Hydroxyurea debate revives: suitable drug for poor nations?

The debate over the use of hydroxyurea plus ddI in the treatment of HIV disease has been revived at the World AIDS Conference, despite a study which showed that hydroxyurea offered no additional benefit to an antiretroviral combination.

Efficacy research

Dr Rob Murphy from Chicago presented 24 week data on 97 individuals randomised to efavirenz, ddI/d4T with or without hydroxyurea. There was no significant difference in the proportions achieving viral loads below 50 copies/ml between the two treatment arms. Among those on hydroxyurea, 72% of treatment-naive patients and 73% of treatment-experienced patients achieved an undetectable result, while among those on placebo 76% and 50% of the naive and experienced patients respectively had an undetectable viral load. As expected, CD4 increases were blunted in the hydroxyurea group.

For some experts, such as Dr Bernard Hirschel of Switzerland, this study confirms the lack of efficacy of hydroxyurea. Speaking against the proposition that ‘Hydroxyurea has an important role as a component of antiretroviral therapy’ at yesterday's debate in Durban, Dr Hirschel said, “ Immune restoration or preservation does occur after long term viral suppression with hydroxyurea-containing combinations but, to my mind, the difference in comparison with other effective combinations remains to be established.” He cited unpublished research by Dr F Garcia of Argentina that also found no difference in response to treatment when hydroxyurea was added to ddI/d4T/indinavir.

However, Dr Franco Lori of Italy made a persuasive case for ongoing research into hydroxyurea. He outlined the PANDA study of 12 chronically-infected individuals who had viral loads suppressed to an average of 2000 copies after 40 weeks of treatment. At week 120, the average viral load had dropped by one log and most had achieved undetectable viral load. Improvement in immune markers also occurred.

Following a structured treatment interruption, the hydroxyurea patients had a transient increase in viral load to about 5,000 copies/ml. After 8 weeks off treatment, viral load levels had returned to baseline and the CD4 count had been maintained. In contrast, individuals who interrupted HAART had rapid viral rebound and CD4 decline.

Dr Lori argued that these surprising results warrant further study and he suggested a randomised, long-term clinical trial comparing highly active antiretroviral therapy with ddI/hydroxyurea.

Side-effects

In addition to doubt about the efficacy of hydroxyurea, there have been concerns about increased rates of adverse event due to the hydroXurea/ddI/d4T combination. Peripheral neuropathy and pancreatitis have been a particular concern, and US authorities last year issued a warning about the dangers of pancreatitis due to hydroxyurea/ddI.

However a meta-analysis of 20 ACTG studies conducted by Dr Murphy and presented as a poster at the conference found no clear evidence of a relationship between hydroxyurea and pancreatitis, although rates of pancreatitis were higher among those treated with ddI.

Another study presented at the World AIDS Conference by Dr M Agostini found a low incidence of haematological toxicity among 48 individuals taking hydroxyurea/ddI/d4T and no cases of pancreatitis.

During the debate, Dr Lori commented that once-daily dosing of ddI and the addition of d4T exacerbate adverse events associated with hydroxyurea/ddI. He suggested that 200 mg ddI twice daily plus hydroxyurea may limit peak levels of ddI in the blood and reduce the risk of side effects including pancreatitis.

An option in resource-poor settings?

During the Hydroxyurea Debate several physicians from resource-poor settings argued that cheap antiretroviral options, such as ddI/hydroxyurea, are imperative.

Durban medical practitioner Dr A Misra told the conference that he regularly uses ddI/hydroxyurea and finds it an effective antiretroviral option. Nevertheless, only about 40% of his patients can afford the 450 Rand (£45) it costs per month. Dr Misra told aidsmap that even people on medical insurance can only afford at best AZT/3TC.

“As much as we appreciate what the researchers do, they don’t actually appreciate what the ground costs or ground incomes are for black families across Africa,” Dr Misra said. “Most individuals find it difficult to afford 100 Rand per month for any sort of medical therapy. They are talking about HAART.... but that costs about 67000 Rand per month.”

During the session, Dr Hirschel admitted that if ddI/hydroxyurea was his only choice, he would probably take it and hope to have a good response. He continued: “I realise that this may be false hope. I also realise that most people prefer false hopes to no hope at all. But that is psychology, that is maybe religion but that is not really science.”

Dr Hirschel said that until the results of the PANDA study are confirmed in larger, randomised studies, hydroxyurea should not form the basis of therapeutic application in Africa or elsewhere.