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Two Year Analysis of Stavudine Extended-Release/Prolonged Release Capsules (XR/PRC) as Compared to Stavudine Immediate-Release (IR): Efficacy and Safety
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Two Year Analysis of Stavudine Extended-Release/Prolonged Release Capsules (XR/PRC) as Compared to Stavudine Immediate-Release (IR): Efficacy and Safety
Written by Judith Aberg, MD, Washington University, St Louis, Missouri
43rd ICAAC Abstracts, American Society for Microbiology, September, 2003 Session 84 - Poster Session - Antiretroviral Therapy Abstract: H-843 H.M. BRETT-SMITH, L. REYNOLDS, L. BESSEN, V. RUTKIEWICZ Bristol-Myers Squibb, Wallingford, CT.
Stavudine (d4T) XR/PRC provides equivalent 24 hour exposure to d4T IR, but has 1/2 the peak and 2-3 fold higher trough plasma levels. The expected results would be that there would be less toxicity in the extended release form given the peak or highest levels would be lower but that it could be given once a day providing the convenience of only having to take one pill a day. The initial week 48 efficacy and safety data demonstrated comparability, but as we have seen with other studies, clinically relevant differences in outcomes may be seen over longer periods of time. Brett-Smith and colleagues presented the 2 year data based upon enrollment of 2 cohort studies rolling over into a long term follow-up study.
Initially, subjects were enrolled into either Study 096 or Study 099 both of which were randomized, double-blind, placebo-controlled studies in antiretroviral naïve subjects. In 096, 74 subjects received d4T XR/PRC and 76 received d4T IR. In 099, 392 subjects received XR/PRC and 392 received IR. Primary endpoints of both studies were proportion of subjects having HIV RNA < 400 copies/mL at 48 weeks. Both studies demonstrated comparable efficacy between the 2 formulations with a trend for improved safety (less adverse events) in the XR arm.
At 1 year of either study, subjects could elect to rollover into an open-label common long-term dosing study (study 110). Safety data are cumulative from start of therapy through on-going dosing as of March 2003.
Baseline demographics of the open-label study included median age 33 years, 30% female, 46% white, 22% Hispanic, 20% Black. Median baseline values: HIV RNA 4.8 log10 copies/mL and CD4 277 cells/µl. Median time on treatment: 115 wks. The most common regimen-related adverse events were dizziness, peripheral neurologic symptoms (PNS)* and rash.
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The authors concluded that the overall two-year efficacy and safety for d4T XR/PRC are comparable to IR, with trends which favor XR for safety events such as peripheral neuropathy and lipodystrophy. One of the difficulties interpreting this data is that lipodystrophy was not prospectively defined therefore it is not clear how individual sites reported this. Afterwards, the principal investigators contacted the sites who reported lipodystrophy and asked them to classify an event as either lipohypertrophy (increased abdominal girth, buffalo hump or breast enlargement) or lipoatrophy (facial, extremity or subcutaneous wasting) or both. Given this, I do not know how useful this data is and certainly does not sway me one way or the other. I think the d4T XR will be useful for the convenience of once daily dosing however the adverse effects are similar to the current twice daily formulation. Clinical events of special interest such as pancreatitis and lactic acidosis were too few for clinical interpretation. I personally still think that d4T is prescribed in doses that are too high and look forward to future pharmacokinetic studies that may suggest lower doses can be prescribed thereby decreasing the associated toxicities.
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