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Randomized noninferiority trial of two maternal single-dose nevirapine-sparing regimens to prevent perinatal HIV in Thailand

Lallemant, Marca,b,c; Le Coeur, Sophiea,b,c,d; Sirirungsi, Wasnac; Cressey, Tim R.a,b,c; Ngo-Giang-Huong, Nicolea,b,c; Traisathit, Patrineee; Klinbuayaem, Viratf; Sabsanong, Prapang; Kanjanavikai, Prateeph; Jourdain, Gonzaguea,b,c; Mcintosh, Kennethb,i; Koetsawang, Supornjon behalf of the PHPT-5 study investigators

doi: 10.1097/QAD.0000000000000865
EPIDEMIOLOGY AND SOCIAL
Free

Objectives: Perinatal single-dose nevirapine (sdNVP) selects for resistance mutations. The objective of this trial was to compare two maternal sdNVP-sparing regimens with standard zidovudine (ZDV)/sdNVP prophylaxis.

Design: PHPT-5 was a randomized, partially double-blind placebo-controlled, noninferiority trial in Thailand (NCT00409591). Study participants were women with CD4+ of at least 250 cells/μl and their infants.

Methods: All women received ZDV from 28 weeks’ gestation and their newborn infants for one week. Women were also randomized to receive NVP-NVP (reference): maternal intrapartum sdNVP with a 7-day ‘tail’ of ZDV along with lamivudine, and infant NVP (one dose immediately, another 48 h later); infant-only NVP: maternal placebos for sdNVP and the ‘tail’, with infant NVP; LPV/r: maternal LPV/r starting at 28 weeks. Infants were formula-fed. HIV-diagnosis was determined by DNA-PCR.

Results: Four-hundred and thirty-five women were randomized between January 2009 and September 2010. Accrual was terminated prematurely following a change in Thai guidelines recommending antiretroviral combination therapy for all pregnant women. Data on 405 mothers and 407 live-born children were analyzed. Baseline characteristics were similar between arms. Intent-to-treat transmission rates were 3.8% (95% confidence interval: 1.2–8.6) in NVP-NVP, 1.6% (0.2–5.6) in infant-only NVP, and 1.4% (0.4–5.1) in LPV/r arms. As-treated rates were 2.2% (0.5–6.4), 3.2% (0.9–7.9), and 1.5% (0.2–5.2), respectively. Factors independently associated with transmission were prophylaxis duration less than 8 weeks (adjusted odds ratio 15.5; 3.6–66.1) and viral load at baseline at least 4 log10copies/ml (adjusted odds ratio 10.9; 1.3–91.5). Regimens appeared well tolerated.

Conclusion: Transmission rates in all arms were low but noninferiority was not proven. Antiretroviral prophylaxis for at least 8 weeks before delivery is necessary to minimize transmission risk.

aUnité Mixte Internationale 174, Institut de Recherche pour le Développement (IRD)-PHPT, Chiang Mai, Thailand

bDepartment of Immunology and Infectious, Diseases, Harvard School of Public Health, Boston, Massachusetts, USA

cDepartment of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand

dUnité Mixte de Recherche 196, Centre Français de la Population et du Développement, (INED-IRD-Paris V University), Paris, France

eDepartment of Statistics, Faculty of Science, Chiang Mai University, Chiang Mai

fSanpatong Hospital, Ministry of Public Health, Sanpatong

gSamutprakarn Hospital, Ministry of Public Health, Samutprakarn

hBanglamung Hospital, Ministry of Public Health, Chonburi, Thailand

iChildren's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA

jFamily Health Research Center, Mahidol University, Bangkok, Thailand.

Correspondence to Sophie Le Coeur, MD, PhD, IRD174-PHPT, 187/10 Changklan Rd., Changklan, Muang, Chiang Mai 50100, Thailand. Tel: +66 0 53 819 125; fax: +66 0 53 819 130; e-mail: sophie.lecoeur@phpt.org

