HIV Reports
Nevirapine Concentrations in Preterm and Low Birth Weight HIV-Exposed Infants Implications for Dosing Recommendations Reneé de Waal, MBChB,* S. Max Kroon, MBChB, FCPaed,† Sandi L. Holgate, MBChB, FCPaed,‡ Alan R. Horn, MBChB, FCPaed, PhD,† Lloyd J. Tooke, MBChB, MMed, FCPaed,† Jennifer Norman, MSc,* Peter Smith, PhD,* Marc Blockman, MBChB, BPharm, MMed,* Mark F. Cotton, MMed, FCPaed, PhD,‡ Helen M. McIlleron, MBChB, PhD,* and Karen Cohen, MBChB, MMed, MSc* Abstract: World Health Organisation guidelines recommend nevirapine 2 mg/kg/d for HIV-exposed infants 2 kg. In 116 low birth weight infants, nevirapine 2 mg/kg/d until 14 days, and 4 mg/kg/d thereafter, was safe (1 mild possibly related rash) and achieved target plasma concentrations. Concentrations decreased with treatment duration. Routine dose increase at 14 days should be considered. Key Words: nevirapine, preterm and low birth weight infants, therapeutic drug monitoring, prevention of mother-to-child transmission of HIV (Pediatr Infect Dis J 2014;33:1231–1233)
W
orld Health Organisation (WHO) and South African HIV management guidelines recommend extended courses of nevirapine for HIV-exposed infants. Nevirapine is recommended for at least 4 weeks post-delivery if the infant is exclusively formula fed, and is continued for 6 weeks or longer if the infant is breastfed.1,2 Prematurity is associated with immature drug metabolism3 and nevirapine safety, efficacy and pharmacokinetic data in preterm and low birth weight (LBW) infants are limited. WHO guidelines recommend a dose of 2 mg/kg/d for LBW infants1 but recommend a much higher dose for infants >2 kg (4–6 mg/kg/d). Nevirapine auto-induces its metabolism and requires dose doubling after 2 weeks when used for HIV-1 treatment.4 South African prevention of mother-to-child transmission of HIV-1 (PMTCT) guidelines recommend 2 mg/kg/d from day 0 to 14 in LBW infants, increased to 4 mg/kg/d from day 15, because of concerns that WHO guidelines, which do not include dose doubling, might result in subtherapeutic concentrations.2 Routine therapeutic drug monitoring (TDM) (measurement of plasma drug concentrations to determine if dose adjustment is required) was recommended in the 2010 (but not the 2013) WHO guidelines.5 The target plasma trough concentration, >0.1 mg/L, is 10 times the in vitro IC50 of nevirapine6 and was used as the target in PMTCT studies in term infants.7–9 We describe nevirapine concentrations from routine TDM, short-term safety and characteristics of preterm and LBW infants managed according to South African guidelines between June 2010 and February 2011. Accepted for publication May 14, 2014. From the *Division of Clinical Pharmacology, Department of Medicine, and †Department of Paediatrics, University of Cape Town, Cape Town; and ‡Department of Paediatrics and Child Health, Stellenbosch University, Stellenbosch, South Africa. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Karen Cohen, MBChB, MMed, MSc, Division of Clinical Pharmacology, K45 Old Main Building, Groote Schuur Hospital, Observatory, Cape Town 7925, South Africa. E-mail: [email protected]. Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0891-3668/14/3312-1231 DOI: 10.1097/INF.0000000000000453
MATERIALS AND METHODS We included all HIV-exposed infants who received nevirapine with TDM while inpatients at 3 hospitals in South Africa. Local guidelines recommended nevirapine dosing according to current weight, with doubling of the mg/kg dose at 14 days. Laboratory instructions recommended that trough blood samples be taken as close as possible to the next nevirapine dose. We measured plasma nevirapine concentrations using a high-performance liquid chromatography tandem mass spectrometry assay validated over the concentration range 0.08–20 mg/L. We collected clinical data, nevirapine dose and dose and sampling times from hospital and laboratory records. We defined “correct dose” as less than 25% deviation from that recommended for age and weight. To quantify the change in plasma concentrations after dose doubling at 14 days, we performed an analysis restricted to infants with concentrations measured both before and after 14 days, and in whom the correct dose was documented to have been given. For those with more than 1 sample in either time window, we used the mean of the repeated concentrations. We used linear mixed-effects regression, which accounted for repeated sampling within infants, to assess the effects of covariates on nevirapine concentration. We used Stata 11.0 for the statistical analyses.10 The research ethics committees of Cape Town and Stellenbosch Universities approved the study.
