Abstract
Objectives:
Drug-drug interactions limit current antiretroviral (ARV) treatment options for HIV-infected children with tuberculosis (TB). Rifampicin (RIF) induces UDP-glucuronosyltransferase activity, accelerating the clearance of raltegravir (RAL). We sought to establish an optimal and safe dose of RAL when administered with RIF to HIV and TB co-infected children.
Design:
P1101 is a Phase I/II open-label dose-finding study of RAL with RIF for children 2 to < 12 years of age beginning treatment for HIV and active TB.
Setting:
Four sites in South Africa.
Methods:
Chewable RAL was given at 12 mg/kg per dose twice daily (twice the usual pediatric dose) with two nucleoside reverse transcriptase inhibitors. Intensive RAL pharmacokinetic sampling was conducted 5 to 8 days after ARV therapy was initiated; a fourth ARV agent was then added.
Results:
Children were recruited into two age-defined groups: Cohort 1 (2 to <6 years old) and Cohort 2 (6 to <12 years old). Pharmacological targets (geometric mean (GM) AUC12h of 14–45 μM-h and GM C12h ≥75 nM) were reached in both Cohort 1 (28.8 μM-h and 229 nM) and Cohort 2 (38.8 μM-h and 228nM). The RAL-based ART was well tolerated by most participants: one participant discontinued treatment due to Grade 4 hepatitis that was possibly treatment-related. At Week 8, 22 of 24 participants (92%) had HIV RNA concentrations below 400 copies/mL; 19 of 24 (79%) were below 50 copies/mL.
Conclusions:
Giving 12 mg/kg twice daily of the chewable RAL formulation achieved PK targets safely in HIV-infected children receiving RIF for TB.
Keywords: Africa, antiretroviral therapy, paediatrics, pharmacogenomics/drug, interactions, opportunistic infections, tuberculosis
1. INTRODUCTION
The burden of tuberculosis (TB) among HIV-infected adults and children is very high in many resource-limited settings. There were an estimated 10 million new TB cases in 2017, with about 9% in people living with HIV, 72% of whom were from Africa.[1] In Cape Town, South Africa, 70% of adult patients who began antiretroviral therapy (ART) either had a previous episode of active TB or had been treated for TB within the first year of initiating ART.[2] Up to a quarter of children in South Africa starting ART have been reported to be receiving TB treatment.[3, 4] Bacille-Calmette-Guerin vaccine (BCG) disease is also common in HIV-infected children, particularly as immune reconstitution inflammatory syndrome (IRIS) in the first few weeks after administration of ART. In the Nevirapine Resistance Study (NEVEREST), BCG disease was the most common form (71%) of IRIS, exceeding TB.[5] Although usually localized, BCG disease is sometimes treated with a Rifampicin (RIF)-containing regimen for fear of disseminated of BCG in immunocompromised children. Incident TB has also been described after the start of ART. [4, 5] Therefore a high proportion of children on ART in TB prevalent areas require TB treatment.
Drug-drug interactions between TB treatment and ART are known to complicate treatment. RIF, an essential component of first-line antibacterial regimens for TB, is usually combined with isoniazid (INH) and pyrazinamide (PZA) for drug susceptible TB.[6] RIF is a strong inducer of uridine diphosphate-glucuronosyltransferase and P-glycoprotein cytochrome P450 enzymes.[7–10] These interactions complicate formulating an ART regimen.
World Health Organization (WHO) guidelines for ART in HIV and TB co-infected infants and children recommend triple nucleoside analogue reverse transcriptase inhibitor (NRTI) combinations in children under three years of age and efavirenz (EFV)-based treatment regimens for first-line therapy in those above three years, without dose-adjustment of EFV. For children already receiving ART, the recommendations vary depending on the background regimen already in place. This may involve continuing nevirapine or adding extra ritonavir to lopinavir and ritonavir (LPV/r), known as ‘super-boosting’ LPV/r.[11] Although adequate drug exposure can be maintained by ‘super-boosting’ LPV/r, this approach is complex and may be poorly tolerated due to poor palatability, toxicity and extra dosing volume.[12, 13] Drug-drug interactions and the current complexity of treating young children with HIV and TB coinfection has driven efforts to identify better-tolerated, potent, simple agents for inclusion in ART regimens that can be used in those also receiving TB treatment.
