Table 3.
Safety endpoints comparing INSTI + DRV/r dual therapy vs. SOC.
| INSTI + DRV/r | SOC | INSTI + DRV/r vs. SOC | |
|---|---|---|---|
| Participants | 158 | 160 | |
| SAFETY AND TOLERABILITY | |||
| Serious Adverse Events (SAEs) by MedDRA SOC Terms reported to end of trial | |||
| Number of events [participants]i | 4 [4] | 5 [4] | p = 0.986l |
| Gastrointestinal disorders | 1 [1] | 0 [0] | |
| Hepatobiliary disorders | 1 [1] | 0 [0] | |
| Infections and infestations | 1 [1] | 1 [1] | |
| Injury, poisoning and procedural complications | 0 [0] | 1 [1] | |
| Psychiatric disorders | 0 [0] | 3 [2] | |
| Renal and urinary disorders | 1 [1] | 0 [0] | |
| SAE rate (per 100-person years) (95% CI) | 1.9 (0.7, 5.0) | 2.3 (1.0, 5.6) | |
| Rate Ratiom(95% CI) | 0.81 (0.20, 3.22) | 1 (ref) | p = 0.763 |
| Hazard Ratiog(95% CI) | 1.01 (0.25, 4.02) | 1 (ref) | p = 0.993 |
| Grade 3/4 clinical and laboratory adverse events (AEs) by MedDRA SOC Terms reported to end of trial | |||
| Number of events [participants]i | 13 [13] | 25j[19] | p = 0.280l |
| Blood and lymphatic system disorders | 1 [1] | 3 [3] | |
| Gastrointestinal disorders | 1 [1] | 0 [0] | |
| Hepatobiliary disorders | 1 [1] | 6 [4] | |
| Infections and infestations | 1 [1] | 1 [1] | |
| Injury, poisoning and procedural complications | 0 [0] | 1 [1] | |
| Investigations | 6 [6] | 8 [7] | |
| Metabolism and nutrition disorders | 1 [1] | 0 [0] | |
| Nervous system disorders | 0 [0] | 1 [1] | |
| Pregnancy, puerperium and perinatal conditions | 0 [0] | 1 [1] | |
| Psychiatric disorders | 0 [0] | 3 [2] | |
| Renal and urinary disorders | 2 [2] | 1 [1] | |
| Grade 3/4 AE rate (per 100-person years) (95% CI) | 6.1 (3.5, 10.5) | 11.6 (7.9, 17.2) | |
| Rate Ratiom(95% CI) | 0.52 (0.26, 1.08) | 1 (ref) | p = 0.079 |
| Hazard Ratiog(95% CI) | 0.65 (0.32, 1.32) | 1 (ref) | p = 0.237 |
| ART Modifying Events by MedDRA SOC Terms reported to end of trial | |||
| Number of events [participants]i | 4 [4] | 6 [4] | p = 0.986l |
| Gastrointestinal disorders | 1 [1] | 0 [0] | |
| Hepatobiliary disorders | 1 [1] | 1 [1] | |
| Investigations | 0 [0] | 3 [2] | |
| Psychiatric disorders | 1 [1] | 2 [2] | |
| Psychiatric disorders + Metabolism and nutrition disorders + Psychiatric disorders | 1 [1] | 0 [0] | |
| ART modifying AE rate (per 100-person years) (95% CI) | 1.9 (0.7, 5.0) | 2.8 (1.3, 6.2) | |
| Rate Ratiom(95% CI) | 0.67 (0.17, 2.67) | 1 (ref) | p = 0.575 |
| Hazard Ratiog(95% CI) | 1.04 (0.26, 4.15) | 1 (ref) | p = 0.959 |
| Notable Events reported to end of trial | |||
| Number of events [participants]i | |||
| Pregnancy | 1 [1] | 2 [2] | p = 1.000l |
| Suicidal ideation | 0 [0] | 1 [1] | p = 1.000l |
| Drug induced liver injury | 2 [2] | 1 [1] | p = 0.621l |
| COVID-19 contact | 1 [1] | 0 [0] | p = 0.497l |
| ART REGIMEN | |||
| On initial regimen at end of trial (n (%)) | 145 (91.8%)a | 131 (81.9%)b | |
| Not on initial regimen at end of trial (n (%)) | 13 (8.2%) | 29 (18.1%) | |
| ART changes [Number of participants] | 19 [14] | 40 [32] | |
| Increase in viral loadc | 7 [7] | 0 [0] | |
| Combination of failure indicatorsd | 0 [0] | 1 [1] | |
| Simplification | 3 [3] | 9 [7] | |
| Drug availabilitye | 2 [2] | 0 [0] | |
| Adverse event | 3 [3] | 6 [3] | |
| Patient/carer decision | 0 [0] | 1 [1] | |
| Pregnancya | 1 [1] | 0 [0] | |
| Concomitant drug interaction | 0 [0] | 1 [1] | |
| Change in National clinical guidelines | 0 [0] | 21 [21] | |
| Adverse event AND Patient/carer decisiona | 1 [1] | 0 [0] | |
| Otherf | 2 [2] | 0 [0] | |
| Unknown | 0 [0] | 1 [1] | |
| Treatment interruption > 31 days [Number of participants] | 1 [1] | 1 [1] | |
| Time to first ART change by end of trialn[excluding changes for changes in national clinical guidelines] | |||
| Total number of ART changes [Number of participants] | 20 [14] | 20 [13] | |
| Hazard Ratiog (95% CI) | 1.12 (0.52, 2.38) | 1 (ref) | p = 0.777 |
| LIPIDS/GLUCOSE | Adjusted differenceh (95% CI) p-value | ||
| Mean change in fasting total cholesterol (mg/dL) to week 24 from baseline (SE) | 4.3 (2.0) | −2.2 (2.0) | 6.4 (0.9, 11.9) p = 0.022 |
