Recent Study Results

Since 1987, the work accomplished by the ACTG has had a profound impact on the well-being of people living with HIV. Clinical trials and laboratory studies conducted by the ACTG have made major contributions to optimizing antiretroviral therapy (ART), managing drug resistance, preventing and treating co-infections, evaluating acute and long-term toxicities, and demonstrating the importance of pharmacogenomics in predicting drug toxicities. Results of these studies have helped establish the paradigm for the management of HIV disease and form the basis of current treatment guidelines. This progress in the treatment of people living with HIV has resulted in dramatic reductions in AIDS mortality in the U.S. and other countries of the developed world. Below are some of the results from our most recent studies.

 

A5327, Sofosbuvir-Containing Regimens Without Interferon For Treatment of Acute HCV in HIV-1 Infected Individuals (SWIFT-C), October 2017

27 persons participated in Cohort 2 of this study and all completed the treatment. All participants were male and all had well controlled HIV on antiretrovirals. The main purpose of this cohort was to see if the fixed-dose combination ledipasvir (LDV)/sofosbuvir (SOF) is a safe and effective treatment for early hepatitis C virus (HCV) infection in people also infected with HIV.

The results showed that for all participants, 8 weeks of LDV/SOF resulted in an undetectable HCV viral load 12-weeks after treatment was completed, which is considered a cure. There was also no effect on the kidney function of participants who were on an HIV regimen containing tenofovir disoproxil fumarate (TDF). These results support 8 weeks of treatment with LDV/SOF for HIV-infected persons with early HCV infection. An abstract based on this analysis was presented at the American Association for the Study of Liver Diseases (AASLD) Meeting in Washington, DC in October 2017.

 

A5320, Viral Hepatitis C Infection Long-term Cohort Study (V-HICS), October 2017

130 persons with both HCV/HIV and 125 persons with HCV alone who were considered cured (had achieved sustained virologic response (SVR) prior to entering the A5320/V-HICS study) were followed with study visits including blood tests for HCV RNA every 6 months. The study team examined the rate of HCV recurrence, defined as a “new” positive HCV RNA test result among 205 participants (116 with both HIV/HCV and 89 with HCV alone) who had at least one year of follow-up on the study.

Overall, the rate of HCV recurrence was quite low and similar in participants with and without HIV infection. However, two individuals had HCV recurrence. The first person who experienced HCV recurrence was HIV coinfected and was found to be positive for HCV RNA at 93 weeks after the completion of HCV treatment; this individual did not report practices known to increase the chance of HCV. The second person with HCV recurrence was infected with HCV alone and was found to be positive for HCV RNA at 37 weeks after treatment completion; this individual reported drug use after achieving SVR, which may have led to reinfection.  

These study results are preliminary and the A5320/V-HICS study team will continue to monitor participants for HCV recurrence.

 

A5353, A Study to Evaluate Dolutegravir plus Lamivudine Dual Therapy for the Treatment of Naïve HIV-1-infected Participants, July 2017

This study enrolled 120 participants living with HIV who had never taken any medication for the treatment of HIV. The main purpose of this study was to see if the combination of two anti-HIV medicines, dolutegravir (DTG, Tivicay) and lamivudine (3TC, Epivir) taken once a day, will provide a safe, effective, and well-tolerated treatment for HIV. Since some HIV medicines have side effects and are costly, there is interest in whether HIV can be successfully controlled with fewer than three HIV drugs.

The main results of the study were presented at the July 2017 Conference of the International AIDS Society, which took place in Paris, France. In summary, the combination of dolutegravir plus lamivudine was found to be effective in about 90% of the study participants at 24 weeks of treatment. While this is a promising result, it needs to be further investigated in larger clinical trials before it can be considered for routine use. Two large studies are already underway to answer this important question.

 

A5300/I2003, Study of MDR TB Cases and Their Household Contacts: Operational Feasibility to Inform PHOENIx Trial Design, 02/17/17

A total of 284 participants who have or had tuberculosis (TB) that is resistant to many drugs that are used to treat TB (multi-drug resistant TB; MDR TB) and 1007 participants that live or lived with them were included in this analysis. The main purpose of this analysis was to determine the willingness of the household contacts of MDR TB patients to be tested for HIV. The team also wanted to learn about factors that affected a household contact’s willingness to be tested for HIV. All adult and child household contacts were offered HIV testing if they had never been tested or if they last tested HIV-negative more than one year ago.