Integrase strand transfer inhibitors (INSTIs) are well tolerated and have been proposed as an alternative for use together with TB treatment. Raltegravir (RAL), the first INSTI studied in children, is approved by the U.S. Food and Drug Administration (FDA) for treatment of newborns, infants, and children of all ages, and is available in formulations that are well tolerated in children. However, investigation of the optimal dose of RAL in conjunction with RIF has so far only been conducted in adults. In one study involving healthy adults, doubling the dose of RAL when given with RIF partially addressed the impact on enzyme induction, resulting in adequate RAL pharmacokinetic parameters.[10] However, the increased clearance of RIF on Ctrough concentrations (C12h) was still evident, and could lead to virologic failure. In the Phase III QDMRK study, inferior antiviral efficacy was seen when RAL was given as 800 mg once daily compared to 400 mg twice daily (HIV RNA <50 copies/mL at Week 48: 83% versus 89%).[14] Trough (C12h) concentrations were correlated with antiviral effect, with patients in the lowest quartile for C12h showing the highest rate of virologic failure.[15] Based on these data, a minimum target for GM C12h of approximately 75 nM is now considered to be more appropriate than the previous target of 33 nM.
The pharmacokinetics of RAL in combination with RIF during treatment of HIV and TB were studied in a small group of adults who started RAL in combination with tenofovir disoproxil fumarate and lamivudine after initiation of RIF.[16] Some received the standard dose of 400 mg RAL twice daily while others received RAL 800 mg twice daily while taking RIF, followed by 400 mg twice daily four weeks after RIF discontinuation. The 800 mg dose of RAL overcompensated for enzyme induction by RIF, and only small decreases were seen in AUC0–12 and C12h during RIF co-administration with the usual dose of 400 mg. The safety and efficacy of RAL given as 400 mg twice daily or 800 mg twice daily during treatment for TB with RIF-containing anti-TB regimens was examined in the ANRS 12180 Reflate TB trial.[17] This study involved random, balanced assignment of 155 antiretroviral-naïve adults into one of three arms to receive EFV (600 mg daily) or RAL at 400 mg or 800 mg twice daily. The fraction of participants with HIV plasma viral RNA concentration <50 copies/mL at 24 and 48 weeks of treatment was similar in all three arms, suggesting that RAL at a dose of 400 mg twice daily might be an alternative to EFV for ART in adults with HIV/TB coinfection.
However, the pharmacokinetic profiles of many medications with hepatic clearance are markedly different in younger children compared to adults, and doses that are proportionately higher (when compared by body weight) are more often required to achieve similar pharmacokinetic profiles.[18] Here we describe the safety and pharmacokinetics of this combination in HIV-infected infants and children receiving ART and RIF-containing therapy for TB in a Phase I/II dose-finding study of RAL conducted at four sites in South Africa.