RESULTS We received 204 samples from 116 infants (median 1 per infant, range 1–5). Mean gestational age at birth was 31.5 weeks [standard deviation (SD) 3.1]. Median age at first TDM was 7 days [interquartile range (IQR) 6–10]. Median birth weight was 1310 g (IQR 1020–1620). The 41 infants who had at least 1 sample taken after 14 days’ dosing had lower gestational age and birth weight on average than the 69 infants who had samples taken in the first 14 days only: mean gestational age at birth was 30 weeks (SD 2.6) and 32 weeks (SD 3.2, n = 67, P = 0.0002) and median birth weight was 1160 g (IQR 900–1310) and 1420 g (IQR 1190–1780, n = 67, P 0.1 mg/L, so no dose adjustments were recommended. Six infants had concentrations above 10 mg/L, all at 0.1 mg/L). the dose had not been correctly increased after 14 days. The dose administered was not documented in 19 samples. In infants who had received the correct dose and had repeated samples, concentrations were significantly lower after 14 days: median 4.2 mg/L (IQR 2.7–5.8) and 2.3 mg/L (IQR 1.4–3.3) before and after 14 days, respectively (n = 23, Wilcoxon signed rank, P < 0.0001). The median decrease in concentration was 1.5 mg/L (IQR 0.3–3.4). The lowest trough concentration was 0.6 mg/L, at 42 days. In a linear mixed-effects model adjusting for treatment duration, gestational age at birth and nevirapine dose, concentrations decreased by 2.4% [95% confidence interval (CI) 1.5–3.3] for each day on treatment and by 6.5% (95% CI 3.3–9.7) for each week of gestational age, and increased by 10.6% (95% CI 1.5–20.5) for each mg/kg dose increase. Outcome data were available for 110 infants. Seventy-seven were discharged, 28 were transferred to other facilities (usually lower levels of care) and 5 died. The cause of death was necrotizing enterocolitis in 2 infants, sepsis in 2 infants and unknown in 1 infant. None of the deaths were thought to be drug related. One infant had a petechial rash possibly related to nevirapine. It was not recorded whether the rash started before or after the first nevirapine dose. It resolved without stopping nevirapine. Alanine transferase (ALT) concentrations were available for 46 infants. One infant had an alanine transferase of 53 IU/L (reference range 2–25 IU/L) 4 days after starting nevirapine (nevirapine concentration 1.5 mg/L), which decreased to 29 IU/L after 5 days without interruption of nevirapine dosing. HIV polymerase chain reaction results were recorded for 36 infants, at a median age of 34 days (IQR 15–43). One, at 34 days, was positive. The infant’s nevirapine concentration (at 27 days) was 2.0 mg/L.
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DISCUSSION Nevirapine concentrations were above the target for PMTCT of 0.1 mg/L in all preterm and LBW infants in our sample. The PMTCT target is based on in vitro data only,6 and is much lower than the target of 3.0 mg/L for treatment of HIV infection, which is based on a randomized controlled trial and cohort studies in adults.11 Reassuringly, concentrations in our sample were higher than those reported in term infants (median birth weight 3 kg) dosed with 2 and 4 mg/kg/d before and after 14 days, respectively: median 1.1 mg/L (IQR 1.0–1.4) at 14 days and 1.5 mg/L (IQR 1.0– 1.8) at 8 weeks.9 Six infants had concentrations above 10 mg/L, all within 15 days of birth, with no associated toxicity. Those high concentrations are probably related to prematurity, which is known to be associated with immature drug metabolism.3Even with dose increase from 2 to 4 mg/kg/d at 15 days, concentrations decreased with duration of treatment. This probably reflects auto-induction of nevirapine metabolism and maturation of hepatic function. Our analysis of TDM results and data collected from retrospective record review has several limitations. Dose and sampling time were sometimes missing, and might not have been recorded accurately. Not all infants were dosed strictly according to the guidelines. No prospective safety data were collected, so adverse events might be underestimated. We did not review maternal records and maternal drug history was poorly documented in infant records, so we were unable to assess the influence of in utero nevirapine exposure on concentrations. HIV polymerase chain reaction results were available for only 36 infants and reflect prevention of HIV transmission peripartum rather than through breastfeeding. We found that a daily nevirapine dose of 2 mg/kg/d, doubled to 4 mg/kg/d at 2 weeks, achieved adequate plasma concentrations without significant toxicity in preterm and LBW infants. In view © 2014 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 33, Number 12, December 2014
of the decrease in concentrations that we observed after 14 days, and the fact that TDM is not widely available and is no longer recommended, modifying WHO PMTCT nevirapine dosing recommendations to include routine dose doubling at age 14 days in this patient group should be considered. Further studies are necessary to adequately describe nevirapine pharmacokinetics, safety and efficacy in LBW and preterm infants to guide PMTCT dosing. REFERENCES 1. World Health Organization. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. Geneva: WHO Press; 2013. 2. South Africa Department of Health, South African National AIDS Council. The South African Antiretroviral Treatment Guidelines. Pretoria: National Department of Health; 2013. 3. Johnson TN. The development of drug metabolising enzymes and their influence on the susceptibility to adverse drug reactions in children. Toxicology. 2003;192:37–48. 4. Boehinger Ingelheim Pharmaceuticals Inc. Full Prescribing Information: Viramune. USA: Boehinger Ingelheim Pharmaceuticals Inc.; 2012.
