Maraviroc is the first CCR5 receptor antagonist for the treatment of HIV-infected patients and was approved for use in the USA in April 2007. Hepatoxocity has been reported within 1 month of starting maraviroc in a small proportion of patients, and caution has been advised when administering maraviroc to patients with pre-existing liver dysfunction or who are coinfected with either hepatitis B virus (HBV) or hepatitis C virus (HCV). However, there have been no reports of reactivation of HBV in patients treated with maraviroc.
We saw a 67-year-old man coinfected with HIV and HBV who had originally initiated antiretroviral therapy in 1994. His current regimen when presenting to our institution included tenofovir/emtricitabine, darunavir, tipranavir, ritonavir and raltegravir. His CD4+ cell count was 219 cells/μl, HIV-1 RNA level 56 820 copies/ml, HBV DNA level undetectable, and hepatic transaminases were normal [AST (aspartate aminotransferase) 18 IU/l, alanine aminotransferase (ALT) 16 IU/l]. HIV genotypic resistance testing revealed pan-nucleoside/tide reverse transcriptase inhibitor resistance, as well as efavirenz, nevirapine and raltegravir resistance. A coreceptor tropism assay indicated a CCR5-tropic virus. His therapeutic regimen was adjusted to include tenofovir/emtricitabine for his chronic HBV infection, and ritonavir, darunavir, etravirine, and maraviroc at a reduced dose of 150 mg twice daily for his HIV.
Eight months after initiation of his new regimen, his CD4+ cell count had risen to 287 cells/μl and HIV RNA level had fallen to 20 copies/ml. However, the patient's tranaminases had risen almost ten-fold (AST 140 IU/l, ALT 166 IU/l). HBV DNA level was elevated at 5 751 900 copies/ml. There had been no reported lapse in the patient's tenofovir/emtricitabine therapy. HBV resistance testing revealed L180M and M204V mutations predicting lamivudine resistance but not tenofovir resistance. Maraviroc was discontinued and atazanvir was added to his regimen. Over the course of the next 10 months, the patient's elevated transaminases returned to normal and his HBV DNA level once again became undetectable without the addition of a second anti-HBV agent.
In the MOTIVATE 1 and 2 trials, the incidence of grade 3 and 4 elevations in AST and ALT associated with maraviroc ranged from 3% to 4%, which was not significantly different from that found in the placebo group . Only 5% of the participants in the MOTIVATE 1 trial and 7% of those in the MOTIVATE 2 trial were coinfected with hepatitis B and 8% of coinfected patients experienced a grade 2 or greater increase in ALT level . There were no reports of hepatitis B reactivation in this population. Nevertheless, the prescribing information for maraviroc includes a warning that prescribers should use caution when administering maraviroc to patients who are coinfected with hepatitis B.
Maraviroc-induced HBV reactivation is theoretically possible since blockade of CCR5 receptors could diminish cell-mediated immune responses against HBV. CC ligand 3 (CCL3), CCL4 and CCL5 are three important chemokines that activate natural killer cells, macrophages and T lymphocytes through the CCR5 receptor and are required for recruitment of activated immune cells to the HBV-infected liver . CCR5 receptors have also been shown to be up-regulated in HBV-specific CD8+ cells from patients with chronic hepatitis B with low levels of viremia, again suggesting that the CCR5 receptor is important in maintaining viral suppression .
Although an alternative explanation for the HBV reactivation could be lack of effective antiviral therapy, this is not likely in our opinion. The patient did not report any interruption in his therapeutic regimen, which is supported by the observed improvement in his HIV RNA. Furthermore, simply removing maraviroc from his regimen appears to have effectively inhibited HBV replication again. There is an ongoing study evaluating hepatic transaminase elevations in patients coinfected with HIV and either HBV and/or HCV who are receiving maraviroc , and changes in plasma HBV DNA levels are being monitored as a secondary outcome measure. However, this study is not estimated to be completed until mid 2015 but, hopefully, the results will shed more light on this possible association between maraviroc use and HBV reactivation.
Conflicts of interest
There are no conflicts of interest.
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