1 of 24

Victor Musiime, MBChB, MMed, PhD�Associate Professor, Makerere University�Senior Research Consultant, Joint Clinical Research Centre�Kampala, Uganda

Antiretroviral Therapy through the Ages: Optimal Regimens for Children and Adolescents Living with HIV

2 of 24

Dual Regimens

Long acting injectable ART*

Options for second line ART*

Contents

*ART: antiretroviral therapy

3 of 24

Background

Children and adolescents face life long ART* amidst treatment fatigue and long term toxicities
ART regimens should be easy to take, have low risk of toxicity, but yet remain highly effective
Approaches for optimisation

Single tablet regimens
Dual therapy
Long acting injectables

*ART: antiretroviral therapy

4 of 24

Dual Regimens

Early studies among CLHIV* showed that dual NRTI based regimens were associated with inferior virologic response, compared to triple (2NRTI+1NNRTI or PI) based regimens [Romanelli RMC et al. J Pediatr 2006]

Recent studies among adults with integrase inhibitor based regimens (dolutegravir + lamivudine) showed non inferiority virologically, compared triple ART regimens

GEMINI 1 and 2 [Cahn P, et al. J Acquir Immun Defic Syndr 2020]
TANGO [van Wyk et al. CID 2020]

Long acting injectable dual regimens (cabotegravir + rilpivirine) non inferior virologically to triple oral ART regimens [Orkin C et al. NEJM 2020; Swindels S et al. NEJM 2020]

*CLHIV – Children Living with HIV

5 of 24

Dual Regimens among Children and Adolescents

DANCE Study

Among Naïve adolescents: Preliminary results at IAS 2023

D3 (PENTA 21)

Among ART experienced children and Adolescents: Ongoing

6 of 24

DANCE [NCT03682848]

Safety and Efficacy of Dolutegravir/Lamivudine (DTG/3TC) in Therapy-naive Human Immunodeficiency Virus-1 (HIV-1) Infected Adolescents

Puthanakit T et al, IAS 2023

7 of 24

Weeks	0	1*	4	8	12	16	24	36	48	60	72	84	96	108	120	132	144

ART-naïve
≥12 to <18 years of age
Plasma HIV-1 RNA 1,000 to 500,000 c/mL
Weighing ≥40 kg
Meet all other inclusion and no exclusion criteria

[N=30]

Follow up on DTG/3TC FDC tablet (50mg/300mg) administered once daily

Treatment Phase

Primary Analysis

Week 48

End of Study

Final Analysis

Week 144

Enrollment

Day 1

(Baseline)

Extension Phase

DANCE Study Design: Single arm open label clinical trial�

Puthanakit T et al, IAS 2023

Protocol 205861 - DANCE

8 of 24

Viral Suppression at Week 96

Puthanakit T et al, IAS 2023

Protocol 205861 - DANCE

9 of 24

Immunological response

Puthanakit T et al, IAS 2023

Protocol 205861 - DANCE

10 of 24

Safety

Puthanakit T et al, IAS 2023

Protocol 205861 - DANCE

11 of 24

DANCE Study Conclusions

DTG/3TC* was well tolerated, demonstrated high efficacy, and a high resistance barrier in ART naïve adolescents

Results and adult data support use of DTG/3TC as a 1^st line ART^ option in adolescents

Puthanakit T et al, IAS 2023

*DTG/3TC – dolutegravir/ lamivudine; ^ART – antiretroviral therapy

12 of 24

D3 (PENTA 21) [NCT 04337450]

A randomised non-inferiority trial with nested PK to assess DTG/3TC fixed dose formulations for the maintenance of virological suppression in children with HIV infection aged 2 to <15 years

13 of 24

D3 Study design

2 to <15 years old,

virologically suppressed on first-line ART,

(N = 370)

DTG/3TC

(N=185)

DTG + 2 NRTIs (control arm)

(N=185)

RANDOMISATION 1:1

PK SUBSTUDIES in children on DTG/3TC

Intensive PK and PD with full PK curves at steady state in weight band groups using WHO weight band-aligned dosing
Population PK with sparse PK samples

Follow-up: Study visits at weeks 4, 12; then 12 weekly until the last patient reaches 96 weeks

Primary outcome measure: Confirmed HIV-1 RNA ≥50 c/mL by 96 weeks

14 of 24

Long Acting Injectables: Cabotegravir/rilpivirine

15 of 24

Ongoing research on CAB+RPV in LMIC*

*LMIC – Low and middle income countries

16 of 24

Ongoing research: The LATA Trial

17 of 24

Options for 2^nd line ART: The CHAPAS-4 trial

NRTI backbone randomisation:

TAF/FTC OD
abacavir (ABC) or zidovudine (ZDV) with lamivudine (3TC) (standard-of-care, SOC)

Anchor drug randomisation:

Dolutegravir (DTG) OD,
darunavir (DRV/r*) OD
atazanavir (ATZ/r*) OD
lopinavir (LPV/r*) BD

