# Abstract

 

## Objectives: To respond to the primary safety objective of the Perinatal HIV Prevention Trial 1 (PHPT-1) by studying the evolution of haematological parameters according to zidovudine exposure duration in HIV-1−infected pregnant women. 

## Design: Multicenter, randomized, double-blind, controlled trial of different durations of zidovudine prophylaxis. 

## Setting: 27 hospitals in Thailand. 

## Participants: 1,436 HIV-infected pregnant women in PHPT-1. 

## Intervention: Zidovudine prophylaxis initiation at 28 or 35 wk gestation. 

## Outcome measures: Haemoglobin level, leucocytes, total lymphocyte counts, and absolute neutrophil counts were measured at 26, 32, and 35 wk and at delivery. The evolution of haematological parameters was estimated between 26 and 35 wk (zidovudine/placebo) and between 35 wk and delivery to compare a long versus short zidovudine exposure. For each parameter, linear mixed models were adjusted on baseline sociodemographic variables, HIV clinical stage, CD4 count, and viral load. 

## Results: Between 26 and 35 wk, haemoglobin, leucocytes, and absolute neutrophil counts decreased in zidovudine-exposed compared to unexposed women (mean difference [95% CI] −0.4 [−0.5 to −0.3], −423 [−703 to −142], −485 [−757 to −213], respectively). However, between 35 wk and delivery, the haematological parameters increased faster in women exposed to long rather than short durations of zidovudine (0.1 [0.0 to 0.1]; 105 [18 to 191]; 147 [59 to 234], respectively). At delivery, the differences were not statistically significant, except for mean haemoglobin level, which remained slightly lower in the long zidovudine treatment group (difference: 0.2 g/dl). Zidovudine had no negative impact on the absolute lymphocyte counts. 

## Conclusion: Zidovudine initiated at 28 wk gestation rather than 35 wk had a transient negative impact on the evolution of haematological parameters, which was largely reversed by delivery despite continuation of zidovudine. This result provides reassurance about the safety of early initiation of zidovudine prophylaxis during pregnancy to maximize prevention of perinatal HIV. # Editorial Commentary **Background:** Pregnant women who are infected with HIV are at high risk of passing on the virus to their unborn baby during pregnancy, labour, and breastfeeding. Around 15%--30% of babies born to HIV-positive women will themselves become infected, if the woman avoids breast-feeding but does not use any other means of preventing the virus from being passed on. However, if a drug, zidovudine (AZT), is given during pregnancy the chance of HIV being passed on to a baby drops from around 23% to around 8%. In some settings it may not be realistic to give the standard course of zidovudine, from 28 weeks of pregnancy, because of its cost and complexity. A number of trials have therefore looked at whether standard-course and short-course zidovudine are equivalent at reducing the risk of passing on HIV from mother to baby. One trial, the Perinatal HIV Prevention Trial-1 (PHPT-1) found that the short treatment course was substantially less effective at preventing HIV from being passed on from mother to baby. Current international guidance therefore recommends starting zidovudine at 28 weeks of pregnancy. However, zidovudine does have several side effects, including anemia; it can also cause a drop in the levels of certain types of white blood cell, and is thought to be toxic to bone marrow. The researchers who had carried out the PHPT-1 trial therefore wanted to do a subsequent analysis of data from that trial to find out whether there were any differences in these safety outcomes between standard and short course zidovudine. **What the trial shows:** In total 1,436 women were recruited into the trial and assigned to receive either zidovudine from 28 weeks of pregnancy until delivery (standard course; 769 women), or from 35 weeks to delivery (short course; 667). Blood tests were performed at 26, 32, and 35 weeks of pregnancy and then at delivery, and the main outcomes assessed in this secondary analysis were the hemoglobin levels (to check for anemia), and levels of white blood cells, including the levels of two particular types (neutrophils and lymphocytes). The researchers found that standard-course zidovudine resulted in a drop at 35 weeks in the levels of hemoglobin and white blood cells, relative to short-course zidovudine. However, by the time of delivery these levels had recovered and no significant differences could be observed between the two arms of the trial. Women receiving standard-course zidovudine were more likely to experience severe anemia, which although a rare event in both arms of the trial, could have serious outcomes. **Strengths and limitations:** The original trial from which these data were collected was a relatively large, randomized study and in which there was a low rate of loss to follow up. Although no formal sample size calculation was performed for the analyses presented here, the study probably had sufficient power to detect small differences in the outcomes assessed. A key limitation of this study is that the analyses presented here are a secondary exploration of data from the PHPT-1 trial and should therefore be seen as hypotheses to test in further studies, rather than as definitive conclusions. **Contribution to the evidence:** The analyses presented here add to the findings of the parent trial, PHPT-1, by providing additional data about the toxicity of zidovudine. Other trials have not clearly established whether there are differences between short- and standard-course zidovudine in terms of their toxicity. The findings support current guidelines recommending standard-course zidovudine therapy for HIV-positive pregnant women. It is also crucial that efforts are made to ensure women worldwide can get access to facilities for monitoring the status of their HIV infection, and then receive highly active antiretroviral therapy when it is needed. # RESULTS 

## Participants and Baseline Data The baseline characteristics of 1,436 pregnant HIV-infected women included in the PHPT-1 trial between June 1997 and December 1999 have already been described \[[8](#)\]. The main characteristics are described in [Table 1](#), and participant flow is described in [Figure 1](#). In total, 667 HIV-1 women were randomized to the short zidovudine regimen and 769 women to the long regimen. ::::table-wrap

::: caption
Maternal Characteristics at 26 Wk Gestation According to Randomization
Arm
:::