Received 4 June, 2015

Revised 19 August, 2015

Accepted 20 August, 2015

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Introduction

Thai national 2007 [1] and WHO 2006 guidelines for prevention of mother-to-child transmission (PMTCT) of HIV in nonbreastfeeding women [2] recommended until their 2010 revision [3] that women not requiring antiretroviral treatment for their own health – CD4+ cell count at least 250 cells/μl – receive zidovudine (ZDV) from 28 weeks’ gestation (or as soon thereafter as possible) with single-dose nevirapine (sdNVP) at onset of labor, and the newborn sdNVP at 48–72 h of life, in addition to 1 week of ZDV. This regimen was simple, well tolerated, and efficacious, reducing HIV mother–child transmission (MTCT) to approximately 2% [4]. However, if women or infected infants exposed to nevirapine for PMTCT initiated nonnucleotide-reverse-transcriptase (NNRTI)-based antiretroviral therapy (ART) for their own health, virologic efficacy was decreased, possibly due to HIV resistance mutations [5–7][5–7][5–7]. These mutations could be partially prevented by administering a two or three-drug ‘tail’ to the mother, starting immediately after sdNVP, and lasting 1–4 weeks postpartum [8–10][8–10][8–10]. Moreover, a trial in Botswana had showed that sdNVP, given only to the child at birth, resulted in an intrapartum transmission rate not significantly higher than sdNVP provided to both mother and child [11]. In light of these results, and emerging information that the protease inhibitor ritonavir-boosted lopinavir (LPV/r) by itself could lower viral load over a 2–3-month period to a similar extent as LPV/r with ZDV and lamivudine [12], we designed a three-arm noninferiority trial to compare the Thai standard of the time (ZDV from 28 weeks’ gestation with sdNVP to mother and child) with two NVP-sparing regimens: ZDV starting at 28 weeks along with infant-only peripartum NVP, and ZDV together with LPV/r from 28 weeks, with no NVP. Lamivudine (3TC) was not added to LPV/r in order to avoid additional drug resistance and potential hepatotoxicity after 3TC interruption in a country where chronic hepatitis B infection is endemic [13,14][13,14].

Following the 2010 revision of the WHO PMTCT guidelines [3], the Thai Ministry of Public Health modified its guidelines on 1 October 2010 to recommend ZDV + 3TC + LPV/r in all pregnant women regardless of their immunological status, starting after the end of the first trimester of pregnancy [15]. Enrollment in our protocol was stopped and, upon recommendation by the Data Safety Monitoring Board (DSMB), the study was unblinded and preliminary results communicated to the coinvestigators. We report here the efficacy and safety results of the trial.

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Methods

Trial design

PHPT-5 (NCT00409591) was a multicenter, phase 3, randomized, partially double-blind, and placebo-controlled trial for women not eligible to initiate HAART during pregnancy for their own health, that is, with CD4+ cell counts of at least 250 cells/μl. All women received 300 mg of ZDV twice daily starting at 28 weeks’ gestation or as soon as possible thereafter and 300 mg orally every 3 h during labor, and all infants received 2 mg of ZDV per kilogram every 6 h for 1 week after birth (6 weeks if their mothers had received ZDV for <4 weeks). The three randomized arms were as follows:

  1. NVP-NVP arm [4]: maternal intrapartum sdNVP 200 mg tablet (Boehringer-Ingelheim, Germany) in addition to a 7-day ‘tail’ of ZDV 300 mg together with 3TC 150 mg twice daily starting immediately after delivery, and infant NVP (6 mg orally immediately after birth and again 48–72 h after birth; for newborns weighing <2500 g, the dose was reduced to 2 mg/kg).
  2. Infant-only NVP arm: maternal placebos for sdNVP and the ‘tail,’ and infant NVP as in arm A.
  3. LPV/r arm: maternal LPV/r 400/100 mg twice daily (Aluvia, Abbott Park, Illinois, USA) from 28-weeks’ gestation or as soon as possible thereafter until delivery.
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Participants

Eligible participants were confirmed HIV-infected pregnant women, participating in the Thai national PMTCT program, who intended delivery and postnatal care at one of 43 study sites. Women were enrolled if they had provided written informed consent, were above 18 years of age, antiretroviral treatment-naive (except for PMTCT of HIV), 28–36 weeks’ gestational age, with CD4+ cell count at least 250 cells/μl, and had the following laboratory values within 14 days of enrollment: hemoglobin more than 8.5 g/dl, absolute neutrophils more than 750 cells/μl, platelets more than 50 000 cells/μl, serum alanine aminotransferase less than 5× the upper limit of normal, and serum creatinine less than 1.5× the upper limit of normal. On 4 June 2010, following Thai adult treatment recommendations [15], the CD4+ exclusion criteria for women were raised from less than 250 to less than 350 cells/μl. Other exclusion criteria were WHO class III/IV HIV-associated disease, life-threatening fetal anomalies, active tuberculosis or contraindications to the study drugs.

