Pediatric Urgent Start of HAART (PUSH)

Pediatric Urgent Start of HAART (PUSH)

Grant: Post-Stabilization vs Urgent Start of HAART in HIV-1 Infected Children with Severe Co-infections

Signature Page

The signatures below constitute the approval of this protocol and the attachments, and provide the necessary assurances that this trial will be conducted according to all stipulations in the protocol, including all statements regarding confidentiality, and according to legal and regulatory requirements.

Co-Principal Investigator:

02/19/15

Signed: ______Date: ______

Grace John Stewart, MD, PhD

Co-Principal Investigator:

Signed: ______Date: __02/19/2015______

Dalton Wamalwa, MBChB, MMed (Paeds), MPH
Table of Contents

Signature Page

List of Abbreviations and Acronyms

Key Roles

Summary

Figure 1. Overview of study design

1 Background and literature review

1.1 HIV-1 infected individuals are often diagnosed with HIV-1 in the setting of a severe co-infection

1.2 Children with HIV-1 present for care late and late-presenters have high mortality following ART

1.3 The ideal timing of ART in the context of severe co-infection is unknown and may differ by coinfecting pathogen

1.4 There are limited data on pediatric IRIS following ART

1.5 The mechanisms underlying IRIS in children may differ from adults

1.6 Challenges to initiating ART in Kenyan children

2 Rationale

3 Hypothesis

4 Study objectives

5 Study design and methodology

5.1 Study design

Table 1. Summary of proposed outcomes, eligibility, and procedures

5.2 Study area description

5.3 Study population

5.4 Inclusion and exclusion criteria

5.5 Representation of women, children and minorities

5.6 Co-enrollment guidelines

5.7 Sample size considerations

Table 2. Sample size calculations*

6 Recruitment, screening, consent, and enrollment procedures

6.1 Recruitment

6.2 Screening

6.3List of screening data collection procedures

Figure 2. Flow chart of recruitment, screening, enrollment and randomization procedures

6.4 Enrollment

6.5 List of enrollment data collection procedures

6.6 Management of Study participants during hospitalization

Table 3. Pre-enrollment, enrollment and post-randomization procedures administered during hospitalization by hospital and Study staff

