A 72-week randomized study of the safety and efficacy of a stavudine to zidovudine switch at 24 weeks compared to zidovudine or tenofovir disoproxil fumarate when given with lamivudine and nevirapine

Abstract

Background: Due to superior long-term toxicity profiles, zidovudine (AZT) and tenofovir disoproxil fumarate (TDF) are preferred over stavudine (d4T) for first-line antiretroviral regimens. However, short-term d4T use could be beneficial in avoiding AZT-induced anaemia.

Methods: We randomized (1:1:1) 150 treatment-naive Thai HIV-infected adults with CD4(+) T-cell count <350 cells/mm(3) to arm 1 (24-week GPO-VIR S30(®) [d4T plus lamivudine (3TC) plus nevirapine (NVP)] followed by 48-week GPO-VIR Z250(®) [AZT plus 3TC plus NVP]), arm 2 (72-week GPO-VIR Z250(®)) or arm 3 (72-week TDF plus emtricitabine [FTC] plus NVP). Haemoglobin (Hb), dual energy x-ray absorptiometry, neuropathic signs, estimated glomerular filtration rate (eGFR), CD4(+) T-cell count, plasma HIV RNA and adherence were assessed.

Results: In an intention-to-treat analysis, mean Hb decreased from baseline to week 24 in arm 2 compared with arm 1 (-0.19 versus 0.68 g/dl; P=0.001) and arm 3 (0.48 g/dl; P=0.010). Neuropathic signs were more common in arm 2 compared with arm 3 (20.4 versus 4.2%; P=0.028) at week 24. There were no differences in changes in peripheral fat and eGFR from baseline to weeks 24 and 72 among arms. CD4(+) T-cell count increased more in arm 1 than arms 2 and 3 from baseline to week 24 (168 versus 117 and 118 cells/mm(3); P=0.01 and 0.02, respectively) but the increase from baseline to week 72 was similar among arms.

Conclusions: A 24-week d4T lead-in therapy caused less anaemia and greater initial CD4(+) T-cell count increase than initiating treatment with AZT. This strategy could be considered in patients with baseline anaemia or low CD4(+) T-cell count. If confirmed in a larger study, this may guide global recommendations on antiretroviral initiation where AZT is more commonly used than TDF.

Figure 1. Diagram SEARCH 003 patient disposition

GPO-VIR S30® is a fixed-dose combination that contains stavudine (d4T) 30 mg, lamivudine (3TC) 150 mg, and nevirapine (NVP) 200 mg. GPO-VIR Z250® is a fixeddose combination that contains zidovudine (AZT) 250 mg, 3TC 150 mg and NVP 200 mg. Truvada® is a fixed-dose combination that contains tenofovir disoproxil fumarate (TDF) 300 mg and emtricitabine (FTC) 200 mg. Arm 1 received GPO-VIR S30® twice daily for 24 weeks followed by GPO-VIR Z250® twice daily for 48 weeks. Arm 2 received GPO-VIR Z250® twice daily for 72 weeks, and arm 3 received Truvada® once daily and NVP 200 mg twice daily for 72 weeks. AE, adverse event; ARV, antiretroviral; LPV/r, lopinavir/ritonavir; LTFU, lost to follow-up; NNRTI, non-nucleoside reverse transcriptase inhibitor.

Figure 2. Comparison of toxicity primary endpoints between treatment arms by intention to treat analysis

Figure 2A. Mean hemoglobin change from baseline Figure 2B. Mean peripheral fat change from baseline assessed by dual energy x-ray absorptiometry Figure 2C. Mean estimated glomerular filtration rate change from baseline assessed by modification of diet in renal disease formula Figure 2D. Proportions of patients with neuropathic signs assessed by detailed neuropathy examination GPO-VIR S is a fixed dose combination that contains stavudine (d4T) 30 mg, lamivudine (3TC) 150 mg, and nevirapine (NVP) 200 mg. GPO-VIR Z is a fixed dose combination that contains zidovudine (AZT) 250 mg, 3TC 150 mg, and NVP 200 mg. Truvada is a fixed dose combination that contains tenofovir 300 mg and emtricitabine 200 mg. All arms received standard doses of antiretrovirals. Arm 1 received GPO-VIR S twice daily for 24 weeks followed by GPO-VIR Z twice daily for 48 weeks. Arm 2 received GPO-VIR Z twice daily for 72 weeks, and arm 3 received Truvada once daily and NVP 200mg twice daily for 72 weeks.

