Without intervention, the risk of mother-to-child HIV transmission in the breastfed population is 35%–40%.1,2 Single-dose nevirapine (sdNVP) to the mother at onset of labor and sdNVP to the newborn within 24–72 hours after birth remains part of treatment for prevention of mother-to-child HIV transmission (pMTCT) in most resource-limited countries.2,3 This simple and affordable intervention reduces mother-to-child HIV transmission by 40% and has benefited thousands of babies since its introduction in 2000.
Nevirapine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent antiviral activity, but a low genetic barrier, with one mutation causing high-level resistance. It is rapidly absorbed when given orally and passes quickly through the placenta. The primary elimination pathway for nevirapine is oxidative metabolism by cytochrome P-450 3A4 and 2B6 enzymes.4 The drug has a long elimination half-life in pregnant women using a single 200-mg dose at labor (median 61–66 hr). This leads to persisting subtherapeutic plasma concentrations, which, given its low genetic barrier to resistance,5,6 means a single dose can lead to primary nevirapine resistance in 15%–75% mothers.7–9
Clinically, nevirapine resistance has 3 major implications. First, the efficacy of nevirapine or other NNRTIs in combination antiretroviral therapy (ART) may be diminished when a patient harbors resistant virus. Indeed, studies in sub-Saharan Africa suggest that recent exposure to sdNVP (<6 months) is associated with increased risk for virological and clinical failure.7,10–13 Second, nevirapine-resistant strains may be transmitted to others, limiting their treatment options. Third, nevirapine resistance could reduce the efficacy of sdNVP in subsequent pregnancies,14,15 although data suggest nevirapine resistance fades in these women over time and sdNVP remains effective for prophylaxis in subsequent pregnancies.16,17
Updated World Health Organization (WHO) guidelines therefore now recommend adding zidovudine + lamivudine for 7 days postpartum to cover the prolonged presence of subtherapeutic nevirapine concentrations after sdNVP at labor onset.18–20 Recent studies show adding single-dose tenofovir + emtricitabine to sdNVP and short-course zidovudine further reduces NNRTI resistance.21–23 Of note, none of these interventions fully eradicated nevirapine resistance,19 which therefore remains a serious and growing concern.
A different approach to limit nevirapine resistance development would be a pharmacological intervention to reduce nevirapine elimination half-life. Carbamazepine is a low cost widely available anticonvulsant, an inducer of cytochrome P-450 3A4 enzymes, which passes into breast milk and might decrease nevirapine elimination half-life and resistance development in the mother. A pilot study comparing 8 different CYP3A induction strategies with different drugs demonstrated that elimination half-life of sdNVP was reduced most (by 35%) by adding single-dose carbamazepine in healthy volunteers.4
In this phase II trial, we therefore investigated whether the addition of single-dose carbamazepine, as CYP3A4 enzyme inducer, would diminish nevirapine resistance development by reducing elimination half-life after exposure to sdNVP at onset of labor in HIV-infected, pregnant, Tanzanian women.
HIV-1–infected, pregnant women attending antenatal clinics in Moshi, Tanzania, were recruited from Kilimanjaro Christian Medical Centre (KCMC) as the consultant hospital, 3 primary and 1 tertiary antenatal care units. Counseling and voluntary HIV testing (by the dual rapid-test algorithm) was offered routinely to all pregnant women attending antenatal services in these clinics as part of the national pMTCT program. Women testing positive received posttest counseling and were informed about the trial. Eligible HIV-infected women were as follows: aged 18–40 years, CD4 count >200 cells per cubic millimeter (ie, did not qualify for ART at the time), antiretroviral (ARV) naive, living within the catchment area, not intending to relocate during study participation, willing to adhere to the follow-up schedule, able and willing to give informed consent, and to regularly attend the antenatal clinic. Exclusion criteria were: previously treated with ARVs including sdNVP in a previous pregnancy and serious illness that required systemic treatment/hospitalization. Women who qualified for ART (ie, CD4 <200 cells/mm3) were referred for care and not enrolled. Written consent was obtained where possible; for eligible women who could not read, consent was obtained orally and documented by a witness. The study was approved by institutional review boards of KCMC, Moshi, Tanzania, and Radboud University Nijmegen Medical Centre, The Netherlands. The study is registered with ClinicalTrials.gov, number NCT00294892.
