Following the characterization of a human betaretrovirus in patients with primary biliary cirrhosis(PBC),pilot studies using antiretroviral therapy have been conducted as proof of principal to establish a link of viru...Following the characterization of a human betaretrovirus in patients with primary biliary cirrhosis(PBC),pilot studies using antiretroviral therapy have been conducted as proof of principal to establish a link of virus with disease and with the eventual aim to find better adjunct therapies for patients unresponsive to ursodeoxycholic acid.In the first open label pilot study,the reverse transcriptase inhibitor lamivudine had little demonstrable biochemical or histological effect after 1 year.Whereas,lamivudine in combination with zidovudine was associated with a significant reduction in alkaline phosphatase as well as improvement in necroinflammatory score,cholangitis and ductopenia over a 12 mo period.A double blind,multi-center randomized controlled trial using lamivudine with zidovudine for 6 mo confirmed a significant reduction in alkaline phosphatase,ALT and AST in patients on antiviral therapy.However,none of the patients achieved the stringent endpoint criteria for normalization of alkaline phosphatase.Furthermore,some patients developed biochemical rebound consistent with drug resistance.A major fault of these studies has been the inability to measure the viral load in peripheral blood and therefore,provide a direct correlation between improvement of hepatic biochemistry and reduction in viral load.Nevertheless,viral mutants to lamivudine with zidovudine were later characterized in the NOD.c3c4 mouse model of PBC that has been used to test other antiretroviral regimens to betaretrovirus.The combination of tenofovir and emtricitabine reverse transcriptase inhibitors and the HIV protease inhibitor,lopinavir were found to abrogate cholangitis in the NOD.c3c4 mouse model and the same regimen normalized the liver tests in a PBC patient with HIV and human betaretrovirus infection.This combination antiretroviral therapy has now been used in a double blind randomized controlled crossover study for patients with PBC followed by an open label extension study.Only a third of the PBC patients were able to tolerate the lopinavir but those maintained on tenofovir,emtricitabine and lopinavir experienced sustained and clinically meaningful reduction in hepatic biochemistry.While we await the histological and virological evaluation,it is clear that better tolerated regimens of antiretroviral treatment will be required in future clinical trials.展开更多
基金Supported by Research support from Alberta Innovates Health Solutions, Canadian Institutes for Health Research (to Mason AL, MOP 97798)Canadian Liver Foundation relevant to this manuscript
文摘Following the characterization of a human betaretrovirus in patients with primary biliary cirrhosis(PBC),pilot studies using antiretroviral therapy have been conducted as proof of principal to establish a link of virus with disease and with the eventual aim to find better adjunct therapies for patients unresponsive to ursodeoxycholic acid.In the first open label pilot study,the reverse transcriptase inhibitor lamivudine had little demonstrable biochemical or histological effect after 1 year.Whereas,lamivudine in combination with zidovudine was associated with a significant reduction in alkaline phosphatase as well as improvement in necroinflammatory score,cholangitis and ductopenia over a 12 mo period.A double blind,multi-center randomized controlled trial using lamivudine with zidovudine for 6 mo confirmed a significant reduction in alkaline phosphatase,ALT and AST in patients on antiviral therapy.However,none of the patients achieved the stringent endpoint criteria for normalization of alkaline phosphatase.Furthermore,some patients developed biochemical rebound consistent with drug resistance.A major fault of these studies has been the inability to measure the viral load in peripheral blood and therefore,provide a direct correlation between improvement of hepatic biochemistry and reduction in viral load.Nevertheless,viral mutants to lamivudine with zidovudine were later characterized in the NOD.c3c4 mouse model of PBC that has been used to test other antiretroviral regimens to betaretrovirus.The combination of tenofovir and emtricitabine reverse transcriptase inhibitors and the HIV protease inhibitor,lopinavir were found to abrogate cholangitis in the NOD.c3c4 mouse model and the same regimen normalized the liver tests in a PBC patient with HIV and human betaretrovirus infection.This combination antiretroviral therapy has now been used in a double blind randomized controlled crossover study for patients with PBC followed by an open label extension study.Only a third of the PBC patients were able to tolerate the lopinavir but those maintained on tenofovir,emtricitabine and lopinavir experienced sustained and clinically meaningful reduction in hepatic biochemistry.While we await the histological and virological evaluation,it is clear that better tolerated regimens of antiretroviral treatment will be required in future clinical trials.
