RESISTANCE IS COMMON IN PAEDIATRIC

PATIENTS FAILING ART IN SOUTH AFRICA

Gillian Hunt

17 October 2019

XXVIII INTERNATIONAL WORKSHOP ON HIV DRUG RESISTANCE

AND TREATMENT STRATEGIES

ART SCALE-UP AND EMERGENCE OF HIV DRUG RESISTANCE

Children on ART are at an increased risk of developing antiretroviral

drug resistance

limited paediatric

formulation options

poor palatability of

medications

inadequate dosing due

to weight change

exposure to maternal ART

limited knowledge of ARV

drug pharmacokinetics

and pharmacodynamics

dependence of caregivers

for adherence

LEVELS OF RESISTANCE IN CHILDREN

WHO Global HIVDR report 2017

STUDY RATIONALE

• A national facility based study of HIVDR among children on ART

who are experiencing virological failure was conducted between

March 2017 – March 2019

• Specific Objectives:

– To determine the prevalence of HIVDR (defined as ≥ 1 drug

resistance mutation by genotype) in children on ART with

virological failure (VF; Viral Load ≥ 1000 copies/ml).

• By regimen

• By age group

STUDY DESIGN

• Cross-sectional survey conducted at 42 high volume sentinel ART sites in 9

provinces

• Consecutive sampling of eligible

patients

– Ages ≤19 years

– On ART for >1 year

– Recent VL ≥1000 copies/ml

– Any regimen

– Collect whole blood and

minimal clinical information

• Next generation sequencing to

look for mutations associated with

HIVDR

DEMOGRAPHIC DATA AMONGST 911 PARTICIPANTS:

Median Age

was 13 years

(IQR 9, 15)

41% of all participants were

in 10 – 14 years age group,

28% were age ≥15 years,

32% were aged ≤ 9 year

47% were in

Primary school

54% were

male

63% of all participants were

aware of HIV status30% of children aged 5 – 9 years

73% of children aged 10 – 14 years

93% of children aged 15 – 19 years

60% of the

participants were

cared for by their

parents, 20% were

looked after by

grandparents

TREATMENT HISTORY AMONGST 911 PARTICIPANTS:

47% were receiving

PI-based regimens

47% were receiving

NNRTI-based

regimens

NRTI backbones:

ABC: 69%

AZT: 21%

TDF: 7%

The most commonly

used NNRTI was EFV

The most commonly

used PI was LPV/r

36% prior or current

infection with TB

18% had

documented

exposure to PMTCT. However, in most children

(52%) PMTCT exposure

was not recorded.

13% had

documented poor

adherence

ABC: abacavir. AZT: zidovudine. TDF: tenofovir. EFV: efavirenz. LPV?r” ritonavir-boosted lopinavir. TB:

tuberculosis. PMTCT: prevention of mother to child transmission

88

5

78

71

60

81

8

5963

42

95

1

94

78 77

90

12

81

69

60

0

20

40

60

80

100

Resistance - any PI Resistance NNRTI Resistance NRTI Resistance Dual NRTI/NNRTI

Resistance

Proportions (%) of participants with resistance

Total cohort PI Regimen NNRTI Regimen NRTI Regimen

89

8

7074

54

87

6

71

82

66

89

5

79

71

61

88

3

83

6257

0

20

40

60

80

100

Resistance - any PI Resistance NNRTI Resistance NRTI Resistance Dual NRTI/NNRTI

Resistance

Proportions (%) of participants with resistance, by age

group

Ages 0 – 4 years Ages 5 – 9 years Ages 10 – 14 years Ages 15 – 19 years

PREDICTORS OF RESISTANCE

• Modified poisson regression was performed to assess predictors of

resistance:

– Univariate analysis:

– Sex, age group, disclosure status, PMTCT exposure, time with virological failure, viral

load NOT associated with levels of resistance.

– Failing a NRTI regimen ((OR 1.12) or NNRTI regimen (1.18) was associated with presence

of resistance

– Multivariate analysis:

– Failing a NNRTI-based regimen was strongly associated with HIVDR (adjusted OR 1.18,

95% CI 1.07 – 1.30).

LIMITATIONS

• The study did not achieve expected sample size. The study also used facility HIV care

providers/clinic staff to collect this data on the lab request form, in facilities where staff

shortages are well documented. In many sites recruitment was incomplete and subject to

HCW availability and willingness to participate

• High volume paediatric sites were included in the study. This approach possibly introduced

bias to the study results if there is significant difference in characteristics between the high

and low volume sites.

• In addition, participants were selected at the discretion of the site HCW, with the intention to

offer a resistance test when clinically warranted. This survey then possibly did not recruit

participants who were known to be poorly adherent.

NEW TREATMENT GUIDELINES FOR SOUTH AFRICA: NRTI

BACKBONES

• Children ≥10 years of age TLD

• Children <10 years of age ABC+3TC+LPV/r

• Amongst older children with no PI resistance:

– 5% had high-level / intermediate resistance to TDF +3TC

– 51% were resistant to 3TC and susceptible to TDF

• Amongst younger children with no PI resistance:

– 31% had high-level / intermediate to ABC + 3TC

– 44% had resistance to 3TC and low-level resistance to ABC

ABC: abacavir. AZT: zidovudine. TDF: tenofovir. EFV: efavirenz. LPV/r: ritonavir-boosted lopinavir. TB: tuberculosis. PMTCT:

prevention of mother to child transmission

CONCLUSION

• HIVDR is highly prevalent in paediatric patients failing ART in SA, with 9 in

10 patients harbouring resistance to NNRTI and/or NRTI.

