Expert Opinion on Pharmacotherapy
ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20
Antiretroviral treatment in HIV-infected children who require a rifamycin-containing regimen for tuberculosis Helena Rabie, Eric H. Decloedt, Anthony J. Garcia-Prats, Mark F. Cotton, Lisa Frigati, Marc Lallemant, Anneke Hesseling & H. Simon Schaaf To cite this article: Helena Rabie, Eric H. Decloedt, Anthony J. Garcia-Prats, Mark F. Cotton, Lisa Frigati, Marc Lallemant, Anneke Hesseling & H. Simon Schaaf (2017) Antiretroviral treatment in HIV-infected children who require a rifamycin-containing regimen for tuberculosis, Expert Opinion on Pharmacotherapy, 18:6, 589-598, DOI: 10.1080/14656566.2017.1309023 To link to this article: http://dx.doi.org/10.1080/14656566.2017.1309023
Published online: 27 Mar 2017.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ieop20 Download by: [University of Stellenbosch]
Date: 10 April 2017, At: 09:21
EXPERT OPINION ON PHARMACOTHERAPY, 2017 VOL. 18, NO. 6, 589–598 http://dx.doi.org/10.1080/14656566.2017.1309023
REVIEW
Antiretroviral treatment in HIV-infected children who require a rifamycin-containing regimen for tuberculosis Helena Rabiea,b, Eric H. Decloedtc, Anthony J. Garcia-Pratsd, Mark F. Cottona,b, Lisa Frigatia,b, Marc Lallemante, Anneke Hesselingd and H. Simon Schaafa,d a Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa; bChildren’s Infectious Diseases Clinical Research Unit, Stellenbosch University, Cape Town, South Africa; cDivision of Clinical Pharmacology, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa; dDesmond Tutu TB Centre, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; ePediatric HIV Program, Drugs for Neglected Diseases Initiative, Geneva, Switzerland
ABSTRACT
ARTICLE HISTORY
Introduction: In high prevalence settings, tuberculosis and HIV dual infection and co-treatment is frequent. Rifamycins, especially rifampicin, in combination with isoniazid, ethambutol and pyrazinamide are key components of short-course antituberculosis therapy. Areas covered: We reviewed available data, for which articles were identified by a Pubmed search, on rifamycin-antiretroviral interactions in HIV-infected children. Rifamycins have potent inducing effects on phase I and II drug metabolising enzymes and transporters. Antiretroviral medications are often metabolised by the enzymes induced by rifamycins or may suppress specific enzyme activity leading to drug-drug interactions with rifamycins. These may cause significant alterations in their phamacokinetic and pharmacodynamic properties, and sometimes that of the rifamycin. Recommended strategies to adapt to these interactions include avoidance and dose adjustment. Expert opinion: Despite the importance and frequency of tuberculosis as an opportunistic disease in HIV-infected children, current data on the management of co-treated children is based on few studies. We need new strategies to rapidly assess the use of rifamycins, new anti-tuberculosis drugs and antiretroviral drugs together as information on safety and dosing of individual drugs becomes available.
