Collins IJ, Jourdain G, Hansudewechakul R, Kanjanavanit S, Hongsiriwon S, Ngampiyasakul C, et al. Long-term survival of HIV-infected children receiving antiretroviral therapy in Thailand: A 5-year observational cohort study. Clin Infect Dis. 2010; 51(12):1449-57.
Over 4 million HIV-infected persons in low- and middle-income countries were receiving antiretroviral therapy (ART) by the end of 2008, including 275,700 children, for an estimated 38% coverage of children in need of treatment.(1) In a multi-country study of children on ART in sub Saharan Africa, the two year survival rate was 93% and the lost to follow-up rate was 10%.(2) Although data are accumulating on the long-term effectiveness of ART among adults,(3) few data are available on long term outcomes from ART among children beyond two years of follow-up.
To evaluate the survival rate of children on ART up to 5 years and identify factors associated with mortality
Forty public hospitals in urban and peri-urban settings across Thailand
HIV-infected children who initiated ART
Previously untreated children <18 years who initiated ART from January 1, 1999 through January 21, 2009 were included. ART was provided free of charge as part of a pilot program in 1999 and expanded to national scale-up in 2002. Since 1999, HIV-infected children born to mothers who participated in prevention of mother to child transmission clinical trials were enrolled and followed as a prospective cohort since birth ("birth cohort"). These children received early HIV testing and co-trimoxazole prophylaxis at 6 weeks of age. Since 2002, any HIV-infected children presenting at participating hospitals were enrolled (referred cohort). Children initiated ART if they were CDC clinical stage B or C, or CD4% less than 20% if <2 years of age, or less than 15% if ≥2 years of age. Children attended the clinic monthly for physical exam, drug refills, and adherence counseling. Children were seen by a physician every month for the first three months and then every three months thereafter. CD4 and viral load testing were conducted at the start of ART and then every six months. Loss to follow-up (LTFU) was defined as a missed scheduled visit and no contact for > 6 months. Telephone calls and home visits were made to trace children who were LTFU. In Thailand, nucleoside reverse-transcriptase inhibitor (NRTI) dual therapy have been provided since 1999, protease inhibitor (PI)-based HAART has been available since 2002, and non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based regimens since 2003. Children who initiated dual therapy were switched to AART as soon as it was available.
Mortality was measured from the date of ART initiation until the date of death or last visit. Cause of death was ascertained by physician report if the death occurred in the hospital and by caregiver interview by the physician if the child died at home. Clinical records were reviewed by 2 independent physicians. The Kaplan-Meier method was used to estimate survival for the first 5 years of ART. Analyses were based on intent-to-continue treatment, ignoring treatment changes, interruptions or terminations. Differences in survival curves by baseline characteristics were tested using the log-rank test. The Cox proportional hazards model was used to evaluate the effect of baseline risk factors on survival during ART. Missing values were imputed.
Of the 578 children initiating ART, 19% were enrolled in the birth cohort initiating ART at a median age of 13 months, and 81% were enrolled in the referred cohort, initiating ART at a median age of 7.6 years. Ten percent of children started ART during the first year of life. Median duration of follow-up was 53 months. Overall, 7.3% died, 6.6% were LTFO, and 9.9% withdrew from the study. Mortality rates were 10.2 deaths for 100 person-years during the first 6 months decreasing to 0.62 deaths per 100 persons years after 6 months of therapy.
The probability of survival among children <12 months of age at ART initiation was 89.6% (95%CI [78.4%-95.2%]) at 6 months, 84.3% (95%CI [71.9%-91.5%]) at 1 year and 76.7% (95%CI [63.2%-85.8%]) at 5 years. Among children who were 12 months of age or older at ART initiation, survival was 95.7% (95%CI [93.5%-97.1%]) at 6 months and one year and 94.0% (95%CI [91.4%-95.8%]) at 5 years. Most deaths among children 12 months or older occurred in the first six months of ART, however deaths among infants were observed throughout follow-up. Cause of death was available in 95% (40/42) of cases, with the primary cause of death most frequently related to infection. The most frequent causes of death were pneumonia (n=11), sepsis (n=6), and diarrhea (n=4).
In multivariate analyses, those at increased risk for mortality were children who started ART at <12 months of age (aHR, 7.1; 95%CI [2.7-18.6]) (compared to a reference group of children ≥8 years), those with low CD4% at baseline, with a 67% increase risk for mortality per 5% decrease in baseline CD4 % (aHR, 1.67; 95% CI [1.25-2.17]), and declines in unit weight for height z score among older children (aHR 2.32, 95%CI [1.64-3.33]), but not among infants (aHR 1.10, 95%CI [0.78-1.56] p=.003 for interaction). The mortality risk for low CD4% at baseline was greater for those >12 months of age at ART initiation (aHR 2.27, 95%CI [1.3-4.0]) compared with those <12 months (aHR, 1.39, 95%CI [1.02-1.89]) (p=.13 for interaction). When the analyses was limited to those children whose initial ART regimen was HAART, risk factors for mortality were consistent with those for the overall cohort (data not provided).
Data from this study show 94% 5 year survival rates among children who were 12 months or older at ART initiation. However, children who initiated ART as infants based on clinical or immunological criteria had significantly higher risk of mortality that persisted throughout the follow-up period. Low weight-for-height z scores and low CD4 cell percentage, particularly among children older than 12 months, were associated with increased mortality.
Data are from a large number of public hospitals in Thailand, both in urban and peri-urban settings providing important data on long term survival on children on ART. However, it is not clear how representative the sites and site populations are to the overall pediatric population on treatment in Thailand. Furthermore, these children received regular viral load testing and second-line treatments, which were not generally available in routine-care settings. Although loss to follow-up at 5 years was low (6.6%), the authors reported that it was higher among those followed since birth, though the rate was not reported. Unreported deaths in those patients who are LTFU have led to underestimates of mortality in other studies among adults
This study emphasizes the need for early diagnosis and treatment of all HIV-infected infants. WHO guidelines recommend earlier diagnosis of HIV among HIV-exposed infants with virologic testing conducted at 4-6 weeks of age and immediate initiation of ART in all HIV-infected infants regardless of immunologic or clinical status.(4) Improvements in access to and scale-up of early infant diagnosis as well as improved linkages between prevention of mother to child transmission of HIV and antiretroviral treatment programs are needed to facilitate scale-up of early treatment in HIV-infected infants. Prospective data should be collected on the impact of these new treatment strategies on infant and child survival. This study also demonstrates that mortality rates among children who initiate ART after one year of age in Thailand appear consistent with those of developed countries.
- WHO. Towards universal access: scaling up priority HIV/AIDS interventions in the health sector, Progress Report 2009.
- The KIDS ART-LIC Collaboration. Low risk of death, but substantial program attrition, in pediatric HIV treatment cohorts in sub-Saharan Africa. J Acquir Immune Defic Syndr 2008;49:523-31.
- Sanne IM, Westreich D, Macphail AP, Rubel D, Majuba P, Van Rie A. Long term outcomes of antiretroviral therapy in a large HIV/AIDS care clinic in urban South Africa: a prospective cohort study. J Int AIDS Soc. 2009 Dec 17;12:38.
- WHO. Report of the Who Technical Reference Group Paediatric HIV/ART Care Guidelines Group Meeting. 2008.