![](<>):::: <figure> <p><img src="" /></p> <figcaption>Flow of Participants</figcaption> </figure> In the entire study population, at pre-entry visit planned at 26 wk of gestation, the median (interquartile range [IQR]) haemoglobin level was 10.7 (10.0 to 11.4) g/dl, the leucocyte count was 8,670 (7,200 to 10,300) cells/mm^3^, the absolute neutrophil count was 6,002 (4,896 to 7,300) cells/mm^3^, and the absolute lymphocyte count was 1,919 (1,476 to 2,425) cells/mm^3^. Median (IQR) length of gestation was 39.0 (38.0 to 40.0) wk. Median gestational ages at pre-entry and at randomization visit were 25.7 (24.6 to 26.4) wk and 27.9 (27.3 to 28.1) wk, respectively. The median duration of the first period (pre-entry to 35-wk visit) and the second period (35-wk visit to delivery) considered for analysis were 9.0 (8.0 to 9.9) wk and 4.3 (3.9 to 4.8) wk, respectively. The durations of the periods did not differ significantly according to randomization arms. 

## Outcomes The observed evolutions of the mean haemoglobin, leucocyte, absolute neutrophil count, and absolute lymphocyte count, between 26 wk of gestation and delivery, are presented in [Figure 2](#) by randomization arms. The mean haemoglobin level increased steadily between 26 wk and delivery in women randomized to the short regimen ([Figure 2](#)A). In women randomized to the long regimen, haemoglobin decreased slightly from 26 to 32 wk, and then increased until delivery. The mean haemoglobin levels, similar at pre-entry in both groups, were significantly lower in women randomized to the long regimen at 32 and 35 wk gestation and, to a lesser extent, at delivery. The mean leucocyte ([Figure 2](#)B) and neutrophil ([Figure 2](#)C) counts decreased slightly until 35 wk 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 wk gestation in women randomized to the long regimen, but did not differ between the two groups at delivery. The lymphocyte counts ([Figure 2](#)D) remained stable until 35 wk of gestation and then increased until delivery, with no difference between the two groups. <figure> <p><img src="" /></p> <figcaption>Haematological Parameters between 26 Weeks' Gestation and Delivery in HIV-Infected Women According to Zidovudine Exposure<br /> Measurements occurred at the same visit in the two groups. All values are expressed as means and 95% CIs. Comparison of long (zidovudine exposure from 28 wk of gestation) versus short (zidovudine exposure from 35 wk of gestation) regimens was done by Student's t-test. Broken line, short arm; solid line, long arm. \*<em>p</em> < 0.05, \*\* <em>p</em> < 0.01, \*\*\*<em>p</em> < 0.001.<br /> (A) Haemoglobin level.<br /> (B) Leucocyte counts.<br /> (C) Absolute neutrophil counts.<br /> (D) Absolute lymphocyte counts.</figcaption> </figure> We have also presented the evolution of the haematological parameters from a safety perspective. [Table 2](#) presents the percentages of women with anaemia at different severity grades (following the WHO guidelines \[[17](#)\] as well as those of the table of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS \[[18](#)\]) and the percentages of leucopenia, neutropenia, and lymphopenia at pre-entry, at 32 and 35 wk of gestation, and at delivery, according to the randomization arms. ::::table-wrap
::: caption
Distribution of Anaemia, Leucopenia, Neutropenia, and Lymphopenia in
HIV-Infected Pregnant Women, According to Randomization Arms
:::

![](<>):::: Between the pre-entry and 35-wk visits, we found that, after adjustment on variables at baseline, zidovudine intake still had a negative impact on the evolution of haemoglobin level, leucocyte counts, and absolute neutrophil counts, as shown by the 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/mm^3^/wk, *p* = 0.003; −485 (−757 to −213) cells/mm^3^/wk, *p* < 0.001, respectively ([Table 3](#)). Zidovudine exposure, however, had no negative impact on the evolution of absolute lymphocyte counts (166 [0 to 332] cells/mm^3^/wk, *p* = 0.05). ::::table-wrap
::: caption
Association between Zidovudine Exposure on the Haematological
Measurements Evolution in HIV-Infected Pregnant Women According to
Randomization Arms
:::

![](<>):::: During the second period, between the 35-wk visit and delivery, after adjustment, the haemoglobin level, leucocyte count, and absolute neutrophil count increased significantly faster in women randomized to the long regimen than women in the short regimen, as shown by the 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/mm^3^/wk, *p* = 0.02, 147 (59 to 234) cells/mm^3^ /wk, *p* = 0.001, respectively. There were no differences in the absolute lymphocyte counts ([Table 3](#)). The predicted means are described in [Table 3](#). Other than zidovudine exposure, the factors independently associated with a negative evolution of haematological parameters were low body mass index, multiparity, low CD4 count, an advanced HIV clinical stage, and high baseline viral load (unpublished data). 

## Blood Transfusions Overall, eight (0.6%) pregnant women received blood transfusions. All were exposed to zidovudine from 28 wk gestation (8/754 versus 0/656, *p* = 0.01). Among these women, two were transfused because of a haemorrhage (at delivery and at 7 d before delivery). One woman with a thalassemia trait received packed red cell transfusions at 45 and 37 d before delivery. The remaining five women were transfused at 0, 2, 4, 25 and 64 d before delivery because of anaemia, including one woman with a haemoglobin level of 4.6 g/dl who delivered a stillborn.


Extracted trial result:
Outcome: absolute neutrophil count between 26 and 35 wk (continuous)
Intervention: Zidovudine prophylaxis initiation
Comparator: placebo
Intervention group size: 754
Intervention mean: -485
Comparator group size: 656
Comparator mean: 0
Notes: given as estimated change and no std given, also in figure and graphic format