MATERIALS AND METHODS
Study Design:
IMPAACT P1101 is a Phase I/II open label, multicenter study conducted at four sites in South Africa. The protocol design initially allowed simultaneous enrollment into two age-stratified cohorts (Cohort 1: 2 to <6 years of age; Cohort 2: 6 to <12 years of age). A third cohort opened in 2017 for children aged 4 weeks to <2 years of age; data from Cohort 3 will be the subject of a subsequent report. On the day of enrollment, two NRTIs were initiated, along with the chewable tablet formulation of RAL at a dose of 12 mg/kg per dose (twice the recommended dose) twice daily (maximum dose: 800 mg). Intensive RAL pharmacokinetic (PK) sampling was performed 5–8 days after ART was initiated, then a fourth antiretroviral (ARV) agent was added, usually EFV or ‘super-boosted’ LPV/r according to local recommendations. RAL was continued until anti-tuberculous therapy was completed. RAL was stopped if PK analysis revealed an AUC0–12 h ≥ 63 μM-h. This upper limit was chosen as it was the geometric mean exposure seen among healthy adult participants in a study of the effect of a supratherapeutic dose (1600 mg) of raltegravir on the QTc interval[19]. Each age cohort started with a mini-cohort of six participants. If the mini-cohort met both safety and PK targets, then six additional participants were enrolled to make up a full cohort of n=12 evaluable participants. Each cohort was assessed independently.
Initially under protocol Version 1.0, participants were evaluated at entry; at weeks 1, 4 and 8 after ART initiation; then every 4 weeks on therapy; at discontinuation of RAL and TB treatment; and 4 and 12 weeks off RAL treatment. An additional monitoring visit at two weeks of ART was added in protocol Version 2.0 based on recommendations from the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network Study Monitoring Committee following the occurrence of a Grade 4 toxicity by the second participant enrolled in the study. Clinical and laboratory assessments were completed at each visit. The primary definition of virologic response was ≥1-log10 reduction in HIV-1 RNA copies/mL from baseline or HIV-1 RNA ≤400 copies/mL. A secondary, more stringent definition of virologic response was achieving HIV RNA ≤50 copies/mL. Virologic failure was defined as failure to respond at Week 8 with a reduction in viral load (HIV RNA (copies/mL) to <400 copies/mL or <1-log10 drop from baseline viral load. At week 8, if a participant met the definition for virologic failure but the site clinician believed that there had been a good clinical response to therapy and that the viral load was likely to continue to decrease, RAL was continued. If at Week 12 the definition of virologic failure was still met, RAL was stopped and the treatment regimen was changed according to local treatment standards.
Participants:
Children with HIV infection 2 to less than 12 years of age were eligible to enroll in the age defined cohorts if they were receiving treatment for pulmonary TB or tuberculous adenitis with RIF and at least one other drug for TB, for at least one week and not more than 20 weeks. Potential enrollees were excluded from participation if they were pregnant or breastfeeding, known or suspected or known to have multidrug resistant or extremely drug resistant TB, had protein calorie malnutrition, acute serious infections other than TB requiring active treatment (e.g. Pneumocystis jirovecii), or any clinical or laboratory event at entry grade 4 or higher per Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. Participants currently receiving systemic cytotoxic chemotherapy (or who had stopped such therapy within 12 months) were not allowed to enroll. During the study, participants were not permitted to receive other integrase strand transfer inhibitors (e.g. dolutegravir), zolpidem, antiepileptic drugs, exogenous cytokines, rifabutin, and other agents likely to alter the PK of RAL.
Pharmacologic Analysis:
RAL plasma concentrations were measured at the University of Alabama at Birmingham using a validated, isocratic, reverse-phase high-performance liquid chromatography/tandem-mass spectrometry method, as previously described.[20] The linear calibration range was 10 to 10,000 ng/mL from a 200-μL plasma sample. Whole blood was collected at time 0 (pre-dose) and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after a witnessed dose of RAL.
Dose-Finding Process:
To establish a recommended dose for each age cohort, the initial mini-cohort of six evaluable participants was assessed based on the Week 1 intensive PK results and safety data through week 4. The dose was considered safe for the mini-cohort if (1) none of the first six participants had experienced death, a life-threatening Grade 4 adverse event (AE) deemed at least possibly related to RAL, or any Grade 4 event probably or definitely attributable to the study medication, and (2) no more than two of these six participants had permanently discontinued study drug due to a Grade 3 or Grade 4 AE deemed at least possibly treatment related. (These safety criteria were used in the Phase I/II study that established the dose of RAL that was approved by the U.S. Food and Drug Administration for treatment of HIV infection in children not receiving rifampin or other medications that alter hepatic metabolism of RAL [20]Pharmacologic targets were geometric mean (GM) AUC0–12h of 14–45 μM-h and GM C12h ≥75 nM (33 ng/mL). If the mini-cohort passed both safety and PK guidelines, then an additional six participants were enrolled into the age cohort to achieve a full cohort of 12. Each full cohort was evaluated based on week 4 safety data and PK results following similar guidelines as above with a modified safety criterion: no more than 33% of these participants had permanently discontinued study drug due to a Grade 3 or a Grade 4 AE that was deemed at least possibly treatment related.
