Treatment of advanced AIDS-associated Kaposi sarcoma in resource-limited settings: a three-arm, open-label, randomised, non-inferiority trial
The Lancet, March 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.
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)
1077HS/4: Predictors of Viremia in Postpartum Women on Antiretroviral Therapy
Journal of Acquired Immune Deficiency Syndrome, January 2020
Undetectable viral load is associated with optimal health outcomes for people living with HIV. However, among women living with HIV who have recently given birth and are on ART, there are high rates of viremia, which typically occurs because women are struggling to take their medication every day. 1077HS/4 sought to better understand the characteristics of post-partum women with viremia in order to understand how best to support their adherence.
The study enrolled a subset of women who were part of the PROMISE study. PROMISE was originally designed during the era when women living with HIV were instructed to take ART during pregnancy and then stop after delivery if they had strong immune systems. PROMISE enrolled postpartum women with good immune function (CD4 counts > 400 cells/mm3) from 56 sites in Argentina, Botswana, Brazil, China, Haiti, Peru, Thailand, and the U.S. between December 2011 and November 2014. Women were randomly assigned to continue their ART (828 women) or discontinue it (825 women) under their providers’ supervision. When deemed medically necessary, women who discontinued treatment were put back on ART. 1077HS/4 looked at a subset of PROMISE women who were on ART during study follow-up: those in the group asked to continue ART (802 women) and those who discontinued ART but later restarted for a medical reason (137 women). Over 144 weeks of follow-up, researchers evaluated the frequency with which women experienced viremia (>1000 copies/mL), their ART adherence (self-reported missed doses), and their self-reported health.
The study found that viremia was common among all women who had recently given birth who were continuing on ART (~20%) and that most viremia was due to difficulty taking medication rather than drug resistance (only 12% had viremia due to resistance). Younger women, women who started ART later in pregnancy, and women enrolled from the South American/Caribbean region had the highest rates of viremia during follow-up. Women in the group who discontinued ART and restarted later had very similar rates of viremia compared to women who continued ART after delivery. Among women with viremia, many never returned to an undetectable viral load during the follow-up period. Information from this study and others like it can be used to design programs to support the adherence of post-partum women on ART and tailor these adherence interventions to women’s unique needs.
A5288: Diverse Drug Resistance Profiles among People Experiencing Virologic Failure on Second-line ART in Resource Limited Settings
Clinical Infectious Diseases, November 2019
A5288 assessed third-line antiretroviral treatment (ART) in individuals who were failing second-line ART. This publication aimed to define resistance profiles among individuals failing second-line ART in low- and middle-income countries (LMIC), as this information is vital to optimize individual patient management and to develop treatment guidelines for this group. Of the 653 individuals screened for A5288, more than three-quarters (78%) had resistance to one or more drugs. One-fifth (20%) of participants showed resistance to at least one drug in a drug class, 32% showed resistance to at least one drug in two drug classes, and 26% showed resistance to at least one drug in all three commonly available drug classes. Susceptibility to at least one second-line regimen was preserved in 59% of individuals, as was susceptibility to etravirine (78%) and darunavir/r (97%). Susceptibility to a second-line regimen was significantly higher among women, younger individuals, those with higher nadir CD4+T-cell count, and those who had received LPV/r, and was lower among prior nevirapine recipients.
Therefore, highly divergent HIV drug resistance profiles, ranging from no resistance to resistance to three drug classes, were seen among individuals failing second-line ART in LMIC. These results underscore the need for ready access to resistance testing and newer antiretrovirals for optimal management of third-line ART in LMIC.
A5260s: Fungal Marker β-D-Glucan Increased After Antiretroviral Therapy, Associated with Fat Gains
Open Forum Infectious Diseases, November 2019
A5260s was a sub-study of A5257 in which ART-naïve individuals with HIV were randomized to receive atazanavir (ATV)/ritonavir (r), darunavir/r, or raltegravir. The objectives of A5260s were to compare cardiovascular markers, body composition, and immune activation between those initiating the three different regimens. This analysis in the A5260s study found that, among participants of A5257, beta-D-glucan (BDG, a marker of fungal translocation) increased over two years, irrespective of whether individuals were randomized to either of the two protease inhibitors or the integrase inhibitor. This finding may be as a result of ongoing intestinal damage that occurs despite successful ART. The study also found that BDG was associated with larger fat gains on therapy, supporting prior data from ACTG 5260s showing that a marker of intestinal injury was a strong predictor of fat gains on treatment. This research highlights the potential effect of gut dysfunction on metabolic comorbidities in HIV.
