Letter: biochemical response to combination anti‐retroviral therapy in patients with primary biliary cirrhosis

Mason, Andrew L.; Montaño-Loza, Aldo J.; Saxinger, Lynora

doi:10.1111/apt.12575

Cited by 6 publications

(6 citation statements)

References 9 publications

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“…The preliminary 6-month data of placebo versus controls prior to crossover showed biochemical improvement from baseline with TDF/FTC and LPR/r therapy (Fig. 1 ), which was nearly double of previously observed in the AZT/3TC study [ 84 ]. However, the patients unable to tolerate the 6-month therapy were offered the opportunity to continue on TDF/FTC alone.…”

Section: Clinical Experience With Antiretroviral Therapy In Patients supporting

confidence: 53%

“…Patients treated with daily lamivudine 150 mg (3TC) and zidovudine 300 mg (AZT) developed a 66 IU/mL mean reduction in ALP, whereas those receiving daily tenofovir/emtricitabine 300/200 mg (TDF, FTC) and lopinavir/ritonavir 800/200 mg (LPRr) for 6 months ( n = 13) experienced a mean ALP reduction of 114 IU/mL [two-way ANOVA, * P < 0.001, ** P < 0.05; adapted from ref. 84 with permission] …”

Section: Clinical Experience With Antiretroviral Therapy In Patients mentioning

confidence: 99%

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Role of Novel Retroviruses in Chronic Liver Disease: Assessing the Link of Human Betaretrovirus with Primary Biliary Cirrhosis

Sharon

Mason

2015

Curr Infect Dis Rep

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A human betaretrovirus resembling mouse mammary tumor virus has been characterized in patients with primary biliary cirrhosis. The agent triggers a disease-specific phenotype in vitro with aberrant cell-surface expression of mitochondrial antigens. The presentation of a usually sequestered self-protein is thought to lead to the loss of tolerance and the production of anti-mitochondrial antibodies associated with the disease. Similar observations have been made in mouse models, where mouse mammary tumor virus infection has been linked with the development of cholangitis and production of anti-mitochondrial antibodies. The use of combination antiretroviral therapy has been shown to impact on histological and biochemical disease in mouse models of autoimmune biliary disease and in clinical trials of patients with primary biliary cirrhosis. However, the HIV protease inhibitors are not well tolerated in patients with primary biliary cirrhosis, and more efficacious regimens will be required to clearly link reduction of viral load with improvement of cholangitis.

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Section: Clinical Experience With Antiretroviral Therapy In Patients supporting

confidence: 53%

Section: Clinical Experience With Antiretroviral Therapy In Patients mentioning

confidence: 99%

Role of Novel Retroviruses in Chronic Liver Disease: Assessing the Link of Human Betaretrovirus with Primary Biliary Cirrhosis

Sharon

Mason

2015

Curr Infect Dis Rep

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“…Furthermore, alkaline phosphatase levels were then completely normalized after the institution of ursodeoxycholic acid therapy 26 . Also, preliminary results from a randomized control trial of combination Truvada and Kaletra therapy for patients with PBC have reported significant improvement in reduction in alkaline phosphatase, with demonstrable incremental improvement as compared to a prior study using Combivir alone 27 .…”

Section: Discussionmentioning

confidence: 93%

Impact of combination antiretroviral therapy in the NOD.c3c4 mouse model of autoimmune biliary disease

