Abstract
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, non-inferiority trial in Thailand (NCT00409591). Subjects were women with CD4 ≥250 cells/mm3 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 A) NVP-NVP (reference): maternal intrapartum sdNVP with a 7-day “tail” of ZDV+lamivudine, plus infant NVP (one dose immediately, another 48 hours later); B) Infant-only NVP: maternal placebos for sdNVP and the “tail”, plus infant NVP; C) LPV/r: maternal LPV/r starting at 28 weeks. Infants were formula-fed. HIV-diagnosis was determined by DNA-PCR.
Results
435 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% CI: 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 <8 weeks (aOR 15.5; 3.6–66.1) and viral load at baseline ≥4 log10 copies/mL (aOR 10.9; 1.3–91.5). Regimens appeared safe.
Conclusions
Transmission rates in all arms were low but non-inferiority was not proven. Antiretroviral prophylaxis for ≥8 weeks before delivery is necessary to minimize transmission risk.
Keywords: HIV, Prevention of Mother-to-child transmission, Antiretroviral Therapy, Clinical trial, Thailand
INTRODUCTION
Thai national 2007 [1] and WHO 2006 guidelines for prevention of mother-to-child transmission of HIV (PMTCT) in non-breastfeeding women [2] recommended until their 2010 revision [3] that women not requiring antiretroviral treatment for their own health—CD4 count ≥250 cells/mm3— receive zidovudine (ZDV) from 28 weeks’ gestation (or as soon thereafter as possible) plus single-dose nevirapine (sdNVP) at onset of labor, and the newborn sdNVP at 48 to 72 hours of life, plus one week of ZDV. This regimen was simple, safe and efficacious, reducing HIV mother-child transmission (MTCT) to approximately 2% [4]. However, if women or infected infants exposed to nevirapine for PMTCT initiated non-nucleotide-reverse-transcriptase (NNRTI)-based antiretroviral therapy for their own health, virologic efficacy was decreased, possibly due to HIV resistance mutations [5–7]. These mutations could be partially prevented by administering a 2- or 3-drug “tail” to the mother started immediately after sdNVP and lasting 1–4 weeks postpartum [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, plus emerging information that the protease inhibitor (PI) ritonavir-boosted lopinavir (LPV/r) by itself could lower viral load (VL) over a 2–3 month period to a similar extent as LPV/r plus ZDV-plus-lamivudine [12], we designed a 3-arm non-inferiority 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 plus infant-only peripartum NVP; and ZDV plus 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].
Following the 2010 revision of the WHO PMTCT guidelines [3], the Thai Ministry of Public Health modified its guidelines on October 1st 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 co-investigators. We report here the efficacy and safety results of the trial.
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 ≥250/mm3. 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 hours during labor, and all infants received 2 mg of ZDV per kilogram every six hours for one week after birth (6 weeks if their mothers had received ZDV for <4 weeks). The three randomized arms were:
NVP-NVP arm (reference [4]): maternal intrapartum sdNVP 200 mg tablet (Boehringer-Ingelheim, Germany) plus a 7-day “tail” of ZDV 300 mg plus 3TC 150 mg twice daily starting immediately after delivery, and infant NVP (6 mg orally immediately after birth and again 48–72 hours after birth; for newborns weighing <2500 g, the dose was reduced to 2 mg/kg).
Infant-only NVP arm: maternal placebos for sdNVP and the “tail,” and infant NVP as in arm A.
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.
Participants
Eligible subjects 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 >18 years of age, antiretroviral treatment-naive (except for PMTCT of HIV), 28–36 weeks’ gestational age, with CD4 count ≥250 cells/mm3, and had the following laboratory values within 14 days of enrollment: hemoglobin >8.5 g/dL, absolute neutrophils >750 cells/mm3, platelets >50,000 cells/mm3, serum alanine aminotransferase <5X the upper limit of normal, and serum creatinine <1.5X the upper limit of normal. On June 4, 2010, following Thai adult treatment recommendations [15], the CD4 exclusion criteria for women were raised from <250 to <350 cells/mm3. Other exclusion criteria were WHO class III/IV HIV-associated disease, life-threatening fetal anomalies, active tuberculosis or contraindications to the study drugs.
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 June 4, 2010 by CD4 count (below or ≥350 cells/mm3). 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 PL doses as well as tail treatments were accessible in a blinded fashion at any participating hospital with the use of a code.