Antiretroviral Treatment Interruptions Look Different in Postpartum Women than in Men
Wolters Kluwer, November 2019
The short-term safety of treatment interruptions (a necessary part of cure studies) is not well-established, particularly in women and racially diverse populations. NWCS 371(also supported by the IMPAACT network) explored the viral rebound kinetics and safety associated with treatment interruptions among women who underwent ART discontinuation postpartum as part of the international, randomized-controlled PROMISE trial, comparing these results to those from men in historic ACTG interruption trials (ACTG NWCS 371 analytic treatment interruption pooled analysis). The estimated median time to viral rebound among these women was two weeks. An estimated 6 percent of women remained virally suppressed at 30 weeks.
A significantly higher proportion of women in PROMISE (25.4 percent) were virologically suppressed (<400 copies/uL) at 12 weeks compared to ACTG NWCS 371 participants (6.5 percent, p < 0.01). While there were significant differences between participants in PROMISE and ACTG NWCS 371 beyond sex (including older age, longer duration on ART, higher proportion of NNRTI-based regimens, and initiation of ART during acute or early infection in the ACTG NWCS study), researchers found these data striking, as many characteristics of the participants in PROMISE favored more rapid rebound. This study demonstrates that inclusion of women in future cure studies is safe. Future studies of cure research should include both men and women in order to fully represent all people living with HIV.
A5334s: Differences in Drug Interactions Between those with HCV, HIV, and HIV/HCV Coinfection
British Journal of Clinical Pharmacology, October 2019
One form of treatment for Hepatitis C virus (HCV) is composed of ombitasvir, paritaprevir/ritonavir- plus dasabuvir (OBV/PTV/r + DSV), and weight-based ribavirin. Study A5334s, a pharmacokinetics sub-study to A5329 (which evaluated this interferon-free HCV treatment among people living with HIV), sought to understand if concentrations of raltegravir changed after this HCV treatment was initiated among people living with HIV and HCV.
Compared to raltegravir levels before initiating HCV therapy, raltegravir levels four weeks after co-administration of this HCV combination in people living with HIV and HCV were unexpectedly lower in the majority (73%) of participants, although confidence intervals were wide. These decreases in raltegravir exposures were not suspected to be clinically important, as there were no HIV virologic failures reported in this group. Nonetheless, study A5334s reminds us to study drug-drug interactions carefully in those living with HIV on HCV treatment.
Raltegravir Pharmacokinetics Before and During Treatment with Ombitasvir, Paritaprevir/Ritonavir Plus Dasabuvir in Adults with HIV-1 and Hepatitis C Virus Co-Infection: AIDS Clinical Trials Group Sub-Study A5334s.
A5334s: Differences in Drug Interactions Between those with HCV, HIV, and HIV/HCV Coinfection
British Journal of Pharmacology, October 2019
One form of treatment for Hepatitis C virus (HCV) is composed of ombitasvir, paritaprevir/ritonavir- plus dasabuvir (OBV/PTV/r + DSV), and weight-based ribavirin. Study A5334s, a pharmacokinetics sub-study to A5329 (which evaluated this interferon-free HCV treatment among people living with HIV), sought to understand if concentrations of raltegravir changed after this HCV treatment was initiated among people living with HIV and HCV. Compared to raltegravir levels before initiating HCV therapy, raltegravir levels four weeks after co-administration of this HCV combination in people living with HIV and HCV were unexpectedly lower in the majority (73%) of participants, although confidence intervals were wide. These decreases in raltegravir exposures were not suspected to be clinically important, as there were no HIV virologic failures reported in this group. Nonetheless, study A5334s reminds us to study drug-drug interactions carefully in those living with HIV on HCV treatment.
Raltegravir Pharmacokinetics Before and During Treatment with Ombitasvir, Paritaprevir/Ritonavir Plus Dasabuvir in Adults with HIV-1 and Hepatitis C Virus Co-Infection: AIDS Clinical Trials Group Sub-Study A5334s
Linked Dual-Class HIV Resistance Mutations Associated with Treatment Failure
JCI insight, September 2019
Ultrasensitive sequencing of HIV can reveal drug resistance mutations present at very low frequencies, but the clinical significance of those viral resistance mutations remains unknown.