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Randomization and blinding

Randomization was performed centrally by fax, balancing treatment assignments in a ratio of 1 : 1 : 1. Participants were randomly assigned in blocks of six, stratified by site, gestational age (below or ≥32 weeks) and until 4 June 2010 by CD4+ cell count (below or ≥350 cells/μl). Randomization lists were encrypted in a database before study initiation. Maternal sdNVP and ZDV + 3TC tail in arms A and B were double blinded. Replacement NVP or matching placebo doses as well as tail treatments were accessible in a blinded fashion at any participating hospital with the use of a code.

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Follow-up

Women had an obstetrical examination and hematologic and biochemical testing every month until delivery. After delivery, they were seen at 7–10 days, 1 and 6 months for physical examination and laboratory tests. Viral load (Abbott m2000 RealTime HIV-1 assay; Abbott Molecular Inc., Des Plaines, Illinois, USA) and CD4+ cell count were measured at baseline and delivery. Cesarean section was planned upon decision of the obstetrical team, following the national guidelines [1]. Also by Thai guidelines, women were advised not to breastfeed, and formula milk was provided to mothers who, in the judgment of the medical team, would have difficulty purchasing it [1].

Infants were examined at birth, 7–10 days, 1, 2, 4, and 6 months. At each visit, the child's interval history was recorded and a physical examination performed. Blood was obtained for HIV diagnosis at birth (within 24 h), 7–10 days, 1, 2, 4, and 6 months, hematology at birth, 7–10 days and 1 month, and chemistry at birth and 7–10 days.

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Primary endpoint

Real-time DNA polymerase chain reaction (PCR) assay was performed on peripheral blood spotted onto filter papers, dried, and stored at –20°C [16]. The primary endpoint was infant HIV infection: two positive PCR tests in blood obtained on two separate occasions. Infants were considered uninfected if PCR results were negative twice after one month of age. For HIV-infected infants, transmission was labeled ‘in utero’ if the sample obtained within 3 days of birth was positive and ‘intrapartum’ when it was negative [17]. Twins and triplets were considered as a single entity, infected if at least one was HIV infected.

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Safety and adherence

Adverse event grading was based on the Division of AIDS, NIAID Table [18]. Serious adverse events (SAEs) were reported to the Ministry of Public Health, and to GlaxoSmithKline and Boehringer Ingelheim if possibly related to study drugs. Study drug adherence was assessed at each visit by counting pills. Maternal NVP/placebo intake was directly observed. At each visit, mothers were interviewed about adherence to formula feeding.

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Sample size

The study was designed to test for noninferiority between the experimental and participants arms, that is, 95% confidence that the transmission rate difference does not exceed a predefined delta of 1.5%, considered as relevant from a clinical and public health perspective in Thailand. Based on our previous PHPT-2 study, we estimated the transmission rate in the reference group at 1.1% [4]. Using a one-sided approach, a sample size of 664 evaluable participants per arm would ensure 80% power to rule out a difference greater than the predefined delta (PASS Package, Kaysville, Utah, USA). Assuming 5% unevaluable, 699 women per arm were required.

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Statistical methods

Characteristics were compared among treatment groups using χ2 and Kruskal–Wallis tests. Noninferiority was tested by intent-to-treat and as-treated analyses using the exact confidence intervals (CIs) of the difference in transmission rates. Univariate and multivariate analyses including baseline, pregnancy, and delivery characteristics were performed to identify factors associated with transmission using logistic regression.

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Ethics

The ethics committees of the Thai Ministry of Public Health, the Faculty of Associated Medical Sciences of Chiang Mai University, the Harvard School of Public Health and local hospitals approved the protocol. All study sites complied with research regulations of the United States Department of Health and Human Services.

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Results

Between 9 January 2009 and 30 September 2010, 1210 HIV-infected pregnant women were screened for eligibility and 435 randomly assigned to study treatment. Enrollment, loss to follow-up, pregnancy outcomes, and available endpoints for each treatment group are summarized in Fig. 1. Among the 435 women randomized, one was lost to follow-up and six withdrew before delivery. A total of 428 women delivered in the study including four who had stillbirths. Four hundred thirty children were born alive, including 425 single, four twin, and one triple births. Owing to the fact that they delivered after the study was unblinded, 23 women and their infants were not included in the final analysis. This analysis is restricted to data from enrollment until 6 months after birth/delivery.

Fig. 1

Fig. 1

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Characteristics of the women, deliveries, and infants

Characteristics of the women and newborns are presented in Table 1. At baseline, the median [interquartile range (IQR)] age was 27 (23–32) years, gestational age 28.6 (28.1–30.4) weeks, median CD4+ 453 (363–577) cells/μl and viral load 4.0 (3.4–4.4) log10 copies/ml. Almost all women were in WHO stage 1, and 4.9 and 3.2% of women were infected with hepatitis B and C virus, respectively, with no difference between arms. Twenty-one women had been exposed to ART previously for PMTCT, seven in each arm.

