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Early and Late Toxicities of the First-line Antiretroviral Regimen in Johannesburg, South Africa
Emily Wong*1, D Murdoch2, J Yarrow3, J Wing4, C Feldman4, and W Venter3,4
1Univ of California, San Francisco, US; 2Duke Univ Med Ctr, Durham, NC, US; 3Reproductive Hlth and HIV Res Unit, Johannesburg, South Africa; and 4Univ of the Witswatersrand, Johannesburg, South Africa
Background: Concern has emerged about toxicities of stavudine
(d4T) -containing regimens used in the global antiretroviral roll-out. While
d4T will be increasingly phased out, its low cost and inclusion in fixed-dose
combinations ensures its continued widespread use. Understanding the time to
onset of antiretroviral (ARV) toxicities in a South African population is
critical for clinical management and may help guide planned drug
substitutions.
Methods: Retrospective review of the first 305
consecutive non-pregnant, adult patients initiated on publicly funded HAART at
Johannesburg Hospital ARV clinic from April to June 2004. Time-to-event
analysis was performed for toxicities observed during the first 24 months of
follow-up. For each toxicity, incidence rates were calculated during the first
and second year of treatment and expressed in events per person-year (95%CI).
Results: Of 305 patients, followed for 431
person-years, 303 (99%) initiated on d4T/lamivudine (3TC)/efavirenz (EFZ), and
2 (1%) initiated on d4T/3TC/nevirapine (NVP). We observed 3 distinct
side-effect profiles: early, constant, and late onset of toxicity. Early
toxicities were central nervous system (CNS) side effects (n = 91;
overall incidence 0.29; 0.23 to 0.35) and rash (n = 80; overall
incidence 0.23; 0.19 to 0.29). CNS toxicity was greater in year 1 (0.42; 0.34
to 0.51), than in year 2 (0.05; 0.02 to 0.11). Similarly, rash peaked in year 1
(0.32; 0.25 to 0.41) compared to year 2 (0.07; 0.04 to 0.14). Constant onset of
toxicity from year 1 to year 2 was seen in peripheral neuropathy (n = 89)
year 1, 0.27 (0.21 to 0.34) vs year 2, 0.22 (0.15 to 0.32) and lactic acidosis (n
= 20) year 1, 0.04 (0.02 to 0.07) vs year 2, 0.06 (0.03 to 0.12). Late onset of
toxicity was characteristic of lipodystrophy (n = 40), with an overall
incidence 0.10 (0.07 to 0.13), and 0.03 (0.02 to 0.06) and 0.21 (0.15 to 0.31)
during years 1 and 2, respectively. Of the 60 regimen changes, 54 (90%) were
due to treatment-related toxicities: 22 (37%) lipodystrophy, 19 (32%)
peripheral neuropathy, 9 (15%) lactic acidosis, 3 (5%) CNS side effects, and 1
(2%) rash.
Conclusions: d4T-specific toxicities (peripheral
neuropathy, lipodystrophy, and lactic acidosis) appear to be significant and
cumulative. Other toxicities (CNS side effects and rash) appear within the
first year and rarely necessitate regimen change. Low-cost alternatives with
lower toxicities are urgently needed.
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