Treatment outcomes in perinatally-HIV-infected children and adolescents after

10+ years on antiretroviral therapy

Kim Anderson, Rudzani Muloiwa, Mary-Ann Davies

Maskew et al. AIDS 2016

Number of children on ART

The approaching wave of HIV+ adolescents

Johnson et al. PIDJ 2012

Cohort study results after ≥10 years on ART?

Not comparable locally.Local studies…? Nothing >3 years on ARTOur study: median follow-up 12 years

Study Country NMedian follow-up

time (years) Viral suppression CD4>500Dollfus et al. (2010) France 210 15 56% 59%

De Mulder et al. (2012)

Spain 243 15 61% 66%Van Dyke et al. (2011) USA 451 11 68%Collins et al. (2017) UK/Ireland 131 11 74% 38%

Who was included in this study?• Perinatally-infected children

• Age at ART initiation < 12

• Initiation at GSH between 2002 and 2005

• Attended GSH paediatric/adolescent ID clinic (G26) for a minimum of 10 years since ART initiation

= 127 patients

Study design: retrospective cohort (folder review)

Who was excluded?

349 children started ART (2002 – 2005):

• 150 transferred out (43%)• 33 lost to follow-up (9%)• 29 died (8%)• 10 missing records (3%)

127 remained at the clinic ≥10 years (36%)

Study objectivesPrimary

• Virologic outcomes (viral loads)

• Immunologic outcomes (CD4s)

Secondary

• Growth outcomes (heights & weights)

• ART history (drugs)

• Clinical outcomes: opportunistic infections & hospital admissions

• Drug resistance

Definitions• Viral suppression: VL <400• Viral failure: 2 consecutive VLs >1000, after at least 24 weeks since

ART start

Cohort characteristics at ART start, at 10 years since ART start and at last visit

Characteristic At ART start At 10 years At last visit

Female (%; n/N) 51% 65/127

Median (IQR) age (years) 2.6 1.3 - 4.9 15.1 13 - 17.7

Median (IQR) CD4 count (cells/µl) 502 275 - 813 768 589 - 987 686 545 - 859

Mean (95% CI) CD4 percent 13.7 13.6 - 13.9 29.6 27.7 - 31.4 29.3 27.6 - 31

Severe immune suppression* (%; n/N) 63% 76/121 3% 3/107 4% 5/127

CD4 count > 500 cells/µl (%; n/N) N/A 86% 92/107 79% 100/127

Growth stunted (HAZ <-2) 73% 82/113 33% 37/113 31% 40/127

PI-based regimen (%; n/N) 36% 46/127 66% 84/127 69% 87/127

HIV-RNA < 400 copies/ml (%; n/N) N/A 74% 81/109 80% 101/127

*WHO classification

Starting regimens

• NNRTI-based in 64%, PI-based in 36%

• Most common regimens:

AZT + 3TC + NVP (61%)

d4T + 3TC + LPV/rtv (21%)

d4T + 3TC + rtv (8%)

AZT + 3TC + LPV/rtv (6%)

• Drug switches made in 64 patients (50% of cohort) due to lipodystrophy, at median age of 11 (d4T, AZT, DDI)

10% of cohort had documented drug resistance• 13/16 patients tested had drug resistance

• 20% (26/127) of the cohort were transferred out and subsequently transferred back again, predominantly for adolescent support

Transfers

Regimens at last visit

• 50% on 1st-line (n=63; 49% on NNRTIs & 51% on PIs)• 43% on 2nd-line• 1.5% on salvage regimen (4 drugs)• 1.5% on 3TC monotherapy• 4% on no ART

Last visit outcomesStratified by those on 1st vs 2nd line ART

• Proportion virally suppressed

86% vs 77% (p=0.183)

• Proportion with CD4 count >500

92% vs 71% (p=0.003)

worse immunologic outcomes on 2nd line ART

Stratified by those on NNRTI vs PI• Proportion virally suppressed

89% vs 78% (p=0.169)• Proportion with CD4 count >500

94% vs 77% (p=0.003)worse immunologic outcomes on PI

• 10 year probability of VF : 57%

• Children on NNRTI-based

regimens had a higher 10-year

probability of VF (66 %)

compared to those on a PI-

based regimen (43%)