Received 3 November 2016 Accepted 16 March 2017
1. Introduction The World Health Organization (WHO) estimated that 10.4 million people were newly diagnosed with tuberculosis (TB) in 2015 including 5.9 million men, 3.5 million women, and 1.0 million children (10% of cases); 11% of new cases were human immunodeficiency virus (HIV) infected [1]. The overlapping epidemiology of TB and HIV, with its epicenter in subSaharan Africa, is well documented. The challenges of diagnosis and management of TB and HIV coinfection in children, the efficacy of antiretroviral therapy (ART) in reducing both HIV infection through preventing mother-to-child HIV transmission (pMTCT) and TB disease in HIV-infected children are also known [2–4]. Prior to wide-spread ART access, HIV was associated with increased TB mortality, delayed response to anti-TB treatment and high recurrence of TB [5,6]. The diagnosis of TB in a child is often made prior to diagnosing HIV infection; a TB diagnosis should prompt screening for HIV [3]. Screening for TB disease is a key component of the ART initiation process. TB is also frequently diagnosed during the first 3 months after ART initiation, which may be unmasking immune reconstitution inflammatory syndrome. There is a marked decline in incident TB in children thereafter; however, TB remains more common in CONTACT Helena Rabie
[email protected] PO Box 241, Cape Town, 8000, South Africa
KEYWORDS
Children; drug-drug interaction; HIV; rifamycin; tuberculosis
HIV-infected children on ART than in HIV-uninfected children [3,7,8]. Timely ART initiation is the key strategy for reducing morbidity and mortality in TB-HIV coinfected children. Early mortality still occurs in children who access ART late [9]. Cotreatment of TB and HIV is complicated, in large part due to drug–drug interactions (DDIs) between ART and anti-TB treatment, especially for first-line anti-TB drugs. The rifamycins, which include rifampicin (RIF), rifabutin (RBT), and rifapentine (RFP), are important for the treatment and prevention of drugsusceptible TB. RIF, the most commonly used rifamycin, underpins current short-course regimens for drug-susceptible TB in adults and children [10–12]. If rifamycins cannot be used because of resistance or intolerance, WHO recommends extending treatment duration beyond six months [13]. The rifamycins, particularly RIF, are known for their significant DDIs with antiretroviral drugs (ARVs) of all classes including the non-nucleoside reverse transcriptase inhibitors (NNRTIs) which include nevirapine (NVP) and efavirenz (EFV), the protease inhibitors (PIs) and the integrase inhibitors (INSTI), with varying degrees of clinical significance. This is particularly concerning in young children because of fewer therapeutic options and formulations for both infections [13]. DDIs may produce subtherapeutic concentrations of ARVs and are
Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University.
© 2017 Informa UK Limited, trading as Taylor & Francis Group
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Article highlights ●
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Despite the prevalence of children with tuberculosis dually infected with HIV there are few pharmacokinetic studies addressing combined antituberculosis and antiretroviral treatment in children and no peer reviewed data on the newer antiretroviral drugs or antituberculosis drugs. Nevirapine drug-drug interaction with rifampicin can be overcome with increased dosing of nevirapine and potentially forgoing the lead-in dose. The efavirenz dose does not require adjustment during rifampicin cotreatment. This may be due to co-treatment with isoniazid. Efavirenz metabolism is determined by genotype. Doubling the dose of lopinavir/ritonovir (4:1) in children does not resolve the drug-drug interaction with rifampicin, but super-boosting does. This is a key difference between children and adults. There is only one study assessing the drug-drug interactions of antiretroviral drugs with rifabutin in children. Here, using rifabutin with lopinavir/ritonavir gave significant toxicity.
WHO dosing recommendations, RIF exposures in young children are considerably lower than in adults, especially in infants [16,17]. Additional data are required to better understand the underlying reasons and how to optimize RIF dose in children including for severe forms of TB. In adults doses of RIF 35 mg/ kg is safe and reduces time to culture conversion; this is a potential strategy to shorten treatment for pulmonary TB and to optimize treatment for TB meningitis [18]. These strategies must also be evaluated in children. In adults, these high RIF doses have nonlinear dose exposure relationships due to saturation of enzymes involved in RIF metabolism [19,20]. This key finding would potentially have implications for interactions with other drugs that require careful consideration and investigation. These higher RIF doses have not yet been studied in children; however, a pediatric trial is planned for 2017 (Opti-Rif Kids, Hesseling).
This box summarizes key points contained in the article.
2.2. ART in children implicated in ART failure in children [14]. Complex DDIs may also increase drug concentrations leading to adverse effects. The treatment of TB and of HIV in children is rapidly evolving, with recent changes to dosing guidelines for first-line anti-TB treatment, the introduction of new ARVs, and the increasing availability of new anti-TB drugs and regimens. The aim of this review is to explore the available data on cotreatment with rifamycins and ARVs in HIV-infected children specifically focusing on pharmacokinetic (PK) studies supporting such treatment. We performed PubMed and Scopus searches to identify PK studies in children receiving a rifamycin and ARVs. Adult data are included where there are no pediatric information or if we felt it important to highlight inherent differences between children and adults.