Table 1

Table 1

At delivery, median gestational age was 38.7 (37.8–39.7, 13.3% ≤37 weeks) with no difference between arms. The median duration of ZDV therapy was 10.1 (8.6–11.1) weeks. Thirty-one percent of deliveries were by cesarean section –47% of these before onset of labor. The median CD4+ was 552 (414–689) cells/μl, and the median viral load at delivery was significantly lower in the LPV/r arm (1.6 log10 copies/ml) than in the two other arms (3.6 log10 copies/ml) (P < 0.001). The median infant birth weight was 3.0 kg (2.7–3.3), with no difference between arms (Table 1).

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Study drug administration and adherence

There was no difference in timing of study drug administration between the NVP-NVP and infant-only NVP arms (Table 1). Adherence to study visits was above 99% in women and 100% in infants. Based on the pill count of drug returned, adherence was above 90% in 96.8% of the women for ZDV (similar in the three arms), and in 95.2% of them for LPV/r. Four percent (17/405) of women did not receive the intrapartum ZDV and 3% (8/263) did not receive the ZDV + 3TC/placebo tail (no difference between study arms). Adherence to postnatal ZDV prophylaxis as assessed by the pediatrician was excellent in 98% of the infants. Only six infants (1.2%) received ZDV for less than 6 days, whereas 5.4% received it for more than 1 month because their mothers had received less than 4 weeks of ZDV prophylaxis (no difference between arms). Eight women did not receive their study drug before labor, five in the NVP-NVP arm and three in the infant-only NVP arm. All infants received their first NVP dose and only one did not receive the second dose.

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Efficacy analysis

End points were available for 402 (98.8%) of the 407 live-born infants included in the analysis. A total of nine HIV transmissions occurred with no significant difference between groups (Table 2). Five transmissions were considered to have occurred in utero and four intrapartum. The as-randomized transmission rate among those in the NVP-NVP group was 3.8% (95% CI: 1.2–8.6), 1.6% (0.2–5.6) in the infant-only NVP group and 1.4% (0.4–5.1) in the LPV/r group. The difference in transmission rate between infant-only NVP and the reference arm (NVP-NVP) was –2.2% (–5.5% to +1.1%) and that between LPV/r and the reference arm was –2.3% (–5.5% to +0.8%). The upper limit of the CI of the difference in rates between infant-only NVP and NVP-NVP as well as LPV/r and NVP-NVP fell within the predefined noninferiority limit of 1.5%.

Table 2

Table 2

As-treated transmission rates were as follows: 2.2% (0.5–6.3), 3.2% (0.9–8.0), and 1.5% (0.2–5.2), respectively (Table 2). The transmission rate difference between infant-only NVP and the reference arm (NVP-NVP) was 1.0% (–2.3 to +4.3%) and that between LPV/r and the reference arm was –0.7% (–3.4 to +2.0%). In both comparisons the upper limit of the CI of the difference in rates exceeded the predefined noninferiority threshold of 1.5%.

Among the nine transmitting mothers, maternal viral load at entry ranged from 3.1 to 5.7 log10 copies/ml, CD4+ cell count from 261 to 628 cells/μl, ZDV prophylaxis duration from 27 to 77 days (six <4 weeks), four women delivered prematurely, and only one delivered by cesarean section (but after onset of labor).

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Risk factors for transmission

Univariate and multivariate analyses of factors associated with HIV transmission are provided in Table 3. By univariate analysis, the gestational age at start of ZDV, and baseline viral load and CD4+ cell count were significantly associated with transmission, as well as premature delivery and duration of antiretroviral prophylaxis less than 8 weeks. In the multivariate analysis, factors remaining independently associated with transmission were viral load at least 4 log10 copies/ml at baseline (adjusted odds ratio 10.9; 95% CI: 1.3–91.5) and duration of antiretroviral prophylaxis less than 8 weeks (adjusted odds ratio 15.5; 3.6–66.1).

Table 3

Table 3

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Maternal and infant safety

Table 4 provides the maternal and infant safety events for each arm. Fifty-four women (13.1%) experienced 64 SAEs during pregnancy. The rate was significantly higher in the LPV/r arm compared with the two other arms combined (21.4 vs. 12.4%, P = 0.024). Overall SAEs were related to pregnancy (47%), delivery complications (14%), or infections (19%); only 3% were related to HIV. During pregnancy, women in the LPV/r arm had more frequent hypercholesterolemia and hypertriglyceridemia than in the other two arms combined (P < 0.01). No severe rashes were observed and only mild rashes occurred in two mothers 10 days postpartum (Table 4a).

