Impact of combination antiretroviral therapy in the NOD.c3c4 mouse model of autoimmune biliary disease.
Bottom Line: 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.Combination 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.
Affiliation: Department of Medicine, University of Alberta, Edmonton, AB, Canada.Show MeSH
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Mentions: Since MMTV reverse transcriptase enzyme is sensitive to zidovudine and tenofovir and the MMTV aspartyl protease can be inhibited by lopinavir 17–19, we tested the effect of commercially available combinations of reverse transcriptase inhibitors including emtricitabine and tenofovir (Truvada™; Gilead, Foster City, CA, USA) as well as lamivudine and zidovudine (Combivir™; GlaxoSmithKline, Triangle Park, NC, USA) on disease development in NOD.c3c4 mice. To evaluate the effect of combination antiretroviral therapy, the protease inhibitors lopinavir and ritonavir (Kaletra™; AbbVie, North Chicago, IL, USA) were also used where the ritonavir acts to potentiate the activity of lopinavir 19. Following 3 months of intervention, marked differences were observed in necroinflammatory disease, in cholangitis and in total Ishak score in mice treated with antiretroviral therapy vs. placebo (Fig.3). Of note, antiretroviral regimens with Truvada had no evidence of cholangitis at the end of treatment (Fig.3). Furthermore, the inclusion of Kaletra with either combination of reverse transcriptase inhibitors was associated with incremental improvement in histological scores. Intervention with all antiretroviral regimens was associated with a significant reduction in mean alkaline phosphatase levels from baseline after 4 and 12 weeks treatment (P < 0.005 and P < 0.0001, respectively, one way anova, Fig.4A). However, when individual combinations were compared with placebo, only the combination of Truvada with Kaletra showed a significant difference after 1 month and both Truvada regimens with and without Kaletra showed significant reductions in mean alkaline phosphatase levels of more than 40 IU/L after 3 months therapy (P < 0.01 vs. placebo, Fig.4A). To further verify that Truvada and Kaletra therapy attenuated liver disease in the NOD.c3c4 mice, we determined the serum ALT levels, which were significantly reduced with this combination therapy compared to placebo (Fig.4B). Taken together, the biochemical and histological data suggest that regimens including Truvada had a significant impact on liver disease.
Affiliation: Department of Medicine, University of Alberta, Edmonton, AB, Canada.