HIV Reports

Review of Tenofovir Use in HIV-infected Children Linda Aurpibul, MD* and Thanyawee Puthanakit, MD†‡ Abstract: Tenofovir disoproxil fumarate (TDF) is approved by the Food and Drug Administration for use in children ages 2 years and older and is recommended by the World Health Organization for use as a preferred first-line nucleotide reverse transcriptase inhibitor in adults and adolescents ages 10 years and older. The simplicity of once daily dosing, few metabolic side effects and efficacy against hepatitis B virus make TDF suitable for use in a large scale program. Unlike thymidine analoge nucleoside reverse transcriptase inhibitors (NRTIs); tenofovir does not induce multi-NRTI resistance mutations, so more NRTI options are available for future second-line-regimens. Fixed-dose combinations of TDF with other ARVs as a single tablet regimen are now widely available for adults and adolescents, but none are available for young children. Current information on TDF including the pharmacokinetics, safety and tolerability in children and adolescents was reviewed. A dosing regimen according to body-weight-band has been established for pediatric use. Safety concerns of TDF mainly relate to its effects on renal function and bone mineral density. Regular monitoring of renal function in high-risk patients, including those on other nephrotoxic drugs, may be warranted to detect adverse renal effects. Long-term-data on renal and bone outcomes among HIV-infected children is needed. Lessons learned from clinical studies will help clinicians balance the risks and benefits of TDF and design appropriate antiretroviral regimens for children in different circumstances. Key Words: tenofovir, children, HIV (Pediatr Infect Dis J 2015;34:383–391)

T

he success of antiretroviral therapy (ART) has dramatically changed the prognosis and natural history of pediatric HIV infection. A significant decline in morbidity and mortality has led to an increasing number of children entering their adolescent years.1 Current treatment strategies aim at improving quality of life for HIVinfected children and adolescents so that they can enter adult life as healthy as possible. Ongoing efforts have been made to develop novel antiretroviral agents with greater potency, higher tolerability and better safety profiles for the young population who need life-long therapy. Tenofovir disoproxil fumarate (TDF) is an orally bioavailable ester prodrug of tenofovir (TFV). It is a nucleotide reverse-transcriptase inhibitor which has demonstrated inhibitory activity against HIV and also hepatitis B virus (HBV). Its active metabolite, intracellular TFV diphosphate (TFV-DP), is a competitive inhibitor of HIV-1 Accepted for publication September 10, 2014. From the *Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand; †Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; and ‡HIVNAT, Thai Red Cross AIDS Research Center, Bangkok, Thailand. L. Aurpibul is funded in part by the National Research University Project under Thailand's Office of the Higher Education Commission. T. Puthanakit is funded in part by the National Research University Project of Commission of Higher Education and the Ratchadapiseksomphot Endowment Fund (HR 1161A-55), the Integrated Innovation Academic Center (IIAC), C ­ hulalongkorn University Centenary Academic Development Project, and the Senior Researcher Scholar, Thai Research Fund (TRF). The authors have no conflicts of interest to disclose. Address for correspondence: Thanyawee Puthanakit, MD, Division of Infectious Diseases, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand. E-mail: [email protected] Copyright © 2014 by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3404-0383 DOI: 10.1097/INF.0000000000000571

reverse-transcriptase enzyme and terminates the growing DNA chain. TDF has a long serum half-life of 17 hours which allows for convenient once-daily dosing. The intracellular half-life of TFV-DP ranges from 70 to 150 hours regardless of concomitant ART used.2–5 In the fasting state, 25% of the drug is absorbed, with bioavailability increasing to 40% when administered with a high-fat-meal.6 TFV is mainly eliminated unchanged by the kidneys; thus, dose adjustment is required in patients with significant renal impairment. TFV is not a substrate, inducer or inhibitor of the cytochrome p450 enzyme system. It appears less likely to cause mitochondrial toxicity when compared to nucleoside reverse-transcriptase inhibitors (NRTIs).7 This property may explain why TDF has less of an effect on lipid profiles and lower risk of lipodystrophy compared to many NRTIs. In HIV-infected adults, TDF is a recommended first-line drug, replacing the thymidine analoge NRTIs stavudine and zidovudine. There are several fixed-dose combinations (FDC) that contain TDF: TDF/emtricitabine/efavirenz (Atripla),8 TDF/emtricitabine/rilpivirine (Complera)9 and TDF/emtricitabine/elvitegravir/cobicistat (Stribild).10 Other TDF-containing FDC’s are still in clinical trials including TDF/lamivudine/efavirenz (Matrix Laboratories Ltd, Hyderabad, India; ClinicalTrials.gov identifier: NCT01160120). The once-daily co-formulated agents with simple dosing requirements can help improve adherence.11 This could make the difference between success and failure of ART, especially for adolescents.12 However, currently, there is no TDF-containing FDC available for preadolescent children.