Investigators used ultrasensitive single-genome sequencing (which detects very rare mutations on a single genome), on samples from the ACTG 5208/ OCTANE Trial (which assessed the response to NVP-containing ART among women who had prior exposure to single dose NVP 6–24 months before study entry and initiation of ART). They found that dual-class drug resistant mutations that were linked on the same genome were significantly associated with ART failure. Importantly, two single-class ART resistance mutations or dual-class mutations that were not linked on the same genome were not associated with subsequent treatment failure. Although nevirapine is no longer first-line, this finding of the impact of dual-class resistance on a single viral genome is likely to be true of other ART classes and highlights the powerful technologies (such as ultrasensitive sequencing) developed by investigators in the ACTG.
ACTG DACS 325: Screening and Enrollment by Sex in HIV Clinical Trials in the United States
Clinical Infectious Diseases, September 2019
While women represent about one-quarter of adults living with HIV in the United States, many HIV clinical trials enroll fewer than 25% women. ACTG DACS 325 sought to assess how people living with HIV are recruited into the network’s clinical trials and whether ACTG enrolled proportionally lower percentages of women compared to men from the United States (and if so, why).
This analysis included all ACTG trials recruiting people living with HIV in the United States from 2003 (when the screening database started) through 2013. Data from 31 trials recruiting at 99 clinical research sites across the United States resulted in information on almost 11,000 persons. About one fifth (19%) of those screened were women living with HIV. Among those assessed, 28% did not enroll, which was only slightly higher than the 27% observed among men. These results did not differ when considering race, ethnicity, or age. Researchers were not able to investigate gender identity as it was not added to the ACTG screening questions until 2017. The most common reasons for people not enrolling were not meeting trial requirements or persons opting-out, and these reasons did not differ by sex. Pregnancy, breastfeeding, and trial contraceptive requirements were rarely reported as reasons to not enroll, though researchers speculate that women for whom these requirements applied may have been excluded (or excluded themselves) from trial consideration prior to screening.
Because the data around some of the factors relevant to participant recruitment (for example, childcare access, transportation, or participant reimbursement) were not available in the database, researchers were not able to address their role in recruitment sex differences in this study. Investigators concluded that efforts to expand screening of women for trial eligibility is needed to improve rates of enrollment.
ACTG Study A5338 Raises Potential Concern about Standard DMPA Dosing Frequency among African Women Receiving HIV and TB Treatment
The Lancet HIV, September 2019
Tuberculosis (TB) coinfection among pregnant women living with HIV is associated with poor outcomes so effective contraception to prevent unintended pregnancy is of paramount importance for young women with HIV and TB. However, hormonal contraceptives can fail as result of drug-drug interactions (DDI) between these agents and TB or antiretroviral treatments (ART). The A5338 study was designed to identify the ideal dosing frequency for DMPA among women with HIV-TB coinfection and determine whether a 150 mg injection of DMPA was effective in preventing ovulation.
Participants were on RIF-based TB treatment and EFV-based ART and given DMPA at study entry, with levels of the active metabolite of DMPA measured every 2 weeks. Their results were compared with those from women taking DMPA, but neither ART nor TB treatment, from the control arm of a separate study (A5093). The results of A5338 demonstrate that EFV-based ART in combination with RIF-based TB treatment reduced the amount of DMPA to a level associated with a risk of ovulation in 12 percent of women. Researchers also found that DMPA was cleared faster among women with HIV on ART AND RIF-based TB treatment, suggesting that more frequent dosing might be necessary.
The Impact of ART on the Efficacy of Vaginally Delivered Hormonal Contraception
The Lancet HIV, September 2019
ACTG Changes Guidelines
Effective family planning, which often involves the use of hormonal contraception, is an important component of care for women living with HIV. Unfortunately, some hormones have drug interactions with some antiretrovirals that may jeopardize hormone effectiveness or tolerability. Non-orally administered hormones may reduce the risk of these drug-drug interactions. The A5316 team sought to determine whether estrogen and progestin administered by a vaginal ring would be affected by oral ART containing either efavirenz or atazanavir/ritonavir.
Overall, 84 women participated in A5316 across 21 ACTG and IMPAACT sites in Asia, South America, sub-Saharan Africa, and the United States. The woman were either not yet on ART or were receiving ART containing efavirenz- or atazanavir/ritonavir, and agreed to use a vaginal ring containing ethinyl estradiol and etonogestrel continuously over 3 weeks. The results showed that hormone concentrations were significantly changed by both types of ART. Efavirenz-based ART decreased both ethinyl estradiol and etonogestrel hormones, raising concerns for lack of efficacy and the risk of unintended pregnancies. While the atazanavir/ritonavir-based ART increased progestin exposure (providing reassurance that the contraceptive effectiveness would be maintained), it decreased estrogen exposure, which may increase the risk of mid-cycle bleeding.