After 28 weeks gestation, eligible women who had provided informed consent were allocated 1:1 to receive either the national standard care at the time of sdNVP (200 mg) or sdNVP plus single-dose carbamazepine (sdNVP/CBZ, 400 mg) orally at onset of labor (open-label). Nevirapine (and carbamazepine if allocated) was handed to the woman at enrollment following standard antenatal policy, ideally at 28 weeks of pregnancy at her routine checkup visit and at the latest just before delivery following standard antenatal policy. In both groups, sdNVP suspension was administered to the baby within 24–72 hours after birth. The randomization list was generated as alternate allocations by the study pharmacist (ie, was quasi randomized) and was held centrally at the KCMC pharmacy. Allocations were made by local medical officers at antenatal clinics phoning the pharmacist: as there were 4 local antenatal clinics, the next allocation was concealed to study teams until it was made. Participants were asked to take study drugs at onset of labor pain and to come to the labor ward for delivery. If the woman vomited within 30 minutes of study drug(s) administration or did not deliver within 48 hours, a second single dose of nevirapine (not carbamazepine) was given. When the women presented in labor, a study nurse confirmed study drug(s) ingestion by direct observation of intake at the clinic or by asking the women when they had taken study drug(s) already at home. Replacement drugs were provided for those who had not taken them. The time of ingestion of study drugs was recorded in the case report form. As the national guidelines recommended, all women (100%) in the trial opted to exclusively breastfeed for 6 months and then wean rapidly.
Objectives, Outcomes, and Follow-up
The primary objectives were to determine the effect of adding single-dose carbamazepine on sdNVP pharmacokinetics and nevirapine resistance development in the women. The first coprimary outcome was therefore nevirapine plasma concentration 1 week postpartum. Blood samples were taken 1 week postpartum (and at delivery) for pharmacokinetic evaluation. The second coprimary outcome was the proportion of women with any of the following major nevirapine resistance mutations L100I, K101P, K103N, V106A/M, V108I, Y181C/I, Y188C/L/H, G190A9,24 on majority sequencing 6 weeks postpartum. Secondary outcomes were any positive HIV RNA polymerase chain reaction test of the newborn and adverse events (including any grade of toxicity in laboratory safety tests taken 1-week postpartum) possibly/probably/definitely related to study drugs.
Hematology and biochemistry tests were determined at enrollment and 1 week postpartum. CD4 cell counts and quantitative plasma HIV-1 RNA were assayed just after delivery. Infants were tested just after birth, week 6, and month 4 by HIV-1 RNA polymerase chain reaction assays. Blood was taken at delivery and 1 week postpartum, and plasma stored for bioanalysis of nevirapine plasma concentrations, done in the Department of Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, using high-performance liquid chromatography (HPLC) (lower limit of quantification 0.05 mg/L).25 Resistance was assayed in plasma stored from samples with >500 copies per milliliter at delivery and the 6-week antenatal visit at the Department of Virology of the University Medical Centre Utrecht, The Netherlands (samples < 500 copies/mL, the lower limit of quantification of the resistance assay, were assumed to have no important resistance mutations).