Sharon

Chen

Zhang

et al. 2014

Liver International

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Background & AimsThe NOD.c3c4 mouse model develops autoimmune biliary disease characterized by spontaneous granulomatous cholangitis, antimitochondrial antibodies and liver failure. This model for primary biliary cirrhosis (PBC) has evidence of biliary infection with mouse mammary tumour virus (MMTV), suggesting that the virus may have a role in cholangitis development and progression of liver disease in this mouse model. We tested the hypothesis that MMTV infection is associated with cholangitis in the NOD.c3c4 mouse model by investigating whether antiretroviral therapy impacts on viral levels and liver disease.MethodsNOD.c3c4 mice were treated with combination antiretroviral therapy. Response to treatment was studied by measuring MMTV RNA in the liver, liver enzyme levels in serum and liver histology using a modified Ishak score.ResultsCombination therapy with the reverse transcriptase inhibitors, tenofovir and emtricitabine, resulted in a significant reduction in serum liver enzyme levels, attenuation of cholangitis and decreased MMTV levels in the livers of NOD.c3c4 mice. Furthermore, treatment with the retroviral protease inhibitors, lopinavir and ritonavir, in addition to the reverse transcriptase inhibitors, resulted in further decrease in MMTV levels and attenuation of liver disease in this model.ConclusionsThe attenuation of cholangitis with regimens containing the reverse transcriptase inhibitors, tenofovir and emtricitabine, and the protease inhibitors, lopinavir and ritonavir, suggests that retroviral infection may play a role in the development of cholangitis in this model.

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“… 6 , 20 , 21 Indeed, we have used the NOD.c3c4 mouse model to demonstrate that specific HIV reverse transcriptase and protease inhibitors decrease betaretrovirus load in the liver and ameliorate cholangitis, suggesting a more direct role for viral infection in the autoimmune biliary disease. 20 , 35 While randomised controlled trials in PBC patients with zidovudine/lamivudine 300/150 mg lead to a significant but not substantial reduction in alkaline phosphatase levels, it is notable that the interim analysis of combination anti-retroviral therapy using lopinavir/ritonavir 800/200 mg and tenofovir/emtricitabine 300/200 mg resulted in a significant and substantial reduction in hepatic biochemistry 36 , 37 equivalent to improvements observed with the new Farnesoid-X receptor agonist, Obeticholic acid. 38 Further studies demonstrating immune responses to HBRV are required to demonstrate that the detection of HBRV integrations is more than an epiphenomenon.…”

Section: Discussionmentioning

confidence: 99%

Frequent proviral integration of the human betaretrovirus in biliary epithelium of patients with autoimmune and idiopathic liver disease

Wang

Indik

Wasilenko

et al. 2014

Aliment Pharmacol Ther

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BackgroundA human betaretrovirus (HBRV) has been linked with primary biliary cirrhosis (PBC) following the detection of viral particles in biliary epithelium by electron microscopy and cloning of the betaretrovirus genome from biliary epithelium and peri-hepatic lymph nodes. Evidence for viral infection was found in the majority of PBC patients' peri-hepatic lymph node samples. However, less than a third of the liver samples had detectable HBRV, whereas others were unable to detect betaretrovirus infection or noted the presence of virus in the liver of patients with other diagnoses.AimsTo address the hypothesis that the betaretrovirus may be below the limits of detection in the liver, biliary epithelial cells (BEC) were investigated for the evidence of infection.MethodsLigation-mediated PCR and next generation sequencing were used to detect proviral integrations in liver, lymph nodes and BEC isolated from liver transplant recipients. Hybridisation-based assays were used to detect betaretroviral RNA in BEC.ResultsUnique HBRV integrations and betaretrovirus RNA were detected in the majority of biliary epithelia derived from patients with PBC, autoimmune hepatitis and cryptogenic liver disease but rarely in other liver transplant recipients with primary sclerosing cholangitis and other hepatic disorders. HBRV integrations were commonly found in PBC patients' lymph nodes but rarely in whole liver samples.ConclusionsHuman betaretrovirus infection is frequently observed at the site of disease in patients with primary biliary cirrhosis and also in biliary epithelium of patients with autoimmune hepatitis and cryptogenic liver disease.

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Letter: biochemical response to combination anti‐retroviral therapy in patients with primary biliary cirrhosis

Cited by 6 publications

References 9 publications

Role of Novel Retroviruses in Chronic Liver Disease: Assessing the Link of Human Betaretrovirus with Primary Biliary Cirrhosis

Role of Novel Retroviruses in Chronic Liver Disease: Assessing the Link of Human Betaretrovirus with Primary Biliary Cirrhosis

Impact of combination antiretroviral therapy in the NOD.c3c4 mouse model of autoimmune biliary disease

Frequent proviral integration of the human betaretrovirus in biliary epithelium of patients with autoimmune and idiopathic liver disease

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