The pharmacokinetics of nevirapine when given with isoniazid in South African HIV-infected individuals [Short communication]

Decloedt, Eric H.; Mwansa-Kambafwile, Judith; Walt, Jan-Stefan van der; McIlleron, Helen; Denti, Paolo; Smith, Peter J.; Wiesner, Lubbe; Rangaka, Molebogeng X; Wilkinson, Robert J.; Maartens, Gary

doi:10.5588/ijtld.12.0427

Cited by 13 publications

(11 citation statements)

References 7 publications

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“…It is recommended that INH (and other hepatotoxic drugs) be withheld in case a patient's transaminase exceed 3 times the upper limit of normal level if associated with symptoms or 5 times the upper limit of normal if the patient is asymptomatic [2] [6] [22] [23]. The finding of the case series is consistent with the available literature emphasizing that stopping INH as soon as INH hepatotoxicity is diagnosed improves mortality risk.…”

Section: Discussionsupporting

confidence: 67%

“…Case 4 remained on HAART holiday for several weeks and liver function tests normalized on the 25 th day after stopping INH. Although, previous findings show that there is no statistically significant association between ARVs (especially Nevirapine) and developing INH associated hepatotoxicity [6] [22], Cases 1 and 4 show a clinical association between Nevirapine and severity of INH hepatotoxicty. It is important to note that the findings from previous studies which showed that the association of Nevirapine and INH hepatitis was not statistically significant were limited by the small number of patients that were studied [13] [19].…”

Section: Discussionmentioning

confidence: 69%

“…As previously noted by Weisiger's finding [2], it was quite a challenge identifying a culprit drug (INH) from ARVs which also have a potential to cause hepatotoxicity. Previous studies indicate that ART is associated with INH hepatitis-the relative risk is higher among patients taking Nevirapine than those taking Efavirenz based HAART regimens-although the association was not statistically significant [6] [22]. Cases 2 and 5 were on Lopinavir/Ritonavir and Efavirenz respectively, they continued their HAART uninterrupted and recovered.…”

Section: Discussionmentioning

confidence: 90%

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Isoniazid Preventive Therapy Associated Hepatotoxicity among Children Living with HIV: Descriptive Case Series at Mildmay Uganda HIV/AIDS Clinic, Uganda

Nsobya¹,

Nsobya²,

Nakaweesi³

et al. 2015

IJCM

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Provision of Isoniazid Preventive Therapy (IPT) as part of the comprehensive TB/HIV prevention intervention for people living with HIV & AIDS was recommended by WHO in 2011. Literature shows that Isoniazid (INH) associated hepatotoxicity is a common drug adverse event among people taking INH, and that it's associated with a high risk of mortality. These case series document INH associated hepatotoxicity in HIV-infected children receiving IPT in a resource constrained setting. They also further describe the challenges and lessons learnt while providing routine IPT among HIV-infected children in a resource-limited setting where laboratory tests for liver function monitoring are not performed routinely. The case series describe observed cases which presented to the Mildmay Uganda HIV/AIDS clinic between December 2013 and March 2014. The findings demonstrate that: 1) there was a 1.5% INH related hepatotoxicity incidence among children of four to ten years old; 2) 20% death rate-one out of the five children died and; 3) hepatotoxicity events on average occurred at 10.8 weeks after INH initiation while at the same time, all the cases had liver enzymes elevated above 10 times the upper normal limit values and reported late for medical intervention. The insidious onset of symptoms and signs of INH related hepatotoxicity coupled with lack of adequate resources needed to manage the condition were the major challenges to provision of routine IPT among children living with HIV in resource-limited settings in sub-Sahara Africa. Clinical vigilance, continuous education of clients and caretakers about the * Corresponding author. L. Nsobya et al. 385 side effects or adverse events of INH and routine laboratory examination of liver function tests during follow-up of IPT in HIV-infected children are recommended to enhance early detection and prompt management of IPT associated hepatotoxicity.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 90%

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Isoniazid Preventive Therapy Associated Hepatotoxicity among Children Living with HIV: Descriptive Case Series at Mildmay Uganda HIV/AIDS Clinic, Uganda

Nsobya¹,

Nsobya²,

Nakaweesi³

et al. 2015

IJCM

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“…Currently available limited data advises that the concurrent administration of isoniazid with nevirapine is relatively safe [12, 13]. In a brief report by Decloedt et al, an evaluation of the pharmacokinetics of nevirapine when given with isoniazid showed that co-administration was associated with a 24% increase in median nevirapine area under the curve within the first 12 h. This result was, however, not statistically significant and the sample size used in this study was too small to establish the effect of slow and fast isoniazid acetylators on nevirapine as it is possible that the inhibiting effect of isoniazid in slow acetylators may be more pronounced [14]. …”

Section: Introductionmentioning

confidence: 82%

Tolerability of Isoniazid Preventive Therapy in an HIV-Infected Cohort of Paediatric and Adolescent Patients on Antiretroviral Therapy from a Resource-Limited Setting: A Retrospective Cohort Study