2. Current recommendations for ART and treatment of TB in children 2.1. Treatment of TB in children A 2009 WHO review of available data on dosing, efficacy, and safety of first-line anti-TB medications in children led to an increase in WHO-recommended doses of first-line anti-TB drugs [15]. The current daily dose recommendations are: RIF 15 mg/kg (range 10–20 mg/kg), isoniazid (INH) 10 mg/kg (7– 15 mg/kg), pyrazinamide (PZA) 35 mg/kg (30–40 mg/kg), and ethambutol (EMB) 20 mg/kg (15–25 mg/kg) [11,15]. To prevent selective ingestion and its risk for developing resistance, to facilitate ease of use and to reduce pill burden, RIF is coformulated with INH and PZA as a fixed-dose combination (FDC) during the intensive phase, and RIF and INH during the continuation phase, both in new dispersible tablet formulations available in over 30 countries (http://www.tballiance.org/childfriendly-medicines). The effect of the increased dose of RIF (almost double the previous dose) on DDIs with CYP450 metabolized medications, including ARVs has not been characterized. Of note, the doses of RIF for TB treatment in children may change with emerging data showing that even with revised
The latest WHO guidance for the public health approach to ART in children is from 2016 [13]. Lopinavir, a PI, coformulated with another PI, ritonavir in a 4:1 ratio (LPV/r) with two nucleoside reverse transcriptase inhibitors (NRTIs) is the first-line regimen of choice in children below 3 years and 3.0 ng/mL day) with TDM in low weight and recommended Therapeutic Cmin n = 13, young children who are at risk of Sub-therapeutic Cmin n = 1 and Supraunderdosing. therapeutic Cmin n = 12. Consider omitting lead-in dose in 43% of the children on anti-TB therapy achieved children younger than 2 years adequate NVP trough concentrations.
Pediatric recommendation based on available data
13 of 15 children (87%) had a LPV Cmin >minimum Increase the ratio of LPV:r to 1:1 Double dosing or therapeutic concentration (1 mg/L) (superboosting) superboosting is Doubling the dose of LPV/r given acceptable However if c 2 489 (482–503) mg/m LPV Cmin were >1 mg/l in 60% (12/20) compared twice daily is not recommended in available, rifabutin is LPV:r 4:1 but at double the with 2 of 24 (8%) controls (P < 0.001). children recommended recommended dose LPV:ratio 1:1 The percentage of modeled morning trough LPV/r at standard weight concentrations below target upon band doses superboosting was 10.7% (95% CI 3.3% to 19.6%) and off TB therapy and without superboosting was 15% (95% CI 5.1%–27.7%). The median value of the difference between the modeled morning troughs below the 1 mg/L threshold was −4.4% (95% CI −12.1%–1.4%), confirming the non-inferiority of LPV exposure upon superboosting LPV/r (1:1) over standard regimen LPV/r (4:1) No data in children Rifabutin is recommended No data in children Rifabutin is recommended No data in children
291.9 (274.3–308.6)c mg/m2 LPV:r ratio 1:1
13.9 (13.1–15.0)c mg/kg
13.9 (12.3–15.2)c mg/kg
5.3 (4.0–7.8)a mg/kg
350.9 ± 59.8b mg/m2/day
169.9 (148.4–252.9)a mg/m2/day
349 (294–417)a mg/m2/day
Finding
Metabolized by liver UGT1A1 AUC is altered recommended, but some Doubling data supports leaving the the dose is dose unchanged Dolutegravir Primary Metabolized by liver Only registered for children UGT1A1 more than 40 kg and 12 kg. UGT1A3, UGT1A9, CYP3A4 No data on cotreatment Coadministration with RIF causes a reduction in DTV AUC by 54%, Doubling the daily dose recommended a Median (range); bMean ± standard deviation; cMedian (interquartile range); AUC = area under the concentration time curve; C12 = concentration at 12 h post dosing; Cmin = minimum concentration (trough); TDM = therapeutic drug monitoring; NVP = nevirapine; EFV = efavirenz; LPV/r = lopinavir/ritonavir; LPV = lopinavir; r = ritonavir; TB = tuberculosis *The cohort consisted of 20 children of whom 7 had TB # CYP2B6 is the major enzyme involved
Atazanavir Darunavir Raltegravir
Lopinavir/ ritonavir (LPV/r)
Efavirenz (EFV)
Nevirapine (NVP)
Antiretroviral
Dose when dosed with rifampicin
Pediatric interaction data
Table 1. Rifampicin and antiretroviral drug–drug interaction studies in children and comparable recommendations in adults. 592 H. RABIE ET AL.