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. VL (Abbott m2000 RealTime© HIV-1 assay) and CD4 cell count were measured at baseline and delivery. C-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, one, two, four and six 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 hours), 7–10 days, one, two, four and six months, hematology at birth, 7–10 days and 1 month, and chemistry at birth and 7–10 days.
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.
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.
Sample size
The study was designed to test for non-inferiority between the experimental and reference arms i.e. 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 1-sided approach, a sample size of 664 evaluable patients 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 patients per arm were required.
Statistical Methods
Characteristics were compared among treatment groups using chi-square and Kruskal–Wallis tests. Non-inferiority was tested by intent-to-treat and as-treated analyses using the exact confidence intervals 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.
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.
RESULTS
Between January 9, 2009 and September 30, 2010, 1,210 HIV-infected pregnant women were screened for eligibility and 435 randomly assigned to study treatment. Enrollment, loss to follow-up, pregnancy outcomes, and available end points for each treatment group are summarized in Figure 1. Among the 435 women randomized, one was lost to follow-up and 6 withdrew before delivery. A total of 428 women delivered in the study including 4 who had stillbirths. 430 children were born alive, including 425 single, 4 twin, and 1 triple births. Because 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.
Figure 1. Participants flow chart.
*Among the 775 women who were not enrolled: 26 moved to another town or were lost to follow-up, 13 delivered before pre-enrollment evaluations, 22 terminated their pregnancy, 369 started highly active antiretroviral therapy, 272 did not meet the inclusion criteria, 66 had other reasons and 7 women, already screened, were not randomized following the termination of the study after the changes in the national guidelines.
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/mm3 and VL 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, 7 in each arm.
Table 1.
Characteristics of women at enrollment, delivery and neonates
| Maternal Characteristics at enrollment
|
NVP-NVP (N=138)
|
Infant-only NVP (N=129)
|
LPV/r (N=145)
|
All (N=412)
|
|---|---|---|---|---|
| Median Age (Interquartile range)(IQR) (years) | 27 (23.0–32.0) | 28 (23.0–33.0) | 27 (23.0–32.0) | 27 (23.0–32.0) |
| Median gestational age at enrollment (IQR) (weeks) | 28.7 (28.3–31.0) | 28.6 (28.1–30.4) | 28.4 (28.1–30.4) | 28.6 (28.1–30.4) |
| Median CD4 count (IQR) (cells/mm3) | 456 (366–577) | 452 (360–568) | 451 (363–583) | 453 (363–577) |
| Median Viral load (IQR) (log10 copies/mL) | 4.0 (3.5–4.6) | 3.9 (3.4–4.3) | 4.1 (3.4–4.5) | 4.0 (3.4–4.4) |
| WHO classification stage 2 (%) | 2.9 | 1.6 | 2.1 | 2.2 |
| Median gestational age at start of ZDV (IQR) (weeks) | 28.4 (28.0–29.0) | 28.3 (28.0–28.9) | 28.3 (28.0–29.0) | 28.3 (28.0–28.9) |
| Median Hemoglobin level (IQR) (g/dL) | 11.2 (10.4–11.8) | 11.0 (10.4–11.6) | 11.1 (10.5–11.7) | 11.1 (10.4–11.7) |
| Hepatitis B surface antigenemia (%) | 4.4 | 5.4 | 4.8 | 4.9 |
| Hepatitis C antibodies (%) | 4.4 | 2.3 | 2.8 | 3.2 |
| Exposure to PMTCT during a previous pregnancy (%) | 4.9 | 5.0 | 4.6 | 4.8 |
| Delivery Characteristics (excluding women who delivered after study unblinding)
|
NVP-NVP (N=135)
|
Infant-only NVP (N=128)
|
LPV/r (N=142)
|
All (N=405)
|
|---|---|---|---|---|
| Median length of gestation at delivery (IQR) (weeks) | 38.7 (37.8–39.6) | 38.9 (37.9–40.0) | 38.5 (37.6–39.5) | 38.7 (37.8–39.7) |
| Median duration of ZDV therapy (IQR) (weeks) | 10.1 (8.4–11.1) | 10.3 (9.1–11.4) | 10.0 (8.6–11.1) | 10.1 (8.6–11.1) |
| Median time from onset of labor to maternal study drug administration (hours) | 3.0 (1.7–5.9) | 2.9 (1.5–5.6) | - | 3.0 (1.6–5.6) |