© 2014 Lippincott Williams & Wilkins
Nevirapine in LBW Infants
5. World Health Organisation. Antiretroviral Drugs for Treating Pregnant Women and Preventing HIV Infection in Infants: Recommendations for a Public Health Approach. Geneva: WHO Press; 2010. 6. Koup RA, Merluzzi VJ, Hargrave KD, et al. Inhibition of human immunodeficiency virus type 1 (HIV-1) replication by the dipyridodiazepine BI-RG587. J Infect Dis. 1991;163:966–970. 7. Mirochnick M, Fenton T, Gagnier P, et al. Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. J Infect Dis 1998;178:368–374. 8. Musoke P, Guay LA, Bagenda D, et al. A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006). AIDS. 1999;13:479–486. 9. Shetty AK, Coovadia HM, Mirochnick MM, et al.; HIVNET 023 Study Team. Safety and trough concentrations of nevirapine prophylaxis given daily, twice weekly, or weekly in breast-feeding infants from birth to 6 months. J Acquir Immune Defic Syndr. 2003;34:482–490. 10. StataCorp. Stata Statistical Software: Release 11. College Station, TX: StataCorp LP; 2009. 11. la Porte CJL, Back DJ, Blaschke T, et al. Updated guidelines to perform therapeutic drug monitoring for antiretroviral agents. Rev Antivir Ther. 2006;3:4–12.
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Nevirapine Concentrations in Preterm and Low Birth Weight HIV-Exposed Infants Implications for Dosing Recommendations Reneé de Waal, MBChB,* S. Max Kroon, MBChB, FCPaed,† Sandi L. Holgate, MBChB, FCPaed,‡ Alan R. Horn, MBChB, FCPaed, PhD,† Lloyd J. Tooke, MBChB, MMed, FCPaed,† Jennifer Norman, MSc,* Peter Smith, PhD,* Marc Blockman, MBChB, BPharm, MMed,* Mark F. Cotton, MMed, FCPaed, PhD,‡ Helen M. McIlleron, MBChB, PhD,* and Karen Cohen, MBChB, MMed, MSc* Abstract: World Health Organisation guidelines recommend nevirapine 2 mg/kg/d for HIV-exposed infants 2 kg. In 116 low birth weight infants, nevirapine 2 mg/kg/d until 14 days, and 4 mg/kg/d thereafter, was safe (1 mild possibly related rash) and achieved target plasma concentrations. Concentrations decreased with treatment duration. Routine dose increase at 14 days should be considered. Key Words: nevirapine, preterm and low birth weight infants, therapeutic drug monitoring, prevention of mother-to-child transmission of HIV (Pediatr Infect Dis J 2014;33:1231–1233)
W
orld Health Organisation (WHO) and South African HIV management guidelines recommend extended courses of nevirapine for HIV-exposed infants. Nevirapine is recommended for at least 4 weeks post-delivery if the infant is exclusively formula fed, and is continued for 6 weeks or longer if the infant is breastfed.1,2 Prematurity is associated with immature drug metabolism3 and nevirapine safety, efficacy and pharmacokinetic data in preterm and low birth weight (LBW) infants are limited. WHO guidelines recommend a dose of 2 mg/kg/d for LBW infants1 but recommend a much higher dose for infants >2 kg (4–6 mg/kg/d). Nevirapine auto-induces its metabolism and requires dose doubling after 2 weeks when used for HIV-1 treatment.4 South African prevention of mother-to-child transmission of HIV-1 (PMTCT) guidelines recommend 2 mg/kg/d from day 0 to 14 in LBW infants, increased to 4 mg/kg/d from day 15, because of concerns that WHO guidelines, which do not include dose doubling, might result in subtherapeutic concentrations.2 Routine therapeutic drug monitoring (TDM) (measurement of plasma drug concentrations to determine if dose adjustment is required) was recommended in the 2010 (but not the 2013) WHO guidelines.5 The target plasma trough concentration, >0.1 mg/L, is 10 times the in vitro IC50 of nevirapine6 and was used as the target in PMTCT studies in term infants.7–9 We describe nevirapine concentrations from routine TDM, short-term safety and characteristics of preterm and LBW infants managed according to South African guidelines between June 2010 and February 2011. Accepted for publication May 14, 2014. From the *Division of Clinical Pharmacology, Department of Medicine, and †Department of Paediatrics, University of Cape Town, Cape Town; and ‡Department of Paediatrics and Child Health, Stellenbosch University, Stellenbosch, South Africa. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Karen Cohen, MBChB, MMed, MSc, Division of Clinical Pharmacology, K45 Old Main Building, Groote Schuur Hospital, Observatory, Cape Town 7925, South Africa. E-mail: [email protected]. Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0891-3668/14/3312-1231 DOI: 10.1097/INF.0000000000000453