Figure 2. Comparison of toxicity primary endpoints between treatment arms by intention to treat analysis

Figure 2A. Mean hemoglobin change from baseline Figure 2B. Mean peripheral fat change from baseline assessed by dual energy x-ray absorptiometry Figure 2C. Mean estimated glomerular filtration rate change from baseline assessed by modification of diet in renal disease formula Figure 2D. Proportions of patients with neuropathic signs assessed by detailed neuropathy examination GPO-VIR S is a fixed dose combination that contains stavudine (d4T) 30 mg, lamivudine (3TC) 150 mg, and nevirapine (NVP) 200 mg. GPO-VIR Z is a fixed dose combination that contains zidovudine (AZT) 250 mg, 3TC 150 mg, and NVP 200 mg. Truvada is a fixed dose combination that contains tenofovir 300 mg and emtricitabine 200 mg. All arms received standard doses of antiretrovirals. Arm 1 received GPO-VIR S twice daily for 24 weeks followed by GPO-VIR Z twice daily for 48 weeks. Arm 2 received GPO-VIR Z twice daily for 72 weeks, and arm 3 received Truvada once daily and NVP 200mg twice daily for 72 weeks.

Figure 2. Comparison of toxicity primary endpoints between treatment arms by intention to treat analysis

Figure 2A. Mean hemoglobin change from baseline Figure 2B. Mean peripheral fat change from baseline assessed by dual energy x-ray absorptiometry Figure 2C. Mean estimated glomerular filtration rate change from baseline assessed by modification of diet in renal disease formula Figure 2D. Proportions of patients with neuropathic signs assessed by detailed neuropathy examination GPO-VIR S is a fixed dose combination that contains stavudine (d4T) 30 mg, lamivudine (3TC) 150 mg, and nevirapine (NVP) 200 mg. GPO-VIR Z is a fixed dose combination that contains zidovudine (AZT) 250 mg, 3TC 150 mg, and NVP 200 mg. Truvada is a fixed dose combination that contains tenofovir 300 mg and emtricitabine 200 mg. All arms received standard doses of antiretrovirals. Arm 1 received GPO-VIR S twice daily for 24 weeks followed by GPO-VIR Z twice daily for 48 weeks. Arm 2 received GPO-VIR Z twice daily for 72 weeks, and arm 3 received Truvada once daily and NVP 200mg twice daily for 72 weeks.

Figure 2. Comparison of toxicity primary endpoints between treatment arms by intention to treat analysis

Figure 2A. Mean hemoglobin change from baseline Figure 2B. Mean peripheral fat change from baseline assessed by dual energy x-ray absorptiometry Figure 2C. Mean estimated glomerular filtration rate change from baseline assessed by modification of diet in renal disease formula Figure 2D. Proportions of patients with neuropathic signs assessed by detailed neuropathy examination GPO-VIR S is a fixed dose combination that contains stavudine (d4T) 30 mg, lamivudine (3TC) 150 mg, and nevirapine (NVP) 200 mg. GPO-VIR Z is a fixed dose combination that contains zidovudine (AZT) 250 mg, 3TC 150 mg, and NVP 200 mg. Truvada is a fixed dose combination that contains tenofovir 300 mg and emtricitabine 200 mg. All arms received standard doses of antiretrovirals. Arm 1 received GPO-VIR S twice daily for 24 weeks followed by GPO-VIR Z twice daily for 48 weeks. Arm 2 received GPO-VIR Z twice daily for 72 weeks, and arm 3 received Truvada once daily and NVP 200mg twice daily for 72 weeks.