EXPERT OPINION ON PHARMACOTHERAPY
also became available in tablet and powder formulations. Options to treat infants are fewer than for older children and adults. In a controlled trial, where infants were randomized to receive LPV/r vs. NVP, LPV/r provided better virological suppression regardless of previous exposure to NVP or maternal EFV as pMTCT strategy [21,22]. Children infected with HIV despite NVP-based pMTCT are likely to harbor archived NVPresistant viruses. The proportion of children with, and the implications of, archived resistant viruses tends to change over time in children who remain suppressed on therapy [23]. Initiating therapy with LPV/r and switching to EFVbased therapy is feasible regardless of initial NNRTI resistance, but requires viral load monitoring before and after switching to ensure suppression (Table 1) [58]. LPV/r is currently the most widely available PI and is used in children requiring second-line ART after failing an NNRTIbased initial regimen. In healthy adult volunteers, 2 strategies were evaluated to overcome the DDI of LPV/r in cotreatment with RIF; adding RTV to achieve a LPV:RTV ratio of 1:1, the socalled ‘superboosting’ strategy (LPV/RTV), or doubling the dose of LPV/r. In one study, 32 healthy volunteers received LPV/r 400/100 mg twice daily for 15 days. RIF 600 mg was introduced on day 11 and from day 16 participants received LPV/r 800/200 mg twice daily or LPV/r 400/100 mg twice daily with RTV 300 mg twice daily (superboosting). Twelve participants withdrew due to adverse events (laboratory abnormalities of which none were serious). The adjusted-dose regimens did not always compensate for the accelerated metabolism of LPV by RIF. Although the study was not designed to assess the difference in the 2 strategies, the trough concentrations during superboosting tended to be higher [39]. Further significant safety concerns in healthy volunteers were found in a second study. Originally, 40 participants were due to enroll in a cotreatment study assessing 600/150 or 800/200 mg twice daily but the study was stopped after 9 of the first 11 volunteers experienced grade 3 and 4 increases in aspartate transaminase (AST) and alanine transaminase (ALT) [40]. In a doseescalation study of LPV/r tablets given with RIF 600 mg daily in stable, virologically suppressed HIV-infected adults without TB, 85.7% of cases receiving the standard LPV/r dose had subtherapeutic LPV trough concentrations at the end of the first week. With doubling of the standard dose, only 22% of cases had subtherapeutic LPV trough concentrations; comparing favorably with participants not on RIF (9.5%; p = 0.39). Doubling of the LPV/r dose was well tolerated with only 2 participants experiencing asymptomatic grade 3–4 increase in hepatic enzymes. Also, a significant number of participants achieved an appropriate LPV concentration at 1.5 times the recommended LPV/r dose [59]. This strategy of double-dosing LPV/ r tablets is now preferred in HIV-infected adults on LPV/r and RIF cotreatment. Two PK studies of LPV/r, one with LPV/RTV superboosting and one with LPV/r double dosing were done in children on RIF. In the first study, PK data was compared in 15 children receiving LPV/r superboosted with RTV liquid during RIF cotreatment and 15 controls on LPV/r without RIF. The trough between the 2 groups was not significantly different, but a significant reduction in the median LPV maximum concentration (Cmax) (P = 0.018) and median AUC0-12 (P = 0.036) was
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shown in the children on RIF. All children received more than 230 mg/m2 per dose of LPV and RTV with a median dose of 291.9 mg/m2 (range 274.3–308.6 mg/m2). No children had significant increases in AST and/or ALT and both groups had a similar percentage of non-suppressed viral loads [60]. In the second study, doubling the dose of LPV/r liquid was studied in 20 children, median age 1.25 (0.98–1.93) years, receiving 10 mg/kg of RIF and compared to 24 HIV-infected controls without TB. Children on RIF received a median dose of 489 mg/m2 (482–503 mg/m2) twice daily of LPV whilst on RIF. At this dose, the pre-dose LPV concentrations were