MATERIALS AND METHODS We included all HIV-exposed infants who received nevirapine with TDM while inpatients at 3 hospitals in South Africa. Local guidelines recommended nevirapine dosing according to current weight, with doubling of the mg/kg dose at 14 days. Laboratory instructions recommended that trough blood samples be taken as close as possible to the next nevirapine dose. We measured plasma nevirapine concentrations using a high-performance liquid chromatography tandem mass spectrometry assay validated over the concentration range 0.08–20 mg/L. We collected clinical data, nevirapine dose and dose and sampling times from hospital and laboratory records. We defined “correct dose” as less than 25% deviation from that recommended for age and weight. To quantify the change in plasma concentrations after dose doubling at 14 days, we performed an analysis restricted to infants with concentrations measured both before and after 14 days, and in whom the correct dose was documented to have been given. For those with more than 1 sample in either time window, we used the mean of the repeated concentrations. We used linear mixed-effects regression, which accounted for repeated sampling within infants, to assess the effects of covariates on nevirapine concentration. We used Stata 11.0 for the statistical analyses.10 The research ethics committees of Cape Town and Stellenbosch Universities approved the study.
RESULTS We received 204 samples from 116 infants (median 1 per infant, range 1–5). Mean gestational age at birth was 31.5 weeks [standard deviation (SD) 3.1]. Median age at first TDM was 7 days [interquartile range (IQR) 6–10]. Median birth weight was 1310 g (IQR 1020–1620). The 41 infants who had at least 1 sample taken after 14 days’ dosing had lower gestational age and birth weight on average than the 69 infants who had samples taken in the first 14 days only: mean gestational age at birth was 30 weeks (SD 2.6) and 32 weeks (SD 3.2, n = 67, P = 0.0002) and median birth weight was 1160 g (IQR 900–1310) and 1420 g (IQR 1190–1780, n = 67, P 0.1 mg/L, so no dose adjustments were recommended. Six infants had concentrations above 10 mg/L, all at 0.1 mg/L). the dose had not been correctly increased after 14 days. The dose administered was not documented in 19 samples. In infants who had received the correct dose and had repeated samples, concentrations were significantly lower after 14 days: median 4.2 mg/L (IQR 2.7–5.8) and 2.3 mg/L (IQR 1.4–3.3) before and after 14 days, respectively (n = 23, Wilcoxon signed rank, P < 0.0001). The median decrease in concentration was 1.5 mg/L (IQR 0.3–3.4). The lowest trough concentration was 0.6 mg/L, at 42 days. In a linear mixed-effects model adjusting for treatment duration, gestational age at birth and nevirapine dose, concentrations decreased by 2.4% [95% confidence interval (CI) 1.5–3.3] for each day on treatment and by 6.5% (95% CI 3.3–9.7) for each week of gestational age, and increased by 10.6% (95% CI 1.5–20.5) for each mg/kg dose increase. Outcome data were available for 110 infants. Seventy-seven were discharged, 28 were transferred to other facilities (usually lower levels of care) and 5 died. The cause of death was necrotizing enterocolitis in 2 infants, sepsis in 2 infants and unknown in 1 infant. None of the deaths were thought to be drug related. One infant had a petechial rash possibly related to nevirapine. It was not recorded whether the rash started before or after the first nevirapine dose. It resolved without stopping nevirapine. Alanine transferase (ALT) concentrations were available for 46 infants. One infant had an alanine transferase of 53 IU/L (reference range 2–25 IU/L) 4 days after starting nevirapine (nevirapine concentration 1.5 mg/L), which decreased to 29 IU/L after 5 days without interruption of nevirapine dosing. HIV polymerase chain reaction results were recorded for 36 infants, at a median age of 34 days (IQR 15–43). One, at 34 days, was positive. The infant’s nevirapine concentration (at 27 days) was 2.0 mg/L.
