. Future studies will need to explore the impact of these changes in muscle and inflammation on physical function and other complications, including cardiometabolic risk.

    To read the full manuscript, click here.

  • Understanding Latency Among People Living with HIV in Low- and Middle-income Countries

    Medicine, September 2021.

    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.

    To read the full manuscript, click here.


  • Central monitoring in a randomized, open-label, controlled phase 3 clinical trial for a treatment-shortening regimen for pulmonary tuberculosis

    Contemporary Clinical Trials, May 2021

    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 trials104, 106355. Advance online publication. https://doi.org/10.1016/j.cct.2021.106355


    The ACTG is pleased to share the primary results of Study 31/A5349, which were presented at the 51st virtual Union World Conference on Lung Health on October 21st, 2020. This important study showed that the four-month regimen of rifapentine, isoniazid, pyrazinamide, and moxifloxacin (RPT-MOX) was non-inferior to the currently recommended six-month regimen of rifampicin, isoniazid, ethambutol, and pyrazinamide for the treatment of drug-susceptible pulmonary TB. RPT-MOX was also safe and well-tolerated by patients. A second four-month regimen of rifapentine, isoniazid, pyrazinamide, and ethambutol failed to meet the non-inferiority margin.

    To put this study in historical context, the last time pulmonary TB treatment was successfully shortened for drug-susceptible TB was 48 years ago, when the British Medical Research Council (MRC) published results showing a six-month regimen was as effective as the standard 18-month regimen at that time. Despite many trial attempts to shorten TB therapy since, the standard treatment regimen for drug-susceptible pulmonary TB has remained at six months.

    Thirteen countries contributed to Study 31/A5349, a phase 3, open-label, randomized controlled clinical trial, at 34 clinical sites. Approximately 2,500 people aged 12 years and older participated in the study, including 214 people with HIV infection. The study was led by the CDC Tuberculosis Trials Consortium (TBTC) in collaboration with the ACTG. ACTG sites enrolled two-thirds of participants and TBTC sites enrolled one-third.

    Participants with HIV infection were enrolled in a staged fashion to allow for drug-drug interaction studies between rifapentine and efavirenz, which is why the number was relatively small. Reassuringly though, the participants did just as well as those without HIV, and the RPT-MOX regimen was also non-inferior and safe in these participants.

    “Shortening treatment for TB has been front and center in the TB TSG scientific agenda for decades, and this new regimen that reduces treatment by two months will facilitate significant progress in global tuberculosis control,” said Dr. Susan Swindells of the University of Nebraska Medical Center and a co-chair of the study.

    “This trial demonstrates the value of collaborative efforts between the ACTG and other networks,” added Dr. Richard Chaisson of Johns Hopkins University, another co-chair of the trial.

    Shortening TB treatment to four months instead of six represents a major advancement in the management of this age-old infectious disease. Congratulations to the study team and participating sites for this astounding achievement!


    July 30, 2019 pendari Uncategorized

    In our last newsletter, we highlighted the opening of the historic PHOENIx (Protecting Households On Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients (A5300B/I2003B/) trial. Last week, NIAID/NIH featured the news in its media spotlight. Read their coverage of the study here.

  • CAB Member Highlight: Morenike Giwa Onaiwu, Houston, TX

    July 30, 2019 pendari Uncategorized

    Morenike Giwa Onaiwu approaches her role as a CAB member through a social justice lens. Since joining the CAB 10 years ago, she has worked to address the issues of particular concern to her local community of Houston, TX, including the role that stigma plays in limiting testing. “We need to have more acceptance, we need to have better policies, we need to have better treatments, we need to eradicate stigma because stigma kills,” she says.

    Morenike argues that HIV research needs to better address the multitude of the factors that result in disparities and suboptimal outcomes among people with multiple marginalizations – especially related to the intersections of various identities, including gender, race, age, ability, and mental health. “We’ve made progress in this area, but there is still a great need,” she notes.