Participants were enrolled from 16 sites in 8 countries (Botswana-1 Brazil-1, Haiti-1, India-2, Kenya-1, Peru-2, South Africa-7 and Thailand-1). The results of the study showed HIV testing was offered to 98% of household contacts who did not already know their HIV status or were tested more than one year ago. Of those who were offered HIV testing, 71% agreed to be tested and 5% were found to be HIV-positive. Willingness to be tested varied substantially by site; 4 sites had 100% testing, but 5 sites had less than 50%. Testing did not differ between men and women, but testing was lower in children than adults. One-third of the contacts who did not want to be tested were contacts of HIV-infected MDR TB patients. Of those who gave reasons for not being tested, common reasons were a perception of low risk of HIV infection (23%), not wanting repeat testing (9%), not being ready (5%), not enough time (3%), and fear of disclosure (3%). Contacts of HIV-positive MDR TB patients were more likely to test positive compared to contacts of HIV-negative MDR TB patients (8% versus 2%).

In summary, it is important to address perceptions of risk to improve rates of HIV testing, especially among contacts of HIV-positive MDR TB patients because they are at higher risk for having HIV.

 

A5342, A Phase I Study to Evaluate the Safety, Tolerability, and Effect of a Human Monoclonal Antibody, VRC-HIVMAB060-00-AB (VRC01), on Markers of HIV Persistence in ART-treated, HIV-infected Adults, 02/17/17

A total of 40 people were enrolled into this study.  Each participant had 4 intravenous infusions: 2 infusions of the monoclonal antibody VRC01 and 2 infusions of saline (salt water).  The two main purposes of this study were to see if VRC01 is safe and well tolerated in individuals with HIV, and also to see if it helps to remove HIV infected cells from the body.  We compared the results of the VRC01 group to the placebo group for the first part of the study, and then also compared ‘before’ to ‘after’ VRC01 for both groups combined.

At the current time, the team has completed only some of the testing from the study.  The infusion of VRC01 was safe and well tolerated.  There were no serious side effects that were related to the infusions during the study.  The VRC01 did not have any significant impact on any of the measures of the HIV in the blood of study participants.  Specifically, there was no difference in the number of HIV infected cells among CD4+T cells in the blood, or in the proportion of participants who had measurable levels of HIV in the cell-free part of the blood (plasma).

The study team is working on several tests on the remaining samples from the study to try to understand the reason why the antibody had no effect on the levels of HIV in blood, and to determine if the antibody had any effects on the immune system.  These results will become available over the next several months and may be presented at a future scientific meeting. 

 

A5348, Phase II Trial of Retreatment Strategies for Difficult-to-Treat Hepatitis C Virus (HCV)-Infected Individuals Who Have Failed Prior Direct Acting Antiviral (DAA)-Based Regimens, 02/17/2017

Seven persons participated in this study, which was closed before the study could be fully enrolled due to slow rate of participants joining the study. The main purpose of the study was to see if two different regimens for retreating hepatitis C (HCV) were safe and effective, after an initial treatment with sofosbuvir-based treatment had failed to cure hepatitis. The two regimens studied were 12 weeks of the combination of ledipasvir/sofosbuvir with ribavirin or 24 weeks of ledipasvir/sofosbuvir without ribavirin.

The results of the study showed that all 7 participants enrolled had undetectable HCV virus 12 weeks after stopping therapy (“SVR12”), which is generally interpreted as a cure of HCV. They will continue to be followed until 24 weeks after therapy. No participants had to stop treatment and there were no serious complications of HCV treatment.

These results were co-presented with data from a similar non-ACTG study of HCV mono-infected individuals, conducted by Gilead, also treated with 12 weeks of LDV/SOF + RBV or 24 weeks of LDV/SOF.

 

A5321, Decay of HIV-1 Reservoirs in Patients on Long-Term Antiretroviral Therapy: The ACTG HIV Reservoirs Cohort (AHRC) Study, 02/17/2017

About 350 people have been enrolled into this long-term study. The study is being done to try to determine which factors contribute to the persistence of HIV (how long the virus remains) in your body over time when you are taking anti-HIV medications.  The team believed that the following may be important:

  • viral load (the amount of HIV in your blood),
  • CD4 cell count (a measure of your body’s ability to fight infection),
  • when you started taking anti-HIV medications (in relation to when you were first infected),
  • genetics (features [or traits] that you were born with),
  • the amounts of your anti-HIV medications that are in your body.