Mudzviti

Shamu²,

Chimbetete³

et al. 2019

Drugs - Real World Outcomes

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BackgroundTreating patients with latent tuberculosis infection (LTBI) to prevent development of active disease is an essential strategy for eliminating TB. There are concerns regarding the use of isoniazid due to the potential for hepatotoxicity. This study was conducted to determine the incidence of adverse hepatic events after isoniazid preventive therapy (IPT) commencement in a cohort of HIV-infected paediatric and adolescent patients on antiretroviral therapy (ART).MethodsThis was a retrospective records review, using data from HIV-infected paediatric and adolescent patients collected during routine clinical visits at Newlands Clinic, Harare, Zimbabwe. Patients included in the analysis had commenced IPT between January 2014 and June 2015 (inclusive) whilst receiving ART. A survival analysis was conducted for the period that participants were receiving IPT with end-points defined by grade 3 or grade 4 elevations in alanine aminotransferase (ALT) levels.ResultsData from 438 patients commenced on IPT were analysed; 202 (46.1%) of them were female. The median age at IPT commencement was 10 (IQR = 7–12) years. Twenty-eight patients developed grade 3 or 4 elevations in ALT. Concomitant use of nevirapine as part of an ART regimen was the only factor that showed a statistically significant association with ALT elevation [relative risk (RR): 2.7; confidence interval (CI): 1.2–6.3, p = 0.012] compared with those not receiving nevirapine. The incidence of grade 3 or 4 elevations in ALT was 31.5/100 person-years (CI 20.9–45.5).ConclusionThe incidence of IPT-associated ALT elevations was high in this population. We recommend vigilant monitoring of liver enzymes for patients receiving IPT, especially in patients concomitantly receiving nevirapine.

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“…However, food intake is known to decrease the bioavailability of INH (24), and we were unable to evaluate pharmacokinetics in the absence of feeding. Concomitant medicines frequently used in LBW infants included theophylline and NVP, neither of which should impact the pharmacokinetic parameters of INH (25,26).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Isoniazid in Low-Birth-Weight and Premature Infants

Bekker

Schaaf

Seifart

et al. 2014

Antimicrob Agents Chemother

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dIsoniazid (INH) is recommended for use as posttuberculosis exposure preventive therapy in children. However, no pharmacokinetic data are available for INH treatment in low-birth-weight (LBW) infants, who undergo substantial developmental and physiological changes. Our objectives in this study were to determine the pharmacokinetic parameters of INH at a dose of 10 mg/kg of body weight/day and to define its pharmacokinetics relative to the arylamine N-acetyltransferase-2 (NAT2) genotype. An intensive prospective pharmacokinetic sampling study was conducted at Tygerberg Children's Hospital, South Africa, in which we measured INH blood plasma concentrations at 2, 3, 4 and 5 h postdose. Twenty LBW infants (14 male, 16 exposed to HIV) were studied. The median birth weight was 1,575 g (interquartile range, 1,190 to 2,035 g) and the median gestational age was 35 weeks (interquartile range, 34 to 38 weeks). The NAT2 acetylation statuses of the infants were homozygous slow (SS) (5 infants), heterozygous intermediate (FS) (11 infants), and homozygous fast (FF) (4 infants). Using a noncompartmental analysis approach, the median maximum drug concentration in blood serum (C max ) was 5.63 g/ml, the time after drug administration to reach C max T max ) was 2 h, the area under the concentration-time curve from 2 to 5 h (AUC 2-5 ) was 13.56 g · h/ml, the half-life (t 1/2 ) was 4.69 h, and the elimination constant rate (k el ) was 0.15 h ؊1 . The alanine aminotransferase levels were normal, apart from 2 isolated values at two and three times above the normal levels. Only the three-times-elevated value was repeated at 6 months and normalized. All LBW infants achieved target INH blood plasma concentrations comparable to the adult values. Reduced elimination was observed in smaller and younger infants and in slow acetylators, cautioning against higher doses. The safety data, although limited, were reassuring. More data, however, are required for newborn infants.

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The pharmacokinetics of nevirapine when given with isoniazid in South African HIV-infected individuals [Short communication]

Cited by 13 publications

References 7 publications

Isoniazid Preventive Therapy Associated Hepatotoxicity among Children Living with HIV: Descriptive Case Series at Mildmay Uganda HIV/AIDS Clinic, Uganda

Isoniazid Preventive Therapy Associated Hepatotoxicity among Children Living with HIV: Descriptive Case Series at Mildmay Uganda HIV/AIDS Clinic, Uganda

Tolerability of Isoniazid Preventive Therapy in an HIV-Infected Cohort of Paediatric and Adolescent Patients on Antiretroviral Therapy from a Resource-Limited Setting: A Retrospective Cohort Study

Pharmacokinetics of Isoniazid in Low-Birth-Weight and Premature Infants

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