Role Of Nucleoside Analogs Research Articles

Management of HBV-related cirrhosis: Role of nucleoside analogs

In the management of HBV related cirrhosis of the liver, viral suppression with safe and effective antiviral agents is essential. Besides, antiviral therapy for long term use in cirrhotics should be safe and affordable with low risk of drug resistance. Treatment of compensated HBV cirrhosis can diminish the risk of hepatic decompensation and progression to hepatocellular carcinoma [HCC]. Regression of fibrosis and reversal of cirrhosis have also been reported with antiviral therapy. Further, in decompensated cirrhosis, although liver transplantation is considered as the definitive therapy, inhibition of viral replication before transplantation can delay the need for liver transplant and also prevent HBV recurrence in the post-transplantation period. These patients while on antiviral therapy need close monitoring for viral resistance and adverse events, besides continued surveillance for HCC. This article reviews the literature on the role of nucleoside analogues in the management of HBV related chronic liver disease.

Cytopathies mitochondriales au cours de l’infection par le VIH

The tremendous progress achieved during the last few years with the use of highly active antiretroviral therapy in suppressing HIV replication together with improvements in immunity have been tempered by a growing number of new adverse effects. Mitochondrial toxicity is one aspect of these long-term toxicities of antiretroviral drugs, with the role of nucleoside analogs particularly underlined. Some cases of impaired mitochondrial function have been clearly identified, such as pancreatitis due to didanosine, neuropathy due to zalcitabine, myopathy due to zidovudine, and lactic acidosis due to stavudine. These mitochondrial toxicities can affect several organs, presenting different patterns of symptoms: from asymptomatic to states with few symptoms despite huge metabolic abnormalities whose prognosis is immediately life-threatening. Beyond the inhibition of DNA polymerase gamma using nucleoside analogs, responsible for decreasing mitochondrial DNA in certain targeted organs, it appears that several physiopathologic mechanisms interact to explain this observed toxicity, HIV itself plays a role, and the underlying genetic pool needs to be better identified. Such cases mean that, it is imperative to avoid cumulated toxicities caused by associated treatments. With serious cases, or persistent symptoms despite discontinuing the nucleoside analogs responsible for such toxicity, one must propose vitamins, mitochondrial co-factors, or anti-oxidants. However, the future lies in the use of potent, less toxic nucleoside analogs, and in developing compounds belonging to other classes of antiretrovirals.

The Role of Nucleoside Analogues in the Treatment of Chronic Lymphocytic Leukemia-Lessons Learned from Prospective Randomized Trials

The newer purine nucleoside analogues (PNA), fludarabine (FAMP) and cladribine (2-chlorodeoxyadenosine, 2-CdA) have been synthesized recently and introduced into the treatment of chronic lymphocytic leukemia (CLL). The results of large phase II studies indicate that FAMP and 2-CdA are similarly active in CLL. Unfortunately, no prospective randomized study comparing the results of the treatment of CLL patients with FAMP and 2-CdA has been published so far. Significantly higher overall response (OR) and complete remission (CR) in patients treated initially with PNA than with chlorambucil or cyclophosphamide based combination regimens has been recently confirmed in five prospective multicentre randomized trials. These studies have also shown longer response duration in patients treated with PNA than with conventional chemotherapy. Overall survival progression free and events free survival were similar in patients treated with PNA and with chlorambucil or other alkylating agent based regimens. However, the majority of randomized trials were designed as cross over studies and most patients, treated with conventional chemotherapy were given PNA when refractory or in early relapse, which may influence the survival time. The results of a randomized study have shown a higher incidence of neutropenia and infections in patients treated with PNA than with chlorambucil. However, the frequency of autoimmune hemolytic anemia, pure red cell aplasia, secondary neoplasms and Richter's syndrome seems to be similar in patients treated with PNA and standard alkylating agents based chemotherapy. In conclusion, alkylating agents still have an important place in the routine management of the majority of CLL patients. They are in general safe, given on an out patients basis and significantly cheaper than PNA. PNA should be routinely used as second line treatment, and possibly as first line therapy in younger patients, who are candidates for potentially curative treatment such as stem cell transplantation and/or monoclonal antibodies.

The role of nucleoside analogues in hepatitis B infection

All eyes are on the nucleoside analogues famciclovir and lamivudine regarding their potential as treatments for hepatitis B infection. At present, interferon-α is the only agent approved for this indication. Clinical trials have indicated that interferon-α is only effective in some 40% of patients infected with hepatitis B virus (HBV); thus, new therapies are urgently required. Currently, both lamivudine and famciclovir are in clinical trials for hepatitis B infection. An update of progress in this field of research was presented during a SmithKline Beecham-sponsored symposium at the International Conference on Infectious Disease [ Hong Kong; June 1996 ].