The team wanted to understand whether the level of HIV in the blood is related to activity of your immune system (your body’s infection-fighting system). We know from previous work that markers of immune activity that indicate ongoing inflammation in the blood are higher in people with HIV than in people who do not have HIV.  This is true even when the HIV is well controlled with medications.

In this study, it was found that people who had higher levels of inflammation and HIV before starting anti-HIV medications tended to have higher levels of inflammation and HIV using special blood tests long after they started taking anti-HIV medications, and even when they had undetectable viral loads on regular blood tests.  This is what we mean when we say “the die is cast”, e.g. what happens before starting treatment, how your body reacts to HIV before starting to take the medicines is the most important factor determining the amount of HIV left in your body when you take the medicines.  This information tells us that we need to find ways to protect the immune system as early as possible after HIV infection and limit the inflammation that develops. One way to do this would be to start anti-HIV medications as soon as possible after HIV infection.

The results we have so far also suggest we need new treatments to reduce inflammation in people with HIV, even if they have undetectable viral loads. The ACTG is studying a number of potential ways to reduce this inflammation. We hope that these future treatments will also improve health in people living with HIV. You may be interested in asking about those studies to your research nurse.

 

A5322, HAILO: Long-term Follow-up of Older HIV-infected Adults in the ACTG, 02/17/2017

Frailty and impairments in neurocognitive function are closely related problems that can occur, especially in older adults. We previously found that impairments in neurocognitive function were very closely related to frailty in HIV-infected adults. However, the overlap of frailty and neurocognitive impairment, and their impact on poor outcomes (like disability, falls, and death) in HIV-infected persons is unknown. Among HAILO participants, the team found that presence of frailty, with or without neurocognitive impairment, was associated with a greater risk of falls, disability or death in HIV-infected adults than having only neurocognitive impairment. Although frailty and neurocognitive impairment may be similar, interventions aimed at improving frailty may have greater impact on poor outcomes than interventions targeting cognition alone. 

 

A5307, Essentiality of Isoniazid in Tuberculosis Therapy, 02/17/2017

A total of 69 people enrolled into this study. This study was done to see if it might be possible to treat tuberculosis (also known as TB) differently in the future. TB is disease caused by a bacterial infection; in this study, the infection was in the lungs. The current treatment for TB is a combination of four drugs for 2 months followed by two drugs for 4 more months. The team wanted to know if one of the drugs (isoniazid) was really necessary at the beginning of treatment.

Study participants were treated for about 2 weeks with one of four combinations of anti-TB drugs. The results of the study showed that there was no difference in how well the different drug combinations reduced the amount of TB, with or without isoniazid. There were very few negative side effects to any of the drugs or drug combinations. These results may help guide how some of these drugs could be studied in combinations for treatment of TB in the future.

 

A5308, A Prospective, Single-arm, Open-Label Study to Evaluate the Effect of Fixed-Dose Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate on T-cell Activation, Absolute CD4+ T-cell Count, Inflammatory Biomarkers and Viral Reservoir in Treatment-naive HIV-1 Controllers, 02/17/2017

While the primary endpoint for the study is still being analyzed, the A5308 team analyzed a sub-component of the study that only pertains to the viral decay portion of the study, for which 22 of the 38 A5308 participants agreed to be a part of and completed. 

The main purpose of this substudy is to see how quickly HIV disappears from the blood of HIV controllers after starting antiretroviral therapy (ART) and compare it to what happens in non-controllers.  The study found extremely small numbers of long-lived infected cells in HIV controllers and differences between controllers and non-controllers in how quickly these cells disappeared from the blood after starting ART. The results will help researchers better understand where HIV is hiding in the body and provide insight on how the HIV reservoir differs between HIV controllers and non-controllers. The analysis of A5308 is continuing and we hope to have additional findings later this year.

 

A5317, Effects of Telmisartan on Fibrotic and Inflammatory Contributors to End-Organ Disease in HIV-Infected Patients Well Controlled on Antiretroviral Therapy, 02/17/2017

Results from 34 participants were included in the lymph node (gland) analysis and 30 in the adipose tissue (fat) analysis. The main purpose of this study was to find out if telmisartan would decrease scar tissue in the lymph node and fat in people who taking antiretroviral therapy (ART). This is an important question because the answer could identify a way to increase CD4 cells and decrease the risk of heart attacks and other diseases in persons living with HIV.