All dosed according to WHO weight-bands
PK and toxicity sub-studies

*ritonavir - 100mg & 25mg tabs

Trial Drugs

Trial design: Factorial 4X2 open label

Musiime V et al. IAS 2023. abstract - OALBB0503

18 of 24

Sites and Population

		n (%) or median (IQR)
Male		497 (54%)
Age (years)		10 (8, 13)
WHO stage	1/2	778 (85%)
	3/4	141 (15%)
CD4 (cells/mm³) (n=906)		669 (413, 971)
VL (copies/ml)		17 573 (5 549, 55 700)
Weight-for-age		-1.6 (-2.4, -0.9)
Height-for-age		-1.6 (-2.3, -0.8)
BMI-for-age		-1.0 (-1.7, -0.4)
1st-line NRTI ABC 53% ZDV 47%
1st-line NNRTI EFV 56% NVP 44%
Years on 1st-line ART		5.6 (3.3, 7.8)

Characteristics (n=919)

Trial sites and partners

Uganda: JCRC Kampala, JCRC Mbarara
Zambia: UTH, ADCH
Zimbabwe: UZCRC, Mpilo Hospital
Project coordination: UZCRC
Trial coordination and communication: MRC CTU at UCL
Other partners: Radboud University, University of Cape Town, York University

19 of 24

Viral Load < 400 copies/ml�(primary endpoint)

NRTI backbone

Anchor drug

VL suppression was high in all arms

*VL – viral load

20 of 24

Adverse events: NRTI backbone

Low rates of AEs overall
No evidence of difference between ABC or ZDV (SOC) and TAF

* Week 12; treatment-unrelated; primary cause: hypotension/shock/toxic shock (secondary: severe malnutrition; candidiasis of oesophagus, trachea, bronchi or lungs)

	ABC or ZDV (SOC) N=461	TAF N=458
	Patients (% of patients) Events	Patients (% of patients) Events
ART-modifying (p=0.84)�(any grade)	12 (2.6%) 21	11 (2.4%) 19
Grade 3/4 (p=0.93)	64 (13.9%) 92	63 (13.8%) 81
SAE (p=0.84)	14 (3.0%) 14	15 (3.3%) 17
Hospitalisation	13 (2.8%) 13	14 (3.1%) 16
Death	0 (0.0%)	1* (0.2%)

21 of 24

Adverse events: Anchor drug

More grade 3/4 AEs, mostly hyperbilirubinemia, occurred for ATV/r vs. LPV/r
DTG fewer grade 3/4 AEs vs. LPV/r
No evidence of difference for ART-modifying events or SAEs

† ATV/r vs. LPV/r p<0.0001; DRV/r vs. LPV/r p=0.31; DTG vs. LPV/r p=0.02

* Week 12; treatment-unrelated

	LPV/r N=227	ATV/r N=231	DRV/r N=232	DTG N=229
	Patients(% of patients) Events	Patients (% of patients) Events	Patients (% of patients) Events	Patients (% of patients) Events
ART-modifying(p>0.3)	7 (3.1%) 11	5 (2.2%) 11	4 (1.7%) 8	7 (3.1%) 10
Grade 3/4†	26 (11.5%) 35	69 (29.9%) 92	20 (8.6%) 28	12 (5.2%) 18
Raised bilirubin	1 (0.4%) 1	57 (24.7%) 66	1 (0.4%) 1	0 (0.0%) 0
SAE (p>0.1)	10 (4.4%) 10	5 (2.2%) 6	8 (3.4%) 9	6 (2.6%) 6
Death	0 (0.0%) 0	0 (0.0%) 0	0 (0.0%) 0	1* (0.4%) 1
Hospitalisation	9 (4.0%) 9	5 (2.2%) 6	8 (3.4%) 9	5 (2.5%) 5

22 of 24

CHAPAS – 4 conclusions

TAF/FTC and DTG were virologically superior to ABC/3TC or ZDV/3TC (SOC) backbone and comparators (ATV/r, LPV/r) respectively, with a favourable safety profile
There was a trend to DRV/r being superior to ATV/r & LPV/r
TAF/FTC, DTG, DRV/r had favourable safety profiles
Child-friendly fixed-dose combinations of TAF/FTC (+DTG or DRV/r or ATV/r) would increase access to safe, effective second-line ART options for children

23 of 24

Summary

Great steps taken to optimize antiretroviral therapy for children and adolescents

Dual regimens and long term injectables provide opportunities for prolonged care

The CHAPAS 4 results provide opportunities for FDC of TAF, DTG and DRV/r for 2^nd line ART and support their inclusion on the WHO PADO* 5 priority list

*PADO -Paediatric Antiretroviral Drug Optimization

24 of 24

Acknowledgements

Alasdair Bamford, Great Ormond Street Hospital, London, UK

Ivan Mambule, Joint Clinical Research Centre, Kampala, Uganda