Didanosine-ribavirin combination: synergistic combination in vitro, but high potential risk of toxicity in vivo

In a recent issue of AIDS, Klein et al. [¹] studied the interaction existing among didanosine, ribavirin and IFN-α. The authors showed a synergistic effect of these drugs against HIV-1 in vitro, particularly between didanosine and ribavirin, without an in-vitro evidence of a cytotoxic effect. They concluded that this novel triple combination has the potential to provide simultaneous activity against HIV and hepatitis C virus (HCV).

Nucleoside reverse transcriptase inhibitors (NRTI) are currently the backbone of antiretroviral treatment. In-vitro studies have shown that they may inhibit the replication of mitochondrial DNA. They act by inhibiting gamma polymerase, leading to mtDNA depletion. Clinical studies have demonstrated that some clinical toxicities of these agents may depend on impaired mitochondrial function or replication. Indeed, the clinical use of fialuridine led to a fatal liver failure, as a consequence of severe mitochondrial dysfunction, which occurs in most patients exposed to the drug for longer than 10 weeks. The finding that NRTI may interfere with mtDNA synthesis has led to many studies evaluating these effects in vitro.

Such studies suggested a ranking of zalcitabine > didanosine > stavudin > lamivudine > zidovudine > abacavir > tenofovir for effects on mitochondrial polymerase gamma [²]. Several cases of fatal lactic acidosis have recently occurred in HIV-HCV-co-infected patients treated both for HIV (stavudine, didanosine) and HCV (IFN-α 2b 3 million unit three times a week plus ribavirin) have been described. Furthermore, a recent report on a large series of co-infected patients treated for both HIV and HCV infection (IFN plus ribavirin), demonstrated that the combination of stavudine and didanosine as a part of a concomitant antiretroviral regimen was significantly associated with an increased risk of developing hyperlactatemia [^3-5].

Because the need to treat hepatitis C in HIV patients has recently become a significant issue, clinicians should be aware of the potential overlapping toxicity of both treatments. If possible, depending upon the patient's immunological status, hepatitis treatment should precede antiretroviral therapy to reduce the risk of toxicity. When both treatments have to be administered concomitantly, the choice of NRTI must be oriented toward drugs with lower mitochondrial γ polymerase affinity, mainly if ribavirin is used. This approach could be useful to increase the safety of therapy for co-infection and to avoid cases of fatal lactic acidosis [⁶].

In conclusion, in-vitro evidence of the enhanced activity of a drug combination should be regarded with caution when the same drugs are used in vivo, above all, if clinical data show a well-defined potential risk of life-threatening toxicity.