• Cardiovascular Risk and Health Among People With Human Immunodeficiency Virus (HIV) Eligible for Primary Prevention: Insights From the REPRIEVE Trial

    December 1, 2021 Alexis Sexton Publications

    Clinical Infectious Diseases, December 2021.

    As survival among people living with HIV has improved, heart disease has become a leading cause of illness and death. While careful assessment of risk factors and health behaviors to guide medication use and lifestyle changes can reduce risk and prolong life, the accuracy of otherwise well-established heart disease risk scores has not been tested among people living with HIV. Similarly, health behaviors have not been well-categorized among people living with HIV, nor do we know how they relate to risk.

    A5332 (REPRIEVE) included 7382 participants whose average age was 50, and among whom 31% were women.

    REPRIEVE used the most commonly used heart disease risk score, the Pooled Cohort Equations (PCE), which uses age, sex, race, high blood pressure, diabetes, high LDL cholesterol, and smoking to predict risk. In REPRIEVE, the median score was 4.5%, which means that participants had a less than 5% chance of having a heart disease event (like a heart attack) over the next 10 years. Almost a third of participants had a risk score less than 2.5%.

    Investigators also used Life’s Simple 7, which uses measures of smoking, diet, physical activity, body mass index, blood pressure, total cholesterol, and glucose to evaluate heart health. The median score was 9 (out of a possible 14). One third of participants had two or fewer ideal behaviors; only 105 (1.4%) participants had five or more ideal behaviors.

    Importantly this study elucidated that the most commonly used heart disease risk score did not reflect common unhealthy behaviors among people living with HIV, including poor diet, high body mass index, and low physical activity. These behaviors were present across participants, regardless of their level of heart disease risk, suggesting that lifestyle interventions may be important to prevent heart disease among people living with HIV, and should be used to complement conventional treatment.

    To read the full manuscript, click here.

  • Assessing the Relationship Between Greater Muscle Fat and Lower Muscle Area and Inflammation and Immune Activation after Starting ART

    JAIDS, August 5, 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 and analyzed abdominal computed tomography (CT) scans at baseline and week 96 for muscle amount and fattiness and used 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.

  • Distinct Lipidomic Signatures in People Living With HIV: Combined Analysis of ACTG 5260s and MACS/WIHS

    September 8, 2021 Alexis Sexton Publications

    JCEM, September 2021.

    While the field has made huge strides in HIV treatment, HIV and its treatment can cause metabolic complications and the distinct effects of HIV itself and antiretroviral therapy (ART) on specific metabolic pathways are not known. A5260s aimed to better understand whether HIV or HIV medications affect metabolism in the body and whether HIV or its treatment affects how the body handles metabolites, lipids, and sugar.

    NWCS 412 utilized novel technology (metabolomics and lipidomics) to assess several hundred metabolites and lipid subspecies that are involved in pathways of cholesterol, sugar control, and fat storage. The study measured these metabolites and lipid subspecies in HIV-seronegative individuals from the Multicenter AIDS Cohort Study/Women’s Interagency HIV Study Combined Cohort Study (MACS/WIHS) and in people living with HIV from A5260s before and after initiating ART [tenofovir/emtricitabine plus atazanavir/ritonavir (ATV/r) or darunavir/ritonavir (DRV/r) or raltegravir (RAL)].

    Compared to HIV-seronegative individuals, ART-naïve people living with HIV exhibited an altered metabolome that suggests increased lipid production and increased inflammation. This indicates that HIV itself can change metabolism. People living with HIV taking RAL vs. ATV/r or DRV/r also had more inflammation and alterations in fat metabolism. These findings suggest that people living with HIV could benefit from closer monitoring for metabolic complications after starting HIV treatment, including newer HIV treatments. More studies are needed to further understand the cardiometabolic consequences of HIV and its treatment.

    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.

     

  • Plasma Citrate and Succinate Are Associated With Neurocognitive Impairment in Older People With HIV

    Clinical Infectious Diseases, August, 2021.

    NWCS 447 investigated a possible biological mechanism that may be an underlying factor causing brain impairment in people who are aging with HIV. This mechanism is triggered by persistent activation of a particular type of immune cell and results in accumulation of citrate and succinate in blood, reflecting a shift in cellular metabolism that may adversely affect the nervous system. Researchers evaluated the hypothesis that this metabolic shift would be linked to reduced walking speed and poorer performance on tests of memory and thinking. To do so, they measured citrate and succinate along with walking speed and memory in participants in the ACTG HAILO study who generously donated their time and samples to enable the research. The study included 957 people living with HIV who ranged in age between 40–78 years. On average, those with higher citrate and succinate levels had slower walking speeds and poorer memory than those with lower levels. This was particularly true for participants older than 60 years. These results confirm the research hypothesis and suggest that this shift in metabolism may underpin age-related brain impairment. Medications, supplements, and other interventions that affect this metabolic shift may benefit walking speed, memory, and thinking in people living with HIV.

