Apples to Apples? A Comparison of Real-World Tolerability of Antiretrovirals in Patients with Human Immunodeficiency Virus Infection and Patients with Primary Biliary Cholangitis

Abstract

We previously characterized a human betaretrovirus and linked infection with the development of primary biliary cholangitis (PBC). There are in vitro and in vivo data demonstrating that antiretroviral therapy used to treat human immunodeficiency virus (HIV) can be repurposed to treat betaretroviruses. As such, PBC patients have been treated with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), alone and in combination with a boosted protease inhibitor or an integrase strand transfer inhibitor in case studies and clinical trials. However, a randomized controlled trial using combination antiretroviral therapy with lopinavir was terminated early because 70% of PBC patients discontinued therapy because of gastrointestinal side effects. In the open-label extension, patients tolerating combination therapy underwent a significant reduction in serum liver parameters, whereas those on NRTIs alone rebounded to baseline. Herein, we compare clinical experience in the experimental use of antiretroviral agents in patients with PBC with the broader experience of using these agents in people living with HIV infection. While the incidence of gastrointestinal side effects in the PBC population appears somewhat increased compared to those with HIV infection, the clinical improvement observed in patients with PBC suggests that further studies using the newer and better tolerated antiretroviral agents are warranted.

Linking Human Betaretrovirus with Autoimmunity and Liver Disease in Patients with Primary Biliary Cholangitis

“…Using ligation-mediated PCR and next generation sequencing, we identified HBRV proviral integrations in the biliary epithelium of the majority of PBC patients tested [69] (see NCI Retroviral Integration Database; rid.ncifcrf.gov [90]). In several case series and clinical trials, ART has been shown to improve histological and biochemical outcomes, and reduce viral load with combination ART [56][57][58][59][60]66,67]. Both humoral and cellular immune responses to HBRV have been demonstrated in patients with PBC [46,91].…”

“…Ultimately, the activity of ART to reduce betaretrovirus load and improve biochemical and histological parameters of cholangitis in the NOD.c3c4 model [55] and in patients with PBC [55][56][57][58][59][60]66,67] can provide the consistency required for a causal association. Clinical trials using repurposed HIV antiretroviral regimens in PBC patients have consistently shown significant reduction in alkaline phosphatase levels indicative of biochemical improvement in cholangitis [55][56][57][58][59][60]66,67]. A proportion of these studies included liver biopsy assessment and revealed concurrent improvement in cholangitis and the inflammatory activity [57,58,66].…”

“…A proportion of these studies included liver biopsy assessment and revealed concurrent improvement in cholangitis and the inflammatory activity [57,58,66]. Even if these measures did not meet the stated endpoints of the studies, the clinical improvements coinciding with reduction in HBRV is clear indication that retroviral infection plays a central role in mediating liver disease in PBC [59]. An obvious challenge with these clinical trials includes the use of repurposed HIV ART that was not developed for inhibition of betaretrovirus infection.…”

“…In case series and clinical trials using combination ART to treat PBC patients, improvements in cholangitis have been linked with reduced viral load [56][57][58][59][60]. Notably, the gold standard of meeting randomized controlled trial study endpoints has not been achieved to date due to the lack of tolerability of combination ART and the lack of antiviral efficacy of repurposed ART used to treat HIV.…”

“…Consequently, the question of whether PBC has an autoimmune or an infectious etiology is important to resolve because it has a direct bearing on the translational investigation of the disease process. On the one hand, we have clinical trials emphasizing immunosuppression [25] and, on the other, trials adopting an antimicrobial approach [56][57][58][59][60]66,67] (Figure 1). levels of B and T cell subsets, as well as reduced parameters indicative of lymphocyte activity in general [62][63][64][65].…”