PHARMACOKINETIC DATA AND DRUG INTERACTIONS Data from the phase I/II dose-escalation study of once daily TDF among HIV-infected adults showed a dose-related effect on viral load and demonstrated that 300 mg is the most appropriate dose.13 A comparison of pharmacokinetic parameters in adult and pediatric studies is shown in Table 1. The first pharmacokinetic study in 18 HIVinfected US children ages 6–16 years found that a median TDF dose of 208 mg/m2 body surface area (which fell within ±5% of the dose calculated as 8 mg/kg body weight) resulted in lower area under curve (AUC) and the maximum level after the dose was administered,14 compared to these parameters in adults taking the 300 mg dose.13 In 40 Thai children ages 3.1–17.7 years (median 12.2) who received TDF at the dose of 7.6 (±1.2) mg/kg or 215 (±26) mg/m2, in combination with lamivudine and efavirenz, the 90% confidence interval (CI) for the geometric mean AUC fell within ±20% of that reported in adults and parameters did not differ between those above or below age 12 years.13,15–17 When combined with the results of the previous modeling study which documented higher intracellular TFV-DP concentration in children and adolescents aged between 8.6 and 17 years,2 drug exposure is expected to be appropriate at the approved dose. Drug interactions between TDF and protease inhibitors(PIs) have been well documented. In general, TDF decreases drug exposure of atazanavir,18 while boosted PIs increase drug exposure of TDF.19,20 Thus, to reduce the risk of subtherapeutic concentration, atazanavir must always be boosted with ritonavir (atazanavir/r) when used concomitantly with TDF.21 A study of US children (median age 14 years) demonstrated a trend toward a decrease in TFV renal clearance in children who received TDF with atazanavir/r. However, the 90% CIs of AUC and C24 of TFV overlapped with the target range for all combinations.22 The recently published population pharmacokinetics data

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The Pediatric Infectious Disease Journal  •  Volume 34, Number 4, April 2015

Aurpibul and Puthanakit

TABLE 1.  Pharmacokinetic Parameters of TDF in Children and Adolescents Age in Years, Median Median Daily (Range) Number TDF Dose

Year/Countries/ Authors

Adult studies  2001/US/Barditch39 (34–44)   Crovo et al13  2008/US/Kiser 23 (18.6–24.9)   et al19 Pediatric studies  2004/US/Hazra 11.9 (6.2–16.2)   et al14  2011/France/ 5–18   Bouazza et al20  2011/US/King 14 (8–17)   et al22 14 (13–17)

Pharmacokinetic Parameters Parameters Median

AUC (ng∙h/mL) Cmax (ng/mL) Cmin (ng/mL)

38

300 mg

ATV/r

22

300 mg

ATV/r

GMT (95% CI)

2762 (2392–3041) 254 (221–292)

18

208 mg/m2

NA

17

NA NA 300 mg

2700 (1610) NA 3250 (1960) NA 3100 (1100–7800) 350 (170–920)

56 (40) 80 (60) 60 (30–300)

13

300 mg

DRV/r

2700 (1600–5600) 320 (170–720)

50 (30–200)

17

300 mg

ATV/r

3300 (2100–6700) 390 (130–680)

70 (30–150)

15.2 (12.3–17.6)

20

210 mg/m2

NNRTI, PI

GMT (90% CI) Mean (SD) Mean (SD) Median (range) Median (range) Median (range) GMT (95% CI)

2920 (1800–5590) 302 (187–485)

93

Boosted PI (LPV/r, SQV/r, IDV/r) Without LPV/r With LPV/r EFV

2730 (2410–3100) 363 (319–414)

48 (40–57)

12.2 (3.1–17.7)

40

214 mg/m2

NNRTI

2640 (1230–5110) 260 (130–520)

50 (20–120)

13 (10–17)  2013/Thai/  Prasitsuebsai et al23  2013/Thai/  Aurpibul et al15

Concomitant Antiretroviral Drugs

Median (range)