Table 4

Table 4

The rates of adverse pregnancy outcomes (Table 4b) including stillbirth, preterm, very preterm delivery, low and very low birth weight and small for gestational age (defined as <10th percentile of the Thai norms [19]) did not differ between the LPV/r arm and the two other arms combined.

One hundred SAEs were reported among 75 infants (18.4%) until 6 months of age (Table 4c), with no differences between arms. Most events were related to infections, 11% possibly related to ART (mostly anemia and neutropenia), and 13% to HIV. There was one neonatal death from congenital heart malformation at one day of life in the infant-only NVP group. In the LPV/r group, one death occurred at 30 days, following surgery for congenital intestinal obstruction.

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Discussion

This three-arm randomized clinical trial compared, in a formula-fed population, two NVP-sparing maternal regimens with the regimen that was recommended by WHO at the time of the trial, third-trimester ZDV with sdNVP [2]. The trial was stopped early because of a change in the Thai guidelines for PMTCT prophylaxis, and consequently full accrual was not achieved. Thus, although the observed transmission rates in the three arms were low and similar, both in the intention-to-treat and in the as-treated analyses, the trial could not demonstrate the noninferiority of the experimental arms compared with the reference. Nevertheless, several important conclusions can be drawn.

In multivariate analysis, two critical risk factors for transmission were identified: antiretroviral treatment of less than 8 weeks during pregnancy, and high baseline maternal HIV viral load. Late commencement of maternal antiretroviral prophylaxis poses its risk through two separate mechanisms: first, transplacental HIV transmission before antiretrovirals have reached the fetus to provide preexposure prophylaxis and before maternal viral load has been reduced, and, second, residual circulating maternal virus at delivery, the time of highest risk of transmission. The first of these two mechanisms applies to all prophylactic regimens but particularly to those containing drugs that readily cross the placenta, such as ZDV. The second pertains particularly to regimens containing drugs such as LPV/r that lower maternal viral load but may not readily cross the placental barrier. Two studies of LPV/r in women during pregnancy have shown that viral load consistently drops below 400 copies/ml and usually below 50 copies/ml 8–10 weeks after starting LPV/r alone [20], or as part of a HAART regimen [21]. Similarly in a sub-study of this trial [22], all women achieved viral load below 400 copies/ml after 8 weeks of ZDV with LPV/r therapy.

The risk posed by high viral load at delivery could probably be minimized by antiretroviral intensification in the peripartum period. Two or three-drug infant postexposure prophylaxis appears to be effective even when mothers present at delivery and have received no prophylaxis [23]. Data from this study suggest that 8 weeks is the interval below which women and their infants may need perinatal intensification, such as sdNVP and, in their infants, 4 weeks of combination antiretrovirals, as recommended in national and international guidelines [9,15][9,15]. The benefit of postnatal antiretroviral intensification should be evaluated in this high-risk situation.

Viral load at entry was significantly associated with overall transmission whereas viral load at delivery was not. We believe the latter finding was a consequence of the fact that LPV/r, which probably prevents intrapartum transmission primarily through reduction in viral load [24–26][24–26][24–26], was administered in only one arm. In the other two arms, ZDV was the only drug administered during pregnancy, along with sdNVP to mother and/or infant at delivery. ZDV in this setting blocks transmission primarily by transplacental pre/postexposure prophylaxis in the fetus (and has little effect on viral load) [27–30][27–30][27–30][27–30], and sdNVP, which also readily crosses the placenta, very likely also functions primarily by this mechanism [31,32][31,32].

The fact that two transmissions in the NVP-NVP group occurred in women who had not received their assigned NVP treatment confirms that ideal prophylaxis should not have to depend on delivering a critical drug (sdNVP) in a setting where it may not be readily available, and in this sense a regimen such as LPV/r with one or two nucleotide-reverse-transcriptase inhibiting (NRTI) drugs taken during pregnancy is more accident-proof.