| Median time from maternal study drug administration to delivery (hours) | 4.4 (1.9–8.4) | 4.0 (1.6–7.8) | - | 4.2 (1.7–8.1) |
| Median duration of membranes rupture (hours) | 0.5 (0.1–2.0) | 0.3 (0.1–2.2) | 0.6 (0.1–3.5) | 0.5 (0.1–2.7) |
| C-section delivery (%) | 28.9 | 31.3 | 31.7 | 30.6 |
| Among C-section, % before onset of labor and rupture of membranes | 43.6 | 52.5 | 44.4 | 46.8 |
| Median CD4 count (IQR) (cells/mm3) | 533 (400–728) | 515 (401–681) | 558 (434–679) | 552 (414–689) |
| Median Viral load (IQR) (log10 copies/mL) | 3.7 (3.0–4.2) | 3.5 (3.1–4.0) | 1.6 (1.3–2.0) | 3.1 (1.9–3.8) |
| Characteristics of live-born infants
|
NVP-NVP (N=134)
|
Infant-only NVP (N=130)
|
LPV/r (N=143)
|
All (N=407)
|
|---|---|---|---|---|
| Male sex (%) | 49.3 | 53.1 | 46.2 | 49.4 |
| Median Birth weight (IQR) (kg) | 3.0 (2.7–3.3) | 3.0 (2.8–3.3) | 2.9 (2.6–3.2) | 3.0 (2.7–3.3) |
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/mm3, and the median VL at delivery was significantly lower in the LPV/r arm (1.6 log10 copies) than in the 2 other arms (3.6 log10 copies) (p<0.001). The median infant birth weight was 3.0 kg (2.7–3.3), with no difference between arms (Table 1).
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 3 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 received 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 6 infants (1.2%) received ZDV for less than 6 days, while 5.4% received it for more than one month because their mothers had received less than four weeks of ZDV prophylaxis (no difference between arms). Eight women did not receive their study drug before labor, 5 in the NVP-NVP arm and 3 in the infant-only NVP arm. All infants received their 1st NVP dose and only 1 did not receive the 2nd dose.
Efficacy analysis
End points were available for 402 (98.8%) of the 407 live-born infants included in the analysis. A total of 9 HIV transmissions occurred with no significant difference between groups (Table 2). Five transmissions were considered to have occurred in-utero and 4 intra-partum. 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 confidence interval of the difference in rates between infant-only NVP and NVP-NVP as well as LPV/r and NVP-NVP fell within the pre-defined non-inferiority limit of 1.5%.
Table 2.
Intent-to-treat and as-treated transmission rates
|
|
|
||
|---|---|---|---|
|
|
NVP-NVP
|
Infant-only NVP
|
LVP/r
|
| Intent-to treat
|
N=132
|
N=126a
|
N=138b
|
| HIV infections (in utero) | 5 (3) | 2 (1) | 2 (1) |
| Rates (95% CI) | 3.8% (1.2% to 8.6%) | 1.6% (0.2% to 5.6%) | 1.4% (0.4% to 5.1%) |
| Delta (95% CI) | −2.2% (−5.5% to +1.1%) | −2.3% (−5.5% to +0.8%) | |
|
|
|
|
|
| As treatedc | N=136 | N=125 | N=135 |
|
|
|
|
|
| HIV infections (in utero) | 3 (2) | 4 (2) | 2 (1) |
| Rates (95% CI) | 2.2% (0.5% to 6.3%) | 3.2% (0.9% to 8.0%) | 1.5% (0.2% to 5.2%) |
| Delta (95% CI) | 1.0% (−2.3% to +4.3%) | −0.7% (−3.4% to +2.0%) | |
Excluding 2 concordant triplets
Excluding 4 concordant twins
Protocol deviations included 3 women randomized to the LPV/r group who received sdNVP as well as their infants −2 because of LPV/r toxicity and the other one because she delivered in a non-study hospital. These women were considered in the NVP-NVP group in the as-treated analysis; 5 women randomized to the NVP-NVP arm did not receive intrapartum sdNVP. Among them, the 4 women who delivered a liveborn infant were considered in the infant-only NVP group in the as-treated analysis; 5 women randomized to the Infant-only NVP arm received open label sdNVP intrapartum instead of the study treatment and were considered in the NVP-NVP group in the as treated analysis. There was one report of breast-feeding by the mother.
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 confidence interval of the difference in rates exceeded the predefined non-inferiority threshold of 1.5%.
Among the 9 transmitting mothers, maternal VL at entry ranged from 3.1 to 5.7 log10 copies/mL, CD4 count from 261 to 628 cells/mm3, ZDV prophylaxis duration from 27 to 77 days (6 <4 weeks), 4 women delivered prematurely, and only one delivered by C-section (but after onset of labor).