3020

326

NA 60 (52–68)

mg indicates milligram; m2, square meter; AUC, area under curve; Cmax, the maximum level after the dose was administered; Cmin, the minimal level after the dose was administered; GMT, geometric mean; CI, confidence interval; SD, standard deviation; TDF, tenofovir; ATV/r, atazanavir/ritonavir; EFV, efavirenz; DRV/r, darunavir/ritonavir; NNRTI, non nucleoside reverse-transcriptase inhibitor; PI, protease inhibitor; LPV/r, lopinavir boosted with ritonavir ; SQV/r, saquinavir boosted with ritonavir; IDV/r, indinavir boosted with ritonavir.

in 93 HIV-infected French children showed that ritonavir-boosted lopinavir (lopinavir/r) decreased TFV clearance by 25%,20 leading the authors to propose using a lower dose of TDF when coadministered with lopinavir/r (150 mg for 20–40 kg, 225 mg for >40–55 kg and 300 mg for >55 kg body weight). However, that dosing recommendation has not been adopted in the current US or World Health Organization guidelines. In contrast, some studies in youth reported low TFV AUC even when TDF was used with boosted-PI.14,19,23 More research on drug interactions of TDF with boosted PIs is needed to identify the optimal TDF dose in children. Clinically significant interactions have been reported for TDF with ARVs other than PIs. When coadministered with TDF, didanosine plasma concentration and risk of didanosine toxicities are increased24–26; therefore, TDF and didanosine should generally not be used concomitantly. Based on a pharmacokinetic study showing comparable didanosine AUC among adults who received 250 mg of enteric-coated didanosine tablet in combination with TDF and those who received a standard dose 400 mg didanosine without TDF,27 the dose of didanosine should be reduced from 400 to 250 mg when coadministered with TDF in adults weighing >60 kg. There is no similar information available in children. Prescription of TDF with didanosine should be avoided.

RESISTANCE PROFILE The presence of K65R mutation is associated with a reduced virologic response to TDF. More than 65% of South African adults with subtype C HIV infection and failing TDF-based first-line regimen had the K65R mutation.28 TFV remains active against many clones of HIV which are resistant to didanosine and zidovudine as well as against the multinucleoside resistance mutation Q151M; the presence of the D67N, K70R, T215Y/F or K219Q/E/N mutations did not appear to affect responses to TDF treatment. However, the in vitro TFV activity against HIV isolates is reduced 3-fold in the presence of 3 or more thymidine analoge mutations (TAMs) inclusive of either M41L or L210W.29,30 On the other hand, the lamivudine-associated resistance mutation M184V reduces the adverse impact of TAMs on

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TFV and zidovudine activity and confers reduced viral fitness, and viral replication capacity.31–33 These properties form the rationale for continuation of lamivudine (or emtricitabine) with TDF despite the presence of M184V mutation. In the current World Health Organization guidelines, TDF is proposed to be used in first-line ART regimens as part of an ART sequencing strategy, since emergence of the K65R mutation with first-line failure does not confer resistance to zidovudine, leaving zidovudine available for use in the second-line regimen.

POSITION OF TDF IN ANTIRETROVIRAL TREATMENT TDF as Part of First-line ARV Regimen The World Health Organization guidelines recommend TDF instead of thymidine analoge NRTIs (stavudine and zidovudine) for first-line ART regimens in adults and children older than 10 years of age. Studies in adults demonstrated lower virologic failure rates for TDF/emtricitabine compared to abacavir/ lamivudine when given as a once daily dose regimen with either efavirenz or atazanavir/r,34,35 and also when compared to regimens with a zidovudine/lamivudine backbone.36 The TDF/lamivudine/ efavirenz regimen has comparable virologic efficacy to stavudine/ lamivudine/efavirenz; however, it is associated with better lipid profiles and a lower rate of lipodystrophy in antiretroviral-naive adults.37 In 2014, the US Department of Health and Human Services guidelines recommended TDF as a preferred option for adolescents in Tanner stages 4–5 and as an alternative regimen for those in Tanner stage 1–3. The reluctance of experts to recommend TDF as a first-line in children of all ages is due to limited information about long-term safety and especially bone toxicity. Abacavir, a cytidine analoge, can be administered to young children once daily and, like TDF, does not induce multi-NRTI resistant mutation.38 The drawbacks of abacavir are its cost, lack of wide availability in resource-limited settings, and the need to screen for the human leukocyte antigen HLA-B*5701 allele to reduce the risk of drug hypersensitivity.39 However, screening for may be less of a © 2014 Wolters Kluwer Health, Inc. All rights reserved.

