• 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.

  • 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.

  • 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

  • Poor quality of life and incomplete self-reported adherence predict second-line ART virological failure in resource-limited settings

    January 23, 2021 Alexis Sexton Publications

    AIDS Care, January 2021.

    Lower health-related quality of life and lower adherence have been found to be independent predictors of virologic failure among people starting ART in U.S. clinical trials. A5273 evaluated whether quality of life and self-reported adherence could predict early second-line antiretroviral virological failure in less resource-rich countries.

    A5273 evaluated two second-line ART regimens among individuals from 15 sites in nine low-middle income countries: Brazil, India, Kenya, Malawi, Peru, South Africa, Tanzania, Thailand, and Zimbabwe. The study defined early virological failure as confirmed HIV-1 RNA viral load higher than 400 copies/mL after 24 weeks of second-line ART. Participants completed the quality of life questionnaire (ACTG SF-21), which has eight domains: General Health Perceptions, Physical Functioning, Role Functioning, Social Functioning, Cognitive Functioning, Pain, Mental Health, and Energy/Fatigue.

    Of 500 individuals (51% women, median age 39 years) included in this study, 79% and 75% self-reported complete adherence (no missing doses in the past month) at 4 and 24 weeks after starting second-line ART, respectively. Early virological failure was experienced by 7% and was more common among those who self-reported incomplete adherence. Participants with low quality of life had higher rates of early virological failure.

    A5273 verified that lower quality of life adds to self-reported incomplete adherence in predicting early virological failure. These findings indicate that quality of life and adherence assessments after second-line ART initiation could be implemented as real-time measurements to identify individuals at higher risk of subsequent virological failure in low-middle income countries. These individuals may benefit from interventions to improve quality of life, such as social self-value empowerment and yoga, or to optimize adherence, such as text-message reminders.

    Bottom line: No matter where you live or how you feel about yourself, your quality of life influences your success or failure in taking medicines to treat HIV.

    Torres, T. S., Harrison, L. J., La Rosa, A. M., Zheng, L., Cardoso, S. W., Ulaya, G., Akoojee, N., Kadam, D., Collier, A. C., Hughes, M. D., & for AIDS Clinical Trials Group (ACTG) A5273 Study Group (2021). Poor quality of life and incomplete self-reported adherence predict second-line ART virological failure in resource-limited settingsAIDS care, 1–10. Advance online publication. https://doi.org/10.1080/09540121.2021.1874275

  • A Phase 1/2 Randomized, Placebo-Controlled Trial of Romidespin in Persons With HIV-1 on Suppressive Antiretroviral Therapy

    December 21, 2020 Alexis Sexton Publications

    The Journal of Infectious Diseases, December 2020.

    This exploratory study sought to determine whether romidepsin could awaken latent (‘sleeping’) HIV from its reservoir as part of an HIV cure “kick and kill strategy.” Romidepsin is a histone deacetylase inhibitor drug used to treat cutaneous T cell lymphoma.

    In A5315, a randomized, double-blind, placebo-controlled study, investigators evaluated single doses of romidepsin at different amounts for three Cohorts. There were 43 participants with suppressed viral loads on ART that enrolled to prove this approach was safe. Sixteen participants were then enrolled in a final Cohort to receive romidepsin or placebo. Specialized techniques were used to look for HIV in different ways to see if the romidepsin worked.

    All romidepsin doses were found to be safe and well-tolerated. However, there were no significant increases in HIV levels (meaning it did not activate sleeping HIV), and romidepsin did not appear to reawaken dormant virus from the reservoir at the doses studied, despite evidence that romidepsin had the expected effect on human cells.

    Because studies of histone deacetylase (HDAC) inhibitors as single latency reversal agents, including this study, have failed to show a reduction in the inducible HIV-1 reservoir, other approaches will be needed to achieve a cure for HIV infection.

    Bottom line: HDAC inhibitors like romidepsin will not get us closer to finding a way to eliminate the HIV in people. Negative studies like this help scientists move on to more promising approaches.

    McMahon, D. K., Zheng, L., Cyktor, J. C., Aga, E., Macatangay, B. J., Godfrey, C., Para, M., Mitsuyasu, R. T., Hesselgesser, J., Dragavon, J., Dobrowolski, C., Karn, J., Acosta, E. P., Gandhi, R. T., Mellors, J. W., & ACTG A5315 Team (2020). A phase I/II randomized, placebo-controlled trial of romidepsin in persons with HIV-1 on suppressive antiretroviral therapy to assess safety and activation of HIV-1 expression (A5315). The Journal of infectious diseases, jiaa777. Advance online publication. https://doi.org/10.1093/infdis/jiaa777

  • Hepatitis C Virus (HCV) Direct-Acting Antiviral Therapy in Persons With Human Immunodeficiency Virus–HCV Genotype 1 Coinfection Resulting in High Rate of Sustained Virologic Response and Variable in Normalization of Soluble Markers of Immune Activation

    October 15, 2020 Alexis Sexton Publications

    The Journal of Infectious Diseases, October 2020.