Data analysis:
PK parameters were calculated from RAL concentration-time data using non-compartmental methods (Phoenix WinNonlin version 8.0, Certara USA, Inc., Princeton, NJ). Descriptive analyses and summaries are presented by cohort and in aggregate. Statistical power was insufficient to permit comparisons between cohorts. The safety analysis included all participants exposed to RAL at the final recommended dose for each cohort. The proportion of participants experiencing AEs deemed to be at least possibly treatment-related was bounded by 95% exact confidence intervals (CI). Descriptive statistics were computed for baseline demographics and characteristics. Virologic and immunologic responses were analyzed using an ‘as-treated’ analysis such that only participants who remained on study drug and who had evaluable data were included. Frequency of virologic response (median and interquartile range [IQR] of changes in log10 plasma HIV RNA concentration) and changes in CD4 count and percentage from study entry are presented. SAS version 9.4 (Cary, NC) was used.
RESULTS
Participants
The baseline characteristics of the 26 participants enrolled in Cohorts 1 and 2 are shown in Table 1. All participants were black, with boys slightly exceeding girls. The median baseline HIV-1 plasma viral loads in children were 4.91 log10 copies/mL in Cohort 1 and 4.55 log10 copies/mL in Cohort 2. The median CD4 count was similar between the two groups (559 versus 575 cells/μL). All participants had pulmonary TB at entry; one participant in Cohort 2 also had tuberculous lymphadenitis. The median period of follow up was 36 weeks after RAL initiation.
TABLE 1:
BASELINE CHARACTERISTICS
| Cohort 1 (2 to <6 yr) |
Cohort 2 (6 to <12 yr) |
|
|---|---|---|
| Number | 12 | 14 |
| Median Age (years) (IQR) | 3 (2–5) | 8 (7–9) |
| Gender (M/F) | 7/5 | 7/7 |
| Median CD4 (%) (IQR) | 15 (9–24) | 21 (7–25) |
| Median CD4 (cells/μL) (IQR) | 559 (390–1185) | 575 (142–704) |
| Median HIV-1 (log10 copies/mL) (IQR) | 4.91(4.42–5.42) | 4.55 (4.21–5.09) |
| Other antiretroviral drugs | Efavirenz (n=11) Lopinavir/ritonavir (n=1) |
Efavirenz (n=14) |
Pharmacokinetics
PK analysis was performed in all 26 participants enrolled in both cohorts. As shown in Figure 1, serum RAL concentrations generally reached peak levels 1 hour after dosing and then declined with a GM half-life of 4.3 hours in Cohort 1 and 3.4 hours in Cohort 2. PK targets for C12h and AUC0–12h were achieved in both cohorts (Table 2) at the dose of approximately 12 mg/kg/dose given twice daily (geometric mean: 12.3 mg/kg in Cohort 1 and 12.6 mg/kg in Cohort 2; maximum dose of 14.9 mg/kg). Three participants in Cohort 2 had drug exposures exceeding the protocol defined maximum allowable level of 63 μM-h. Two of these participants had RAL stopped due to this finding and were followed for an additional 12 weeks. In the case of the third participant, the results of the PK analysis were received after treatment for TB was completed and RAL treatment had already been stopped. All three participants with high RAL exposures were asymptomatic and none experienced virologic failure after discontinuation of RAL.