The intended sample size of 100 women per group provided >80% power to detect a 2-fold reduction in the proportion with resistance (from 36% to 18%) with 2-sided alpha = 0.05. Statistical analysis of nevirapine plasma concentrations and mutations was undertaken using SPSS, version 13.0 (SPSS Inc). Categorical variables were analyzed with χ2 tests (or exact tests for expected cell frequency <5) and continuous variables with rank-sum tests. Analyses were based on women still eligible at delivery (Fig. 1). As the primary outcome measures were based on batched laboratory measures, analyses also excluded women who had evidence of noncompliance (carbamazepine detected by HPLC in sdNVP group or no carbamazepine detected by HPLC in sdNVP/CBZ group).
We screened 354 HIV-infected ARV-naive pregnant women between February 2006 and April 2009 (Fig. 1). One-hundred ninety-two (54%) were eligible; the remainder were not eligible (mostly CD4 <200 cells/mm3) or declined to participate. The study was terminated in April 2009 after 192 patients had been enrolled when the new WHO pMTCT regimen (with zidovudine + lamivudine tail) was introduced in Moshi. Groups were reasonably balanced for age, body mass index, weight, CD4 count, hematology and biochemistry parameters at enrollment and delivery (Table 1).
Thirty-four women were randomized but did not take study drugs at delivery. Four (all sdNVP) had CD4 declines to <200 cells per cubic millimeter and were referred for ART. Twenty-one (12 sdNVP, 9 sdNVP/CBZ) did not return after enrolment for subsequent antenatal visits or delivery, 7 (5 sdNVP, 2 sdNVP/CBZ) delivered at home or at nonstudy sites, and 2 (1 sdNVP, 1 sdNVP/CBZ) withdrew or did not want study participation disclosed before or at delivery. Thus 75 sdNVP and 83 sdNVP/CBZ women remained in the study at delivery. One hundred thirty-three of 158 (84%) delivery samples were available [62/75 (83%) sdNVP, 72/83 (87%) sdNVP/CBZ]. Missing samples were not taken or had insufficient volume or clotted before analysis. One woman in the control group had detectable carbamazepine levels and was excluded from analyses.
The median (interquartile range) nevirapine plasma concentrations immediately after delivery were 1.55 (0.88–1.84) mg/L for the sdNVP group and 1.40 (0.93–1.97) mg/L for the sdNVP/CBZ group (Table 2) (rank-sum P = 0.91) [geometric mean ratio: 1.17, 95% confidence interval (CI): 0.76 to 1.81; P = 0.48]. As expected, nevirapine plasma concentrations were significantly reduced in both groups 1 week after delivery [based on matched pairs of measurements, sdNVP geometric mean ratio (1 week:delivery, n = 44) = 0.18, 95% CI: 0.12 to 0.26; sdNVP/CBZ geometric mean ratio (1 week:delivery, n = 54) = 0.10, 95% CI: 0.07 to 0.14): results similar using unmatched data]. In the sdNVP/CBZ group, week 1 nevirapine plasma concentrations were significantly lower compared with the sdNVP group (geometric mean ratio: 0.64, 95% CI: 0.43 to 0.96; P = 0.03; Table 2) with median (interquartile range) nevirapine concentration 0.09 (0.05–0.20) mg/L in the sdNVP/CBZ group versus 0.20 (0.09–0.31) mg/L in the sdNVP group (rank-sum: P = 0.004). Moreover, there was a trend to a greater proportion with undetectable nevirapine levels (<0.05 mg/L) in sdNVP/CBZ than sdNVP groups; 15 of 63 (24%) versus 6 of 52 (12%), respectively (χ2 P = 0.09).