    Coinfection with hepatitis C virus (HCV) is common among people living with HIV. Prior to the advent of HCV direct acting antivirals (DAAs), coinfection was a major cause of liver-related morbidity and mortality, including cirrhosis, liver failure and hepatocellular carcinoma. Fortunately, DAAs lead to sustained virologic response (SVR), or cure, in most patients and has been linked to decreased mortality and cancer. HCV infection is also associated with other non-hepatic conditions including cardiovascular disease, Parkinson’s disease, and type 2 diabetes mellitus. While the causal relationship between HCV infection and these conditions is not fully established, it may be partly explained by HCV-induced systemic inflammation, which has been associated with immune dysfunction, morbidity, and mortality.

    In order to better understand the role of inflammation, study A5329 evaluated the safety, tolerability, and efficacy of HCV treatment with paritaprevir/ritonavir/ombitasvir plus dasabuvir (PrOD) with or without ribavirin (RBV) in virally suppressed people living with HIV HCV genotype-1 coinfection. Researchers examined changes in plasma inflammatory markers, including soluble CD14 (sCD14), Interferon Induced Protein 10 (IP10), soluble CD163 (sCD163), Interleukin-6 (IL-6), Interleukin 18 (IL-18), Monocyte Chemoattractant Protein 1 (MCP1), Autotaxin (ATX), and Macrophage-2-Binding-Protein (Mac2BP), over the course of treatment.

    SVR rate was 93%. At baseline, cirrhosis was associated with higher ATX and MCP1, women had higher ATX and IL-6, older age was associated with higher Mac2BP, higher BMI was associated with higher ATX, and HIV-1 protease inhibitor use was associated with higher sCD14. Among those who experienced SVR, IP-10, ATX, and Mac2BP declined by week two, IL-18 declined by the end of treatment, sCD14 did not change, and sCD163, MCP1, and IL-6 levels only changed at a single time point.

    These findings indicate that markers of immune activation in HIV hepatitis C coinfection are likely partly attributable to age, sex, cirrhosis, BMI, and/or kind of antiretroviral therapy. Paritaprevir/ritonavir-ombitasvir-dasabuvir is a highly effective regimen that is associated with variable declines in immune activation markers.

    Editor’s Clinical Impact Statement: This study confirms the importance of treating hepatitis C to lower inflammation in the body.

    Anthony, D. D., Sulkowski, M. S., Smeaton, L. M., Damjanovska, S., Shive, C. L., Kowal, C. M., Cohen, D. E., Bhattacharya, D., Alston-Smith, B. L., Balagopal, A., & Wyles, D. L. (2020). Hepatitis C Virus (HCV) Direct-Acting Antiviral Therapy in Persons With Human Immunodeficiency Virus-HCV Genotype 1 Coinfection Resulting in High Rate of Sustained Virologic Response and Variable in Normalization of Soluble Markers of Immune Activation. The Journal of Infectious Diseases222(8), 1334–1344. https://doi.org/10.1093/infdis/jiaa254

  • Physical Function Impairment and Frailty in Middle-Aged People Living With Human Immunodeficiency Virus in the REPRIEVE Trial Ancillary Study PREPARE

    The Journal of Infectious Diseases, July 2020.

    As the lifespan of people living with HIV increases, so too do the number of people aging with HIV (nearly half of people living with HIV in the United States are now at least 50 years old). Compared to people without HIV, physical function impairment and frailty are more common and occur at an earlier age in people living with HIV; both have been associated with increased risk of falls, hospitalizations, and death. This paper describes physical function impairment and frailty in middle-aged people living with HIV on stable ART when they enrolled in A5361S (PREPARE), a substudy of REPRIEVE.

    A5361S evaluated 266 people living with HIV in the United States, nearly all in their 40s or 50s (81% male, 47% White, 45% Black, 18% Latinx). Many had high body mass index (BMI) and levels of physical activity were low. The investigators found that while overt frailty was uncommon (6%), physical function impairments and pre-frailty were present in nearly half of participants. Physical function impairments appeared mostly in power (the ability to rise from a chair) or strength (grip), important manifestations of skeletal muscle function.

    These findings suggest that the time it takes you to stand up from a chair may be a useful screening tool in this relatively young population to detect subtle changes in physical function earlier in age. Additionally, greater BMI, physical inactivity, smoking, and hypertension were associated with physical function impairments. These are important modifiable factors to help target interventions to potentially delay or reduce physical function impairments. The team is continuing to assess physical function yearly to understand any effects of statins over time.

    Bottom line: In this relatively younger population with HIV, changes in healthy physical function appeared earlier. Need to learn more about why this happens and the best ways to combat it.

