Lowering the dose of hydroxyurea to 600mg daily minimises its toxicity and maximises antiretroviral efficacy and CD4 cell count gain when taken alongside ddI (didanosine, Videx EC), according to new data from the Research Institute for Genetic and Human Therapy (RIGHT) in Pavia, Italy and Washington DC, published in the April edition of the journal AIDS Research and Human Retroviruses. Based on these results, RIGHT intends to combine hydroxyurea with ddI in a once-daily pill and market it to resource-limited nations in the near future.
The use of hydroxyurea as an adjunct therapy alongside ddI alone, or combined with d4T, was severely discredited in 2001 when a US study (ACTG 5025) reported three cases of pancreatitis among the 65 people on hydroxyurea, with two deaths from complications of pancreatitis. At the same time, a review of over 2,000 patients from the John Hopkins HIV Clinic found a four-fold increased risk of pancreatitis when hydroxyurea was taken with d4T or ddI. Since then, doctors have generally shied away from prescribing hydroxyurea, and it was thought that the use of this potentially useful drug was too limited by its side-effects.
RIGHT 702 is a phase I/II randomised, open-label study, evaluating the safety and antiretroviral activity of three different doses of hydroxyurea given at three dosing intervals in combination with ddI and d4T. This study was designed in 1998-99, preceding data that suggested that combining ddI with d4T (stavudine, Zerit) was suboptimal, and had overlapping toxicities.
Adults with a viral load between 5,000 and 200,000 copies and who had not received antiretroviral therapy in the preceding 28 days were eligible to enter the study, although people with current or prior AIDS, cancer, alcohol or substance abuse, a history of pancreatitis or peripheral neuropathy, ddI or d4T intolerance, previous virological failure on d4T, and pregnant and breast-feeding mothers were excluded.
115 participants were randomised to one of nine treatment arms, to evaluate three total daily doses of hydroxyurea (600mg, 800-900mg, or 1200mg) at three dosing intervals (daily, twice daily and three-times a day). Individuals weighing over 60kg took 40mg d4T twice a day and 400mg ddI once daily. Those weighing less than 60kg took 30mg d4T twice a day and 300mg of ddI once daily. DdI was originally administered as two 200mg buffered, chewable tablets, but when the enteric-coated single capsule version became available, participants switched.
Eighty participants (70% of the total sample) completed the 24 week study, including 74% in the 600mg hydroxyurea group, 74% in the 800-900mg hydroxyurea group, and 61% in the 1200mg hydroxyurea group. The main reasons for discontinuing the study included patient refusal in 16 cases and investigator’s decision in nine cases. Most of the participants who withdrew did so as they became aware of the early termination of the ACTG 5025 study.
The authors note that their data finding indicating the total of 600mg daily dose to be most efficacious is “intriguing.” The primary efficacy endpoint of the study was the proportion of participants with plasma HIV viral loads below 400 copies/ml at 24 weeks; 76%, 51% and 60% achieved this in the 600mg, 800-900mg and 1200mg groups, respectively. This was close to being statistically significant (p=0.081) when 600mg was compared with the other two groups, and became significant (p=0.027) when the too toxic 1200mg dose was removed from the equation. The 600mg group also had the best CD4 and CD8 count outcomes, although only the change in CD8 percentage was statistically significant when compared with the other regimens (p=0.01).
Twice-daily dosing was also found to be the most efficacious, with 72% experiencing less than 400 copies/ml viral load at 24 weeks in the bid dosing group, compared with 57% and 58% in the daily and three-times daily dosing groups. However, CD4 and CD8 count outcomes were broadly similar between the groups, and were not found to be statistically significant.
Most importantly, the researchers found that a 600mg daily dose minimises toxicity, although there was one drug-related death in the study. The authors found that there was a higher frequency of adverse events with increasing daily hydroxyurea doses: 40 vs. 47 vs. 62 events in the 600mg, 800-900mg, and 1200mg groups, respectively. The most frequently reported adverse events were nausea, peripheral neuropathy and diarrhoea.
One serious adverse event occurred in the 600mg group (grade 3/4 amylase increase), whereas four serious events (including one death due to necrotising pancreatitis in the 1200mg group) occurred in the other dosing groups. The authors state that the results of this study confirm that “the use of high-dose hydroxyurea (1200mg daily) can be associated with fatal pancreatitis.”
However, Lori and his colleagues comment that the deaths and severe side-effects that occurred in this study, and also in ACTG 5025, were associated with a 1200mg daily dose of hydroxyurea taken alongside the old buffered chewable tablet formulation of ddI, which resulted in higher peak plasma levels of ddI than the newer, enteric-coated version of ddI, Videx EC.
The authors explain that the superior efficacy of the lowest dose of hydroxyurea is not solely due to fewer side-effects, which might lead to better adherence. They found that both the intention-to-treat and as-treated analyses had similar outcomes (p=0.027 and p=0.037 for the primary endpoints when comparing 600mg with the next highest doses, respectively). “A more logical explanation,” they write, “derives from the observation that increasing doses of hydroxyurea increase the cytotoxic effects of the drug. A dose-dependent, cytostatic/cytotoxic switch probably not only minimised toxicity, but also maximised the potency of hydroxyurea, in that it selected for the cytostatic effects of the drug and prevented, at the same time, drug toxicity at the cellular level.”
They conclude by saying that that “hydroxyurea-didanosine, a synergistic cytostatic and antiviral combination (virostatic), remains a unique therapeutic approach for the treatment of HIV-1 infection. The identification of the optimal daily dose of 600mg of hydroxyurea should mitigate the concerns over mitochondrial toxicity and blunted CD4+ cell increase; however, the nature of this 24-week study precludes evaluation of the long-term risk of neuropathy and mitochondrial damage that may accumulate over time.”
An accompanying press release from RIGHT claims that hydroxyurea and ddI, “when it is paired with a different second nucleoside agent [than d4T] without the additive toxicity,” could lead to enhanced tolerability, and that this combination could be used “in limited resource settings that lack sustainable access to other combination therapies.”
RIGHT’s scientific co-director, Julianna Lisziewicz adds that they plan to “further develop this virostatic combination to be administered as one pill per day and register it for the treatment of HIV/AIDS.”
Lori F et al. Lowering the dose of hydroxyurea minimizes toxicity and maximises anti-HIV potency. AIDS Research and Human Retroviruses 21 (4), 263-271, 2005.