7 Randomization

7.1 Randomization scheme

8 Post-randomization administration of ART

8.1 ART prescription: formulation, regimen and dosage

8.2 ART initiation

8.3 Adherence and disclosure counseling and documentation

8.4 Concomitant medication

8.5Monitoring response to therapy

8.6Treatment interruption

8.7 Changing therapy

Table 4. Potential toxicity that may require changing antiretroviral regimens

Table 5: Suggested ARV substitution in the event of significant toxicity

8.8 Drugs supply and accountability

8.9 ART initiation for discharged subjects

9 Post-randomization follow-up data collection procedures

9.1 Data and specimen collection during post randomization follow-up

Table 6. Schedule of intensive data and specimen collection

9.2 List of follow-up procedures

9.7 Participant retention

9.8 Participant withdrawal

10 Safety monitoring and adverse event reporting

10.1 Data safety and monitoring plan

10.2 Recording adverse events

10.3 Reporting serious adverse events

10.4 Study discontinuation

11 Laboratory considerations

11.1 Local laboratory tests

Table 7. Planned assays to identify immunologic covariates of mortality and IRIS

11.2 Quality assurance and quality control

11.3 Specimen storage

11.4 Biohazard containment

12 Human subjects considerations

12.1 Institutional Review Board

12.2 Risks to subjects

12.3 Adequacy of protection against risks

12.4 Potential benefits of the proposed research to the subjects and others

12.5 Importance of the knowledge to be gained

12.6 Care following study completion

13 Statistical analysis plans

13.1 Endpoints

13.2 Data analysis

13.2.1 Aim 1

13.2.2 Aim 2

13.2.3 Secondary aim

14 Administrative procedures

14.1 Protocol compliance

14.2 Protocol deviations/violations

14.3 Study coordination

14.4 Study monitoring

14.5 Study records

14.6 Use of Information and publications

References

Appendix

List of Abbreviations and Acronyms

3TC Lamivudine

ABC Abacavir

ALTAlanine transaminase

ARTAntiretroviral therapy

AZTZidovudine

CBCComplete blood count

CDCCenters for Disease Control and Prevention

CMVCytomegalovirus

CRPC-reactive protein

d4T Stavudine

ddI Didanosine

DNADeoxyribonucleic Acid

EBVEpstein Barr virus

EFV Efavirenz

ERCEthical Review Committee

EQAExternal quality assurance

GCLPGood Clinical and Laboratory Practice

HAART Highly Active Antiretroviral Therapy

HDLHigh Density Lipoprotein

HIV Human Immunodeficiency Virus

IRBInstitutional Review Board

IRISImmune reconstitution inflammatory syndrome

KNHKenyatta National Hospital

LAMLipoarabinomannan

LDLLow Density Lipoprotein

LPV-RTV Lopinavir-ritonavir (LPV/r)

MCHMaternal Child Health

NCCNairobi City Council

NRTI Nucleoside reverse transcriptase inhibitor

NNRTINon- nucleoside reverse transcriptase inhibitor

NVP Nevirapine

OPHOptimizing Pediatric HAART

PBMCPeripheral blood mononuclear cell

PIProtease Inhibitor

PITCProvider-initiated testing and counseling

PMTCTPrevention of Mother-to-Child Treatment

RNA Ribonucleic Acid

SAESerious Adverse Event

TBTuberculosis

TSTTuberculin skin test

TDFTenofovir

UNUniversity of Nairobi

UWUniversity of Washington

UAUrinalysis

VCTVoluntary counseling and testing

VL Viral load (HIV-1 RNA copies/ml)

WHO World Health Organization

ZDV Zidovudine

Key Roles

Institutions

Funding Agency: National Institutes of Health (2 RO1 HD023412-21)

Collaborating Institutions:University of Washington, Seattle, WA, USA

University of Nairobi, Nairobi, Kenya

Clinical laboratories:University of Nairobi, Nairobi, Kenya

Research Laboratory at KEMRI CDC, Kisumu Kenya

Protocol Development Co-Chairs

Grace John-Stewart, MD, PhD

Professor

Division of Allergy & Infectious Disease, Department of Medicine
International AIDS Research and Training Program, Department of Global Health
University of Washington

