Maternal health outcomes among HIV-infected breastfeeding women with high CD4 counts: results of a treatment strategy trial

Figures & data

Figure 1 Description of the PROMISE 1077 BF/FF women included in the analysis. This analysis includes all women on three-drug ART during pregnancy who were randomized postpartum to continue or discontinue, as well as all women randomized to continue ART at cessation of breastfeeding (black boxes).

Figure 2 CONSORT flow diagram for women included in the analysis (non-enrollment reasons were reported for both the mother and the infant if the randomization occurred for the postpartum component).

Table 1 Baseline characteristics of women in the Maternal Health Cohort of PROMISE 1077 BF/FF

	Randomization arm^a
Characteristic	CTART	DCART	Total
	(N = 801)	(N = 810)	(N = 1611)
Age at randomization (years)
N	801	810	1611
No. of missing	0	0	0
Min–Max	18–42	18–44	18–44
Median (IQR)	27 (23–31)	27 (24–31)	27 (24–31)
Race
Asian (from Indian subcontinent)	0 (0%)	1 (0%)	1 (0%)
Black African	781 (98%)	787 (97%)	1568 (97%)
Indian (Native of India)	20 (2%)	22 (3%)	42 (3%)
BMI (kg/m^2)
N	796	808	1604
No. of missing	5	2	7
Min–Max	16.7–48.9	15.4–47.8	15.4–48.9
Median (IQR)	24.7 (22.3–28.0)	24.8 (22.2–28.1)	24.8 (22.3–28.1)
Number of live infants
0	19 (2%)	16 (2%)	35 (2%)
1	771 (96%)	786 (97%)	1557 (97%)
2	11 (1%)	8 (1%)	19 (1%)
WHO clinical stage
Clinical stage I	772 (96%)	796 (98%)	1568 (97%)
Clinical stage II	29 (4%)	14 (2%)	43 (3%)
Screening CD4+ T-cell count (cells/mm³)
N	801	810	1611
No. of missing	0	0	0
Min–Max	360–2019	355–2353	355–2353
Median (IQR)	726 (593–911)	730 (586–902)	728 (590–906)
350 to <400	20 (2%)	22 (3%)	42 (3%)
400 to <450	25 (3%)	21 (3%)	46 (3%)
450 to <500	40 (5%)	54 (7%)	94 (6%)
500 to <750	340 (42%)	334 (41%)	674 (42%)
≥750	376 (47%)	379 (47%)	755 (47%)

^a CTART, continue ART; DCART, discontinue ART; IQR, Interquartile range.

Table 2 World Health Organization Clinical Stage 2 and 3 events by arm

WHO stage 2 or 3 endpoint	Randomization arm^a				Total (N = 1602)
	CTART (N = 797)		DCART (N = 805)
Subjects with an event	33	(4%)	72	(9%)	105	(7%)
Type of event
Moderate weight loss	17		36		53
Herpes zoster	2		13		15
Fungal nail infection	2		7		9
Severe weight loss	5		3		8
Pulmonary TB	3		4		7
Papular pruritic erupts	1		3		4
Bacterial infections	1		2		3
Chronic diarrhea	0		1		1
Upper respiratory infection	1		0		1
Thrombocytopenia	0		1		1
Recur oral ulceration	0		1		1
Persistent fever	0		1		1
Seborrheic dermatitis	1		0		1

a CTART, continue antiretroviral therapy; DCART, discontinue antiretroviral therapy.

Table 3 Laboratory adverse events^a

Toxicities	CTART (N = 797) grade				DCART (N = 805) grade
	2	3	4	Total	2	3	4	Total
Any Heme Event	85 (11%)	31 (4%)	10 (1%)	126 (16%)	92 (11%)	36 (4%)	8 (1%)	136 (17%)
Any Hematology, Coagulation	10 (1%)	3 (<0.5%)	0 (0%)	13 (2%)	22 (3%)	6 (1%)	1 (<0.5%)	29 (4%)
Platelets	10	3	0	13	22	6	1	29
Any Hematology, RBC	14 (2%)	6 (1%)	6 (1%)	26 (3%)	19 (2%)	3 (<0.5%)	5 (1%)	27 (3%)
Hemoglobin	14	6	6	26	19	3	5	27
Any Hematology, WBC/Differential	69 (9%)	23 (3%)	6 (1%)	98 (12%)	65 (8%)	27 (3%)	2 (<0.5%)	94 (12%)
Absolute Neutrophil Count	69	23	6	98	65	27	2	94
White Blood Cells	1	1	0	2	0	0	0	0
Any Liver/Renal Event	12 (2%)	2 (<0.5%)	0 (0%)	14 (2%)	20 (2%)	9 (1%)	7 (1%)	36 (4%)
Any Liver/Hepatic	10 (1%)	2 (<0.5%)	0 (0%)	12 (2%)	18 (2%)	8 (1%)	7 (1%)	36 (4%)
ALT (SGPT)	10	2	0	12	18	8	7	33
Any Renal	2 (<0.5%)	0 (0%)	0 (0%)	2 (<0.5%)	2 (<0.5%)	1 (<0.5%)	0 (0%)	3 (<0.5%)
Creatinine	2	0 (0%)	0	2	2	1	0	3

^aAnalysis exclusions (N = 1) and participants without follow-up data (N = 10) are not included in the table. At-risk period: from randomization through last on-study safety evaluation.

For any given participant, the highest grade for each safety event is counted.

CTART, continue antiretroviral therapy; DCART, discontinue antiretroviral therapy.