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 VL and CD4 count were significantly associated with transmission, as well as premature delivery and duration of antiretroviral prophylaxis <8 weeks. In the multivariate analysis, factors remaining independently associated with transmission were VL ≥4 log10 copies/ml at baseline (aOR 10.9; 95%CI 1.3–91.5) and duration of antiretroviral prophylaxis <8 weeks (aOR 15.5; 3.6–66.1).
Table 3.
Maternal and infant characteristicsa associated with perinatal HIV transmission
| Odds Ratio (OR) | 95% CI | P value | Adjusted OR | 95% CI | P value | |
|---|---|---|---|---|---|---|
| Maternal characteristics | ||||||
| Gestational age at enrollment ≥30 weeks | 3.2 | 0.9–12.3 | 0.085 | |||
| Length of gestation at start of ZDV (≥30 weeks) | 8.1 | 2.1–31.0 | 0.002 | |||
| Hemoglobin level ≥10 g/dl | 0.5 | 0.1–2.3 | 0.343 | |||
| Viral load ≥4 log10 copies/ml at baseline | 8.0 | 1.0–64.2 | 0.053 | 10.9 | 1.3–91.5 | 0.027 |
| CD4 count <450 cells/mm3 at baseline | 8.4 | 1.0–67.6 | 0.046 | |||
| Viral load * CD4 count interaction | 0.99 | 0.99–1.00 | 0.185 | |||
|
| ||||||
| Delivery Characteristics | ||||||
| Length of gestation at delivery <37 weeks | 5.7 | 1.5–21.8 | 0.012 | |||
| Duration of maternal ARV treatment <8 weeksb | 12.3 | 3.0–41.8 | 0.001 | 15.5 | 3.6–66.1 | <0.001 |
| Viral load at delivery ≥ 3 log10 copies/mL) | 1.8 | 0.5–7.4 | 0.399 | |||
|
| ||||||
| Characteristics of live-born infants | ||||||
| Birth weight < 2500g | 3.5 | 0.9–14.6 | 0.081 | |||
| Female sex | 1.2 | 0.3–4.7 | 0.748 | |||
Characteristics explored in the univariate and multivariate analysis were the following: gestational age at enrollment ≥30 weeks, length of gestational at start of ZDV ≥30 weeks, Hemoglobin level ≥10 g/dL, Viral load ≥ 4 log10 copies/mL at baseline, CD4 count <450 cells/mm3 at baseline, cesarean section, premature rupture of membranes, premature delivery (gestational age less than 37 weeks), duration of ZDV prophylaxis <8 weeks, viral load at delivery ≥3 log10 copies/mL) at delivery, birth weight <2500 grams, sex, interaction of the viral load and CD4 cell count.
Different cutoffs for the duration of ART during pregnancy were examined: a 12-week cutoff could not be tested because no transmission was observed in women with ≥12 weeks ART. The 10-week cutoff was not associated with transmission. The 8 and 6-week cutoffs were both associated with transmission with multivariate models equally fit, while the 4-week cutoff was not. Because our sub-study [22] had shown that all women achieved viral load below 400 copies/mL after 8 weeks of LPV/r+ZDV therapy, the 8-week cutoff was chosen. Also, in terms of public health implications, it seemed more appropriate to use the more inclusive cutoff.
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 to the 2 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 2 arms combined (p<0.01). No severe rashes were observed and only mild rashes occurred in 2 mothers 10 days postpartum (Table 4A).
Table 4.