Several clinical trials of HIV PMTCT have tested maternal and infant regimens similar or close to those in our study. The study by Shapiro and colleagues compared maternal-and-infant NVP at delivery with infant-only-NVP [11] in a regimen where mothers received ZDV monotherapy from 34 weeks’ gestation. Infant infection rates at one month were not different between the maternal-and-infant NVP and the infant-only NVP arms. Intrapartum infections were also not significantly different. The Kesho Bora study compared ZDV-and-sdNVP prophylaxis with LPV/r-based HAART for prevention of MTCT in a mostly breastfed population –78% were ever breastfed [33]. Infant HIV infection rates at 6 weeks of age were not significantly different. The PRIMEVA randomized trial in France compared LPV/r alone with a ZDV + 3TC + LPV/r regimen starting at 26 weeks’ gestation [20]. The rate of virological suppression less than 200 copies/ml 8 weeks after starting was the primary endpoint, and was not significantly different in the two groups. The only transmission was observed in the ZDV + 3TC + LPV/r group. Finally, the large PROMISE trial (P1077, NCT01253538) compared two LPV/r-based regimens (one in addition to ZDV-and-3TC, one in addition to tenofovir-and-emtricitabine) vs. a ZDV-and-sdNVP regimen almost identical to our reference arm. Infant infection rates were 1.8% in the ZDV-and-sdNVP group, 0.5% in the ZDV + 3TC + LPV/r group, and 0.6% in the tenofovir-and-emtricitabine-and-LPV/r group (P < 0.008), showing the superiority of a LPV/r-and-two NRTIs regimen compared with ZDV-and-sdNVP [34]. These rates were lower than those observed in our ‘as-treated’ analysis, perhaps because women in our study initiated ART at 28 weeks (or later) gestation, whereas in PROMISE, median gestational age at enrollment was 26 weeks.

In this study, all interventions appeared well tolerated with low rate of adverse pregnancy outcomes in all arms, but significantly more maternal SAEs in the LPV/r arm. The difference was related to a higher rate of pregnancy disorders in the LPV/r arm. The association between the use of protease inhibitor during pregnancy with the risk of preterm, low birth or stillbirth is debated [34,35][34,35]. The higher incidence of hypercholesterolemia and hypertriglyceridemia observed in women receiving the LPV/r arm compared with the other two arms can be attributed to the well-known dyslipidemic effect of LPV/r [36]. However, these cholesterol or triglyceride elevations were not associated with any acute clinical events. The MONARK study [12] had demonstrated that LPV/r mono-therapy had similar efficacy to ZDV + 3TC + LPV/r in reducing viral load after 24 weeks. Therefore, although ZDV + 3TC + LPV/r would have been a more standard regimen, we chose to use ZDV along with LPV/r to prevent the risk of hepatotoxicity after treatment interruption or additional resistance related to 3TC.

The major limitation in this study was its early closure following the change in Thai National PMTCT guidelines [14], which prevented definitive conclusions about comparative efficacy of the arms. The rise in the CD4+ exclusion criteria for women from less than 250 to less than 350 cells/μl necessitated by new Thai adult treatment recommendations [1] had no impact on the results because randomization was stratified according to the CD4+ level, less or above 350 cells/μl.

In summary, this randomized three-arm trial of antiviral regimens to prevent MTCT of HIV was stopped early because of changes in national treatment guidelines and failed to show the equivalence of the regimens, but it also demonstrated several important points. First, rates of transmission in all three study arms were low. Second, women who received prophylaxis for less than 8 weeks were significantly more likely to transmit HIV, and it appears likely that, when mothers receive a shorter treatment during pregnancy, intensification in the peripartum period would be useful in further reducing transmission.

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Acknowledgements

The authors would like to thank all the women who participated in the trial.