At week 6, 110 (53 sdNVP, 57 sdNVP/CBZ) samples were available for HIV genotyping. For 3 women, plasma volumes were too limited, leaving 107 with valid genotypes. Eleven (21%) of the 52 women in the sdNVP group had 1 or more nevirapine-associated resistance mutations, compared with 6 of 55 (11%) in the sdNVP/CBZ group (odds ratio = 0.46, 95% CI: 0.16-1.34, χ2 P = 0.15). Eight women in the sdNVP group had 1 nevirapine mutation and 3 had 2 mutations (Fig. 2), compared with 5 and 1, respectively, in the sdNVP/CBZ group [poisson incidence rate ratio for number of mutations in sdNVP/CBZ vs. sdNVP = 0.47 (95% CI: 0.19 to 1.17) P = 0.11]. All but 2 of the mutations were detected as mixtures with wild-type nucleotide sequence. Only 1 of 2 mutations in 1 woman in the sdNVP group was already present in a sample stored at the enrollment visit. None of the other nevirapine mutations were already present in enrollment samples. Figure 3 shows the distribution of the nevirapine mutations 6 weeks after delivery. K103N, Y181C/I, and G190A were the most frequently observed nevirapine mutations. The most common mutation was K103N, present in 9 women, alone in 8 women and with G190A in 1.
Combined Pharmacokinetic Resistance Analysis
Nevirapine plasma concentrations 1-week postpartum were available from 14 of 17 (82%) women with mutations versus 71 of 90 (79%) without mutations. Median week-1 nevirapine plasma concentrations were similar in women with [median (interquartile range) 0.12 (0.09–0.29) mg/L] and without [0.11 (0.06–0.22) mg/L] mutations (P = 0.36). However, none of the 15 women with undetectable nevirapine levels at week 1 developed nevirapine resistance compared with 14 of 70 (20%) of those with detectable nevirapine at week 1 (exact P = 0.07). Thus, irrespective of group assignment, women with undetectable plasma concentrations at week 1 were less likely to develop nevirapine-associated mutations after sdNVP for pMTCT.
Samples were available for viral load testing from 102 newborns (93%), of which, 3 were of insufficient quantity or clotted. The overall HIV-1 transmission rate was 6 of 50 (12%) in the sdNVP/CBZ group and 3 of 49 (6%) in sdNVP group (exact P = 0.49). Although not all infants were tested at delivery, 1 of 6 (17%) and 0 of 3 (0%) infected babies in the sdNVP/CBZ and sdNVP groups, respectively, were known to have been infected during the intrauterine period. Three babies (1 sdNVP, 2 sdNVP/CBZ) died at delivery, 1 (sdNVP/CBZ) died in the first 6 weeks after delivery and 1 (sdNVP/CBZ) after 4 months of delivery. There were no adverse events in the infants possibly/probably/definitely related to study medication(s).
Women were similar in all laboratory safety parameters at enrollment (P = 0.06 to P = 0.80) (Table 1). Forty-two adverse events were reported in the sdNVP group and 40 in the sdNVP/CBZ group between enrollment and delivery (ie, before trial intervention), mostly grade 1 (31 sdNVP, 29 sdNVP/CBZ). Only 7 were grade 4 (3 sdNVP, 4 sdNVP/CBZ); 6 women had grade 4 anemia (Hb < 6.5 g/dL) and 1 had AST >10.0 × upper limit of normal.
One week after delivery, women were also comparable in hematology and biochemistry parameters (P > 0.26) except for leucocytes (P = 0.002) and neutrophils (P = 0.009, Table 1). However, nearly all values [27/27 (100%) sdNVP, 37/38 (97%) sdNVP/CBZ] were in the normal range for neutrophils (>1.3 × 109/L) and for leucocytes (27/27 (100%) sdNVP; 38/39 (97%) sdNVP/CBZ) (>2.5 × 109/L). After delivery, 6 adverse events were reported in the sdNVP group and 21 in the sdNVP/CBZ group. Most events were grade 1 (2 sdNVP; 13 sdNVP/CBZ); of the remaining events, 7 were grade 2 (3 sdNVP; 4 sdNVP/CBZ), 3 grade 3 (1 sdNVP; 2 sdNVP/CBZ), and only 2 were grade 4 (2 sdNVP/CBZ), both anemia (Hb < 6.5 g/dL). None of the adverse events (including the grade-4 anemias) were considered possibly/probably/definitely drug related.
