Evaluation of HIV-related Complications

Clinical Center

Investigators

Linked publications, trials & patents

Abstract

At present, there are no clear guidelines as to when antiretroviral (ARV) therapy for human immunodeciency 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 ( Janaki Kuruppu is PI) to estimate the prevalence of hepatic brosis 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 brosis 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. Sixty-two patients have enrolled in the study and undergone liver biopsy. Signicant liver abnormalities, primarily steatohepatitis, but also brosis, have been seen in the 40 patients. A paper describing the histopathologic abnormalities and clinical correlates of these patients has been published. We plan to continue 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 brosis in patients with elevated transaminases but without HBV or HCV co-infection. This study will provide clinically relevant information on the signicance 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 inammation, 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 HAART, 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 ow 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 HAART; preliminary analyses have not identied any SNPs associated with increased or decreased risk of being a non-responder. 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 HAART (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 have undertaken, in collaboration with Merck, a phase 1/2 placebo controlled trial (n=20) of a single dose of pembrolizumab in immunologic non- responders (CD4 cell number of 100-350 cells/mm3, viral load <40). The primary endpoint is safety, but we will also be examining changes in immunologic and virologic markers as well as changes in CD8-mediated killing of HIV- infected cells. The study is open and is currently recruiting patients and we have enrolled 7 patients to date; no patients have enrolled over the past 18 months as a consequence of the COVID pandemic. Weight gain has been associated with the use of INSTIs such as bictegravir or dolutegravir, out of proportion to weight gain seen with other ARVs such as efavirenz, but the mechanism of action responsible for this is currently unknown. Weight gain can be associated with onset or exacerbation of other medical problems such as diabetes and heart disease, with potentially harmful clinical consequences. To better understand what leads to this weight gain, we are in the process of developing a randomized trial to compare the metabolic effects of Biktarvy (which contains bictegravir) to dolutegravir plus Descovy (which contains tenofovir alafenamide and emtricitabine, the 2 other drugs present in Biktarvy), in collaboration with investigators at NIDDK. We plan to utilize metabolic rooms to measure the metabolic rates at baseline and following short-term administration of the drugs to healthy volunteers, and will also examine food intake and changes in biomarkers such as leptin that are related to weight gain. Insights into the mechanism can potentially identify interventions to minimize this weight gain and associated medical issues.