(logrank test, p=0.04)

• 10 year probability of switching

to 2nd-line ART was 45.7%

(95% CI 37.5 -54.8)

• Median time on ART to VF: 5.2

years

Kaplan Meier probability of viral failure (first episode) by initial ART regimen

Factors associated with first episode of VFCovariate Adjusted HR 95% CIGender male 1

female 0.44 0.23 - 0.85Type of regimen NNRTI-based 1

PI-based 0.62 0.20 - 1.98Age (years) 1.05 0.89 - 1.24Programme year 2002 1

2003 0.87 0.41 - 1.842004 0.94 0.19 - 4.792005 0.24 0.05 - 1.18

CD4 category at baseline not severely suppressed 1

severe immune suppression 1.42 0.63 - 3.23Baseline VL > 1 million 1.45 0.62 - 3.37Drug formulations tablets only 1

use of suspensions 3.48 1.13 - 10.75

Viral failure in adolescence

35% probability of experiencing VF between the age of 10 and 18

Hospital admissions

Year since ART start

Number of children with hospital admissions

% of children with

admissions Most common reasons

0 - 1 53 42%LRTI (51%) GE (8%) LRTI & GE (8%) Septicaemia (8%)

1 - 5 43 34%LRTI (40%) PTB (16%) GE (9%) Septicaemia (6%)

5 - 10 24 19% LRTI (45%) Measles (19%) GE (7%)

10 - 14 14 11% LRTI (40%) PTB (20%)

TB burden

• 58/127 (46%) of the children in total were ever on TB treatment since ART start • 51/127 (40%) had TB > 4 weeks since ART start• 33/127 (26%) documented with chronic lung disease

56% of TB cases notvirally suppressed

Time of TB diagnosissince ART start

Numberof TB

episodes

Number not virally

suppressed% not virally suppressed

On TB treatment at ART start or < 4 weeks of ART start 15 N/A

≥ 4 weeks and ≤ 24 weeks 4 N/A

> 24 weeks and ≤ 1 year 5 2 40%

> 1 year and ≤ 5 years 24 14 58%

> 5 years ≤ 10 years 14 9 64%

> 10 years <14 years 9 4 44%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1 2 3 4 5 6 7 8 9 10 11 12 13

Year since ART initiation

Percentage of patients virally suppressed at each year since

ART initiation

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 1 2 3 4 5 6 7 8 9 10 11 12

Year since ART initiation

Percentage of patients with optimal immunologic status at each year since ART initiation

80% “goal”

Conclusions

• After median follow-up of 12 years on ART:

80% virally suppressed

79% optimal immune status

• Long-term virologic and immunologic outcomes were good

overall in children remaining in care for ≥10 years

• Worsening trend in adolescence (virologic and immunologic)

• Transitioning to adult care

contact: kim.anderson@uct.ac.za

Acknowledgements:

• Dr Paul Roux, Kidzpositive and One to One Children’s Fund for initiating ART provision at GSH.

• The children and caregivers attending G26 clinic.

• The dedication of the staff at G26 to their patients.

• The financial assistance of the National Research Foundation (NRF) towards this research is hereby acknowledged. Opinions expressed and conclusions arrived at, are those of the authors and are not necessarily to be attributed to the NRF.

127 start ART 96

Suppressed

75 Viral failure

30 Viral failure

8 Viral failure

1Viral failure

6 Suppressed

68 Suppressed

26 Suppressed

1 Suppressed

38 stay suppressed

18 stay suppressed

5 stay suppressed

31 44

7 stay VF*

52 stay suppressed

4 stay VF

2 stay VF

*2 never suppressed (since ART start)

91 instances of defaulting, which occurred in 40 patients (31% of cohort)

Median age 4

Median age 10

Median age 13

Age 15