This trial provides the first data on adding a single-dose of an enzyme inducer (carbamazepine) to sdNVP for pMTCT in HIV-infected pregnant women. Single-dose carbamazepine significantly reduced nevirapine plasma concentrations 1 week after delivery, with a trend toward fewer resistance mutations. We also found a trend toward lower rates of nevirapine resistance in women with undetectable nevirapine concentrations across the whole population, supporting the validity of this approach.
Nevirapine plasma concentrations were determined in samples obtained immediately after delivery and 1 week postpartum. Overall, these plasma concentrations were comparable with previous studies.6,26,27 Adding single-dose carbamazepine did not affect nevirapine plasma concentrations immediately after delivery, similarly to L'homme et al4 in healthy women. A delay in effect on enzyme induction by single-dose carbamazepine would be expected because increased protein synthesis is required, which takes a few days for maximum impact.4 This is important as the addition of an enzyme inducer should not negatively influence the protective effect of sdNVP on HIV mother-to-child transmission. The delay in enzyme induction and the low concentrations of carbamazepine in breast-milk mean that reductions in infant nevirapine levels are unlikely.28 Indeed, perinatal HIV-1 transmission rates were similar to rates reported in previous studies of women using sdNVP for the first time.2,15,29–31
One week after delivery, nevirapine concentrations were 36% lower in the sdNVP/CBZ group, with a trend toward a higher proportion with undetectable plasma concentrations in this group. Plasma concentrations 1-week postpartum are determined by nevirapine elimination half-life, and, therefore, significantly lower concentrations in the sdNVP/CBZ group directly translate into significantly higher elimination half-life. In a previous pilot study4 in healthy Dutch female volunteers, the nevirapine elimination half-life declined by 35% with additional single-dose carbamazepine, and the median time to undetectable levels was reduced by 23%. Our study differed in study design (single sample only) and subject population, but single-dose carbamazepine seems to reduce nevirapine elimination half-life at least as effectively in HIV-infected pregnant Tanzanian women. As our sample size was determined by the (binary) nevirapine resistance coprimary endpoint, our power to detect changes in nevirapine concentrations was higher, with even 50 patients per group providing at least 80% power to detect a 50% relative decrease in 1-week nevirapine concentration based on standard deviations observed in the pilot study.4
To reduce the emergence of nevirapine resistance after sdNVP, several studies have investigated the addition of other ARVs after delivery. A meta-analysis reported 36% average nevirapine resistance prevalence for women using sdNVP (with or without other ARVs).32 For those women receiving ARVs postpartum, this fell to 4.5%. Although nevirapine resistance drops dramatically with these new strategies including combination “tail” ARVs, the major disadvantages are their complexity and the emergence of lamivudine resistance (due to long intracellular elimination half-life), which is associated with virological and clinical failure in women starting lamivudine-containing ART for their own health.11,33 To preserve its simplicity, Chi et al22 administered a single dose of emtricitabine + tenofovir with sdNVP in 400 women, which also halved nevirapine resistance; 25% versus 12%. As it targets a different mechanism, the pharmacologic approach described here might have an additive effect and also maintains simplicity.
Our study has several limitations. First, we had high loss to follow-up. This is unfortunately not uncommon in pMTCT programs in sub-Saharan Africa.34,35 Traditions, stigmatization, and fear of harassment and rejection accounted for most of our loss to follow-up. More intensive counseling for women using pMTCT prophylaxis and more aggressive methods to identify and locate those not returning for appointments should reduce loss to follow-up rates in future studies. Second, the randomization list was generated as alternate allocations (ie, was only quasi-randomized) by the study pharmacist, who assigned groups centrally and did not include patients herself; previous allocations were concealed from the local medical officers enrolling patients. This together with the open-label allocation could have led to bias, although not in the direct assessment of coprimary outcomes (pharmacokinetics and resistance) which were measured on batched stored samples blinded to allocation. The third limitation was the far smaller sample size for resistance testing than designed, which limited our power to detect differences in resistance between the groups. Finally, the standard HIV genotyping assays could only detect viral mutations found in >20% of the overall HIV population and not subpopulations of mutants. Deep sequencing is planned for future projects.