Figure 3 CD4+ T-cell counts over time (median, 10th and 90th percentile, and proportion <350 cells/mm³). The median CD4+ T-cell counts in the continue (blue) and discontinue (red) arms are shown at each follow-up visit. The proportion with CD4+ T-cells below 350 cells/mm³ are shown across the top of the figure at each time point.

Figure 4 Survival curves for key study findings (A) primary composite endpoint; (B) WHO 2 and 3 events; (C) safety endpoint. A: Primary Composite Endpoint (HR 0.55, p = 0.37). B: WHO 2 and 3 events (HR 0.63, p = 0.01). C: Safety Endpoint (HR 0.95, p = 0.61).

Table 4 Clinical endpoints in women in the Maternal Health Cohort of PROMISE 1077 BF/FF

Endpoint (time to first event)	Continue ART		Discontinue ART		HR^@	p-value
	#	#/100 py^^	#	#/100 py
Primary endpoint
AIDS defining illness or death	3	0.24	8	0.49	0.55 (0.14, 2.08)	0.37
AIDS Defining (WHO IV)	1	0.08	4	0.25	0.36 (0.04, 3.30)	0.35
Death	3	0.24	7	0.43	0.65 (0.17, 2.53)	0.53
Secondary endpoints
HIV/AIDS related events	14	1.14	20	1.24	0.90 (0.45, 1.78)	0.75
Composite endpoint of HIV/AIDS related event^a or death	16	1.30	23	1.43	0.91 (0.48, 1.73)	0.76
Pulmonary TB^b	5	0.40	5	0.31	1.44 (0.41, 5.05)	0.56
Single bacterial pneumonia^b	6	0.49	9	0.56	0.79 (0.28, 2.23)	0.65
Bacterial infections resulting in hospitalization^b	3	0.24	6	0.37	0.59 (0.15, 2.40)	0.46
Composite Endpoint of HIV/AIDS related events and WHO stage II and III events	42	3.47	86	5.61	0.63 (0.43, 0.91)	0.01
WHO II and III events^b	33	2.70	72	4.66	0.60 (0.39, 0.90)	0.01
Toxicity events^c
Grade 2, 3 and 4 toxicity	160	15.3	189	13.9	0.95 (0.76, 1.17)	0.61
Grade 3 and 4 toxicity^b	70	6.0	93	6.2	1.01 (0.74, 1.38)	0.96

py, person years.

^a HIV/AIDS related events refers to the WHO Clinical Stage IV illnesses, pulmonary tuberculosis, and other serious bacterial infections.

^b Post-hoc secondary analyses.

^c Toxicity Event is defined as composite of the time to the first grade 3 or 4 sign or symptom, or grade 2, 3, or 4 hematology or chemistry events whichever comes first.

^@ The HR is for the “Continue triple ARV” arm as compared to the “Discontinue triple ARV” arm.

Table 5 Comparison of maternal health outcomes in PROMISE BF/FF compared to PROMISE HS

Outcome	1077BF/FF^a (N = 1612)			1077HS^b (N = 1652)
	CTART rate per 100 py (95% CI) [number of events]	DCART rate per 100 py (95% CI) [number of events]	^dHR (95%CI)	CTART rate per 100 py (95% CI) [number of events]	DCART rate per 100 py (95% CI) [number of events]	^dHR (95% CI)
Primary efficacy endpoint^c	0.24 (0.18, 0.33) [3]	0.49 (0.41, 0.59) [8]	0.55 (0.14, 2.08)	0.21 (0.16, 0.27) [4]	0.31 (0.25, 0.38) [6]	0.68 (0.19, 2.40)
AIDS defining illness	0.08 (0.05, 0.12) [1]	0.25 (0.20, 0.30) [4]	0.36 (0.04, 3.30)	0.10 (0.08, 0.14) [2]	0.15 (0.12, 0.19) [3]	0.67 (0.11, 4.01)
Death	0.24 (0.18, 0.32) [3]	0.43 (0.36, 0.52) [7]	0.65 (0.17, 2.53)	0.10 (0.08, 0.14) [2]	0.20 (0.17, 0.25) [4]	0.52 (0.09, 2.81)
Primary safety endpoint^e	15.3 (12.8, 18.1) [160]	13.9 (11.9, 16.3) [189]	0.95 (0.76, 1.17)	18.4 (15.7, 21.4) [260]	15.6 (13.2, 18.4) [232]	1.16 (0.97, 1.38)
WHO stage 2 or 3 event	2.70 (2.16, 3.37) [33]	4.66 (4.01, 5.42) [72]	0.60 (0.39, 0.90)	2.08 (1.66, 2.60) [39]	4.36 (3.73, 5.10) [80]	0.48 (0.33, 0.70)

a 95% of women were breastfeeding; **PY: person-years; ***CI: Confidence Interval.

b 1077HS was performed among non-breastfeeding women in Argentina, Botswana, Brazil, China, Haiti, Peru, Thailand, and the United States (Jan 2010-Nov 2014). In 1077HS, the primary efficacy endpoint also included serious non-AIDS-defining cardiovascular, renal or hepatic events. None of these events occurred during 1077HS follow-up.

c HR for the continue ART (CTART) arm as compared to the discontinue ART (DCART) arm.

d Composite of progression to AIDS-defining illness (WHO Stage 4 clinical event) or death.

e Composite of time to first grade 3 or 4 sign or symptom, or grade, 2, 3, or 4 hematology or chemistry events.