Maternal and infant safety
| 4 A. Safety in women
| |||||
|---|---|---|---|---|---|
|
|
NVP-NVP N=138
|
Infant-only NVP N=129
|
LPV/r N=145
|
All N=412
|
p-valuea
|
| Women experiencing at least one SAE | |||||
| Number (%) | 12 (8.7) | 17 (13.2) | 25 (17.2) | 54 (13.1) | 0.092 |
| Number of SAEs | 15 | 18 | 31 | 63 | 0.024 |
| HIV-related | - | 1 | 1 | 2 | |
| Pregnancy related | 5 | 7 | 18 | 30 | |
| Delivery related | 5 | 2 | 2 | 9 | |
| Possibly ART related | - | 2 | 4 | 5 | |
| Infections | 2 | 6 | 4 | 12 | |
| Others | 3 | - | 2 | 5 | |
|
|
|
|
|||
| Number of women with toxicity at least one time at any visit during pregnancy (%) | |||||
|
|
|
|
|
|
|
| Anemia grade ≥ 2 | 8 (5.8) | 4 (3.1) | 2 (1.4) | 14 (3.4) | 0.152 |
| Fasting glucose grade ≥ 2 | 7 (5.3) | 2 (1.6) | 7 (5.0) | 16 (4.1) | 0.595 |
| Fasting cholesterol grade ≥ 3 | 10 (8.1) | 17 (14.7) | 29 (22.0) | 56 (15.1) | 0.009 |
| Fasting triglycerides grade ≥ 2 | 4 (3.2) | 4 (4.3) | 25 (18.9) | 33 (8.8) | <0.001 |
| Total bilirubin grade ≥ 1 | 5 (3.6) | 3 (2.3) | 10 (6.9) | 18 (4.4) | 0.078 |
| SGPT grade ≥ 2 | 4 (2.9) | 1 (0.8) | 7 (4.8) | 12 (2.9) | 0.123 |
|
|
|
|
|
|
|
| Rashes at delivery | - | - | - | - | |
| Rashes at 7–10 days post-partum | 1 (0.7) | 1 (0.7) | - | 2 (0.5) | 0.544 |
| 4 B. Adverse pregnancy outcomes
| |||||
|---|---|---|---|---|---|
|
|
NVP-NVP (N=135)
|
Infant-only NVP (N=128)
|
LPV/r (N=142)
|
All (N=405)
|
p-valuea
|
| Stillbirthsb | 1 (0.7%) | 0 (0%) | 3 (2.1%) | 4 (1.0%) | 0.126 |
| Preterm delivery (<37 weeks) | 17 (12.6%) | 16 (12.5%) | 21 (14.8%) | 54 (13.3%) | 0.542 |
| Very preterm deliveries (<34 weeks) | 2 (1.5%) | 3 (2.3%) | 3 (2.1%) | 8 (2.0%) | 1.000 |
| Low birth weight (<2500g) | 17 (12.7%) | 18 (13.9%) | 21 (14.7%) | 56 (13.8%) | 0.763 |
| Very low birth weight (<2000g) | 3 (2.2%) | 5 (3.9%) | 5 (3.5%) | 13 (3.2%) | 0.776 |
| Small for gestational age (< 10th percentilec) | 6 (4.5%) | 6 (4.6%) | 10 (7.0%) | 22 (5.4%) | 0.359 |
|
|
|
|
|
|
|
| 4 C. Safety in children during the first 6 months
| |||||
|---|---|---|---|---|---|
|
|
NVP-NVP N=134
|
Infant-only NVP N=130
|
LPV/r N=143
|
All N=407
|
p-valuea
|
| Children experiencing at least one SAE | |||||
|
|
|
|
|
|
|
| Number (%) | 26 (19.4) | 26 (20.0) | 23 (16.1) | 75 (18.4) | 0.476 |
| Number of SAEs | 36 | 32 | 32 | 100 | 0.423 |
| Infections | 13 | 11 | 20 | 44 | |
| Birth related | 6 | 7 | 4 | 17 | |
| HIV related | 9 | 4 | - | 13 | |
| Possibly related to ART (anemia/neutropenia) | 2 | 6 | 3 | 11 | |
| Congenital anomaliesb | - | 3 | 2 | 5 | |
| Others | 6 | 1 | 3 | 10 | |
|
|
|
|
|
|
|
| Neonatal deathc | - | 1 | 0 | 1 | |
|
| |||||
| Number of children with toxicity grade at least one time at any visit during the first 6 months (%) | |||||
|
|
|
|
|
|
|
| Anemia grade ≥ 2 at 1 month | 34 (25.4) | 40 (30.8) | 46 (32.2) | 120 (29.5) | 0.437 |
| Anemia grade ≥ 2 at 6 month | 6 (4.5) | 5 (3.8) | 4 (2.8) | 15 (3.7) | 0.759 |
| SGPT grade ≥ 2 at 7–10 days | - | 2 (1.5) | 1 (0.7) | 3 (0.7) | 0.422 |
| Rashes at 7–10 days | 3 (2.2) | 2 (1.5) | 2 (1.4) | 7 (1.7) | 0.898 |
Fisher exact test for the comparison of LPV/r versus (NVP-NVP+Infant-only NVP)
Fisher exact test for the comparison of LPV/r versus (NVP-NVP+Infant-only NVP)
4 stillbirths: one in the NVP-NVP arm subsequent to a rupture of membranes > 48 hours, three in the LPV/r arm including one suspected to be related to domestic violence (history of blunt injuries by spouse and scalp hematoma and intracerebral hemorrhage at autopsy) and 2 from unknown reasons.
