Highlights of Recent ACTG Publications

Lancet HIV

A Landmark ACTG Study Evaluating Second-Line ART Failure in Low- and Middle-Income Countries

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.”

https://www.ncbi.nlm.nih.gov/pubmed/?term=31371262

Lancet HIV

The Impact of ART on the Efficacy of Vaginally Delivered Hormonal Contraception

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.

https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(19)30155-9/fulltext

JCI

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.

https://www.jci.org/articles/view/127413

Clinical Infectious Diseases

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.

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciz442/5498857?searchresult=1

The Journal of Infectious Diseases

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.

https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiz281/5499329

The Lancet

Can Text Messaging Support Adherence for People Failing Secong-Line Therapy in Low- and Middle-Income Countries (MULTI-OCTAVE Study [A5288])

Lancet Digital Health, 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.

https://www.thelancet.com/pdfs/journals/landig/PIIS2589-7500(19)30006-8.pdf

Open Forum Infectious Diseases

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.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372057/?report=reader

Journal of Antimicrobial Chemotherapy

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.

https://academic.oup.com/jac/article/74/5/1376/5296308?searchresult=1