Paediatric HIV Drug Resistance in African Settings

Dr Cissy Kityo Mutuluuza INTEREST Meeting

May 5-9, 2014 Lusaka, Zambia

Background: ART for children in sub-Saharan Africa

2.3 million children with HIV

Treatment coverage estimated at 26% for Africa; 32% for Eastern and Southern Africa

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HIVDR: Predisposing factors in children

– Exposure to antiretroviral medication for PMTCT Extended Nevirapine/Zidovudine Single dose nevirapine

• Higher baseline viral loads, longer time to suppression – Inappropriate dosing because of limited paediatric

formulations and weight changes – Limited training of HCW in pediatric management

• Adherence issues Reliance on adult caretakers Poorly palatable formulations (esp. liquids) 3

Pediatric HIVDR: extra challenges

• Life-long treatment with very

limited number of regimens

available

• HIVDR monitoring initiatives in

Africa have limited pediatric

cohorts

Countries showing resistance data in the HIV-1-infected paediatric population

Rojas Sánchez P , and Holguín A J. Antimicrob. Chemother. 2014;jac.dku104

Resistance studies in HIV-1-infected paediatric populations over time including naive and pretreated

patients

Rojas Sánchez P , and Holguín A J. Antimicrob. Chemother. 2014;jac.dku104

Although majority of HIV infected children live in Sub Saharan Africa, HIVDR data in children only available in 11 (20.7%) of the 53 African countries

Summary of TDR rates in drug-naive HIV-1-infected paediatric populations

Country Sampling Period

Naive Children

Age Range

Subjects with Resistance mutations to (%)

NNRTI NRTI PI 2 Classes

Cameroon 2009 -11 41 0-12 5 2 0 2

Uganda 2004 - 06 39 2-12 0 0 0 0

Uganda (MARCH) 2010 372 0-12 7.5 5.7 0 3.2

Nigeria (MARCH) 2011 100 0-12

3 African countries out of 15 worldwide reporting TDR rates

HIVDR after treatment

• Monitoring initiatives in Africa have limited pediatric cohorts and mainly small numbers

– Published data • Uganda(4), Mozambique (2), Camerron, Senegal, Kenya (2), South

Africa, Ivory Coast, Malawi and Mali

• High proportion of children with drug-resistant HIV-1 infections after first-line ART failure in resource-limited settings (Sigaloff, Lancet Inf Dis 2011)

– Prevalence rates – very variable • NRTI – 0-100%, NNRTI – 0-100%, PI – 0-37%, NRTI & NNRTI – 0-100%

• NNRTI resistance most common: K103N, Y181C • NRTI: M184V en TAMs • PI: only in certain regions (South America, South Africa)

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Monitoring Emerging HIVDR and Associated Factors in Sentinel ART Sites • Cohorts of approximately 130 ART-naive individuals

beginning ART followed for 12 months

• Baseline assessment of HIVDR: Genotyping, ARV history

• 12-month assessment of HIVDR:

– Status (lost to follow-up, stop, switch, still on first-line ART)

– Viral load + genotyping at 12 months if still on first-line ART, or at regimen switch

Implementation of the HIVDR strategy Country HIVDR

WG 5yr plans EWI Surveys of

Emerging Resistance

HIVDR-Transmission

TS

HIVDR database

Accredited genotyping laboratories

Zimbabwe √ √ √ √

√

Zambia √ √ √ √ √

√

Kenya √ √ √

√ √

Malawi √ √ √ √

√ √

South Africa √ √ √

√ √

Tanzania √ √

√

Ethiopia √ √

√ √

√ ° Mozambique √ √ √ √ Paediatric

√ √

Uganda √ √ √ √ Paediatric

√ √

Namibia √ √

√ Paediatric

√ √

Swaziland √ √ √ √ Paediatric

√ √

Botswana √ √ √ √ √ √

° have applied for WHO accreditation

Single-dose NVP

When prophylaxis fails, NNRTI resistance in up to 60% of infants < 6m (Hunt, AIDS 2011)

Children with NVP exposure are less likely to achieve virological suppression on NNRTI-based regimens (Musiime AIDS Res Hum Retroviruses 2009)

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Pediatric HIVDR after PMTCT

Zimbabwe 232 children <18m

Silvia Bertagnolio, Bloemfontein HIVDR workshop November, 2013

Ugandan data underestimate pediatric HIVDR as compared to 100% PMTCT studies with younger children elsewhere in Africa