Defined as <10th percentile of the Thai norms [19]
Fisher exact test for the comparison between the 3 arms
Congenital anomalies: one umbilical polyp, one congenital intestinal obstruction, one agenesis of corpus callosum, one atrial septal defect and one heart malformation.
1 neonatal death from congenital heart malformation at 1 day of life in the infant-only NVP arm.
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 2 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 1 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.
DISCUSSION
This 3-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, 3rd-trimester ZDV plus 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 non-inferiority of the experimental arms compared to 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 pre-exposure prophylaxis and before maternal VL 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 VL but may not readily cross the placental barrier. Two studies of LPV/r in women during pregnancy have shown that VL 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 plus LPV/r therapy.
The risk posed by high VL at delivery could probably be minimized by antiretroviral intensification in the peripartum period. Two- or three-drug infant post-exposure 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, four weeks of combination antiretrovirals, as recommended in national and international guidelines [9, 15]. The benefit of postnatal antiretroviral intensification should be evaluated in this high risk situation.
VL at entry was significantly associated with overall transmission whereas VL 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] 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/post exposure prophylaxis in the fetus (and has little effect on VL)[27–30], and sdNVP, which also readily crosses the placenta, very likely also functions primarily by this mechanism [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-plus-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-plus-infant NVP and the infant-only NVP arms. Intrapartum infections were also not significantly different. The Kesho Bora study compared ZDV-plus-sdNVP prophylaxis with LPV/r-based HAART for prevention of MTCT in a mostly breastfed population −78% were ever breast-fed— [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 <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-plus-3TC, one in addition to tenofovir-plus-emtricitabine) vs. a ZDV-plus-sdNVP regimen almost identical to our reference arm. Infant infection rates were 1.8% in the ZDV-plus-sdNVP group, 0.5% in the ZDV+3TC+LPV/r group, and 0.6% in the tenofovir-plus-emtricitabine-plus-LPV/r group (p<0.008), showing the superiority of a LPV/r-plus-2 NRTIs regimen compared to ZDV-plus-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, while in PROMISE, median gestational age at enrollment was 26 weeks.
In this study, all interventions appeared safe 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 PI during pregnancy with the risk of preterm, low birth or stillbirth is debated [34, 35]. The higher incidence of hypercholesterolemia and hypertriglyceridemia observed in women receiving the LPV/r arm compared to the other 2 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 VL after 24 weeks. Therefore, although ZDV+3TC+LPV/r would have been a more standard regimen, we chose to use ZDV+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 <250 to <350 cells/mm3 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/mm3.
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.
Acknowledgments
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 plus lamivudine, were repackaged in individual blisters at the faculty of pharmacy, Payap University (Chiang Mai).
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.
Appendix
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)
Footnotes
Author Contributions
Conceived and designed the trial: M Lallemant, S Le Coeur, W Sirirungsi, TR 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: TR 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.
References
- 1.Department of Disease Control. National antiretroviral treatment guidelines 2006/2007. Ministry of Public Health; Thailand: 2007. [Google Scholar]
