Telbivudine has activity against HIV-1 (2009)

Telbivudine (LdT) is a L-nucleoside analogue of thymidine with activity against hepatitis B virus (HBV) DNA polymerase. Approval by the Food and Drug Administration (FDA) in October 2006 followed the 007 GLOBE trial. This phase III trial was designed to compare LdT vs. lamivudine (LAM) in individuals with chronic hepatitis B [1]. Despite no studies having investigated the activity and safety of LdT in HIV/HBV coinfection, recommendations from the HIV-HBV International Panel state that LdT has no activity against HIV and it is suggested as a treatment option for HBV infection, when HIV does not require therapy [2]. We report the case of a gentleman with HIV/HBV coinfection in whom LdT therapy suppressed his HIV viral load to less than 50 copies/ml. A 45-year-old gentleman with HIV-1/HBV coinfection was noted in February 2006 to have reverted from HBeAg-negative and anti-HBV-positive to HBeAg-positive and anti-HBV-negative with a serum HBV DNA rise from 8820 copies/ml to 33 600 000 copies/ml. At the time he was antiretroviral and HBV therapy naive. His HIV disease was stable with a CD4 lymphocyte count of 613 cells/μl (36.1%) and a HIV viral load of 14 462 copies/ml. In January of 2008 with a Fibroscan demonstrating a liver stiffness of 12.8 (IQR 0.9) kPa and a serum HBV DNA of 662 000 000 copies/ml he was offered treatment with either triple therapy for both his HIV and HBV (tenofovir, LAM and efavirenz) or dual therapy for his HBV alone [adefovir dipivoxil (ADV) and LdT]. With a CD4 lymphocyte count of 640 cells/μl (36.3%) and a HIV viral load of 8650 copies/ml it was decided to opt for ADV and LdT. This was commenced on 26 February 2008. On review 2 months later he had experienced a fall in his serum HBV DNA to 2782 copies/ml and had suppressed his HIV viral load to less than 50 copies/ml. This was confirmed on repeat bloods 4 weeks later. LdT was discontinued 5 months after it was commenced. At the time of discontinuation of LdT his HIV viral load had increased to 127 copies/ml and then rebounded to 3903 copies/ml 1 month later. Three months after discontinuation, the patient agreed to be rechallenged with LdT for a 2-week duration. On the day of restarting LdT his HIV viral load was 1074 copies/ml, 1 week later 177 copies/ml and 2 weeks later 71 copies/ml (using Roche viral load detection assay the last three readings were 429, 227 and less than 47 copies/ml, respectively). The patient had remained on ADV since commencing antiviral therapy in February. In our opinion, the most likely explanation is that LdT has activity against HIV-1. We do not believe that ADV had an effect on the patient's HIV viral load as it has been shown that low dose ADV does not have any effect on HIV viral load [3]. However, while on LdT and ADV our patient's HIV viral load suppressed to less than 50 copies/ml, whereas 1 month later, while still on ADV monotherapy, it had rebounded to 3903 copies/ml suggesting prior removal of antiviral pressure. In an attempt to determine whether this was a true effect we asked the patient to undergo rechallenge with LdT. Given that rechallenge with LdT for 2 weeks resulted in suppression of the HIV viral load to 71 copies/ml, we believe that this is strong evidence that LdT is active against HIV-1. So far, HIV-1 resistance tests have shown no significant mutations. This is a familiar story. On 30 April 2007 the Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents released a supplement to the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents concerning the use of entecavir (ETV) in HIV/HBV coinfection. Previously, the guidelines had recommended ETV as an option for patients who required treatment for HBV but not HIV infection. The recommendation had been based on in-vitro data showing no significant activity of ETV against HIV-1 [4]. The revision was prompted by a case series of three patients all of whom received ETV without concomitant antiretroviral therapy and experienced a 1 log10 decline in HIV-RNA levels [5]. One patient was shown to develop a M184V mutation thus indicating that ETV may be active against HIV as well as HBV and if used as monotherapy could promote the development of HIV drug resistance. We believe that LdT may have activity against HIV and until further trials have been done it should no longer be recommended as a treatment for CHB in HIV-positive individuals who do not require treatment for their HIV. Contribution of authors E.L. is a SpR who works in the HIV/hepatitis clinic which the patient attends. She recruited the patient to rechallenge with telbivudine, took blood samples and wrote up case report. A.C. processed all viral load samples in the virology laboratory. M.A. worked as consultant virologist. He oversaw the processing of samples and suggested rechallenging with telbivudine. M.N. is a consultant in the HIV/hepatitis clinic. He noted the initial HIV viral load suppression and in discussion with M.A. suggested rechallenge with telbivudine.