325 Ninth Avenue, Seattle WA 98104
Tel: 206-543-4278

Dalton Wamalwa, MBChB, MMed (Paeds), MPH

Senior Lecturer

Paediatrician, Epidemiologist

Department of Paediatrics and Child Health

Kenyatta National Hospital

University of Nairobi

P.O.Box 19676, Nairobi,00202

Tel: +254-020-2714851, +254-733558943

Co-Investigators

PUSH Protocol

19 February, 2015

Version 6

Sarah Benki-Nugent, MS, PhD

Senior Fellow

Department of Medicine
University of Washington

325 9th Avenue
Seattle, WA 98104

Tel:206-685-9713

Lisa Cranmer, MD, MPH

Senior Pediatric Infectious Disease Fellow

Dept. of Pediatrics

University of Washington

325 Ninth Avenue, Box 359300

Seattle, WA 98104

Tel: 206-987-2525

Barbara Lohman Payne, PhD

Research Assistant Professor

Department of Medicine

University of Washington

325 Ninth Avenue, Box 359909
Seattle WA 98119

Lisa A. Mills MD, MSc

Chief, HIV Research Branch

KEMRI-CDC Research and Public Health Collaboration

P.O Box 1578, Kisumu 40100

+254724255632

Hellen Moraa, BSN

Study Coordinator

Department of Paediatrics and Child Health

University of Nairobi

P.O. Box 19676 Nairobi, 00202

Tel: +254-020-2731498

Irene Njuguna MBChB, MSc

Study Physician

Department of Paediatrics and Child Health

University of Nairobi

P.O. Box 19676 Nairobi, 00202

Tel: +254-020-2731498

Julianna Otieno, MBChB, MMed (Paeds),

Pediatrician/Chief Administrator

Jaramogi Oginga Odinga Teaching &Referral Hospital

P.O Box 849 Kisumu 40100

+254 710830431

Vincent Otieno, MBChB

Study Physician

Department of Paediatrics and Child Health

University of Nairobi

P.O. Box 19676 Nairobi, 00202

Tel: +254-020-2731498

Barbra Richardson, PhD

Research Associate Professor,

Department of Biostatistics
University of Washington

325 Ninth Ave, Box 359909,

Seattle WA, 98104
Tel: 206 731-2425, 206 667-7788

Jennifer Slyker, PhD

Acting Instructor

Department of Global Health,

University of Washington

325 9th Avenue
Seattle, WA 98104

Tel:206-897-6696

Clement Zeh Ph.D

Director, HIV Research Laboratory

KEMRI-CDC Research and Public Health Collaboration

P.O Box 1578, Kisumu 40100

+254724255639

Collaborators

Loice Mutai

Head of Department, Paediatrics

Mbagathi District Hospital

P.O Box 20725, 0202

+254721330169

Beatrice Mutai

Paediatrician

Mbagathi District Hospital

P.O Box 20725, 0202

+254733250209

PUSH Protocol

19 February, 2015

Version 6

PUSH Protocol

19 February, 2015

Version 6

Summary

Design:Randomized clinical trial involving hospitalized HIV-1 infected children. Children will be randomized to randomized to urgent (<48 hours) versus earlyantiretroviral therapy (7-14 days). This trial will be unblinded.

Population:Hospitalized HIV-1 infected children who are antiretroviral therapy (ART) naïve ≤ 12 years of age.

Sample size:360 children will be randomized (180 per arm).

Treatment:All children will be treated with ART according to World Health Organization (WHO) and Kenyan national guidelines.

Study duration:Enrollment into the study will occur over the course of 36-48 months and each child will be routinely followed for a maximum of 6 months.

Study sites:Kenyatta National Hospital, Kisumu District Hospital, Nyanza Provincial Hospital, Mbagathi District Hospital (and at least 1 of the following hospitals: Homabay District Hospital, Kisii Level 5 Hospital)

Primary hypothesis:

HIV-1 infected children hospitalized with severe co-infection either may be unsalvageable due to too far advanced immunosuppression/co-infection or may benefit from urgent ART.

Secondary hypotheses:

Urgent ART during an acute infection could potentially result in increased risk of immune reconstitution inflammatory syndrome (IRIS) or drug toxicities/interactions.

Specific aims:

To compare the 6 month all-cause mortality rate, incidence of IRIS, and incidence of drug toxicity in HIV-1 infected children (≤ 12 years old) presenting to the hospital with a serious infection randomized to urgent (<48 hours) versus early ART (7-14 days).
To determine co-factors for mortality, IRIS, and drug toxicity. Potential cofactors will include: baseline weight-for-age, height-for-age, weight-for-height (Z-scores), CD4, HIV-1 RNA, type of co-infection, age, rate of viral load and CD4 change following ART, immune activation markers, pathogen and HIV-1 specific immune responses.

Secondary aim: To determine etiologies of IRIS and to compare immune reconstitution to HIV, TB, EBV and CMV following ART overall and in each trial arm.