    Morenike hopes that she has demonstrated that there’s a place in HIV advocacy for everyone. “I came into this work as a 20-something year old working-class Black woman living in the South; I had a baby on one hip and another on the way – yet I have helped to make lasting changes that have had an impact on the HIV community on a global scale.”

    Ultimately, she looks forward to the day when the ACTG is no longer needed because society will have addressed the systemic inequalities that drive the epidemic and researchers will have found a cure.

  • Investigator Highlight: Rajesh Gandhi, MD, Harvard Medical School, Massachusetts General Hospital

    July 30, 2019 pendari Uncategorized

    Rajesh Gandhi, MD is Professor of Medicine at Harvard Medical School and leader of the Massachusetts General Hospital ACTG Clinical Research Site in the Harvard/Boston/Providence Clinical Trials Unit. He has been involved with the ACTG for almost 20 years. Dr. Gandhi has led or been involved with multiple ACTG trials evaluating the impact of interventions on the HIV reservoir, including the effect on the latent reservoir of initiating intensive therapy in treatment-naïve participants, antiretroviral intensification, latency reversal with an HDAC inhibitor, and modulation of latency reversal with estrogen blockade in women with HIV. Given the need to answer critical questions regarding HIV persistence to inform the development of novel interventions aimed at curing HIV, Dr. Gandhi serves as protocol co-chair of ACTG A5321, a longitudinal cohort study examining a number of immunologic, pharmacologic, and virologic contributors to HIV reservoirs among participants on long-term ART. Dr. Gandhi is a former chair of the HIV-1 Reservoirs and Eradication Transformative Science Group, or Cure TSG, and is now on the ACTG Executive Committee. In addition to his work on HIV reservoirs, Dr. Gandhi has been involved in ACTG studies of therapeutic vaccines, interventions designed to decrease immune activation, and optimal treatment of people with drug-resistant HIV.

    The ACTG values Dr. Rajesh Gandhi’s team-based and mission-based approach to clinical research, which exemplifies the general ethos of the ACTG. Dr. Gandhi looks forward to many more years of productive interactions in the ACTG as it continues to advance our knowledge in improving the lives of people with HIV.

  • Publications

    July 30, 2019 pendari Uncategorized


    The persistence of HIV in sanctuary sites in the human body even in the presence of antiretroviral therapy (ART) is a potential barrier to HIV remission and cure. The central nervous system is one of those sanctuary sites and it has unique properties, in terms of cell composition and antiretroviral penetration. Because neurocognitive function can be compromised even in individuals whose HIV is well treated, it is important to understand HIV persistence in the nervous system. In the ACTG HIV Reservoirs Cohort Study (A5321), virally suppressed individuals with HIV taking long-term ART were tested for persistent HIV in their cerebrospinal fluid.

    The study included 69 participants with well-treated HIV who had their cerebrospinal fluid and blood collected and underwent neurocognitive assessments, which included tests of memory, learning, motor function, and more. Participants were mostly male (97%) and had been on HIV treatment for a long time (median almost 9 years), with a good response to medications (HIV viral loads all <100, and median CD4 count in the normal range). The team examined genetic material of HIV in the cells from the cerebrospinal fluid, as well as from the portion of the fluid without cells. The study revealed that HIV DNA was detected in almost half of participants and was associated with poorer neurological and cognitive function. This persisted even after adjusting for participants’ age and the severity of immune suppression they had experienced in the past.

    The association between HIV genetic material in cerebrospinal fluid with poorer performance on cognitive tests suggests that there may be a link between HIV persistence in the brain compartment and the neurological complications that some people living with HIV experience. Further studies will help determine strategies to reverse this persistence and improve neurological functioning in patients with long-standing HIV.

    Spudich S*, Robertson K*, Bosch R, Gandhi RT, Cyktor J, Mar H, Macatangay B, Lalama C, Rinaldo C, Collier A, Godfrey C, Eron J, McMahon D, Jacobs J, Koontz D, Hogg E, Vecchio A, Mellors J.  Persistent HIV-infected cells in cerebrospinal fluid are associated with poorer neurocognitive performance.  Journal of Clinical Investigation 2019, in press.
    *Authors contributed equally


    There is an ongoing debate in the literature about whether elite controllers require antiretroviral therapy (ART) for secondary benefits, including control for low-level viral replication and reduction of inflammation. ACTG A5308 attempted to resolve this debate by looking at the effect of ART on virologic suppression, the viral reservoir, immune activation, and quality of life in a group of elite controllers enrolled in the ACTG.

