Title

Prevalence and dynamics of drug resistance during dolutegravir-containing treatment in a pediatric population living with HIV-1 (IMPAACT P1093)

Presenter

Ceejay Boyce

Authors

C. Boyce¹, M. Bishop¹, S. Styrchak¹, K. Knowles², C. Vavro³, R. Hazra⁴, E. Townley⁵, R. Nixon⁶, R. Smith⁶, G. Gottlieb^6,7, T. Ruel⁸, A. Wiznia⁹, L. Frenkel^7,6,10, IMPAACT P1093 Study Team

Institutions

¹Seattle Children's Research Institute, Center for Global Infectious Disease Research, Seattle, United States, ²Frontier Science Foundation, Amherst, United States, ³ViiV Healthcare, Research Triangle Park, United States, ⁴Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, United States, ⁵National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States, ⁶University of Washington, Department of Medicine, Seattle, United States, ⁷University of Washington, Department of Global Health, Seattle, United States, ⁸University of California San Francisco, San Francisco, United States, ⁹Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, United States, ¹⁰University of Washington, Departments of Pediatrics and Laboratory Medicine & Pathology, Seattle, United States

BACKGROUND: A secondary objective of IMPAACT P1093, a phase I/II study of dolutegravir (DTG) and optimized background therapy (OBT) in children (4 weeks to <18 years) living with HIV-1 in nine countries in Africa, Americas, and Asia, is to assess changes in HIV-1 genotypes and phenotypes to DTG and OBT in children with/without intermittent viremia or treatment failure.
METHODS: Plasma RNA from participants at enrollment and longitudinal specimens from intermittent viremias or protocol-defined virologic failures were genotyped for resistance, including minority variants, using a laboratory-developed PacBio assay. The prevalence and dynamics of DTG and OBT resistance were assessed using Stanford HIV Database with resistance to PIs, NRTIs, and NNRTIs defined by genotypic susceptibility scores (GSS) =30 and to DTG by GSS =10. Phenotyping of participant-derived recombinant viruses was performed using our single-cycle reporter assay to determine the DTG 50%-effective concentration (EC₅₀) and EC₅₀ fold-change between baseline and later, on-treatment timepoints.
RESULTS: Genotyping at enrollment was successful for 153/169 (90.5%) participants (12/181 specimens unavailable) with resistance detected to PIs (n=22; 14.4%), NRTIs (n=69; 45.1%), NNRTIs (n=73; 47.7%), but not to INSTIs (n=0), including M184V (n=59), L74V (n=16), and K70R (n=13). Intermittent viremia or confirmed failure occurred in 48/169 (28.4%) participants (median viral load: 5,055 copies/mL [IQR: 1,468-36,193 copies/mL]), with DTG-associated mutations detected in 11/48 (22.9% [12.0-37.3%]) (Table 1). Phenotypic analyses of four participants’ genotypes confirmed reduced DTG susceptibility (Table 2). Resistance at enrollment was not associated with viremia or selection of DTG resistance.

Table 1: Summary of genotypic drug resistance detected by virologic outcome

Pre-DTG Genotype History of Prior ARV Exposure at Entry
Virologic Outcome
During DTG-based ART N= Wild-type Drug Resistant No Genotype Naïve Experienced

Viremia

DTG Resistance
G118R (n=6)
Q148K (n=1)
N155H (n=3)
R263K (n=4)

No DTG Resistance

No Genotype
49

11/49 (22.4%)

30/49 (61.2%)

7/49 (16.3%)
12 (24.5%)

3 (27.3%)

8 (26.7%)

1 (12.5%)
33 (67.3%)
PI: 7
NRTI: 22
NNRTI: 22

8 (72.7%)
PI: 1
NRTI: 6
NNRTI: 3

19 (63.3%)
PI: 6
NRTI: 14
NNRTI: 14

6 (75.0%)
PI: 0
NRTI: 2
NNRTI: 5

4 (8.2%)

0

3 (10%)

1 (12.5%)
4 (8.2%)

0

2 (6.7%)

2 (25.0%)

45 (91.8%)

11 (100%)

29 (93.3%)

6 (75.0%)
Suppressed

132

44 (33.3%)

66 (50.0%)
PI: 16
NRTI: 46
NNRTI: 51 22 (16.7%)

13 (9.9%)

