Chronic nucleoside analogues

HBV infection remains a major worldwide public health problem. The World Health Organization estimates that there are still 350 million chronic carriers of the vims, who are at risk of developing chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The success of IFN-a treatment - mainly performed as combined treatment with adenine-arabinoside - has been measured by the normalization of liver enzymes, loss of HBe antigen and of detectable viral DNA in the serum of patients. It has been estimated from several clinical trials that as many as 40% of treated HBV patients would respond to therapy with IFN-a or combined treatment with nucleoside analogues and IFN-a. 

In addition to the NRTI lamivudine (3TC) and the NtRTI adefovir dipivoxU and tenofovir disoproxil fumarate (which has been recently licensed for the treatment of chronic hepatitis B), two other nucleoside analogues, that is, entecavir and L-dT (tel-bivudine) (Fig.4aa), have been licensed for the treatment of HBV infections. Two other compounds 3 -Val-L-dC (valtorcitabine) and L-FMAU (clevudine) (Fig. 4aa) are in clinical development for the treatment of HBV infections, and yet two other compounds, that is, racivir and elvucitabine (Fig. 3), yield potential for the treatment of both HBV and HIV infections. 

HBV RT has been the target for the development of several anti-HBV agents during the last decade. The first HBV RT-inhibitor approved for treatment of chronic infection was the nucleoside analogue lamivudine, which had already been used... 

Lamivudine (Epivir-HBV) is an oral synthetic cytosine nucleoside analogue having antiviral effects against HIV and hepatitis B virus. In patients with chronic hepatitis B, lamivudine is effective in suppressing hepatitis B viral replication, normalizing... 

Park, Y, Savarese, B., Kleiner, D. et al. (1995) Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. New England Journal of Medicine, 333, 1099-1105. 

Lamivudine (3TC, Epivir) is a cytosine nucleoside analogue with activity against HIV-1, HIV-2, and hepatitis B virus. It is approved as part of a multidrug regimen for the therapy of HIV infection in adults and children and has been used for HIV postexposure prophylaxis. Combination products contain lamivudine with either zidovudine (Combivir) or zidovudine and abacavir (Trizivir). The use of low-dose lamivudine in the treatment of chronic hepatitis B is described in Chapter 50. 

Subsequent analysis of stored serum samples showed reduction of HCV RNA levels during treatment and durable eradication of virus in some cases [38]. These early results were confirmed by randomized controlled trials in patients with chronic hepatitis C [39-41]. Durable viral eradication (termed sustained virologic response, or SVR) was achieved in 6% to 15% of patients after six months of treatment with recombinant interferon at doses of 3 to 6 MU administered subcutaneously three times per week. SVR increased to 13% to 25% if treatment was extended to 12 months [41]. The combination of the oral nucleoside analogue ribavirin with recombinant interferon increased SVR to 41% [42-44]. Ribavirin, however, is potentially embryotoxic and induces a dose-dependent hemolytic anemia, a situation that calls for close monitoring during therapy. 

Cheson BD, Vena DA, Barrett J, Freidlin B. Second malignancies as a consequence of nucleoside analogue therapy for chronic lymphoid leukemias. J Clin Oncol 1999 17(8) 2454-60. 

All of the classical antiretroviral agents are 2. .2 -didcoxy-nucleoside analogues. These compounds. share a common mechanism of action in inhibiting the reverse transcriptase of HIV. Because reverse transcriptase acts early in the viral infection sequence, inhihitors of the enzyme block acute infection of cells but are only weakly active in chronically infected ones. Even though the reverse tran.scripta.se inhihitors share a common mechanism of action, their phamtaeo-logical and toxicological profiles differ dramatically. 

Lin, E., Luscombe, C., Wang, Y-Y Shaw, T., and Locarnini, S. (1996) The guanine nucleoside analogue penciclovir is active against chronic duck hepatitis B vims infection in vivo. Antimicrob. Agents Chemother. 40,413—418. 

Perhaps one of the most dramatic examples of hepatic failure and lactic acidosis associated with nucleoside analogues was that which occurred during the course of early clinical trials with an investigational nucleoside analogue fialuridine for treatment of chronic hepatitis B [95]. Seven of fifteen study patients developed progressive liver failure and lactic acidosis. Five of the patients died with severe lactic acidosis two patients underwent emergency liver transplantation and survived. Severe mitochondrial toxicity was proposed as the mechanism for this injury, based in part on the similarity of this presentation to that seen in individuals with inherited disorders of mitochondrial DNA and the presence of histopathological evidence of mitochondrial injury [94, 95]. 

Jacobson KA, von Lubitz DKJE, Daly JW, Fredholm BB (1996) Adenosine receptor ligands differences with acute and chronic treatment. Trends Pharmacol Sci 17(3) 108-113 Jacobson KA, Ji X-D, Li AH, Melman N, Siddiqui MA, Shin KJ, Marquez VE, Ravi RG (2000) Methanocarba analogues of purine nucleosides as potent and selective adenosine receptor agonists. J Med Chem 43(ll) 2196-2203... 

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