A5303: Systemic Inflammatory and Immune Biomarkers in Neurocognitive Changes with Initial ART.
Kevin Robertson, PhD, Investigator, University of North Carolina, Chapel Hill Clinical Research Site
A5303 was entitled “Systemic Inflammatory and Immune Biomarkers in Neurocognitive Changes with Initial ART” and was the largest randomized clinical trial studying neurocognitive outcomes ever conducted in the United States with over 200 treatment naïve participants who were followed after ART initiation for 48 weeks. Within the HIV research community, considerable interest in neurocognitive impairment in HIV as well as the desire to better understand the underlying pathogenesis of HIV-associated neurocognitive disorder (HAND). Biomarkers are an important way of looking at that pathogenesis to try to understand how HAND develops, and why it continues in some on effective antiretroviral therapy.
A5303 researchers found correlations between activated T cells and neurocognitive performance at baseline when viral loads are high, but these correlations were not there after the virus was suppressed with treatment. However, after the virus was suppressed, there were correlations between monocytes and neurocognitive impairment, not there at baseline. This finding fits some theories of which cells (monocytes) are driving HAND. These findings suggest that the driving mechanism behind HAND before ART and on ART may be different. In large part, A5303 confirmed that biomarkers in the periphery, (the blood) provided only weak correlations with neurocognitive impairment, and are likely too distant from the brain to be predictive. Biomarkers from Cerebrospinal Fluid (CSF) are likely more reflective of processes in the brain and central nervous system.
A5303 established that only a few biomarkers sampled in the blood were related to neurocognitive impairment. There is still a need to better understand the pathogenesis underlying continued neurocognitive impairment, and to continue looking for the causes to be able to better treat and prevent HAND.
A5317: Telmisartan Does Not Improve Lymph Node or Fat Fibrosis in Treated HIV Infection
Netanya S. Utay, MD, Investigator, University of Texas Medical Branch at Galveston, Houston AIDS Research Team Clinical Research Site
A5317 was entitled “Telmisartan Does Not Improve Lymph Node or Fat Fibrosis in Treated HIV Infection” and evaluated the effects of telmisartan added to continued suppressive ART on lymph node and adipose tissue (fat) fibrosis (scar tissue). Lymph node fibrosis may limit CD4+ T-cell recovery; lymph node and adipose tissue fibrosis may increase systemic inflammation, leading to other problems like heart disease. Telmisartan decreases inflammation and fibrosis in animal models and other diseases.
A5317 assembled the largest collection of lymph node and adipose tissue samples at multiple time points from participants taking ART. Participants had been taking ART on average over 10 years, with a median CD4 count of 588, and almost all had undetectable viral loads. The researchers found that collagen I, a measure of fibrosis, decreased in lymph node and adipose tissue after 48 weeks of continued ART, and fibronectin, another measure of fibrosis, decreased in adipose tissue over 48 weeks. Telmisartan did not decrease collagen I or fibronectin more than continuing ART alone.
A5317 established that even after a long time, ART continues to decrease scar tissue in the lymph node and fat. Identifying the mechanisms behind this decrease in fibrosis could contribute to the understanding of the pathogenesis of fibrosis in HIV infection and to finding new treatments to decrease the fibrosis further. Experiments to characterize these mechanisms are ongoing.
A5342: VRC01 Infusion Has No Effect on HIV-1 Persistence in ART-Suppressed Chronic Infection
Sharon Riddler, MD, MPH, Investigator, University of Pittsburgh Clinical Research Site
A5342 was entitled “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.” The study enrolled 40 participants; 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 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 only the primary safety and virologic results are available. The infusions of VRC01 were 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 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 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.
A5321: Persistent Immune Activation despite ART: The “Die is Cast” Before ART Initiation.
Rajesh Gandhi, MD, Massachusetts General Hospital Clinical Research Site
The ACTG HIV Reservoirs Cohort (AHRC) study (A5321) is one of the largest longitudinal studies of HIV reservoir decay in infected participants on long-term antiretroviral therapy (ART). About 350 participants have been enrolled in this study. We found that HIV-infected participants who had higher levels of inflammation, immune activation and HIV before starting anti-HIV medications tended to have higher levels of inflammation, activation and HIV using specialized 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 a person's body reacts to HIV before starting to take ART, is the most important factor determining the amount of HIV left in the body when people take treatment. We also found that, although the amount of HIV in the blood correlated with inflammation and activation before ART was started, once people were on long-term ART, there was not a correlation between levels of HIV persistence (cellular DNA, HIV DNA, plasma HIV RNA by single copy assay) and activation or inflammation; this finding suggests that HIV persistence in participants on ART is not driving or being driven by activation or inflammation.