The PHPT-5 study team: L. Decker who oversaw the IT implementation of the trial and the randomization process; Administrative support: A. Lautissier, L. Barra, N. Chaiboonruang, T. Sriwised, T. Tritungtrakul (Intaboonmar), D. Punyatiam, P. Pirom, S. Jitharidkul (Phromsongsil), P. Palidta, S. Vorayutthanakarn, N. Rawanchaikul, S. Nupradit, T. Tankool, W. Champa; Tracking & Supplies: K. Than-in-at, R. Wongsang, M. Inta, N. Mungkhala, P. Saenchitta, K. Oopin, P. Wimolwattanasarn; Safety monitoring: S. S. Chalermpantmetagul, R. Peongjakta, C. Kanabkaew, J. Chaiwan; Sites monitoring: P. Sukrakanchana, B. Ratchanee, J. Thonglo, J. Khanmali, N. Kruenual, N. Krapunpongsakul, N. Krueduangkam, R. Kaewsai (Wongsrisai), R. Wongchai, S. Jinasa, T. Thimakam, W. Pongchaisit, W. Khamjakkaew, S. Thammajitsagul, J. Wallapachai, J. Chalasin, P. Kulchatchai, N. Thuenyeanyong, P. Thuraset, P. Chart, S. Thongsuwan; Data management: S. Barbier, R. Seubmongkolchai, K. Yoddee, S. Tanasri, S. Chailert, N. Naratee, R. Suaysod, K. Chaokasem, R. Jitharidkul, N. Jaisieng, P. Chusut, W. Wongwai, B. Tongpanchang, J. Inkom, A. Lueanyod, T. Chitkawin, W. Chanthaweethip, A. Seubmongkolchai, K. Seubmongkolchai, K. Saopang, R. Malasam, S. Kreawsa, T. Yaowarat (Chattaviriya), A. Wongja, D. Jianphinitnan, K. Ruangwut,S. Suekrasae (Onpha), T. Thanyaveeratham (Chimplee), P. Chailert (Supinya), N. Homkham, P. Pongwaret; Statistics: Nicolas Salvadori and Yvonne Pittelkow;.Laboratory: W. Pilonpongsathorn (Boonprasit), J. Kamkon, P. Moolnoi (Tungyai), P. Pongpunyayuen, Y. Tawon, D. Saeng-ai, L. Laomanit, N. Wangsaeng, P. Khantarag, R. Dusadeepong, S. Surajinda, A. Kaewbundit, P. Punyati, A. Khanpanya, U. Tungchitrapituk, N. Boonpluem, T. Thaiyanant, C. Kasemrat, W. Thimayom, W. Sripaoraya, S. Putthasiraapakorn, W. Danpaiboon, P. Mongkolwat, T. Donchai, P. Sothanapaisan;

The DSMB members: Prof. Scott Hammer, Prof. René Ecochard, Prof. Suwachai Intaraprasert, Assoc. Prof. Rudiwilai Samakoses, Dr Wiput Phoolcharoen;

The pharmacology consultants: Edmund Capparelli, Alice Stek, Mark Mirochnick, Jean-Marc Treluyer.

We are also grateful for the advice and assistance from the Thai Ministry of Public Health: Office of the Permanent Secretary, Departments of Health, Department of Diseases Control, especially, S. Thanprasertsuk, P. Sirinirund, N. Premsri, N. Voramongkol, S. Kanshana, N. Voramongkol, S. Pattarakulwanich, and from the National Institute of Child Health and Human Development: L. Mofenson; as well as the following colleagues who contributed to this project in many critical ways: M. Essex, D. Wirth, and E. Kiley.

Author contributions: Conceived and designed the trial: M. Lallemant, S. Le Coeur, W. Sirirungsi, T.R. Cressey, N. Ngo-Giang-Huong, V. Klinbuayaem, K. McIntosh, G. Jourdain. Enrolled and monitored the patients according to the protocol: P Sabsanong, P. Kanjanovokai. Performed the statistical analysis: P. Traisathit, M. Lallemant. Wrote the first draft of the manuscript: M. Lallemant, S. Le Coeur, K. McIntosh. Contributed to the writing of the manuscript: T.R. Cressey, N. Ngo-Giang-Huong, W. Sirirungsi, P. Traisathit, S. Koetsawang, G. Jourdain. Oversaw the implementation, training, and site coordination: V. Klinbuayaem, S. Koetsawang. All authors reviewed critically the manuscript and agree with the results and conclusions. All authors meet the ICMJE criteria for authorship.

FUNDING: This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), USA [grant number R01 HD052461 and R01 HD056953]; the Ministry of Public Health, Thailand; the Institut de Recherche pour le Développement, France; the Institut National d’Etudes Démographiques, France; and the Thailand International Development Cooperation Agency (TICA). The study drugs provided by Boehringer Ingelheim (nevirapine or placebo) were repackaged at the pharmacy of Children's Hospital, Boston. Study drugs provided by GlaxoSmithKline, ZDV and lamivudine, were repackaged in individual blister at the faculty of pharmacy, Payap University (Chiang Mai).