Figure 1.
Pharmacokinetic profiles of raltegravir in children receiving RAL concurrently with RIF based therapy for tuberculosis. Left Panel: data for children in Cohort 1 (2 to <6 years of age, n=12). Right Panel: Cohort 2 (6 to <12 years of age, n=14). The solid line is median for the group and dashed lines are 10th and 90th percentiles.
TABLE 2.
RALTEGRAVIR PHARMACOKINETIC PARAMETERS
| Cohort 1 (2 to <6 yr) |
Cohort 2 (6 to <12 yr) |
|
|---|---|---|
| Number of Evaluations | 12 | 14 |
| Dose (mg/kg) | 12.3 (10.2) | 12.6 (12.5) |
| Cmax (μM) | 11.7 (76.2) | 13.9 (70.6) |
| T1/2 (h) | 4.3 (74.5) | 3.1 (50.0) |
| AUC12h μM-h | 28.8 (50.2) | 38.8 (38.1) |
| C12h (nM) | 229 (76.3) | 228 (78.4) |
Pharmacokinetic values are presented as geometric mean and coefficient of variation (%). Doses ranged from 10.5 TO 14.9 mg/kg in Cohort 1 and from 9.9 to 14.9 mg/kg in Cohort 2.
Safety Assessments
In Cohort 2, one of 14 participants (7%, with 95% Exact CI 0.2% to 34%), a 9 year old female, experienced an AE at day 16 of ART that was deemed possibly related to RAL. This consisted of Grade 4 elevations of AST and ALT, Grade 3 elevation of total bilirubin, and a clinical diagnosis of Grade 4 hepatitis; drug induced Grade 2 rash was also observed. At the time, this participant was receiving four ARVs (abacavir, 3TC, EFV, and RAL) and anti-tuberculous therapy with RIF, INH, ethambutol and PZA. Other concomitant medications included acyclovir, cotrimoxazole, pyridoxine, acetaminophen, chlorpheniramine, and multivitamins. RAL was permanently discontinued and the study was temporarily paused to accrual to review the safety data. There was no evidence of acute viral hepatitis caused by EBV or Hepatitis A, B, or C, and the child did not have HLA-B*5701. This participant recovered without incident and the hepatic toxicities and rash were deemed to likely be due to IRIS and hypersensitivity reaction to one of the medications. In response to this event, the protocol was modified to evaluate all children at 14 days after treatment began. No other participant experienced AEs that necessitated RAL discontinuation.
In Cohort 1, only one of the 12 participants (8% with 95% Exact CI 0.2% to 38%) had an AE deemed at least possibly related to RAL. This 3-year-old male had Grade 3 elevations of both AST and ALT at week 4. RAL and other ARVs were temporarily held for 3 weeks and then resumed without recurrence of Grade 3 laboratory abnormalities.
Thus, both cohorts passed the protocol safety guidelines for the mini-cohort and the full cohort of 12 participants. In addition, the longer follow-up safety data show that a 12 mg/kg/dose twice daily of oral chewable formulation of RAL met safety targets in these two cohorts of participants receiving rifampin.
Virologic and Immunologic Responses:
Plasma viral loads decreased rapidly in both cohorts, and at 8 weeks, 11 of the 12 (92%, CI [62%, 100%]) evaluable participants in each cohort met the protocol definition of a virologic response, with VL <400 copies/mL. In Cohort 1, 9/12 (75%, CI [43%, 95%]) achieved a viral load reduction to <50 copies/mL, while in Cohort 2, 10/12 (83%, CI [52%, 98%]) achieved this level of suppression (Figure 2).
Figure 2.
Viral Load Response By 8 Weeks of Treatment With RAL
Note: The median (interquartile range) change in plasma log10 HIV-RNA (copies/mL) from baseline was −3.17 (−3.80 to −2.56) for Cohort 1 and −2.79 (−3.42 to −2.09) for Cohort 2.