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DISCUSSION Nevirapine concentrations were above the target for PMTCT of 0.1 mg/L in all preterm and LBW infants in our sample. The PMTCT target is based on in vitro data only,6 and is much lower than the target of 3.0 mg/L for treatment of HIV infection, which is based on a randomized controlled trial and cohort studies in adults.11 Reassuringly, concentrations in our sample were higher than those reported in term infants (median birth weight 3 kg) dosed with 2 and 4 mg/kg/d before and after 14 days, respectively: median 1.1 mg/L (IQR 1.0–1.4) at 14 days and 1.5 mg/L (IQR 1.0– 1.8) at 8 weeks.9 Six infants had concentrations above 10 mg/L, all within 15 days of birth, with no associated toxicity. Those high concentrations are probably related to prematurity, which is known to be associated with immature drug metabolism.3Even with dose increase from 2 to 4 mg/kg/d at 15 days, concentrations decreased with duration of treatment. This probably reflects auto-induction of nevirapine metabolism and maturation of hepatic function. Our analysis of TDM results and data collected from retrospective record review has several limitations. Dose and sampling time were sometimes missing, and might not have been recorded accurately. Not all infants were dosed strictly according to the guidelines. No prospective safety data were collected, so adverse events might be underestimated. We did not review maternal records and maternal drug history was poorly documented in infant records, so we were unable to assess the influence of in utero nevirapine exposure on concentrations. HIV polymerase chain reaction results were available for only 36 infants and reflect prevention of HIV transmission peripartum rather than through breastfeeding. We found that a daily nevirapine dose of 2 mg/kg/d, doubled to 4 mg/kg/d at 2 weeks, achieved adequate plasma concentrations without significant toxicity in preterm and LBW infants. In view © 2014 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 33, Number 12, December 2014
of the decrease in concentrations that we observed after 14 days, and the fact that TDM is not widely available and is no longer recommended, modifying WHO PMTCT nevirapine dosing recommendations to include routine dose doubling at age 14 days in this patient group should be considered. Further studies are necessary to adequately describe nevirapine pharmacokinetics, safety and efficacy in LBW and preterm infants to guide PMTCT dosing. REFERENCES 1. World Health Organization. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. Geneva: WHO Press; 2013. 2. South Africa Department of Health, South African National AIDS Council. The South African Antiretroviral Treatment Guidelines. Pretoria: National Department of Health; 2013. 3. Johnson TN. The development of drug metabolising enzymes and their influence on the susceptibility to adverse drug reactions in children. Toxicology. 2003;192:37–48. 4. Boehinger Ingelheim Pharmaceuticals Inc. Full Prescribing Information: Viramune. USA: Boehinger Ingelheim Pharmaceuticals Inc.; 2012.
© 2014 Lippincott Williams & Wilkins
Nevirapine in LBW Infants
5. World Health Organisation. Antiretroviral Drugs for Treating Pregnant Women and Preventing HIV Infection in Infants: Recommendations for a Public Health Approach. Geneva: WHO Press; 2010. 6. Koup RA, Merluzzi VJ, Hargrave KD, et al. Inhibition of human immunodeficiency virus type 1 (HIV-1) replication by the dipyridodiazepine BI-RG587. J Infect Dis. 1991;163:966–970. 7. Mirochnick M, Fenton T, Gagnier P, et al. Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. J Infect Dis 1998;178:368–374. 8. Musoke P, Guay LA, Bagenda D, et al. A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006). AIDS. 1999;13:479–486. 9. Shetty AK, Coovadia HM, Mirochnick MM, et al.; HIVNET 023 Study Team. Safety and trough concentrations of nevirapine prophylaxis given daily, twice weekly, or weekly in breast-feeding infants from birth to 6 months. J Acquir Immune Defic Syndr. 2003;34:482–490. 10. StataCorp. Stata Statistical Software: Release 11. College Station, TX: StataCorp LP; 2009. 11. la Porte CJL, Back DJ, Blaschke T, et al. Updated guidelines to perform therapeutic drug monitoring for antiretroviral agents. Rev Antivir Ther. 2006;3:4–12.
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