Figure 1. Overview of study design

1 Background and literature review

1.1 HIV-1 infected individuals are often diagnosed with HIV-1 in the setting of asevere co-infection

The majority of HIV-1 infected adults are diagnosed and present for care late in disease. In a recent analysis of the North American ACCORD study of 44,491 HIV-1 infected individuals, 54% of adults presented for care at a disease stage eligible for treatment [1]. Although opportunistic and co-infections in HIV-1 have decreased dramatically following highly active antiretroviral therapy (HAART), many HIV-1 infected individuals continue to be diagnosed with HIV-1 late at the time of a symptomatic co-infection [2]. While this reality motivates public health interventions to encourage earlier HIV-1 testing, late presenters will continue to be prevalent and require strategic approaches to best salvage health outcomes.

1.2 Children with HIV-1 present for care late and late-presenters have high mortality following ART

Pediatric HIV-1 has a much more aggressive course than adult HIV-1, resulting in 2-year mortality for 50% in ART-untreated children [3-5]. However pediatric ART appears to have comparable benefit in children as adults, with marked survival benefit[6]. In the CHER study in South Africa, empiric early ART in asymptomatic infants resulted in 4% 1-year mortality, which was significantly lower than among infants randomized to initiate treatment when they met CD4 or clinical criteria for ART [7]. Although efforts are expanding to detect infant HIV-1, there are fewer efforts to diagnose older children who have asymptomatic HIV-1 infection. Most HIV-1 voluntary counseling and testing (VCT) centers cater solely to adults and even HIV-1 infected caregivers may perceive an asymptomatic child as being unlikely to carry HIV-1. Thus, most children with HIV-1 in Africa remain undiagnosed and when they do present for care, it is in the context of severe co-infection. In a recent systematic review of studies on pediatric ART initiation involving over 19,000 children, the majority from resource-limited settings (17,875), children from resource-limited settings had much lower CD4% at ART initiation (12% vs. 23%, p=0.01) and higher mortality (7.6% vs. 1.6%) than developed countries [8]. The management of hospitalized newly HIV-1 diagnosed children includes aggressive management of co-infection with stabilization or resolution prior to ART initiation. In the process of medical stabilization, ART preparation and adherence counseling, children die. Our proposed trial will test the concept that highly accelerated (urgent) ART in children with severe co-infection will provide survival benefit offsetting the potential risk of IRIS or drug toxicity/failure.

1.3 The ideal timing of ART in the context of severe co-infection is unknown and may differ by coinfecting pathogen

Recently randomized clinical trials in adults have compared survival benefit of earlier versus later ART during acute co-infection. Zolopa and colleagues conducted a US study in HIV-1 infected adults with severe infection (mostly pneumocystis) and found that earlier ART resulted in improved survival [9]. In 2010, Karim et al found that integrated ART in South African TB-coinfected individuals resulted in survival benefit compared with sequential ART (following completion of TB therapy) [10]. Rates of IRIS in the two trial arms were comparable. In contrast to these studies, early ART in cryptococcal meningitis was associated with increased mortality [11]. In addition, an ongoing trial among adults with TB meningitis has not shown benefits of early ART and has noted increased drug adverse events with early ART [12]. These latter studies suggest that CNS infections may be more prone to inflammatory sequelae from earlier ART.

1.4 There are limited data on pediatric IRIS following ART

Immune reconstitution inflammatory syndrome (IRIS) occurs as a result of an exaggerated dysregulatory immune response to either a subclinical or treated co-infection. In the absence of HIV-1, IRIS has been observed in TB-treated children and in re-feeding syndrome, but more recently has been described in ART treated HIV-infected individuals. Because children do not have as many pre-existing latent infections, it is plausible that IRIS incidence and pathogenesis would differ markedly between children and adults. In the few studies conducted on pediatric IRIS to date, incidence rates in children (11-21%) appear similar to those in adults (20%) and vary by pathogen. IRIS is a diagnosis of exclusion and as a result, it is difficult to precisely estimate incidence of IRIS. In both adults and children, IRIS is typically identified in the first 2 weeks to 3 months of therapy, but may appear much later (>12 months after ART initiation). In the limited studies among children, mycobacterium and varicella zoster virus (VZV) are the most common pathogens associated with IRIS [13-15]. There are only 2 prospective studies of pediatric IRIS, both of which excluded children with active opportunistic infections. Unfortunately, most late-presenting children have an active infection and are at risk for IRIS. Determining incidence of and co-factors for IRIS in this broad denominator of children is important for appropriate clinical management.

