In a recent report, we described a patient with HIV-1 infection and chronic hepatitis delta who was treated with oral entecavir (1 mg daily) and did not show any significant fluctuation in plasma HIV-RNA or selection of M184V in HIV-1 during the first 24 weeks of entecavir monotherapy . This observation was in contrast with the original findings reported by US researchers earlier in 2007 , followed by other similar reports .
As we have had the opportunity to follow our patient for longer, we would like to report that, in this individual, mutation M184V in HIV-1 was later selected inspite of having evidence of significant reductions or rebounds in plasma HIV-RNA. This 43-year-old man with hepatitis delta and CD4 counts above 350 cells/mm3 began treatment with entecavir (1 mg/day) in an attempt to ameliorate his liver disease, as recent evidence has suggested that potent new anti-HBV nucleos(t)ide analogues might be efficacious against the delta virus . As in many subjects with chronic hepatitis B superinfected with delta virus, serum hepatitis B virus-DNA was undetectable in our patient. He did not show any significant fluctuation in plasma HIV-RNA after introducing entecavir, with plasma levels remaining around 20 000 copies/ml. HIV-1 genotyping before and every 2 months after beginning entecavir did not show evidence of selection of M184V. However, one further specimen collected at month 8, which was repeated in a separate sample collected 3 weeks later, confirmed the selection of mutation M184V in HIV-1. The patient was then recommended to switch to tenofovir, emtricitabine and efavirenz. One month later, he had undetectable plasma HIV-RNA when the liver enzymes remained slightly elevated.
In a regular control made after 6 months of triple antiretroviral therapy, signs of severe tubular dysfunction, including glucosuria, aminoaciduria and phosphaturia, developed. Serum creatinine remained normal. Removal of tenofovir was then considered, but controversy arose about the most appropriate alternative treatment. Reintroduction of entecavir alone with an abacavir-based triple antiretroviral regimen was put on hold because of concern about the lack of information on potential interactions between entecavir and abacavir, as both are guanosine analogues. A recent experience suggesting a deleterious interference between abacavir and ribavirin in HIV patients with chronic hepatitis C treated with pegylated interferon plus ribavirin [5,6] was the reason for this concern, as ribavirin is similarly a guanosine analogue. Finally, a decision was taken to resume entecavir alone with raltegravir and efavirenz. Three months later, the patient had undetectable plasma HIV-RNA and hepatitis delta viremia continued to decline.
This report highlights the risk of using entecavir without concomitant antiretroviral therapy in HIV/HBV-coinfected patients. Although the lack of significant changes in plasma HIV-RNA in our patient argue against a potent antiretroviral activity of entecavir, the slow selection of mutation of M184V indirectly confirms that enough drug pressure is made. Recent in-vitro findings support this view . While the warning of the Food and Drug Administration against the use of entecavir as monotherapy in HIV/HBV-coinfected patients is rather appropriate, it opens the discussion about which antiretroviral drugs are the most convenient to use alone with entecavir in this population.
We would like to thank Angelica Corral for her excellent technical assistance. This work was supported in part by grants from Fundacion Investigacion y Educacion en SIDA, the European VIRGIL and NEAT networks, and Red de Investigación en SIDA del FIS (ISCIII-RETIC RD06/006).
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