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Study sites, co-investigators and number of participants enrolled

Samutprakarn Hospital, Dr Prapan Sabsanong, Dr Achara Puangsombat (38); Banglamung Hospital, Dr Kamol Boonrod, Dr Prateep Kanjanavikai, Dr Siriluk Phanomcheong (37); Rayong Hospital, Dr Weerapong Suwankornsakul, Dr Warit Karnchanamayul (30); Nopparat Rajathanee Hospital, Dr Boonsong Rawangban, Dr Sadhit Santadusit, Dr Anita Luvira (28); Hat Yai Hospital, Dr Tapnarong Jarupanich, Dr Boonyarat Warachit (24); Nakhonpathom Hospital, Dr Rucha Kongpanichkul, Dr Suthunya Bunjongpak (22); Samutsakhon Hospital, Dr Supang Varadisai, Dr Sawitree Krikajornkitti (20); Bhumibol Adulyadej Hospital, Dr Sinart Prommas, Dr Prapaisri Layangool (19); Chiangrai Prachanukroh Hospital, Dr Jullapong Achalapong, Dr Kanchana Preedisripipat, Dr Rawiwan Hansudewechakul (15); Prapokklao Hospital, Dr Prapap Yuthavisuthi, Dr Chaiwat Ngampiyaskul (14); Nakornping Hospital, Dr Aram Limtrakul, Dr Suparat Kanjanavanit (14); Health Promotion Center Region 10, Dr Suraphan Sangsawang, Dr Kanokwan Jittayanun (13); Khon Kaen Hospital, Dr Thitiporn Siriwachirachai, Dr Trakarn Saelim, Dr Sirijitt Wasanawatna (11); Maharaj Nakhon Si Thammarat Hospital, Dr Sukit Mahattanan, Dr Somsri Kotchawet (11); Phayao Provincial Hospital, Dr Jittapol Hemvuttiphan, Dr Pornchai Techakunakorn (10); Vachira Phuket Hospital, Dr Sompong Wannun, Dr Somnuk Chirayus, Dr Weerasak Lawtongkum (10); Songkhla Hospital, Dr Supha-arth Phon-in, Dr Wannee Limpitikul (10); Mae Chan Hospital, Dr Surachai Piyaworawong, Dr Sudanee Buranabanjasatean (8); Chonburi Hospital, Dr Nantasak Chotivanich, Dr Suchat Hongsiriwon (8); Pathumthani Hospital, Dr Boonrak Wiriyachoke, Dr Kallaya Srinavarat (8); Phaholpolpayuhasaena Hospital, Dr Yupa Srivarasat, Dr Pornsawan Attavinijtrakarn (7); Chiang Kham Hospital, Dr Chaiwat Putiyanun, Dr Vanichaya Wanchaitanawong (6); Phan Hospital, Mr. Sookchai Theansavettrakul, Dr Sivaporn Jungpichanvanich (6); Lampang Hospital, Dr Prateung Liampongsabuddhi, Dr Sukanya Pituksiripan, Dr Kultida Pongdetudom (6); Fang Hospital, Dr Jantana Jungpipun, Dr Areerat Limpastan (6); Panasnikom Hospital, Dr Manoch Chakorngowit, Dr Wisith Pholsawat (6); Regional Health Promotion Centre 6, Khon Kaen, Dr Kraisorn Vivatpatanakul, Dr Narong Winiyakul, Dr Sansanee Hanpinitsak (5); Mahasarakam Hospital, Dr Sakchai Tonmat, Dr Pairoaj Sitsirat, Dr Sathaporn Na-Rajsima (5); Trat Hospital, Dr Sompong Kittipibul, Dr Suleng Laomanotham (5); Bhuddasothorn Hospital, Dr Annop Kanjanasing, Dr Ratchanee Kwanchaipanich (4); Pranangklao Hospital, Dr Surachai Pipatnakulchai, Dr Paiboon Lucksanapisitkul (4); Chomthong Hospital, Dr Arunsri Iamthongin, Dr Apichai Phiyarom (4), Wiangpapao Hospital, Dr Toranong Pilalai (4); Nong Khai Hospital, Dr Nusra Puarattana.aroonkorn, Dr Sathit Potchalongsin (3); Kalasin Hospital, Dr Bunpode Suwannachat, Dr Sakulrat Srirojana (3); Lamphun Hospital, Dr Wanmanee Matanasarawut, Dr Pornpun Wannarit (2); Mae Sai Hospital, Dr Rattakarn Paramee, Dr Sirisak Nanta (2); Health Promotion Hospital Regional Center I, Dr Somsak Wachirachaikan, Dr Surat Sirinontakan (2); Queen Sirikit Hospital, Dr Pradchaya Kerdkrung, Capt. Temsiri Hinjiranandana (2); Buddhachinaraj Hospital, Dr Kanchapan Sukonpan, Dr Narong Lertpienthum (2); Chiang Saen Hospital, Dr Ittipol Chaitha (2); Sanpatong Hospital, Dr Prayoon Khamja, Dr Noppadon Akarathum (0).

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Conflicts of interest

There are no conflicts of interest.

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Keywords:

antiretroviral therapy; clinical trial; HIV; prevention of mother-to-child transmission; Thailand

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