1.5 The mechanisms underlying IRIS in children may differ from adults

IRIS occurs due to immune dysregulation and correlates with severity of immunosuppression (CD4 <100 cells/mm), infecting pathogen, and type of immune response [16]. T-cell responses to pathogens may be lower in children than in adults, which could result in higher pathogen loads and increased susceptibility to IRIS [17, 18]. IFN-gamma responses may be actively suppressed during fetal development [19, 20], but appear to increase rapidly during the first year of life, and it is unknown how evolving Th1-type responses contribute to IRIS during infancy [17, 21]. Dysregulation of regulatory T cell responses appears to be important in some types of IRIS; the frequency of Tregs is highest in cord blood and infancy and may potentially affect the risk of developing IRIS [22, 23]. Additionally, neonatal dendritic cells (DC) differ from adult cells in phenotype and function; an impaired ability to prime antigen-specific Th1 and CD8 T cell responses during infancy could affect propensity for further dysregulation during immune reconstitution [24]. Due to the potential severity of IRIS in children and the large number of children at risk in HIV endemic areas, a detailed evaluation of immune responses and immunoregulatory processes during the development of IRIS will be important in developing strategies to prevent and treat IRIS in children.

1.6 Challenges to initiating ART in Kenyan children

IRIS presents significant challenges to initiating ART in HIV-infected children, particularly those with substantial immunosuppression or acute opportunistic infections. In Kenya, many children are not diagnosed with HIV-1 until they become critically ill; since standard practice is to stabilize acute infections before initiating ART, many children die before ever starting ART [6, 25]. Initiation of ART during acute illness may improve prognosis by speeding immune reconstitution and restoring growth [6]. However, the potential benefits of urgent initiation of ART must be balanced against the potential risk of developing IRIS; which though uncommonly fatal, may present significant morbidity and result in poorer virologic suppression on ART[13]. To date, there have been no randomized trials of timing of ART and the development of IRIS. Urgent ART during an acute infection could potentially result in increased risk of IRIS, particularly if ART begins before total clearance of the offending pathogen. Alternately, delaying ART until the resolution of acute infection leaves the immunosuppressed child at risk for the development of other novel opportunistic infections, and may not reduce the risk of developing “unmasking-IRIS” which occurs when immune responses target a previously undetected pathogen.

2 Rationale

Over 90% of the world’s 2.2 million HIV-1 infected children reside in Africa and public health programs are expanding to both decrease the number of new pediatric HIV-1 infections and to treat children with HIV-1 infection. Unfortunately, HIV-1 infection is under-recognized among children and pediatric HIV-1 infection is often diagnosed late in the setting of a severe co-infection. For these children, there is need to define the optimal time to initiate ART. The primary goal of this study is to determine whether urgent initiation of ART has the potential to reduce mortality in late-diagnosed HIV-1-infected children. Urgent initiation of ART, concurrent with treatment of the acute co-infection, may be associated with increased drug side-effects, difficulty in administration, and increased immune reconstitution inflammatory syndrome (IRIS). These risks may be outweighed by increased survival, prompt decrease in viral replication, faster immune recovery, and better control of both HIV-1 and the concomitant infection.

3 Hypothesis

Primary Hypothesis:

HIV-1 infected children hospitalized with severe co-infection either may be unsalvageable due to too far advanced immunosuppression/co-infection or may benefit from urgent ART.

Secondary hypotheses:

Urgent ART during an acute infection could potentially result in increased risk of IRIS or drug toxicities/interactions.