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concern for Southeast Asian or African population who have a low prevalence of HLA-B5701.40,41

TDF as Part of Second-line or Third-line ARV Regimens By 2012, according to the World Health Organization, 562,000 HIV-infected-children worldwide had been initiated on their first-line treatment regimen of which majority of them used stavudine or zidovudine as NRTI backbone.42 When treatment failure occurs, TDF can be considered as part of a second-line-regimen due to its favorable resistance profile. In PI-naive adults failing an non-NRTI (NNRTI)-based first line regimen without TDF, 83% achieved virologic suppression after switching to TDF/lamivudine/ lopinavir/r.43 In a study of heavily pretreated HIV-infected children, of whom 72% had ≥3 TAM with M41L mutation, adding TDF to the optimized background regimen (OBR) resulted in >1.0 log10 copies/mL reduction of median HIV viral load among 15 of 18 children, with virologic suppression in 6 of 18 children by 48 weeks.44 In a study of HIV-infected adolescents with pre-existing resistance mutations (49% of cases had ≥3 TAMs with either M41L or L210W) randomized to receive TDF or placebo with OBR, 41% of subjects overall achieved virologic suppression, but there was no difference between the TDF and placebo arms.45 This lack of TDF effect might be due to more subjects in the TDF group having baseline genotypic resistance to TDF (49% in TDF group versus 33% in the placebo group) and also to the effectiveness of the OBR. An in vitro study has shown that using TDF and zidovudine concomitantly modulates mutation selection; fewer resistance mutations to either drugs emerge because of a mutually antagonistic drug resistance interaction.46Some experts choose a combination of TDF and zidovudine as NRTIs to construct a second-line or third-line ARV regimen for heavily pretreated patient.

SPECIFIC CONSIDERATIONS FOR TDF USE IN HIVINFECTED CHILDREN AND ADOLESCENTS TDF Drug Approval Process In 2001, TDF was approved by the US Food and Drug Administration (FDA) as a once-daily 300 mg tablet for the treatment of HIV infection in persons ≥18 years of age. In March 2010, it was approved for use in adolescents aged 12–17 years, and for children aged 2 years and above in January 2012.47 The study by Della Negra et al45 documented safety of TDF when used in treatment experienced adolescents ages 12–18 years. Similarly, another study by Seaz-Llorens X demonstrated safety and tolerability of TDF in children aged 2≤16 years consistent with adults.48 The World Health Organization technical update review of available pediatric data concludes that toxicities are similar to those seen in adults and supports rolling out of TDF in treatment programs for children.49 The 2014 Department of Health and Human Services guidelines have different levels of recommendation for the use of TDF in children based on Tanner stage.50 In the 2013 World Health Organization guidelines, TDF is recommended as part of the first line ARV regimen as recommended for HIV-infected children from 10 years of age to adolescents which is aligned with recommendations for adults, while for children ages 3 to 10 kg, based on the recommended pediatric dose of 8 mg/kg/dose once daily (Table 2).21 For FDCs, Truvada (emtricitabine/TDF) is FDA-approved for use in © 2014 Wolters Kluwer Health, Inc. All rights reserved.

Review of Tenofovir Use in Children

TABLE 2.  Dosing Recommendations for TDF for Children ≥2 Years of Age According to US Food and Drug Administration21 Body Weight (kg) 17≤22 22≤28 28≤35 ≥35 Body Weight (kg) 10≤12 12≤14 14≤17 17≤19 19≤22 22≤24 24≤27 27≤29 29≤32 32≤34 34≤35 ≥35

TDF Tablets Once Daily (mg) 150 200 250 300 TDF Oral Powder (40 mg/scoop) Once Daily 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5

adolescents aged ≥12 years and who weigh ≥35 kg. Atripla (emtricitabine/TDF/efavirenz) is FDA-approved for use in adolescents aged ≥12 years and who weigh ≥40 kg.8 TDF/emtricitabine/rilpivirine (Complera)9 and TDF/emtricitabine/elvitegravir/cobicistat (Stribild)10 are not yet approved for patients aged

Review of tenofovir use in HIV-infected children.

Tenofovir disoproxil fumarate (TDF) is approved by the Food and Drug Administration for use in children ages 2 years and older and is recommended by t...
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