Lower doses of d4T produce similar efficacy and reduced side effects
Simon Collins, HIV i-Base
The first approach to the management of d4T-related peripheral neuropathy or lipoatrophy is to switch to alternative drugs that do not cause this side effect. Patients without other options and whose previous treatment history makes them reliant on d4T (stavudine, Zerit) have been managed, often successfully, by dose reduction. A poster at the International AIDS Society meeting in Paris this year reported that dose reduction of d4T in a group of Thai patients improved or resolved lipoatrophy without virologic failure. 
Two posters at the meeting presented further data on this approach.
Koegl and colleagues from private practice in Munich performed a retrospective analysis by chart review of 508 patients starting with d4T between 1995 and 2003. 
Standard doses (30 mg BID if <60 kg and 40 mg BID if >60 kg) were used by 369 patients and reduced doses (20 mg BID if <60 kg and 30 mg BID if >60kg) by 139 patients. Although d4T dosing is based on patient weight, the median dose in the low dose group was 0.857 mg/kg compared to 1.073 mg/kg in the standard dose group (p<0.0001).
Although both groups had similar characteristics (median age 41, range ~25-70+; CD4 230-250; VL 4.5 logs) there were proportionally more women in the low dose group (30% vs 14%). Forty-five per cent of women compared to 23% of men received the low dose regimen.
During the seven-year observation period there was no difference in CD4 or viral load response between the two groups.
Around 70% of each group discontinued d4T and incidence and reason for discontinuation was also similar: 18% vs 20% for virological failure, 26% vs 27% for side effects and 20% vs 25% for other reasons, in the low and standard groups respectively.
However, incidence of peripheral neuropathy was 50% lower in the low-dose group, reported in 13% vs 26% patients (p=0.001). Patients in the low dose arm were also reported as using d4T significantly longer (p=0.02; log rank test) and Kaplan Meier probability of remaining on d4T was 84% vs 74%, 67% vs 55% and 52% vs 41% after one, two and three years in the low-dose vs standard dose arms respectively.
In a second study, Delpierre and colleagues from Tropical and Infectious Disease Unit in Toulouse assessed the virological impact of reduced dose d4T on 43 patients who had been stable on regular dose treatment for a median of 14 months. 
Thirty-nine patients reduced from 40 mg BID to 30 mg BID and four patients reduced from 30 mg BID to 20 mg BID. The main reasons for dose reduction were lipoatrophy in 46%, neuropathy in 23% and hepatic disease in 14% of patients.
Viral load, CD4 and % undetectable were assessed at initiation of full-dose regimen, at the time of reduction and 6 and 12 months follow up. Median duration on lowered dose at assessment was 15 months.
Although 13 patients (30%) discontinued the study this was largely due to poor resolution of the original side-effects that led to the original dose reduction (seven for lipoatrophy, two for PN). Two left as ‘patient decision’ one for unrecorded reasons and only one for virologic failure.
This short study did not find evidence of reduced viral suppression as a result of the change to a reduced dose. The effect of the reduction on side effects was not presented.
Although the easiest way to avoid d4T-associated side effects is to not use d4T, not all patients have this option. If a lower dose produces similar efficacy and reduced toxicity then results from larger studies may provide evidence for wider use of d4T.
This would be particularly important if low dose d4T reduced levels of apoptosis, differentiation and other dysfunction at a cellular level in adipose tissue and this may be the most useful research for BMS to conduct on its once-daily extended release formulation.
The study from Thailand also reported that earlier intervention produced more effective results and even further dose reductions to 50% of standard dose in patients with poor response.
Paediatricians need to pay attention to these findings.
The routine dose of d4T for children has been 1mg/kg/dose administered BID, which is double the total daily dose generally used in adults. For younger children, in whom body surface area is a more appropriate gauge for drug dosing than weight, this is probably okay. For older children it may be that we are using higher doses than they need.
Lipoatrophy is being increasingly reported in children on d4T. With improved assays to study intracellular levels of the triphosphates and metabolites, it would be very helpful to review the pharmacokinetics in children in more detail and dose reduce them also if levels appear high.
- Hanvanich M et al. Reduction of d4T dosage improves lipoatrophy without virologic failure. 2nd IAS Conference, Paris 2003. Abs 749.
- Koegl C, Wolf E, Postel N et al. Low dose stavudine: as effective as standard dose but less side effects. 9th EACS, Warsaw. 25-29 October 2003. Abstract 9.8/5.
- Delpierre C, Cuzin L, Alvarez M et al. Lowering stavudine dosages does not compromise anti-viral efficacy in HIV-infected patients. 9th EACS, Warsaw. 25-29 October 2003. Abstract 9.4/2.