The original pilot study in healthy Dutch female volunteers was performed to identify enzyme inducers that could reduce nevirapine half-life. The mechanisms by which the CYP3A4 enzyme are induced involves the activation of the transcription factors pregnane X receptor and the constitutive androstane receptor.36 Nevirapine is a drug that binds to those receptors, whereafter activation of the CYP3A4 enzyme starts. From the 8 interventions single-dose carbamazepine and phenytoin for 3 or 7 days were shown to decrease the nevirapine half-life significantly.5 We, therefore, chose single-dose carbamazepine as our study intervention because of its simplicity. Single-dose carbamazepine could lead to greater adherence compared with the current national and WHO guidelines and is highly likely to reduce emergence of NNRTI resistance even further. Moreover, single-dose carbamazepine is a very low-cost intervention and even when NRTIs turn out not to be available, carbamazepine is in almost every clinic in resource-limited countries. The current national and WHO guidelines for pMTCT recommend new and more effective but also more complex and expensive regimens than sdNVP alone; their widespread implementation is challenging. A second pharmacokinetic trial (VITA-2; ClinicalTrial.gov ID: NCT01187719) has consequently started to evaluate the effect of 7 days of phenytoin, a different course of an enzyme inducer, also shown to be effective in the previous pilot study, on the pharmacokinetics and resistance of sdNVP in HIV-infected pregnant women in combination with the new recommended WHO and national guidelines. Studies, as the VITA-2 trial, with different enzyme inducers given for an extended period will be in addition to the new WHO pMTCT guidelines combining sdNVP at delivery with zidovudine from the second trimester of gestation and zidovudine + lamivudine labor for 7 days postpartum. The fact that nevirapine resistance is still observed using these approaches suggests pharmacologic interventions such as evaluated in this study may still add benefit.
In conclusion, our study demonstrates that a simple intervention of single-dose carbamazepine in addition to sdNVP alone for antiretroviral prophylaxis for pMTCT considerably reduces the nevirapine plasma concentrations and likely reduces emergence of nevirapine resistance mutations. Enzyme inducers, such as carbamazepine, show new possibilities for pMTCT programs to reduce the development of nevirapine resistance in settings where other options are limited.
We thank all the patients and staff from all the clinics participating in the VITA1 trial. VITA Trial Team: Kilimanjaro Christian Medical College, Moshi, Tanzania: J. Shao, F. Mosha, E. R. Kisanga, E. P. Muro, J. Mushi. Pasua Antenatal Clinic: G. Mariki, Shirima, Salma. Bondeni Antenatal Clinic: M. Kitiwi, M. Hassan. Mawenzi Antenatal Clinic: S. Masawe, A. Mchaki, R. Mushi, M. Chuwa.Majengo Antenatal Clinic: Mandari, Fimbo. Labor ward Kilimanjaro Christian Medical Centre: P. Mlay, Kiwia, Herini, Maleo, Nyalu, Mushi. Department of Virology, University of Utrecht, The Netherlands: R. Schuurman, S. Aitken. MRC Clinical Trials Unit, London, United Kingdom: D. M. Gibb, A. S. Walker, M. J. Thomason. Department of Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands: D. M. Burger, R. L'homme, Q. Fillekes. Biotechnology Laboratory of Kilimanjaro Christian Medical Centre, Moshi, Tanzania: L. Wolters, A. Ndaro, S. Matondo, E. Msuya. Laboratory of Department of Pharmacy Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands: M. Teulen, K. Asouit.
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Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
Africa; carbamazepine; nevirapine; pharmacokinetics; prevention of mother-to-child transmission of HIV