d4T dose can be reduced without loss of effectiveness, meta-analysis reports

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Randomised studies

Phase II pre-licensing studies showed that a 20mg twice daily dose was just as effective as a 40mg twice daily dose, but a 40mg dose was taken forward for phase III licensing studies.

The parallel track expanded access programme (prior to licensing) randomised people who had failed AZT or ddI monotherapy to receive monotherapy with d4T 20mg or 40mg twice daily. There was no survival difference, but a significantly greater incidence of peripheral neuropathy at the higher dose, and the Data Safety Monitoring Board recommended that all patients receiving 40mg should be switched to 20mg twice daily (Anderson 1995).

A randomised Thai study (HIVNAT 002) showed no difference in viral suppression between 30mg and 40mg bid doses in 78 treatment-naïve patients when combined with ddI. No safety findings were reported (Ruxrungtham 2000).

A second randomised study in Thailand (ARV065) found no difference in viral suppression between 30mg and 40mg bid doses in 219 treatment-naïve patients when combined with ddI (Siangphoe 2004).

Glossary

naive

In HIV, an individual who is ‘treatment naive’ has never taken anti-HIV treatment before.

treatment-naive

A person who has never taken treatment for a condition.

efficacy

How well something works (in a research study). See also ‘effectiveness’.

toxicity

Side-effects.

virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.

The ETOX study in Spain randomised 54 treatment-naïve patients to receive 30mg or 40mg of d4T. This study showed equivalent efficacy at week 24, but a higher drop-out rate in the 40mg arm by week 48, together with elevated lactate, reduced mitochondrial DNA levels in plasma and no increase in total body weight or limb fat in the 40mg group (Ribera 2005).

A Barcelona study randomised 60 patients who had undetectable viral load (

A Madrid study randomised 75 patients with viral load below 50 copies/ml to switch to d4T 30mg or stay on d4T 40mg. No significant differences in viral load suppression, lactate or lipids were seen after 24 weeks (Sanchez-Conde, 2004).

Meta-analysis of the post-approval randomised studies showed no significant difference in viral suppression rates between the two doses at week 24 or week 48.

“The confidence intervals for this equivalence estimate are within the ranges set by regulators for declaring equivalence for other antiretrovirals,” the authors conclude.

A systematic review of nine clinical trials of d4T (stavudine, Zerit) shows that a dose of 30mg twice daily has equivalent efficacy to the standard 40mg dose prescribed to adults weighing more than 60kg, with some evidence of fewer side-effects. The review is published this month in the journal Expert Opinions in Pharmacotherapy.

The systematic review was carried out by Dr Andrew Hill of Liverpool University and some of the leading experts in HIV medicine in Europe, including Christine Katlama (director of AIDS research at the Hopital Pitie Salpetriere, Paris), Jose Gatell (current president of the European AIDS Clinical Society) and Vincent Soriano (Hospital Carlos III, Madrid).

They argue that further exploration of d4T dose reduction is warranted given the low cost of a fixed dose d4T/3TC/nevirapine regimen in resource-limited settings in comparison to tenofovir or AZT-based regimens.

The review highlights findings from randomised and non-randomised studies and includes a meta-analysis of the outcomes of randomised studies.

Cohort studies

A retrospective review of a large German cohort of 508 patients showed that d4T 30mg was associated with lower rates of treatment discontinuation and peripheral neuropathy when compared with d4T 40mg, but with no difference in rates of viral suppression over four years of follow-up (Koegl 2003).

Retrospective review of five smaller cohorts showed an improvement in lipoatrophy when switched to a lower d4T dose in one study and no apparent reduction in efficacy in other cohorts where switching took place.

Results

The expert review group concludes that their analysis supports a dose reduction, saying: “There is now sufficient evidence in favour of the 30mg dosage for treatment guideline documents to recommend this as the standard dosage of d4T in patients with body weight > 60kg, with a reduction to 20mg bid for those with body weight

They say that the toxicity profile of d4T justifies action.

“When the dosage of a new drug is chosen for full clinical development, the longer-term toxicity profile is likely to be unknown. Several of the adverse events now associated with d4T: lipoatrophy, lactic acidosis and lipid elevations were not well understood at the time of initial drug approval. There is evidence that these adverse events may be related to d4T dosage.”

“Postapproval reductions in drug dosage have been made for 21% of FDA-approved drugs in the past 19 years, across all therapeutic areas. In the treatment of HIV, the doses of ZDV and ddI have been lowered since initial regulatory approval, owing to dose-related toxicity (anaemia and neutropenia for ZDV, pancreatitis for ddI).”

However, patent holder Bristol Myers Squibb has shown no interest in reducing the dose of d4T despite copious evidence of the toxicities associated with the drug, partly because at the time toxicity evidence was emerging, the company was investing in an extended release, once daily formulation of d4T called Zerit XR that was intended to extend the patent life of the product. (This product remains unlicensed in Europe).

The critical piece of evidence that led to the abandonment of d4T in the developed world came from the Gilead 903 study, which compared tenofovir (Viread) with d4T in treatment-naïve patients. This study showed a significantly higher rate of lipoatrophy in d4T-treated patients (19% after three years), even though the overall serious adverse event rate was similar in both arms of the study.

As a result, d4T has been downgraded by treatment guidelines in the United Kingdom and the United States, and is no longer recommended as a first-line nucleoside analogue.

The authors suggest that a clinical trial comparing lower dose d4T with tenofovir, building on the results of the Gilead 903 study, and set in developing countries, could “potentially show equivalent antiretroviral efficacy with minimal differences in safety profile.”

A lower dose of d4T would also be cheaper; although it is the cheapest nucleoside analogue to manufacture, a dose reduction would shave around $5 from the cost of a first-line fixed dose combination of d4T/3TC/nevirapine.

References

Hill A et al. Systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treatment. Expert Opin Pharmacother 8 (5): 679-688, 2007.

Anderson R et al. Design and implementation of the stavudine parallel track programme. Comparison of safety and efficacy of two doses of stavudine in a simple trial in the US parallel track programme. J. Inf. Dis 171:118-122, 1995.

Koegl C et al. Low dose stavudine: as effective as standard dose but less side effects. Ninth European AIDS Conference (EACS), Warsaw, abstract 9.8/5, 2003.

Milinkovic A et al. A randomized open study comparing the effect of reducing stavudine dose versus switching to tenofovir on mitochondrial function, metabolic parameters, and subcutaneous fat in hiv-infected patients receiving antiretroviral therapy containing stavudine. Twelfth Conference on Retroviruses and Opportunistic Infections. Boston, USA, abstract 857, 2005.

Ribera E et al. A randomized study comparing the efficacy and tolerability of low-dose versus standard-dose stavudine in antiretroviral-naïve patients (ETOX study). Thrid International AIDS Society Conference on HIV Treatment and Pathogenesis. Rio de Janiero, Brazil, abstract TuPe2.4c10, 2005.

Ruxrungtham K et al. A randomised, dose-finding study with didanosine plus stavudine versus didanosine alone in antiviral-naïve, HIV-infected Thai patients. AIDS 14:1375-1382, 2000.

Sanchez-Conde M et al. Dose reduction in stavudine from 40 to 30 mg bid provides similar virological and immunological benefit. XV International AIDS Conference, Bangkok, abstract TuPeB4459, 2004.

Siangphoe U et al. Efficacy and safety of half dose compared to full dose stavudine (d4T) and zidovudine (AZT) in combination with didanosine (ddI) in Thai HIV-infected patients: 96-week results of ACTT002/ARV065 study. XV International AIDS Conference, Bangkok, abstract WePeB5952, 2004.