One hundred ninety-six infants with perinatal HIV infection are included in the analysis. HIV testing was done in the first month of life for 51% (99/196), and before the age of 4 months for an additional 24% (49/196). Sixty (31%) of the 196 children died of HIV-related causes. More than half of the surviving 136 children were still followed in participating clinics at study completion and 35% of the censored children returned to care (). Of the 43 participants who did not return to care, 22/43(51%) had documented transitions in care (). Since the survival of the 17 who moved from the study area cannot be confirmed, the 38/196(19%) remaining children represent the true rate of loss-to-follow up.
Status at EFU of 196 Perinatally HIV-infected Children Followed from Infancy
The median age at HIV-related death of children in the study was 1.9 (1.0–3.4) years; the children who remained in care to the study completion were followed for 12.6 (7.5–15.6) years (). More than half of the children who were lost to follow-up remained in care for more than 6 years (); those children who later returned to care were followed to 10.2 (5.3–14.2) years of age.
As expected, the risk of death decreased significantly in the later birth cohorts (, ). While the probability that children in the early cohort would survive to age 5 was 47%, it increased to 66% and 98% in the intermediate and late cohorts respectively. If children survived the first 5 years, their subsequent risk of death was low: 14% (4/28), 0% (0/36), and 0% (0/26) in the early, intermediate and late cohorts, respectively. None of the children died at age>9 years, although they were followed to maximum ages of 19, 17, and 13 years in the early-late cohorts, respectively.
Demographics, Antiretroviral Use, Progression, and Survival of 196 Perinatally HIV-infected Children Followed from Infancy
Event-Free Survival of 196 Perinatally HIV-Infected Children Followed from Infancy
Of note, morbidity also declined across cohorts, with the percentage of children progressing to CDC clinical category C diagnoses declining from 70% in the early cohort to 38% in the late cohort (p<0.005, ). The progression of 191/196 children, for which baseline information was available, from baseline to EFU through various disease stages is presented in .
Disease Progression of Study Children with Known Baseline
Association of HAART Initiation and Overall Mortality
Of the 196 children in the study, 113 (58%) received HAART: 84% were followed for more than 1 year and half for at least 6.2 years after HAART initiation. In children followed to age 5 years, survival was 88% with HAART vs. 50% without HAART, p<0.0001. None of the 21 children who initiated HAART at age<4 months died; half of these children were followed for more than 4.5 years and up to 11 years. In comparison, the probability of surviving to 4.5 years without HAART was only 62% (p=0.004, log-rank test). Notably, HAART initiation, compared to no HAART, was associated with reduced mortality even after subjects had already progressed to moderate or severe disease (, p<0.0001).
Disease Progression Following Administration of Antiretrovirals
HAART Initiated Before Moderate or Severe Disease
HAART use was associated with a delayed time and reduced proportion of children progressing to moderate disease (). Among the 131 children with documented clinical/immunological data prior to severe disease: 62% (13/21) of children treated with HAART progressed to moderate disease compared to 97% (107/110) of children who did not receive HAART (p<0.0001). HAART compared to no HAART also delayed the age at progression to moderate disease from 0.4 (0.3–0.8) years to 3.0 (1.9–5.8) years (p= 0.0001). Similarly, in children with mild disease at baseline, HAART use was associated with reduced and delayed progression to moderate disease by approximately 3 years, but >50% of these children still progressed to moderate disease ().
In addition to reducing and delaying progression to moderate disease, children who received HAART demonstrated progression to moderate disease primarily as laboratory-based immunosuppression rather than clinical disease. Of the children receiving HAART: 77% (10/13) progressed via immunosuppression, 62% were never diagnosed with a clinical category B condition, and none ever had a clinical category C condition. Of children who did not receive HAART: only 44%, (47/107) progressed via immunosuppression, most (86%) had a clinical category B condition and 47% had later a clinical category C condition (p=0.001).
HAART Initiated after Moderate Disease and before Severe Disease
HAART use after progression to moderate disease was associated with a decreased proportion of children progressing to severe disease and death. Only 8% (3/36) of children who received HAART after the onset of moderate disease progressed to severe disease, and none died (). In comparison, 84% (70/83) of children who did not receive HAART after progressing to moderate disease progressed to severe disease and 4% (3/83) died without progressing to severe disease (, p<0.0001).
HAART initiated even after development of a clinical category B diagnosis was associated with reduced further progression. There were 88 children who had a clinical category B diagnosis before progressing to severe disease, 22 (25%) of whom started HAART. These children were followed for a median of 5.4 (1.8–9.1) and up to 10.9 years after HAART initiation, with only 3 (14%) progressing to severe disease. Of note, only 2 children, both of whom started HAART more than 2 months after their category B diagnosis, developed a clinical category C diagnosis. In contrast, of the 66 (75%) children who did not receive HAART after a clinical category B diagnosis, 54 (82%) progressed to category C diagnosis within 0.8 (0.2–1.5) years. The 12 without further progression were followed for 1.0 (0.4–2.7) and up to 15.2 years.
HAART Initiated After Severe Disease
HAART initiation among children who progressed to severe disease was associated with increased survival: 91% (62/68) survived who received HAART compared to 27% (18/67) who did not receive HAART (p<0.0001, ). HAART administration was not associated with delaying death after identification of severe disease (p=0.15).
While receipt of HAART improved survival after progression to severe disease, 13 children treated only with M/D remained alive through a median follow-up of 4.1 years (2.6–6.0) after progressing to severe disease to a median age of 5.4 years (3.8–7.3) (). Moreover, 76% (47/62) of the children who survived with HAART were treated with M/D for up to 12.7 years after progression to severe disease and before transitioning to HAART; 14 (30%) of these children were treated with M/D for more than 5 years before starting HAART. There were 65 children in the study who had severe disease at initial evaluation (62 at baseline, 3 after ARV); all had progressed to severe disease by 22 months of age, with 75% progressing by 6 months. Survival with vs. without HAART by cohort was: early cohort - 100% (3/3) vs. 17% (4/24), intermediate cohort - 70% (7/10) vs. 21% (3/14), late cohort - 93% (13/14) vs. 0/0.