124 Highly Active Anti-Retroviral Therapy Completely Abrogates Cholangitis in the NOD.C3C4 Mouse Model of PBC

Clinical trial: randomized controlled study of zidovudine and lamivudine for patients with primary biliary cirrhosis stabilized on ursodiol

“…For example, viral breakthrough was shown to coincide with biochemical rebound in the previous zidovudine and lamivudine pilot study and viral resistance was found to occur within 3 months of treatment in the NOD.c3c4 mouse model of PBC. [24][25][26] In this controlled study, patients on zidovudine and lamivudine therapy developed significant biochemical and clinical improvement to the same degree as previously reported in the pilot studies. 21 Patients on combination anti-viral therapy experienced a significant reduction in alkaline phosphatase, serum aminotrans-ferase levels and symptomatic score when compared with those on placebo.…”

“…In these placebo-controlled trials, Zidovudine and lamivudine attenuates the histological disease in mice even though the mice develop virological breakthrough with elevated virus levels in the liver; whereas the addition of protease inhibitors to this regimen for HAART completely abrogates cholangitis in this mouse model of PBC. 24,25 Despite the fact that significant endpoints were not achieved, this proof of principal study provides limited indirect support for the role of a retrovirus infection in PBC, as biochemical and clinical improvements were observed in patients on anti-viral therapy. Although serological evidence for viral infection cannot be demonstrated in most of the patients, we showed that the detection of virus in serum was not because of PCR contamination by demonstrating viral genomic sequence variation.…”

“…Also, there are data to suggest that the combination of zidovudine and lamivudine has limited anti‐viral activity against betaretrovirus infection. For example, viral breakthrough was shown to coincide with biochemical rebound in the previous zidovudine and lamivudine pilot study and viral resistance was found to occur within 3 months of treatment in the NOD.c3c4 mouse model of PBC 24–26 …”

“…Recently, we have found that the NOD.c3c4 mouse expresses MMTV in the damaged bile ducts 23 and have initiated anti‐viral studies, accordingly. In these placebo‐controlled trials, Zidovudine and lamivudine attenuates the histological disease in mice even though the mice develop virological breakthrough with elevated virus levels in the liver; whereas the addition of protease inhibitors to this regimen for HAART completely abrogates cholangitis in this mouse model of PBC 24, 25 …”

“…We believe that the response of PBC patients to anti‐retroviral treatment has the potential to offer additional insight into the aetiology of PBC and a therapeutic alternative for the two‐thirds of patients with a suboptimal responsive to UDCA. Once animal models and in vitro studies identify safe and effective anti‐viral regimens for human betaretrovirus infection, 23–25 additional studies will be required to confirm the efficacy of anti‐viral therapy in PBC patients using more robust endpoints and an increased number of viraemic patients with demonstrable betaretrovirus infection.…”