The only virologic failure in Cohort 1 involved a participant who had RAL held for three weeks due to an AE; care providers also suspected non-adherence to the ART. Non-adherence to treatment was also a contributing factor to the sole virologic failure in Cohort 2, which occurred at week 8. This participant remained a virologic failure through Week 16 and RAL treatment was stopped due to poor adherence, which was thought to be due to social factors.
By week 8 of ART with RAL, CD4 T cell counts rose from baseline by a median of 100 cells/μL (IQR 69.5–229) in Cohort 1 and 163 (29.0–351) cells in Cohort 2. CD4 T cell percentages increased from baseline by 6.10% (1.85–9.70) and 4.9 % (0.70–7.65) in Cohorts 1 and 2, respectively.
DISCUSSION
This phase I/II study was designed to identify a safe dose that would result in PK parameters for RAL when given during RIF co-treatment that would be comparable to those seen in prior dose-finding studies performed in the absence of anti-TB therapy [20]. In both age-defined cohorts presented here, a dose of 12 mg/kg/dose given twice daily of the chewable formulation achieved these goals: the GM AUC12h was well within the protocol defined target range of 14–45 μM-h and trough concentrations at 12 hours exceeded the minimum target of 75 nM. In this small study, this double dose of RAL was safe and tolerated by most participants in both cohorts. Despite active TB, the majority of participants achieved suppression of HIV-1 viral load to <50 copies/mL.
Including HIV infected children with commonly diagnosed coinfections in the evaluation of new agents is essential. However, the presence of coinfection often signifies that these children have more severe disease and are exposed simultaneously to more medications than are those with HIV alone. When AEs occur, this can complicate attribution of the AE to study drug(s). While this has often been a deterrent to this type of research, our small study demonstrates that including HIV and TB co-infected children in PK studies is feasible. With the exception of one child permanently discontinuing RAL due to safety concerns, RAL was well-tolerated option for ART during simultaneous treatment for HIV and TB in children. In Cohort 2, one participant was diagnosed with IRIS but the event was also deemed possibly related to RAL It is, however, a challenge to determine attribution to the study drug when a participant is receiving so many different medications. In this study, three children exceeded the protocol-defined upper limits of drug exposure of 63 μM-h. This threshold value was based on geometric mean AUC 0–12h of RAL in healthy adults receiving RAL observed in a Phase I trial designed to examine any effects of RAL on QTc interval; no cardiac toxicity was associated with a geometric mean concentration of 63 μM-h in these adults and exposures as high as 95.6 μM-h. In this study we observed no evidence of toxicity in the three participants who exceeded the protocol designated designated limit. Moreover, neither of the two children who had RAL stopped temporarily or permanently had high exposures (the AUC0–12h values were 21.48 and 36.99 M-h).Among potential weaknesses of the study is the exclusion of children with complicated TB such as tuberculous meningitis and abdominal TB, in whom drug-drug interactions and drug toxicity may be more likely since additional agents are used to treat TB. Moreover, we are unable to fully assess the potency, durability and antiretroviral activity of RAL and two nucleoside analogue agents in the context of TB therapy, since we added a fourth ARV agent after completion of the intensive PK studies. While this addition was due to concern that children might be exposed to a sub-therapeutic concentration of RAL, additional studies will be required to determine if RAL or other INSTIs are sufficiently potent to promote control of HIV replication in all TB co-infected children.
In HIV and TB co-infected children aged 2 to 12 years, the chewable formulation of RAL at a dose of 12mg/kg/dose twice daily safely achieved PK levels similar to HIV-1-infected children receiving the current recommended dose of 6 mg/kg/dose and not on treatment for TB. Our study provides valuable data in the quest for safer, potent treatment agents that can be used in HIV and TB co-infected children.
ACKNOWLEDGEMENTS
Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH), all components of the National Institutes of Health (NIH), under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), and by NICHD contract number HHSN275201800001I. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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