Evaluation of HIV-related Complications

Clinical Center

Investigators

Linked publications & trials

Abstract

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 (Janaki Kuruppu is PI) 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. Sixty-two patients have enrolled in the study and undergone liver biopsy. Significant liver abnormalities, primarily steatohepatitis, but also fibrosis, have been seen in the 40 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 cART; 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 cART (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; however, no patients have enrolled over the past 3 years, as a consequence of the COVID pandemic; although the protocol has been re-opened to enrollment, the eligibility criteria are rigorous, making recruitment difficult. Weight gain has been associated with the use of INSTIs such as dolutegravir, as well as the nucleotide reverse transcriptase inhibitor tenofovir alafenamide, 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 have developed a randomized, blinded trial (Janaki Kuruppu is the study PI), in collaboration with investigators at NIDDK, to compare the metabolic effects of dolutegravir to tenofovir alafenamide. 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. We are currently working with the Pharmacy Dept. to identify a company that can package the drugs to allow blinding. Insights into the mechanism can potentially identify interventions to minimize this weight gain and associated medical issues. cART 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, its 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. These results were published in Clinical Infectious Diseases. In the second arm, darunavir levels were found to be decreased by 71-96%, suggesting that the drugs should not be co-administered. These results have been submitted for publication. A second, ongoing study is examining the drug-drug interactions of tenofovir alafenamide with INH/rifapentine. Enrollment is complete, and the samples are currently being analyzed for drug levels.