    A5308 study was a prospective, open-label study of rilpivirine, emtricitabine and tenofovir disoproxil fumarate provided to ART-naïve HIV controllers (n=35) defined as having HIV RNA levels of <500 copies/mL off of therapy. The study found that ART was effective in increasing the proportion of individuals with undetectable residual viremia and decreasing the proportion of CD38+HLA-DR+CD8+ T cells (a marker of immune activation). Researchers also identified a modest but statistically significant improvement in self-reported quality of life. A5308 resolves the question around the value of ART for elite controllers, by demonstrating the clinical benefits of ART in this population.

    Li J, Segal FP, Bosch RJ, Lalama CM, Roberts-Toler C, Delagreverie H, Getz R, Garcia-Broncano P, Kinslow J, Tressler R, Van Dam CN, Keefer M, Carrington M,9, Lichterfeld M, Kuritzkes D, Yu XG, Landay 5, Sax PE; ART reduces T cell activation and immune exhaustion markers in HIV controllers. Clin Infect Dis. 2019 May 25. [Epub ahead of print]

  • MINMON Study Fully Enrolled

    July 30, 2019 pendari Uncategorized

    In November 2018, the ACTG launched enrollment for A5360: A Single-arm Study to Evaluate the Feasibility and Efficacy of a Minimal Monitoring Strategy to Deliver Pan-genotypic Ribavirin-free HCV Therapy to HCV Infected Populations who are HCV Treatment Naïve with Evidence of Active HCV Infection or The MINMON Study. Globally, nearly 71 million people have chronic HCV, of whom an estimated 4-5 million also have HIV. In this context, there is an urgent need for advances in treatment delivery. In some parts of the world, the healthcare system itself – through requiring frequent visits and laboratory monitoring during HCV treatment – can lead to barriers to HCV treatment with the new easy-to-take once a day treatments for HCV cure. The basic premise of the study is to eradicate all of these healthcare system barriers. In A5360, patients (n=400) will be provided HCV treatment with sofosbuvir/velpatasvir (Epclusa) for 12 weeks without any traditional laboratory or clinical monitoring or planned visits.

    We would like to announce now that MINMON is fully enrolled! Enrolling sites are in Africa, Brazil, India, Thailand, and the United States. Following HCV treatment, participants will be followed for an additional 72 weeks to assess the long-term outcomes related to HCV and liver disease, including the incidence of HCV reinfection. Study investigators hypothesize that this “minimal monitoring” for HCV treatment outcomes will result in more cost-efficient and effective paradigms in HCV treatment management, expanding the number of people who can achieve HCV cure worldwide.

  • ACTG Annual Network Meeting

    July 30, 2019 pendari Uncategorized

    The ACTG annual meeting took place June 17-21 in Arlington, VA and drew more than 850 attendees. Highlights included robust discussions about the ACTG research agenda among international investigators, a workshop introducing new investigators to the ACTG, and plenary sessions providing a sneak preview of new ACTG data that will be presented at the 10th IAS Conference on HIV Science, taking place in Mexico City in July. We are also excited to announce the winners of the three ACTG excellence awards this year:

    • Constance B. Wofsy Women’s Health Award: Kimberly Scarsi, PharmD, Northwestern University CRS, University of Nebraska Medical Center
    • John Carey Young Investigator Award: Trevor Crowell, MD, Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS
    • Donna Davis Community Award: Catherine Godfrey, MD, PEPFAR/Office of the Global AIDS Coordinator Department of State

    Thank you to all who were able to attend for making it such a productive meeting and congratulations to our honorees!

    Awardees shown from left: Kimberly Scarsi, Trevor Crowell, and Catherine Godfrey