- 2.World Health Organization. Recommendations for a public health approach. Geneva: World Health Organization; 2006. Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants: towards universal access. [Google Scholar]
- 3.World Health Organization. Antiretroviral drugs for treating pregnant women and preventing HIV infections in infants. Recommendations for a public health approach. 2010 2010 version. [PubMed] [Google Scholar]
- 4.Lallemant M, Jourdain G, Le Coeur S, Mary JY, Ngo-Giang-Huong N, Koetsawang S, et al. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. N Engl J Med. 2004;351:217–228. doi: 10.1056/NEJMoa033500. [DOI] [PubMed] [Google Scholar]
- 5.Jourdain G, Ngo-Giang-Huong N, Le Coeur S, Bowonwatanuwong C, Kantipong P, Leechanachai P, et al. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med. 2004;351:229–240. doi: 10.1056/NEJMoa041305. [DOI] [PubMed] [Google Scholar]
- 6.Lockman S, Shapiro RL, Smeaton LM, Wester C, Thior I, Stevens L, et al. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. N Engl J Med. 2007;356:135–147. doi: 10.1056/NEJMoa062876. [DOI] [PubMed] [Google Scholar]
- 7.Lockman S, Hughes MD, McIntyre J, Zheng Y, Chipato T, Conradie F, et al. Antiretroviral therapies in women after single-dose nevirapine exposure. N Engl J Med. 2010;363:1499–1509. doi: 10.1056/NEJMoa0906626. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Palmer S, Boltz VF, Chow JY, Martinson NA, McIntyre JA, Gray GE, et al. Short-course Combivir after single-dose nevirapine reduces but does not eliminate the emergence of nevirapine resistance in women. Antivir Ther. 2012;17:327–336. doi: 10.3851/IMP1946. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.British Medical Association. British Medical Association guidelines for the management of HIV infection in pregnant women 2012 (2014 interim review) HIV Medicine. 2014;15:1–77. doi: 10.1111/hiv.12185. [DOI] [PubMed] [Google Scholar]
- 10.Van Dyke RB, Ngo-Giang-Huong N, Shapiro DE, Frenkel L, Britto P, Roongpisuthipong A, et al. A comparison of 3 regimens to prevent nevirapine resistance mutations in HIV-infected pregnant women receiving a single intrapartum dose of nevirapine. Clin Infect Dis. 2012;54:285–293. doi: 10.1093/cid/cir798. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Shapiro RL, Thior I, Gilbert PB, Lockman S, Wester C, Smeaton LM, et al. Maternal single-dose nevirapine versus placebo as part of an antiretroviral strategy to prevent mother-to-child HIV transmission in Botswana. AIDS. 2006;20:1281–1288. doi: 10.1097/01.aids.0000232236.26630.35. [DOI] [PubMed] [Google Scholar]
- 12.Delfraissy JF, Flandre P, Delaugerre C, Ghosn J, Horban A, Girard PM, et al. Lopinavir/ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV-infected patients. AIDS. 2008;22:385–393. doi: 10.1097/QAD.0b013e3282f3f16d. [DOI] [PubMed] [Google Scholar]
- 13.Bessesen M, Ives D, Condreay L, Lawrence S, Sherman KE. Chronic active hepatitis B exacerbations in human immunodeficiency virus-infected patients following development of resistance to or withdrawal of lamivudine. Clin Infect Dis. 1999;28:1032–1035. doi: 10.1086/514750. [DOI] [PubMed] [Google Scholar]
- 14.Zuckerman AJ. Hepatitis Viruses. 1996:849–863. [Google Scholar]
- 15.Phanuphak N, Lolekha R, Chokephaibulkit K, Voramongkol N, Boonsuk S, Limtrakul A, et al. Thai national guidelines for the prevention of motherto-child transmission of HIV: March 2010. Asian Biomedicine. 2010;4:529–540. doi: 10.5372/1905-7415.1102.547. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Ngo-Giang-Huong N, Khamduang W, Leurent B, Collins I, Nantasen I, Leechanachai P, et al. Early HIV-1 diagnosis using in-house real-time PCR amplification on dried blood spots for infants in remote and resource-limited settings. J Acquir Immune Defic Syndr. 2008;49:465–471. doi: 10.1097/QAI.0b013e31818e2531. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Bryson YJ, Luzuriaga K, Sullivan JL, Wara DW. Proposed definitions for in utero versus intrapartum transmission of HIV-1. N Engl J Med. 1992;327:1246–1247. doi: 10.1056/NEJM199210223271718. [DOI] [PubMed] [Google Scholar]
- 18.Division of AIDS table for grading the severity of adult and pediatric adverse events Version 1.0. 2004 Dec; clarification August 2009. http://rsc.tech-res.com/Document/safetyandpharmacovigilance/Table_for_Grading_Severity_of_Adult_Pediatric_Adverse_Events.pdf.