    Umbleja, T., Brown, T. T., Overton, E. T., Ribaudo, H. J., Schrack, J. A., Fitch, K. V., Douglas, P. S., Grinspoon, S. K., Henn, S., Arduino, R. C., Rodriguez, B., Benson, C. A., & Erlandson, K. M. (2020). Physical Function Impairment and Frailty in Middle-Aged People Living With Human Immunodeficiency Virus in the REPRIEVE Trial Ancillary Study PREPAREThe Journal of infectious diseases222(Suppl 1), S52–S62. https://doi.org/10.1093/infdis/jiaa249

  • Association of Male Sex and Obesity With Residual Plasma Human Immunodeficiency Virus 1 Viremia in Persons on Long-Term Antiretroviral Therapy

    The Journal of Infectious Diseases, June 2020.

    Persistence of detectable HIV despite perfect ART adherence can be worrisome, because reaching undetectable is a huge goal for many people living with HIV. Why then do some people become undetectable and others do not? We tried to answer this question using information gained from more than 300 participants of A5321. When participants entered A5321, many measurements and samples were taken. We looked at everything that has been done with these measurements and found that males (assigned at birth) and people who were more obese tended to not reach undetectable levels of HIV. Sex-based differences in viral loads have been seen for many years and more studies are ongoing to find out why obesity is important. Some researchers think HIV may hide in body tissues with lots of fat but we did not obtain fat biopsies in A5321 to look at this directly. It’s always beneficial to exercise, but now we see hints that people with lower body mass indexes were more likely to be undetectable. While this will not be true for everyone, it is one of the first insights into why certain people may not reach undetectable levels of HIV.

    Editor’s Clinical Impact Statement: This study tells us ideas to look further into why people have low levels of virus detected despite being on HIV medicines. We still need to understand if these low levels of virus have an adverse impact on people.

    Cyktor, J. C., Bosch, R. J., Mar, H., Macatangay, B. J., Collier, A. C., Hogg, E., Godfrey, C., Eron, J. J., McMahon, D. K., Mellors, J. W., Gandhi, R. T., & ACTG A5321 Team (2020). Male sex and obesity are associated with residual plasma HIV-1 viremia in persons on long-term antiretroviral therapyThe Journal of Infectious Diseases, jiaa373. Advance online publication. https://doi.org/10.1093/infdis/jiaa373

  • Brief Report: Sex Differences in Outcomes for Individuals Presenting for Third-Line Antiretroviral Therapy

    JAIDS, June 2020.

    In resource-limited settings, there are fewer regimens available to people living with HIV compared to individuals in resource-rich countries. There is usually a single “first-line” regimen (mainly dolutegravir-based with efavirenz as an alternative) and a “second-line” regimen (with the protease inhibitors lopinavir/ritonavir or atazanavir/ritonavir, as backbones). The options for people experiencing virological failure on protease inhibitor regimens are very limited. This paper describes the differences in the experiences of men and women who were referred for third-line therapy in ACTG sites in low- and middle-income countries.

    More women entered study A5288 with a resistance pattern suggesting that they could have been suppressed on their current PI-based regimen. Consistent with guidelines, these women were therefore kept on their protease inhibitor-based regimen, with changes in the NRTI backbone as needed. At the end of the study, fewer women than men achieved virological suppression. Women with virological failure more commonly had no new resistance mutations, suggesting incomplete adherence. Women were more likely to have symptoms that they graded as “severe” or that interfered with their daily living, although laboratory values were not significantly more abnormal in women than men. The group of participants that reported severe symptoms was unlikely to achieve virological suppression.

    Based on findings from other ACTG and non-ACTG studies that women have higher protease inhibitor plasma concentrations then men at the same dose, the authors hypothesize that increased drug levels lead to decreased tolerability of the PI regimens. The decrease in tolerability will result in lapses in adherence and ultimate virological failure. Although ART regimens are given at a single dose for men and women, the clinical trials that led to the approval of most antiretrovirals often did not have adequate representation of women.  Interventions designed to improve and mitigate symptoms of ART in women may lead to improved virological success. Moreover, counseling of women should include a systematic assessment of adherence barriers, including tolerability concerns.

    Godfrey, C., Hughes, M. D., Ritz, J., Coelho, L., Gross, R., Salata, R., Mngqibisa, R., Wallis, C. L., Mumbi, M. E., Matoga, M., Poongulali, S., Van Schalkwyk, M., Hogg, E., Fletcher, C. V., Grinsztejn, B., & Collier, A. C. (2020). Brief Report: Sex Differences in Outcomes for Individuals Presenting for Third-Line Antiretroviral TherapyJournal of Acquired Immune Deficiency Syndromes (1999)84(2), 203–207. https://doi.org/10.1097/QAI.0000000000002324