These findings tell us that we need to find ways to protect the immune system as early as possible after HIV infection and limit the inflammation and activation that develops. One way to do this would be to start ART as soon as possible after HIV infection. The results also suggest we need to study whether genetic or viral factors influence HIV levels, activation and inflammation before and during ART. Finally, the results also suggest we need new treatments to reduce inflammation and activation in people with HIV, even if they have undetectable viral loads. The ACTG is studying a number of potential ways to reduce this inflammation and activation. We hope that these future treatments will improve health in people living with HIV.
A5274: Impact of INH adherence on TB incidence and mortality by week 96 in REMEMBER Trial
Amita Gupta, MD, MHS, Baltimore-Washington-India Clinical Trials Unit, co-PI and Investigator, Johns Hopkins University Clinical Research Site
The A5274/REMEMBER trial team previously reported that among those with a negative TB screen (TB disease was ruled out using symptom screen and rapid microbiological diagnosis), a strategy of Empiric 4-drug TB therapy +ART provided no additional benefit in reducing mortality within 24 weeks after ART initiation compared to INH preventive therapy (IPT)+ART.
The secondary analysis examining the 96 weeks results and the impact of adherence to randomized treatment on outcomes in both arms was conducted at 18 ACTG sites in 10 countries (6 in sub-Saharan Africa, 3 in the Americas and 1 in Asia) where TB incidence was at least 100/100,000 and early mortality despite ART was documented in the ART programs. At week 96, there was no statistical difference in mortality between the Empiric and IPT arms; however, at week 96, the Empiric arm had more TB compared to the IPT arm.
The hazard of death was 23% and 20% lower per 10% increase in the proportion of 100% adherence in the Empiric and IPT arms, respectively. Adherence had no effect on TB in the Empiric arm; however, hazard of TB was 17% lower per 10% increase in the proportion of 100% IPT adherence. In conclusion, the primary end point seen at 24 and 48 weeks is sustained at 96 weeks i.e. Empiric TB treatment in patients presenting for ART initiation with low CD4 cell counts below 50 cells/mL did not reduce mortality compared to IPT. There was also a significantly higher rate of confirmed or probable TB in the Empiric arm compared with the IPT arm with most of the events occurring by week 24.
The findings from the analysis of the impact of adherence to randomized treatment on study outcomes, demonstrate that in a population with advanced HIV, adherence to both empiric TB therapy and IPT was associated with improved survival. Adherence to IPT was associated with reduced risk of developing TB, but adherence to empiric TB therapy was not. Supporting IPT+ART initiation and adherence are critical to preventing the high TB incidence and mortality observed in those with advanced HIV.
Using the A5274 data and samples, further PK studies are planned to understand why TB was diagnosed more frequently in the Empiric Arm as are studies of inflammatory and metabolomic biosignatures that may be predictive of risk of death and/or TB in advanced HIV.
A5307: The Essentiality of INH during the First 14 days of TB therapy
Florian von Groote-Bidlingmaier, MD, TASK Applied Science Clinical Research Site, Cape Town, South Africa
A5307 was entitled, “The Essentiality of INH During the First 14 days of TB therapy.” Clinical and animal model studies suggest that isoniazid (INH), one of the key drugs in the treatment of drug-susceptible tuberculosis, contributes a significant level of early bactericidal activity (EBA) during the initial 2 days of treatment, but the bactericidal rates decline significantly beginning at day 3 in patients with uncomplicated, smear-positive pulmonary tuberculosis.
A5307 was a 14-day randomized phase II EBA trial to determine how INH affects EBA in combination with rifampicin, pyrazinamide, and ethambutol (RZE). 69 patients of which 63 completed the study were randomized onto four study arms omitting or replacing INH for either the first 2 days or the remaining 12 days of the study period. Patient demographics were well balanced between arms. Grade 3 or 4 adverse events were rare and not significantly different across arms.
A5307 showed that EBA was not different across all arms and that INH did not appear to significantly add to the 14-day EBA observed with RZE. Unlike earlier studies, significant EBA over 2 days due to INH was not observed. The absence of the expected bi-phasic INH response might be due to the relatively low baseline bacterial load in this study. Lower bacterial loads have been reported in recent EBA studies and it is likely due to early detection of TB.