• Second-line PI regimens remain likely to be highly efficacious in achieving

virological suppression amongst patients failing NNRTI-based regimens.

• Scaling up resistance testing amongst patients failing PI-based regimens

would facilitate access to third-line regimens in SA.

M Yousif, L Levin, J Ledwaba, K Steegen, A Puren, T Kufa-Chakezha, G Aynalem, J Perlman, K

Ayalew, G Kindra, K Diallo, S Carmona, G Sherman, E Raizes

Cato Manor CHC: Ms G Mkhize, Dr Z Legoabe, Dr N Baijnath. Mahatma Gandhi Hospital: Sr C Sangweni, Dr T Subramoney. Newton

A CHC: Mrs ZB Khumalo. Osindisweni Hospital: Mrs NP Ngcobo, Dr T Lushaba, Dr M van Rensburg. Charles James Hospital: Dr L

Buthelezi, Dr S Ntshanga. Impumelelo Clinic (Kwa-Dabeka): Dr J Ramdeen, Dr M Hoque. RK Khan Hospital: Dr PS Subban, Dr J

Brijkumar. GJ Crookes Hospital: Mrs SP Nyawo, Dr P Mazula, Dr Ragunandan. Gamalakhe Hospital: Dr C Luke, Dr K Mabuyi, Sr

Mafunda, Sr N Skhondo. Ndwedwe Hospital: N Mhlongo, Dr O Ayeni, Mrs N Nyembe. Rietvlei Hospital, N Luhadi, Dr J Mitewu.

Northdale Hospital: Dr H Dawood, Dr D Ramsden, Dr Ngoy. Kwa-Msane Clinic: Sr GM Mbuyisa, Dr N Behuhuma, Sr Mdletshe.

Ndumo Clinic: Dr M Mkhabela. Nkonjeni Hospital: Mrs Magagula, Sr T Mthabela, Mrs MM Mkhize. Benedictine Hospital: Mr B

Khumalo, Dr C Linda, Mr T Mkhabela. Catherine Booth Hospital: Dr N Govender, Dr G Parkes, Dr Meryl Govender. Lower Umfolozi

War Memorial Hospital: Mrs CNN Mkhwanazi, Dr A Ricardo, Dr I Gasarasi, Dr N Sukdev. Nseleni Clinic: Dr S Vilakazi, Dr A

Amponsem, Ms T Ngcobo. Eshowe Hospital: Mr N Sangweni, Mrs B Mthabela, Dr N Khuzwayo. Piet Retief Hospital: Mr P

Lekhuleni, Dr JJ Ongole. Rob Ferreira Hospital: Dr G Koete, Sr Nkosi. Tintswalo Hospital: P Mogane, Sr N Mathebula. Shongwe

Hospital: Sr M Nakani, Dr G Tarr. Mankweng Hospital: Dr P Shibambu, Dr T Ntjie. Seshego Hospital: Sr M Rameetse, Dr K

Mushwana. St Rita’s Hospital: Ms A Makola, Ms K Siyema, Dr S Netshisaulu, Dr P Maimele. Lenasia CHC: Matron Bontle. Itireleng

CHC: Sr Mokoena, Sr Bonkolo. Alexandra CHC: Dr S Patz, Dr L Spark. Mthatha Regional Hospital: Dr M Magdevy, Dr Z Mlisana. Frere

Hospital: Dr H Lochan. St Patrick’s Hospital: Dr M Magdevy. Heidedal CHC: Dr N Braham, Dr R van Zyl. Dr George Mukhari Hospital:

Dr JM Mautjana, Dr T Phofa, Dr Z Makatini. Mamelodi Hospital: Dr Ikombele, Sr Tlaka, Sr Masha. Kalafong Hospital: Dr A Haeri

Mazanderani, Dr N du Plessis, Prof T Avenant. Nokuthela Ngwenya CHC: Sr Skosana, Mrs Khumalo. Pholosong Hospital: Dr P

Mogale, Dr L Mkhize. Carletonville Hospital: Sr F Sibongile, P Molehe. Kimberley Hospital: Dr P Jooste. Crossroads CHC: Dr L

Wilson, Dr R Sher. Ubuntu Clinic (Khayelitsha): Mr S Tutu, Sr L Kotelana. EPICENTRE: N Msomi, Z Mkhize, M Mahlambi, C Cawood.

GERMS-SA: M Morapeli, V Ndlovu, N Legare, N Mbhele, S Njikho, I Naidoo, S Mtetwa, L Ingle, T Tlhomelang, M Siyaka, Z Kibi, M

Manaka, K Mawasha, T Modiba, N Pulse, V Quan, L Erasmus.

NICD HIVDR lab: Dr M Yousif, J Ledwaba, V Kana, M Kalimashe,

H Zwane, L Nxumalo, D Chilwane, N Semper.

This study was supported by the Cooperative Agreement number GH001631, funded

by the Centers for Disease Control and Prevention. Its contents are solely the

responsibility of the authors and do not necessarily represent the official views of the

Centers for Disease Control and Prevention of the Department of Health and Human

Services.

We extend our deepest gratitude to all participants in the study.