Safety of Reduced Dose Zidovudine (AZT) Compared With Standard Dose AZT in Antiretroviral-naïve HIV-infected Patients: A Randomized Controlled Trial

Existing formulations for adults include zidovudine 100mg capsule, zidovudine/3TC 300/150mg, zidovudine/3TC/NVP 300/150/200mg, zidovudine/3TC/ABC 300/150/300. Currently, international guidelines recommend a daily dose of 600 mg in 2 divided doses. Pharmacokinetic studies on zidovudine showed a twice daily regimen resulted in higher predose zidovudine-triphosphates (TP) concentrations, the active intracellular metabolite, when compared to the same daily dose given once daily. Further, a small study in Thailand study found doses of zidovudine 200 mg twice daily achieved plasma levels equivalent to the standard international 300 mg twice daily dose in individuals weighing less than 60 kg.

The clinical efficacy of zidovudine has been evaluated in randomized clinical trials using a range of doses from 300 to 1500 mg/day. In an early trial (Nordic Medical Research Councils' HIV Therapy Group 1992) comparing different dosing of zidovudine monotherapy in advanced HIV infection found no differences in death rate, or new AIDS defining events. The incidence of anaemia and leucopenia comparing 400 mg and 1200 mg daily showed a direct dose relationship: 4% to 24% (anaemia) and 3% to 22% (leucopenia) respectively. Another early trial (Fischl 1990) demonstrated an improved survival with the lower dose of zidovudine (63%) versus the high dose (52%), again with significantly more anaemia and neutropenia in the high dose zidovudine arm (p < 0.001).

High doses of zidovudine have led to increased incidence of anaemia and neutropenia, with no impairment in treatment efficacy as measured by CD4 cell count, HIV RNA level or clinical progression. In the context of new recommendations favouring the use of zidovudine over stavudine as first line treatment in resource limited settings, the investigators aim at evaluating the impact of reduced zidovudine (200 mg BID) treatment.

API (active product ingredient) production costs are the most important determinant of antiretroviral drug prices among generic manufacturers. A given percentage reduction in dosage will thus translate into a virtually equivalent percentage in drug pricing. As cART will continue to expand in Least Developed Countries, it is predicted that around 1.5 million people will take zidovudine-based regimen by 2010. Small reductions in the annual per-patient cost of AZT-based regimen could lead to significant reductions in the global cost of HIV treatment: it is estimated a 47 million US dollars savings if 9 million patients will be treated in 2014.

The present study is a prospective, randomised, 48 weeks, phase II trial. Subjects will be recruited through one site: the HIV outpatient clinic of Internal Medicine Department, CNPS Hospital, Yaoundé, Cameroun. Randomisation will be performed at initiation of ART. Patients will be randomised in one of the following treatments arms, in combination with lamivudine and an NNRTI regimen: a low-dose AZT arm (200 mg twice daily)or a standard-dose AZT arm (300 mg twice daily).