119 (90.1%)

Total 181 56 99 26* 17 164
*12 participants specimens unavailable; 14 participants' specimens did not amplify

Table 2: Preliminary findings of phenotypic analyses of DTG-resistant genotypes
Case HIV-1 Subtype Weeks of DTG Treatment
Major Integrase Mutations Minor Integrase Mutations
Replication Capacity^a
DTG EC₅₀ (nM)^b Fold-Change^c
1 C 0
32
None
G118R None
L74I
80
35
1.7±0.29
19±6.1^d
11
2 CRF01_AE 0
20
None
G118R L74I
T66I, L74I
95
29
1.8±0.03
38±3.1^d
21
3 B 162
S147G, R263K E138T
55
12±3.9^e 5.0^f
4 B 51
G118R E138K, V151I
71
19±2.4 8.4^f
^a Replication capacity expressed as the % of HIV-1NL4-3 titer
^b Mean 50% effective concentration ± standard deviation
^c Fold change in EC50 value relative to the corresponding week-0 clone, unless otherwise indicated
^d Bold type indicates a significant difference compared to the EC50 for the corresponding week-0 clone (p < 0.05, ANOVA with Tukey's multiple comparisons test)
^e Bold type indicates a significant difference compared to the EC50 for HIV-1NL4-3 (p < 0.05, ANOVA with Tukey's multiple comparisons test)
^f Fold change relative to HIV-1NL4-3 (EC50 for dolutegravir, 2.3 ± 0.70 nM)

CONCLUSIONS: Selected resistance to DTG was prevalent among participants with viremia, including as minority variants either alone or in addition to majority variants, but was not associated with resistance at enrollment.

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		Pre-DTG Genotype			History of Prior ARV Exposure at Entry
Virologic Outcome During DTG-based ART	N=	Wild-type	Drug Resistant	No Genotype	Naïve	Experienced
Viremia DTG Resistance G118R (n=6) Q148K (n=1) N155H (n=3) R263K (n=4) No DTG Resistance No Genotype	49 11/49 (22.4%) 30/49 (61.2%) 7/49 (16.3%)	12 (24.5%) 3 (27.3%) 8 (26.7%) 1 (12.5%)	33 (67.3%) PI: 7 NRTI: 22 NNRTI: 22 8 (72.7%) PI: 1 NRTI: 6 NNRTI: 3 19 (63.3%) PI: 6 NRTI: 14 NNRTI: 14 6 (75.0%) PI: 0 NRTI: 2 NNRTI: 5	4 (8.2%) 0 3 (10%) 1 (12.5%)	4 (8.2%) 0 2 (6.7%) 2 (25.0%)	45 (91.8%) 11 (100%) 29 (93.3%) 6 (75.0%)
Suppressed	132	44 (33.3%)	66 (50.0%) PI: 16 NRTI: 46 NNRTI: 51	22 (16.7%)	13 (9.9%)	119 (90.1%)
Total	181	56	99	26*	17	164
*12 participants specimens unavailable; 14 participants' specimens did not amplify

Case	HIV-1 Subtype	Weeks of DTG Treatment	Major Integrase Mutations	Minor Integrase Mutations	Replication Capacity^a	DTG EC₅₀ (nM)^b	Fold-Change^c
1	C	0 32	None G118R	None L74I	80 35	1.7±0.29 19±6.1^d	11
2	CRF01_AE	0 20	None G118R	L74I T66I, L74I	95 29	1.8±0.03 38±3.1^d	21
3	B	162	S147G, R263K	E138T	55	12±3.9^e	5.0^f
4	B	51	G118R	E138K, V151I	71	19±2.4	8.4^f
^a Replication capacity expressed as the % of HIV-1NL4-3 titer ^b Mean 50% effective concentration ± standard deviation ^c Fold change in EC50 value relative to the corresponding week-0 clone, unless otherwise indicated ^d Bold type indicates a significant difference compared to the EC50 for the corresponding week-0 clone (p < 0.05, ANOVA with Tukey's multiple comparisons test) ^e Bold type indicates a significant difference compared to the EC50 for HIV-1NL4-3 (p < 0.05, ANOVA with Tukey's multiple comparisons test) ^f Fold change relative to HIV-1NL4-3 (EC50 for dolutegravir, 2.3 ± 0.70 nM)