| Mean change in fasting total cholesterol (mg/dL) to week 48 from baseline (SE) | −0.6 (2.2) | −1.0 (2.2) | 0.3 (−5.7, 6.4) p = 0.916 |
| Mean change in fasting LDL (mg/dL) to week 24 from baseline (SE) | 9.0 (1.7) | −1.0 (1.7) | 9.9 (5.2, 14.6) p < 0.001 |
| Mean change in fasting LDL (mg/dL) to week 48 from baseline (SE) | 2.8 (1.9) | −2.1 (1.9) | 4.7 (−0.7, 10.0) p = 0.088 |
| Mean change in fasting HDL (mg/dL) to week 24 from baseline (SE) | −5.6 (0.9) | −1.8 (0.9) | −3.9 (−6.3, −1.5) p = 0.002 |
| Mean change in fasting HDL (mg/dL) to week 48 from baseline (SE) | −6.4 (1.0) | −2.4 (0.9) | −4.1 (−6.7, −1.4) p = 0.003 |
| Mean change in fasting glucose (mg/dL) to week 24 from baseline (SE) | −2.5 (0.7) | −0.5 (0.8) | −1.9 (−3.9, 0.1) p = 0.063 |
| Mean change in fasting glucose (mg/dL) to week 48 from baseline (SE) | −1.2 (0.8) | 1.0 (0.8) | −2.3 (−4.3, −0.3) p = 0.026 |
| ANTHROPOMETRIC MEASURES | Adjusted differenceh (95% CI) p-value | ||
| Mean change in weight-for-age z-scorek to week 48 from baseline (SE) | 0.19 (0.0) | −0.02 (0.0) | 0.21 (0.1, 0.3) p < 0.001 |
| Mean change in weight (kg) to week 48 from baseline (SE) | 5.08 (0.3) | 3.11 (0.3) | 1.97 (1.1, 2.9) p < 0.001 |
| Mean change in height (cm) to week 48 from baseline (SE) | 3.10 (0.2) | 2.76 (0.2) | 0.36 (−0.2, 0.9) p = 0.230 |
| Mean change in BMI-for-age z-scorek to week 48 from baseline (SE) | 0.23 (0.0) | 0.01 (0.0) | 0.22 (0.1, 0.3) p < 0.001 |
| Mean change in BMI to week 48 from baseline (SE) | 1.25 (0.1) | 0.59 (0.1) | 0.66 (0.3, 1.0) p < 0.001 |
SE, standard error; CI, confidence interval; n, number; P, p-value; MedDRA SOC, MedDRA system organ class.
One participant in INSTI + DRV/r arm changed ART but later returned to initial regimen before end of trial–a positive pregnancy test at week 24 resulted in stop of DTG + DRV/r and re-start of triple ART therapy as per protocol; following 4 days on triple ART therapy, adverse event (vomiting) was reported and participant resumed dual therapy DTG + DRV/r by own decision.
Three participants in SOC arm changed ART but later returned to initial regimen before end of trial—changed ART for simplification, then returned to initial regimen due to adverse event; changed ART for Change in National clinical guidelines then returned to initial regimen due to adverse event; ART was stopped at week 72 for unknown reason followed by restart at week 84 due to patient/carer decision.
Increase in viral load defined as confirmed VL ≥50 copies/mL. Note that one participant had confirmed VL ≥50 copies/mL but did not change ART. This decision was made by the investigator based on examination of subsequent viral load data, in consultation with the participant, family and the SMILE chief investigator.
Combination of failure indicators defined as “Any combination of increase in VL/falling CD4/progression/resistance”.
EVG withdrawal from the market as a single entity.
ART changes for “other” reasons include “Transition to three component therapy”; “Persistent cough”.
Adjusted for stratification factors: Age (≥6 < 12 yrs; ≥12 < 18 yrs) and Region (African; Non-African).
Adjusted for stratification factors and baseline value.
Number of events [participants] shows total number of events reported in participants. When participants have multiple events, the total number of events reported are higher than number participants in brackets.
Atazanavir had probable/definitive causal relationship to 9 increased bilirubin events reported in SOC arm.
Based on British 1990 Reference data (0–23 years).
Chi-squared test or Fisher's exact test used, as appropriate, to compare number of participants with ≥1 events between arms.
Adjusted for stratification factors and event clustering within individuals.
With the exception of changes for change in national clinical guidelines, any other ART changes for any reason are included in the analysis of time to first ART change. Regimen interruptions for >31 days are considered as ART discontinuations and are also included in the analysis.