    To read the full article, click here.

  • Exploring Cardiac Safety of Two Oral, Well-Tolerated Anti-TB Medicines when Taken Together

    The Lancet, July 2021.

    In 2012, bedaquiline and delamanid were the first new drugs approved for tuberculosis in more than 40 years. Both are oral and well-tolerated and intended to be used in patients who have drug-resistant TB. Historically, these individuals have had few treatment options and those regimens often included very toxic medicines. While bedaquiline and delamanid have a number of benefits, each drug modestly prolongs the QTc interval on the electrocardiogram (ECG). Because having a prolonged QTc can be a precursor to more serious cardiac toxicities (such as abnormal heart rhythms), the World Health Organization (WHO) recommended against using the two drugs together (as no one had carefully assessed the cardiac risk of doing so).

    To address this knowledge gap, the randomized, controlled DELIBERATE trial (A5343), evaluated adding bedaquiline, delamanid, or both to background therapy in participants with multidrug resistant TB to accurately determine QTc effects of each drug alone versus together. ECGs were done frequently over the 24 weeks of treatment, in triplicate, and they were interpreted by an expert central reader. To be sure there were no adverse cardiac effects, early participants in the study were hospitalized and monitored carefully. A5343 found that adding delamanid to bedaquiline resulted in no more than additive QTc effects; no participants had grade 3 or 4 QTc events; and the study drugs were well-tolerated, including among people living with HIV. In exploratory analyses, eight-week sputum culture conversion was high in all groups and sustained in the combined treatment arm. These data suggest that co-administration of bedaquiline and delamanid among individuals with a normal QTc at baseline results in acceptable cardiac safety. Preliminary microbiology data were also encouraging in terms of treating drug-resistant TB. Based on these results, the WHO lifted their restriction on concurrent use of bedaquiline and delamanid, allowing them to be administered together among those patients who may need them the most.

    To read the full manuscript, click here.

  • Assessment of Coronary Artery Disease With Computed Tomography Angiography and Inflammatory and Immune Activation Biomarkers Among Adults With HIV Eligible for Primary Cardiovascular Prevention

    JAMA Network Open,  June 2021.

    Myocardial infarction and other atherosclerotic cardiovascular disease (ASCVD) events occur 1.5 to 2 times more often among people living with HIV than in the general population, but the prevalence of ASCVD among people living with HIV is not well understood. In this analysis from the mechanistic sub-study of the REPRIEVE Trial, investigators performed cardiac CT scans to determine the prevalence and composition of coronary artery disease among 755 REPRIEVE participants. They then assessed the findings to determine associations with traditional risk factors and biomarkers of immune activation and vascular and systemic inflammation.

    The median age of the participants in this cohort was 51 years. Sixteen percent were female, 35 percent were Black, and 97 percent  had a plasma HIV viral load <400cp/mL. Overall, 49 percent showed evidence of atherosclerotic plaque in imaging, with significant plaque found even among participants who had the lowest ASCVD risk scores. Coronary artery plaque was more commonly detected among people who were older, male, White, had a family history of premature CVD, had hypertension, had elevated fasting glucose, and had higher LDL cholesterol levels. Markers of immune activation and vascular inflammation were also higher in people with detectable plaque. These data confirm that people living with HIV, including those with well-controlled viremia, have a significant coronary artery plaque burden and that inflammation and immune activation are important drivers of this excess cardiovascular disease risk. REPRIEVE will determine whether pitavastatin can prevent cardiovascular events in this at-risk population and whether the effect seen in this analysis is mediated through statins’ cholesterol lowering or anti-inflammatory effects.

    To read full manuscript, click here.

  • Participant Perspectives and Experiences Entering an Intensively Monitored Antiretroviral Pause

    AIDS Research and Human Retroviruses, June 2021.

    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.

    To read the full manuscript, click here.

  • Higher colorectal tissue HIV infectivity in cisgender women compared with MSM before and during oral preexposure prophylaxis

    AIDS, April 2021.

    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 prophylaxisAIDS (London, England), 10.1097/QAD.0000000000002907. Advance online publication. https://doi.org/10.1097/QAD.0000000000002907

  • Randomized Trial of Ruxolitinib in Antiretroviral-Treated Adults with HIV

    Clinical Infectious Diseases, March 2021.

    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 HIVClinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, ciab212. Advance online publication. https://doi.org/10.1093/cid/ciab212