Telmisartan did not change the amount of scar tissue in lymph nodes or fat. Fat had less scar tissue after 48 weeks of continuing ART, with or without telmisartan. The amount of scar tissue in the lymph nodes was similar to what we have seen in people not taking ART. These findings are important because other drugs may be needed to decrease lymph node scar tissue. The effects of the decrease in scar tissue in fat are being investigated.

 

A5274/REMEMBER: Reducing Early Mortality and Early Morbidity by Empiric Tuberculosis Treatment Regimens, 02/17/2017

A total of 850 individuals with very low CD4 counts (an indication that their infection-fighting system is not working very well) participated in the A5274/REMEMBER study in 10 countries. At study entry, participants were assigned by chance to the empiric TB treatment group or to the isoniazid preventive therapy (IPT) group. The three analyses being presented deal with the following topics: hepatotoxicity (liver damage) in the IPT group, treatment adherence in both groups, and risk factors for death in both groups.  The primary analysis of this study was present in 2016, this time the team analyzed three secondary analyses.

Risk factors for hepatotoxicity were examined in the 426 individuals assigned to IPT. Thirty-one (31), or a little over 7% of these people had hepatotoxicity. People who tested positive at entry for exposure to a virus that affects the liver and those whose liver tests showed damage at entry were at higher risk of having hepatotoxicity. This finding is important because it suggests that clinicians should carefully and regularly monitor individuals with these characteristics when starting them on IPT and ART.

The team also examined what the chances were of developing TB or of dying based on adherence (how consistently participants were able to take their study treatment) over almost 2 years on study. In both groups, the risk of dying went down as adherence got closer to 100%. The risk of developing TB after almost 2 years on study was relatively low in both arms, but was actually twice as high in the empiric TB treatment group: about 6% chance in the TB treatment group compared to a little less than 3% chance in the IPT group. In the IPT group, the risk of developing TB got lower as adherence got closer to 100%. In the empiric TB treatment group, the risk of developing TB did not change as adherence got closer to 100%. These findings suggest that taking IPT without missing any doses lowers people’s chances of dying or developing TB.

In the third analysis, the team found that the risk of death in both treatment groups was higher for people whose immune system function was not improving by the 4th week of the study. People who had a new opportunistic infection (OI) by the 4th week of the study also were at greater risk of dying. These findings suggest that better tests for OIs and identifying ways to improve or repair the immune system could reduce the risk of death in this population.

 

A5331: Modulation of Immune Activation by Aspirin, 09/22/16

The main purpose of this study was to show if Aspirin at either a higher dose (300 mg) or a lower dose (100 mg) performed any better than a placebo (dummy pill) in reducing markers of inflammation and vascular disease in people living with HIV (PLHIV) with an undetectable viral load on HIV meds.  The safety of aspirin was also examined.  The study was a double-blind, randomized, placebo-controlled design, meaning that both study participants and investigators did not know the treatment to which participants were assigned. 

Between August 2014 and March 2015, 121 participants (about 40 per arm) were enrolled at 15 U.S. sites.  98 (81%) of the participants were male, 60 (50%) white non-Hispanic, 27 (22%) current smokers, 19 (16%) were on statins (a type of cholesterol-lowering drug), 7 (6%) on an abacavir-containing HIV regimen, 41 (34%) on an integrase inhibitor containing regimen.  Self-reported adherence to study drug was high with approximately 90% of study participants reporting 100% adherence. 

Aspirin was safe and well tolerated. There were no study discontinuations due to serious adverse events. While aspirin was safe and well-tolerated, neither the high nor low doses of aspirin had much of an effect (and similar effects as placebo/dummy pill) on markers of immune activation or inflammation in the blood (soluble CD14, IL-6, soluble CD163, D-dimer, T-cell or monocyte activation, or the other immunologic endpoints).  Similarly, neither dose of aspirin appeared to have a major effect on vascular function as assessed by flow-mediated dilatation (response of the artery in the arm to tightly inflating a blood pressure cuff).  Both groups taking aspirin had weaker reductions in a test that shows how well aspirin works than what happens in studies of people without HIV.  A5331 wasn’t set up to specifically test this effect however.  This finding suggests that PLHIV may have an impaired anti-inflammatory response to aspirin. 

Conclusions

Aspirin in this study was safe in PLHIV.  No benefit was seen in reducing immune activation or improving vascular function.  This study also suggested that PLHIV seem to have an impaired anti-inflammatory response to aspirin therapy.  Further studies are needed to verify this finding. Therefore, the use of aspirin for the primary and secondary prevention of cardiovascular events in PLHI V should be done according to the current guidelines for the general population.