While the findings are directionally similar to what we’ve seen with ART and oral hormones to date, the vaginal ring ART-hormone interaction often resulted in even larger changes in hormone exposure. A5316 further identified the influence of participant pharmacogenetics on the extent of the drug interaction. The study finding that efavirenz-based ART may jeopardize the effectiveness of hormonal contraception delivered by a vaginal ring has already been included in both the Adult and Adolescent as well as the Perinatal DHHS HIV treatment guidelines, highlighting the influence of this study. The importance of understanding the pharmacology of vaginally administered drugs has particular relevance as vaginal rings are being developed for multipurpose prevention of both HIV and pregnancy.
A Landmark ACTG Study Evaluating Second-Line ART Failure in Low- and Middle-Income Countries
The Lancet HIV, September 2019
Prolonging the success of ART regimens in light of earlier starts and therapy over a lifetime requires innovative monitoring and treatment strategies. The Management Using the Latest Technologies in Resource-Limited Settings to Optimize Combination Therapy After Viral Failure (MULTI-OCTAVE) A5288 study was an open-label phase IV strategy study conducted in 19 sites in 10 lower- and middle-income countries (in Africa, Asia, South America, and the Caribbean) for patients failing second-line ART. This study used newer antiretroviral therapies (ART) and contemporary management approaches, including population-based sequencing to select appropriate antiretrovirals, to evaluate virologic outcomes and emergence of resistance. A5288 is an unprecedented cohort of second-line ART failure in lower- and middle-income countries, incorporating rigorous metrics of adherence measurement (via hair levels) and resistance testing into its design. In an accompanying editorial, A5288 was hailed as “a major step forward in clinical research methods serving a rarely studied population.”
The Impact of ART on the Efficacy of Vaginally Delivered Hormonal Contraception
The Lancet HIV, September 2019
Effective family planning, which often involves the use of hormonal contraception, is an important component of care for women living with HIV. Unfortunately, some hormones have drug interactions with some antiretrovirals that may jeopardize hormone effectiveness or tolerability. Non-orally administered hormones may reduce the risk of these drug-drug interactions. The A5316 team sought to determine whether estrogen and progestin administered by a vaginal ring would be affected by oral ART containing either efavirenz or atazanavir/ritonavir. The results showed that hormone concentrations were significantly changed by both types of ART. The importance of understanding the pharmacology of vaginally administered drugs has particular relevance as vaginal rings are being developed for multipurpose prevention of both HIV and pregnancy.
Latently Infected HIV DNA Cells Trigger Ongoing HIV Immune Responses, Despite Long-Standing Suppression of Plasma Viremia
Journal of Acquired Immune Deficiency Syndrome, August 2019
Although ART suppresses plasma viremia to levels below the level of detection, reservoirs of latently infected cells that lead to viral rebound if ART is stopped persist in people living with HIV. One measure of the latently infected cell population in people on ART is cell-associated HIV DNA, which is comprised of intact and defective proviruses. Authors examined more than 100 individuals on long-term ART in the ACTG HIV Reservoirs Cohort (AHRC) from A5321 and A5001. The study found that HIV antibody levels declined significantly the longer individuals remained on ART and correlated with HIV-specific T cell responses. The study also found that despite many years of therapy (during which plasma HIV RNA was consistently suppressed), HIV antibody and HIV-specific T cell responses correlated with HIV DNA levels, suggesting that the immune system is sensing, but not clearing, infected cells, likely due to persistent immune dysfunction.
PERSISTENCE OF HIV DNA IN CEREBROSPINAL FLUID AND NEUROLOGICAL IMPLICATIONS
Journal of Clinical Investigation, July 2019
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.
DO ELITE CONTROLLERS REQUIRE ART FOR SECONDARY BENEFITS?
Clinical Infectious Diseases, May 2019
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.
OPTIONS Study (A5241) Asks Whether NRTIs are Essential in Salvage Regimens
Journal of Infectious Diseases, May 2019
When people with HIV develop resistance to antiretroviral medications, their clinicians often prescribe previously used nucleoside reverse transcriptase inhibitors (NRTIs), along with other drugs, in the new “salvage” regimen, reasoning that the NRTIs may improve the chances of treatment response. These extra drugs may result in side effects, however, and it is not certain if they’re necessary if other active medicines are included in the salvage regimen. In the OPTIONS trial (ACTG A5241), the AIDS Clinical Trials Group asked whether NRTIs are an essential component of salvage regimens if the regimen has other active medications.
