Twice daily dosing of the nucleoside analogue (NRTI) ddC (zalcitabine, Hivid) may be feasible after a small pilot study showed that the use of the drug in this way in a HAART regimen was effective and safe. The study is published in the February 1st edition of the Journal of Acquired Immune Deficiency Syndromes.
Unlike all the other licensed NRTIs, ddC is dosed three times a day. However, it has an intracellular half-life of ten hours, similar to other NRTIs. Pharmacokinetic modelling suggests that twice-daily dosing of ddC would not result in any decrease in anti-viral activity, and a small retrospective study showed that switching thrice-daily ddC to a twice daily dose of 1.125mg did not result in any loss of effectiveness or lead to an increase in side-effects.
Although ddC is now rarely prescribed, it is a potentially useful drug, particularly, the study investigators suggest for salvage therapy, having an attractive efficacy, side-effect and resistance profile.
Investigators conducted a 24 week pilot-study (with a treatment extension to 48 weeks) comparing the effectiveness and safety of a twice daily ddC dose of 1.125mg in combination with AZT and a protease inhibitor (also dosed twice daily), versus twice daily 3TC, AZT and a protease inhibitor.
The study involved 47 patients in an intent-to-treat analysis. At baseline the mean viral load was a little under 400,000 copies/ml and mean CD4 cell count was 398 cells/mm3. All the patients were antiretroviral naïve.
The primary endpoint of the study was the proportion of patients with a viral load below 400 copies/ml at weeks 24 and 48. At week 24, 42% of the ddC arm and 52% of the 3TC arm met this criterion. A similar pattern was seen at week 48. The difference was not statistically significant.
Secondary endpoints included the proportion of patients with a viral load below 50 copies/ml at weeks 24 and 48, time to first viral load below 400 copies/ml, absolute change in CD4 cell count and frequency and severity of side-effects.
Although a higher proportion of patients in the 3TC arm (44% versus 21% ddC arm) had a viral load below 50 copies/ml at week 24, there was no significant difference by week 48 (17% ddC versus 22% 3TC). Median time to first viral load below 400 copies/ml was faster amongst ddC-treated patients (55 days) than the 3TC group (72 days). The week 48 CD4 cell increases from baseline were 128 cells/mm3 for the ddC patients and 115 cells/mm3 for the 3TC arm.
Similar proportions of patients reported side-effects in both arms of the trial (75% ddC and 71% 3TC). Diarrhoea was the most frequently reported side-effect, accounting for 46% of all adverse events reported in the ddC arm and 24% of cases in the 3TC group. No cases of peripheral neuropathy, a side-effect particularly associated with ddC and the other “d” NRTI drugs, were reported. A total of four patients left the study due to side-effects (three in the ddC arm and one in the 3TC group). There were no serious adverse event reported in the ddC arm, and only one in the 3TC arm.
”Overall, the data show similar antiretroviral activity of the twice-daily ddC-based triple therapy with the 3TC-based regimen”, note the investigators. Commenting on the low proportion of patients achieving a viral load below 50 copies/ml at week 48 the investigators say “this may be related to the high baseline viral load or the choice of cotherapies”. The study protease inhibitors were soft gel saquinavir and nelfinavir, neither of which would now normally be considered for first-line therapy.
They conclude, “these are the first prospective data to support the feasibility of twice-daily dosing of ddC.”
Further information on this website
ddC overview
Anti-HIV drugs - pdf of the booklet in the award winning information for HIV-positive people series
Antunes F et al. Efficacy and tolerability of zalcitabine twice daily (HIVBID Study). J Acquir Immune Defic Syndr 35: 205 – 206, 2004.