Evaluation of HIV-related Complications

Clinical Center

Investigators

Linked publications & trials

Abstract

Our studies focus on improving the management of HIV infection, especially in patients whose response to currently available therapies is suboptimal. We are studying ways to improve the immunity in such patients, as well as to better understand some of the complications that occur in patients receiving therapy, such as inflammation and liver disease. At present, there are no clear guidelines as to when antiretroviral (ARV) therapy for human immunodeficiency virus (HIV) should be stopped in the setting of elevated liver enzymes. In large part, this is due to a limited understanding of the natural history of ARV-related hepatotoxicity. We have undertaken a pilot study to estimate the prevalence of hepatic fibrosis in a cohort of HIV-infected patients who have chronically elevated transaminases while on ARV therapy in the absence of Hepatitis B (HBV) or C (HCV) coinfection. Liver biopsy specimens are being evaluated for fibrosis by microscopic examination, the current gold standard for assessing the nature and severity of liver disease. Fibrosis, as well as other histopathology, is being measured using a validated scoring system. Significant liver abnormalities, primarily steatohepatitis, but also fibrosis, have been seen in the 40/62 patients as reported. We have continued to follow these patients long-term to better understand the natural history of these liver abnormalities, and potentially to repeat a liver biopsy in a subgroup of patients, to examine the histopathologic changes that have occurred over time. We have also examined the predictive value of Fibroscans, which were performed in parallel with other evaluations, for identifying fibrosis in patients with elevated transaminases but without HBV or HCV co-infection. This study will provide clinically relevant information on the significance of elevated transaminases in HIV- infected patients without co-infection with HCV or HBV, and facilitate management of such patients. Biomarkers including D-dimer and IL-6 have been shown to predict mortality in HIV-infected patients, independent of CD4 and viral load. To better understand the mechanism leading to D- dimer elevation, we have undertaken a cross-sectional study to examine markers of coagulation, platelet function, endothelial activation and inflammation, and to identify correlates of elevated D-dimer levels. Our hope is that this analysis will provide insights into which of these pathways is leading to D-dimer elevation. To date we have enrolled approximately 230 HIV+ patients and HIV-volunteers. Preliminary analysis suggests that TNF-alpha, sVCAM, and von Willebrand Factor correlate with levels of D-Dimer. These data suggest that ongoing monocyte activation plays a role in D-dimer elevation. We have enrolled an additional 60 patients to study the correlates of immunologic non-response in patients receiving cART, including 30 subjects and 30 controls. We have examined immunophenotypic characteristics of the patients, as well as looked for evidence of infection with a variety of viral pathogens, including unknown viruses. We are in the process of examining T-cell receptor repertoire diversity, as well as a detailed flow cytometry panel, biomarker panel, and RNA expression levels using microarrays. We have also examined whole exome sequencing of a subset of these patients to see if there are any genetic markers that can distinguish immunologic non-responders from responders to ART; preliminary analyses have not identified any SNPs associated with increased or decreased risk of being a non- responder. We have also started recruiting INR patients as well as controls to undergo BAL to allow studying immune cells in the lung by single cell RNA seq. The goal is to better understand the mechanisms leading to poor immunologic response in HIV-infected patients. Compared to immunologic responders, immunologic non-responders on ART (CD4<350 cells/mm3, with controlled viremia) have increased risk for HIV-related opportunistic complications as well as non-HIV related disorders, including liver, cardiac, metabolic, renal, and CNS disease. To date no interventions have been shown to improve clinically relevant immunologic responses in such patients. Given that PD-1 has been shown to have increased expression on CD4 and CD8 cells in HIV infected patients, and that in certain cancers an anti-PD-1 antibody, pembrolizumab, has shown remarkable biologic activity, we undertook a phase 1/2 placebo controlled trial of a single dose of pembrolizumab in immunologic non-responders (CD4 cell number of 100-350 cells/mm3, viral load <40). Merck is providing pembrolizumab under a CRADA with the NIH. The primary endpoint is safety, but we are also examining changes in immunologic and virologic markers as well as changes in CD8-mediated killing of HIV-infected cells. The study has enrolled 7 patients. Given the difficulties in enrolling patients, in part as a consequence of the COVID pandemic, the study has been closed. One patient was randomized to placebo, the remaining 6 to receive pembrolizumab. The study found that a single dose of pembrolizumab could be safely administered to immunologic non-responders, with no serious adverse events. Pembrolizumab administration led to a decrease in exposed PD-1 in all 6 drug recipients, though nadir levels were higher that seen in other studies. There was no impact on CD4+ or CD8+ T cell numbers, nor on the killing of HIV-infected calls. Data analysis is ongoing. ART is frequently given in combination with drugs such as INH and rifapentine for prophylaxis to prevent activation of tuberculosis in patients with latent tuberculosis infection. Given the potential impact of rifapentine on enzymes important in drug metabolism, such as CYP3A, it’s important to understand drug-drug interactions of ARVs with INH/rifapentine. We have undertaken 2 studies to examine this, in collaboration with investigators in the Pharmacy department. In the first study, the interaction between either dolutegravir or darunavir/cobicistat and INH/rifapentine was studied. The dolutegravir arm was prematurely discontinued following the development of flu-like symptoms and elevated aminotransferase levels in 2 of 4 subjects after the third INH/rifapentine dose. Markedly elevated levels of interferon-gamma, CXCL10, C-reactive protein, and other cytokines were temporally associated with symptoms. Dolutegravir levels were decreased, while INH levels were increased, during co-administration. In the second arm, darunavir levels were found to be decreased by 71-96%, suggesting that the drugs should not be co-administered. A second study is examining the drug-drug interactions of tenofovir alafenamide with INH/rifapentine. Enrollment is complete, drug levels and pharmacokinetic parameters have been determined, and we are in the process of analyzing the data.