Briand N, Lallemant M, Jourdain G, Techapalokul S, Tunthanathip P, Suphanich S, Chanpoo T, Traisathit P, McIntosh K, Coeur SL. Haematological safety of perinatal zidovudine in pregnant HIV-1-infected women in Thailand: secondary analysis of a randomized trial. PLoS Clin Trials 2007 Apr 27;2(4):e11.
To assess the evolution of hematological parameters, including hemoglobin level, leukocytes, absolute neutrophil counts, and total lymphocyte counts, in HIV-infected pregnant women exposed to long (from 26 weeks of gestation to delivery) and short (from 35 weeks of gestation to delivery) courses of perinatal zidovudine.
Randomized, controlled, double-blinded clinical trial. This study is a secondary exploratory analysis of the Perinatal HIV Prevention Trial 1, which compared the safety and tolerance of long versus short zidovudine regimens for the prevention of mother-to-child transmission.(1)
Twenty-seven hospitals throughout Thailand.
From June 24, 1997 to December 9, 1999, 1,437 HIV-infected women were randomly assigned to receive either a long or short course of zidovudine. Women had to have a hemoglobin level higher than 8 g/dl and an absolute neutrophil count higher than 750/mm3. A total of 667 women were randomized to the short regimen and 769 women to the long regimen. Baseline characteristics were similar in both groups, with median age of 24.7 years in the long regimen and 25.0 years in the short regimen. Median CD4 counts were the same for both groups, at 360 cells/mm3. Fifteen and eleven subjects were lost to follow-up in the long and short regimen groups, respectively. One woman receiving the short regimen was excluded when she was found to be HIV-negative. The median length of gestation was 39.0 weeks.
Pregnant women were randomly assigned to receive either a long or short duration of zidovudine. Those in the long group received zidovudine from 28 weeks of gestation to delivery, while women assigned to the short group received placebo from 28 weeks of gestation and then received zidovudine from 35 weeks to delivery. Hematological measurements were performed at the pre-entry visit, and planned at 26 weeks of gestation, at 32 and 35 weeks of gestation, and at delivery upon admission to the maternity unit.
The primary outcomes were hemoglobin level, leukocytes, total lymphocyte counts, and absolute neutrophil counts.
Mean hemoglobin levels increased steadily between 26 weeks and delivery in women randomized to the short regimen. In women randomized to the long regimen, hemoglobin decreased slightly from 26 to 32 weeks, and then increased until delivery. The mean hemoglobin levels, similar at pre-entry in both groups, were significantly lower in women randomized to the long regimen at 32 and 35 weeks of gestation and, to a lesser extent, at delivery. The mean leukocyte and neutrophil counts decreased slightly until 35 weeks and then increased sharply until delivery, with a more rapid decrease and subsequent increase in women randomized to the long regimen. The mean counts were significantly lower at 32 and 35 weeks of gestation in women randomized to the long regimen, but did not differ between the two groups at delivery. The lymphocyte counts remained stable until 35 weeks of gestation and then increased until delivery, with no difference between the two groups. Between the pre-entry and the 35-week visits, after adjustment on variables (maternal age, body mass index, HIV clinical stage, CD4 count, viral load, parity, education level, type of employment, and region of residence) at baseline, zidovudine intake had a negative impact on the evolution of hemoglobin level, leukocyte counts, and absolute neutrophil counts: mean (95% confidence interval [CI]) decrease associated with exposure to zidovudine, -0.4(-0.5 to -0.3) g/dl/wk, p<0.001; -423(-703 to -142) cells/mm3/wk, p=0.003; -485(-757 to -213) cells/mm3/wk, p< 0.001, respectively. Zidovudine exposure, however, had no negative impact on the evolution of absolute lymphocyte counts (166 [0 to 332] cells/mm3/wk, p=0.05). During the second period, between the 35-week visit and delivery, after adjustment, the hemoglobin level, leukocyte count, and absolute neutrophil count increased significantly faster in women randomized to the long regimen than women in the short regimen: mean (95% CI) increase associated with exposure to zidovudine of 0.1 (0.0 to 0.1) g/dl/wk, p<0.001, 105 (18 to 191) cells/mm3/wk, p=0.02, 147 (59 to 234) cells/mm3/wk, p=0.001, respectively. There were no differences in the absolute lymphocyte counts. Over all, five women, all in the long regimen group, received blood transfusions because of anemia.
The authors conclude that women initiating zidovudine at 28 weeks of gestation have a transient decrease of hemoglobin level, leukocytes count, and absolute neutrophil count compared to women initiating zidovudine at 35 weeks. However, by the time of delivery, this initial decrease reverses in women randomized to the long regimen as compared to women randomized in the short regimen, except for hemoglobin levels, which remain lower by 0.2 (0.1 to 0.3) g/dl in women with longer exposure to zidovudine. No negative effect of zidovudine exposure was detected on the lymphocyte count evolution from 26 weeks of gestation to delivery. Women receiving the long regimen were more likely to have severe anemia, although this complication was rare (0.9% versus 0.0%).
According to the Jadad criteria, this study received a high rating. The randomization process was described in detail, the study was double-blinded, and there was description of withdrawals and drop-outs. One drawback was to the lack of measurement for adherence to iron supplementation, though it should be balanced between the two study arms. Additionally, as with all secondary analyses, the study was not designed to assess hematologic safety. The results of this trial should therefore be seen as hypotheses to test in further studies, rather than as definitive conclusions.
In this study, the observed evolution pattern of hematological parameters in women randomized to the short regimen was similar to the physiologic evolution generally described in pregnant women during the third trimester of pregnancy.(2) Other placebo-controlled studies have looked at the impact of zidovudine exposure on hematological parameters. One study showed a lower mean hematocrit at delivery in women exposed to the drug,(3) while others failed to demonstrate any effect.(4, 5) The latter two studies, however, had modest sample sizes and only compared hematologic parameters at delivery.
The benefit of early zidovudine initiation – namely, its greater efficacy in reducing perinatal transmission - is not outweighed by significant disadvantages for the mother in terms of hematologic toxicity. As more and more women receive antiretroviral therapies during pregnancy, monitoring of the hematologic and other side effects of these therapies remains paramount to ensure their safety. Other factors, including cost, logistical ability to provide the drug, and availability of supportive clinical services, should also be considered when determining the optimal duration of zidovudine therapy for a given setting.
- Lallemant M, Jourdain G, Le Coeur S, Kim S, Koetsawang S, et al. A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. Perinatal HIV Prevention Trial (Thailand) Investigators. N Engl J Med 2000 Oct 5;343(14):982-91.
- Taylor DJ, Lind T. Red cell mass during and after normal pregnancy. Br J Obstet Gynaecol 1979 May;86(5):364-70.
- Shaffer N, Chuachoowong R, Mock PA, Bhadrakom C, Siriwasin W, Young NL, et al. Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: a randomised controlled trial. Bangkok Collaborative Perinatal HIV Transmission Study Group. Lancet 1999 Mar 6;353(9155):773-80.
- Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O'Sullivan MJ, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994 Nov 3;331(18):1173-80.
- Wiktor SZ, Ekpini E, Karon JM, Nkengasong J, Maurice C, Severin ST, et al. Short-course oral zidovudine for prevention of mother-to-child transmission of HIV-1 in Abidjan, Cote d'Ivoire: a randomised trial. Lancet 1999 Mar 6;353(9155):781-5.