Swaziland 201 children <18m

Treatment after PMTCT

• Virological failure after 24 weeks of AZT, 3TC, LPV/r vs. AZT,

3TC, NVP: 21.7% vs. 39.6%

(Palumbo, N Eng J Med 2010)

• Baseline resistance to nevirapine was predictive of treatment

failure

• Protease inhibitor preferred to nevirapine in children with

exposure to single dose nevirapine

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MARCH-Uganda study

ART initiation

or switch

~75%

first-line

ARV-naive PMTCT

~15%

second-line

– Prospective cohort study of 360 children in Uganda on ART

– “PASER junior”

MARCH - objectives

- Measure baseline HIVDR prevalence in children

initiating first- or second-line ART

- Monitor virological response to treatment

- Determine prevalence and patterns of HIVDR in

children with detectable viral load

- Identify risk factors for virologic failure and HIVDR

Study design

• Prospective, observational cohort study of 120 HIV

positive children ≤ 12 years at @ of the 3 JCRC sites

• Eligible when initiating first-line ART or switching to

second-line ART due to treatment failure

• Follow-up 2 years, VL testing every 6 months

• HIVDR test if VL >1000 copies/ml at Reference

Laboratory in Kampala

MARCH (sub-)study results

Research question: • What are the factors influencing the timing of

pediatric ART initiation?

Methods • Both quantitative and qualitative data analysis

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Baseline characteristic of children initiating first-line ART

18

19

0

5

10

15

20

25

First-line (n=279) ARV-naive (n=233)

ARV-exp (n=46)

%

Any mutation

NRTI

NNRTI

2-class

Frequencies (%) of HIVDR mutations in patients initiating first-line treatment either ARV-naïve or with previous PMTCT (n=14) or unknown exposure status (n=32)

HIVDR among children initiating first-line ART

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Frequencies (%) of HIVDR mutations in ARV-naïve children initiating first-line treatment at the three JCRC sites.

HIVDR among ARV-naïve children initiating first-line ART, per site

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Resistance patterns before first-line ART initiation

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Factors associated with HIVDR before first-line ART initiation

• 50 children enrolled in MARCH at time of failure of NNRTI-based first-line ART: 29 in Kampala, 18 in Mbale, 3 in Fort Portal

• Baseline characteristics:

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Resistance in children switching to second-line ART

Median age (IQR), years 5.5 (4.0-10.1) WHO clinical stage 3 or 4 23 (46%) PMTCT-exposure 13 (26%) Median duration of first-line ART, months 29.8 (25.1-48.4) ≥ 1 previous ART regimen 24 (48%) Last (“failing”) ART regimen AZT+3TC+EFV/NVP 35 (70%) Triomune 10 (20%) ABC-containing 5 (10%)

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Resistance patterns at switch (n=44)

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MARCH-Uganda: Susceptibility to RT-inhibitors at time of switch

Predicted HIV susceptibility to nucleoside and nonnucleoside reverse transcriptase inhibitors in children with first-line antiretroviral therapy failure (n = 44)

Sigaloff et al, AIDS research and human

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Resistance patterns at switch

TAM-2 pathway preferred?

Conclusions

• Important barriers to care remain for children, accounting for< 35% ART coverage in most African regions

• Even among reportedly ARV-naïve children, drug-resistant virus was present in 8% (MARCH)

• Besides PMTCT exposure, maternal ART use and breastfeeding may be important risk factors for baseline HIVDR

• The PMTCT practices of the last decade (non-use of Maternal HAART) have contributed to early virologic failure. The use of Maternal HAART scale up needs to be monitored for pediatric HIVDR

Conclusions

• Extensive resistance at switch (46% multiple TAMs) due to delayed switching fear of exhausting treatment options in children?

• These high HIVDR rates necessitate continued national surveillance programs to monitor trends. Affordable viral load & drug resistance testing and improved access to alternative combinations of ARVs are urgently needed

Acknowledgements

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PharmAccess, AIGHD, AMC Tobias Rinke de Wit Kim Sigaloff Job Calis Sonia Boender Raph Hamers Sibyl Geelen Michèle van Vugt Michael Boele van Hensbroek University Medical Center,

Utrecht Rob Schuurman World Health Organization

(WHO) Sylvia Bertagnolio

JCRC, Uganda Cissy Kityo Peter Mugyenyi Victor Musiime Joshua Kayiwe Elizabeth Khauda Lillian Nakatudde Andrew Mukuye Bernard Ayebazibwe Michael Owor

European Developing Countries

Trial Partnership

All participants and their parents/caregivers