Can Text Messaging Support Adherence for People Failing Secong-Line Therapy in Low- and Middle-Income Countries (MULTI-OCTAVE Study [A5288])
Lancet Digital Health, May 2019
(ACTG) A5288 (MULTI-OCTAVE) is one of the first studies to look at interventions for medication adherence in lower-income and middle-income countries (LMICs) for individuals failing second line therapy. All participants in this unprecedented prospective interventional study were failing 2nd line ART, with the majority on lopinavir/ritonavir-based ART. Participants were either kept on that regimen or randomized to receiving third line ART regimens based on the results of viral genotyping on enrollment, and followed for a median of 72 weeks.
NWCS 399: CT as Non-Invasive Assessment of Fat Quality
The Journal of Clinical Endocrinology & Metabolism, April 2019
Fat quality or function contributes to risk for diseases such as heart disease, fatty liver disease, and diabetes, and may be as important as fat quantity when assessing the risk of poor health outcomes. In the past, fat quality could only be determined by performing fat biopsies and measuring fat cell size under the microscope. However, measuring fat cell density on a CT scan may also measure fat quality (lower density=poorer quality/more poorly functioning fat cells). NWCS 399 compared data from abdominal subcutaneous fat biopsy specimens, with fat density data from CT scans in the ACTG A5224s (a sub-study of A5202, which randomized adults living with HIV to abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir/ritonavir (ATV/r)).
Over 96 weeks of ART, fat quantity increased (+18%) and fat density decreased (-3%). Mean fat cell area correlated with fat density measured on CT scan both before and after ART and after adjusting for fat quantity, age, race, sex, CD4+ T lymphocyte count, and HIV-1 RNA. Therefore, subcutaneous fat density measured by CT scan served as an accurate representation of subcutaneous fat cell size in adults with HIV on and off ART, suggesting that CT is a useful tool for non-invasive assessment of fat quality.
Underlying Factors Associated with Racial Disparities in HIV Outcomes
Open Forum Infectious Diseases, February 2019
Racial/ethnic disparities in HIV outcomes have persisted despite effective antiretroviral therapy. The landmark ACTG A5257 study, examining initial non-NNRTI based regimens for ART, used clinical and socioeconomic data to assess factors associated with virologic failure and adverse events within racial/ethnic groups. Study authors analyzed data from 1762 participants: 757 self-reported as non-Hispanic black (NHB), 615 as non-Hispanic white (NHW), and 390 as Hispanic. The proportion with virologic failure was higher for NHB (22%) and Hispanic (17%) participants compared with NHWs (9%). Factors associated with virologic failure were poor adherence and higher baseline HIV RNA level. Prior clinical AIDS diagnosis was associated with virologic failure among NHBs only, and unstable housing and illicit drug use for NHWs only. Factors associated with adverse events were female sex in all groups and concurrent use of medications for comorbidities in NHB and Hispanic participants only. This important study shows that modifiable risk factors associated with virologic failure and tolerability of ART differ between racial groups, suggesting interventions to prolong the durability of first-line regimens.
DTG/3TC is Durable Initial Therapy through 48 Weeks
Journal of Antimicrobial Chemotherapy, January 2019
This study is an important subset analysis of the AIDS Clinical Trials Group study A5353, which demonstrated the efficacy and safety of dolutegravir and lamivudine for the initial treatment of HIV-1 infection at week 24 in individuals with HIV-1 RNA levels 1000-500 000 copies/mL for the first time. This study shows the durability of these findings out to 48 weeks and also compares the efficacy of the regimen in participants with baseline HIV-1 RNA ≤100 000 copies/mL versus >100 000 copies/mL. Authors show that – in 120 enrolled eligible participants included in the analysis, 85% (95% CI 77%-91%) had virologic success at 48 weeks. At week 48, 102 of the 120 participants (85%; 95% CI 77%-91%) had virological success. Virological success was similar between those with starting HIV RNA levels below and above 100,000 copies/mL. No new drug resistance mutations were observed in any of the failures and the regimen was well-tolerated. This study, along with the GEMINI study, verifies the durability of DTG/3TC as initial therapy out to 48 weeks for those who are naïve to HIV therapy and have no baseline resistance mutations.