- 19.Tongsong T, Simaraks S, Sirivatanapa P, Sudasna J, Wanapirak C, Kunavikatikul C, et al. Study of intrauterine growth from birthweight at Maharaj Nakhon Chiang Mai Hospital. J Med Assoc Thai. 1993;76:482–486. [PubMed] [Google Scholar]
- 20.Tubiana R, Mandelbrot L, Le Chenadec J, Delmas S, Rouzioux C, Hirt D, et al. Lopinavir/ritonavir monotherapy as a nucleoside analogue-sparing strategy to prevent HIV-1 mother-to-child transmission: the ANRS 135 PRIMEVA phase 2/3 randomized trial. Clin Infect Dis. 2013;57:891–902. doi: 10.1093/cid/cit390. [DOI] [PubMed] [Google Scholar]
- 21.Warszawski J, Tubiana R, Le Chenadec J, Blanche S, Teglas JP, Dollfus C, et al. Mother-to-child HIV transmission despite antiretroviral therapy in the ANRS French Perinatal Cohort. AIDS. 2008;22:289–299. doi: 10.1097/QAD.0b013e3282f3d63c. [DOI] [PubMed] [Google Scholar]
- 22.Cressey TR, Jourdain G, Rawangban B, Varadisai S, Kongpanichkul R, Sabsanong P, et al. Pharmacokinetics and virologic response of zidovudine/lopinavir/ritonavir initiated during the third trimester of pregnancy. AIDS. 2010;24:2193–2200. doi: 10.1097/QAD.0b013e32833ce57d. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Nielsen-Saines K, Watts DH, Veloso VG, Bryson YJ, Joao EC, Pilotto JH, et al. Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. N Engl J Med. 2012;366:2368–2379. doi: 10.1056/NEJMoa1108275. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Gingelmaier A, Kurowski M, Kastner R, Eberle J, Mylonas I, Belohradsky BH, et al. Placental transfer and pharmacokinetics of lopinavir and other protease inhibitors in combination with nevirapine at delivery. AIDS. 2006;20:1737–1743. doi: 10.1097/01.aids.0000242820.67001.2c. [DOI] [PubMed] [Google Scholar]
- 25.Ivanovic J, Nicastri E, Anceschi MM, Ascenzi P, Signore F, Pisani G, et al. Transplacental transfer of antiretroviral drugs and newborn birth weight in HIV-infected pregnant women. Curr HIV Res. 2009;7:620–625. doi: 10.2174/157016209789973628. [DOI] [PubMed] [Google Scholar]
- 26.Else LJ, Taylor S, Back DJ, Khoo SH. Pharmacokinetics of antiretroviral drugs in anatomical sanctuary sites: the male and female genital tract. Antivir Ther. 2011;16:1149–1167. doi: 10.3851/IMP1919. [DOI] [PubMed] [Google Scholar]
- 27.O’Sullivan MJ, Boyer PJ, Scott GB, Parks WP, Weller S, Blum MR, et al. The pharmacokinetics and safety of zidovudine in the third trimester of pregnancy for women infected with human immunodeficiency virus and their infants: phase I acquired immunodeficiency syndrome clinical trials group study (protocol 082). Zidovudine Collaborative Working Group. Am J Obstet Gynecol. 1993;168:1510–1516. doi: 10.1016/s0002-9378(11)90791-1. [DOI] [PubMed] [Google Scholar]
- 28.Watts DH, Brown ZA, Tartaglione T, Burchett SK, Opheim K, Coombs R, et al. Pharmacokinetic disposition of zidovudine during pregnancy. J Infect Dis. 1991;163:226–232. doi: 10.1093/infdis/163.2.226. [DOI] [PubMed] [Google Scholar]
- 29.Sperling RS, Shapiro DE, Coombs RW, Todd JA, Herman SA, McSherry GD, et al. Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1996;335:1621–1629. doi: 10.1056/NEJM199611283352201. [DOI] [PubMed] [Google Scholar]
- 30.Melvin AJ, Burchett SK, Watts DH, Hitti J, Hughes JP, McLellan CL, et al. Effect of pregnancy and zidovudine therapy on viral load in HIV-1-infected women. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;14:232–236. doi: 10.1097/00042560-199703010-00006. [DOI] [PubMed] [Google Scholar]
- 31.Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995;373:123–126. doi: 10.1038/373123a0. [DOI] [PubMed] [Google Scholar]
- 32.Mirochnick M, Fenton T, Gagnier P, Pav J, Gwynne M, Siminski S, et al. Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Pediatric AIDS Clinical Trials Group Protocol 250 Team. J Infect Dis. 1998;178:368–374. doi: 10.1086/515641. [DOI] [PubMed] [Google Scholar]
- 33.Kesho Bora Study G. de Vincenzi I. Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised controlled trial. Lancet Infect Dis. 2011;11:171–180. doi: 10.1016/S1473-3099(10)70288-7. [DOI] [PubMed] [Google Scholar]
- 34.Fowler MG, Quin M, Fiscus SA, Currier JS, Makanani B, Martinson F, et al. PROMISE: Efficacy and Safety of 2 strategies to prevent Perinatal HIV Transmission. CROI. 2015 31LB 2015. [Google Scholar]
- 35.Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. [Accessed on June 4, 2015];Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. 2014 http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf.
- 36.Walmsley S, Bernstein B, King M, Arribas J, Beall G, Ruane P, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med. 2002;346:2039–2046. doi: 10.1056/NEJMoa012354. [DOI] [PubMed] [Google Scholar]