• 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

  • Identifying People During the Acute and Early Phases of HIV

    December 31, 2020 Alexis Sexton Publications

    Clinical Infectious Diseases, December 2020.

    Research suggests many potential benefits to starting antiretroviral therapy (ART) within the first few days or weeks after HIV has been acquired. Studies that enroll participants with early HIV or after early treatment initiation are especially important to test potential strategies to control HIV that don’t depend on lifelong ART. However, it is logistically difficult to diagnose HIV and start ART so soon after acquisition. A5354 attempted to do this at 30 ACTG sites in the Americas, Africa, and Southeast Asia. Sites used any of six criteria to identify people with very early HIV, including combinations of viral load testing, antibody testing, and antigen testing. Researchers utilized new ways of looking at how strongly positive some of these tests were (the signal-to-cutoff ratio) to determine how recently HIV was acquired. The study enrolled 195 participants and started 171 (87.7%) on ART on the day of enrollment and 24 (12.3%) the next day. After enrollment, centralized testing confirmed that 188 (96.4%) participants had acute or early HIV. Four (2.0%) participants had acquired HIV long ago and were now in the chronic phase of HIV while three (1.5%) were found not to have HIV, discontinued ART, and were withdrawn from the study. The signal-to-cutoff ratio correctly identified 99 of 122 (81.2%) participants who were in specific stages of acute or early HIV (Fiebig stages 2-4) with no false-positive results. Because some of the inclusion criteria in A5354 did not require an HIV viral load (which may take several days or more to produce a result), they may be helpful for clinicians and researchers who are trying to accurately diagnose acute or early HIV and start ART quickly.

    How quickly one needs to start HIV treatment is still being investigated. There are no data demonstrating differences in clinical outcomes in starting HIV treatment on the same day of diagnosis versus the within 2-4 weeks of diagnosis.  There is broad consensus that starting therapy as soon as possible is beneficial for the individual, may prevent further transmission of HIV and waiting too long (more than 8-12 weeks) can result in illness. Some of the barriers to initiating treatment on the same day of diagnosis is ensuring that the individual is confirmed to have HIV and starting therapy that is likely to work (meaning no resistance to treatment). This study helps to begin to identify people early on with HIV and allow for more prompt initiation of treatment.

    To read the full manuscript, click here.

  • 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

  • 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. Moreover, 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 still be suppressed on their current PI-based regimen and were therefore kept on that 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,” and this group was less likely to achieve virological suppression.

    Based on findings from other ACTG and non-ACTG studies that women have higher protease inhibitor plasma concentrations than men at the same dose, the authors hypothesize that increased drug levels lead to decreased tolerability of the PI regimens. 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 address or mitigate symptoms of ART in women may lead to improved virological success.

    The main findings of A5288 were published earlier this year in Lancet HIV.

    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

  • Treatment of advanced AIDS-associated Kaposi sarcoma in resource-limited settings: a three-arm, open-label, randomised, non-inferiority trial

     The Lancet, April 2020.

    Dr. Susan E. Krown and colleagues published “Treatment of advanced AIDS-associated Kaposi sarcoma in resource-limited settings: a three-arm, open-label, randomized, non-inferiority trial” from the A5263 trial in The Lancet on April 11, 2020. Optimal treatment regimens for AIDS-associated Kaposi sarcoma (KS) have not been systematically evaluated in low and middle-income countries (LMIC), where the disease is most common. A5263 aimed to study optimal treatment strategies for advanced-stage disease in these settings. Participants with HIV and advanced-stage AIDS-associated KS were recruited from 11 ACTG sites in Brazil, Kenya, Malawi, South Africa, Uganda, and Zimbabwe. Eligible participants were randomly assigned (1:1:1) to receive either intravenous bleomycin and vincristine or oral etoposide (the investigational arms), or intravenous paclitaxel (the control arm), together with standard EFV-based ART.

    Three hundred thirty-four participants were enrolled between October 1, 2013 and March 8, 2018, when the study was closed early due to inferiority of the bleomycin and vincristine plus ART arm. The etoposide plus ART arm had previously closed due to inferiority in March 2016. Week 48 progression-free survival rates were higher in the paclitaxel plus ART arm than in both investigational arms. Rates of adverse effects were equal across arms. Non-inferiority of either investigational intervention for advanced KS in LMICs was not demonstrated. Paclitaxel plus ART should continue to be used in treating advanced AIDS-associated KS in resource-limited settings.

    Krown S., Moser C., Campbell T., MacPhail A., Matining R., Godfrey C., Caruso S., Hosseinipour M., Samaneka W., Nyirenda M., Busakhala N., Okuku F., Kosgei J., Hoagland B., Mwelase N., Oliver V., Burger H., Mngqibisa R., Nokta M., Borok-Williams M. Treatment of Advanced AIDS-associated Kaposi Sarcoma in Resource-Limited Settings: A Three-Arm, Open-Label, Randomised, Non-Inferiority Trial in Five sub-Saharan African Countries and Brazil (ACTG A5263/AMC066). Lancet Vol. 395. Iss 10231. 2020 Apr 11;. doi: 10.1016/S0140-6736(19)33222-2. Epub 2020 Mar. PubMedID: 32145827

  • Participant Perspectives in an HIV Cure-Related Trial Conducted Exclusively in Women in the United States: Results from AIDS Clinical Trials Group 5366

    AIDS Research and Infectious Diseases, April 2020

    Led by Dr. Eileen Scully of John Hopkins University and Dr. Rajesh Gandhi of Massachusetts General Hospital, A5366 is the first HIV cure-related clinical trial conducted entirely in women living with HIV. A5366 was presented at CROI 2020 and showed that women could both be recruited and retained in HIV cure research. Watch the full themed discussion here.

    Of the 31 participants enrolled in the ACTG 5366, 29 agreed to undergo surveys and interviews to elicit their perspectives on the study (10 white; 18 Black/African American, 1 Native American). Almost all respondents reported positive experiences participating in A5366. The study also identified societal and personal motivators for participation, including the hope that HIV would be completely eliminated from the body, that they would never have to think of the virus again, and that they would not experience stigma for having HIV. Reimbursements to defray costs of study participation were reported by one-third of participants to aid in participation.

    This paper showed that it is possible to embed participant-centered outcomes evaluations in ACTG studies. Moreover, these findings highlight the value of assessing psychosocial factors in participating in HIV cure-related research. The findings show us that people living with HIV join clinical trials for many different reasons and help us appreciate the lived experiences of participants. Greater attention should be paid to motivators that can help women overcome barriers of trial participation during the planning phase of clinical trials. Importantly, this study could help in the design and implementation of future HIV cure-related research efforts for women.

    Dube K., Hosey L., Starr K., Barr L., Evans D., Hoffman E., Campbell DM., Simoni J., Sugarman J., Sauceda J., Brown B., Diepstra K., Godfrey C., Kuritzkes DR., Wohl DA., Gandhi R., Scully E.Participant Perspectives in an HIV Cure-Related Trial Conducted Exclusively in Women in the United States: Results from AIDS Clinical Trials Group 5366. AIDS Research and Human Retroviruses. 2020 Apr 09;36(4):268-282. doi:10.1089/aid.2019.0284. PubMedID: 32160755