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Figure 1.  Incidence of Mortality and First Occurrence of Centers for Disease Control and Prevention (CDC) Stage C (CDC-C) and World Health Organization (WHO) Stage 4 (WHO-4) and CDC Stage B (CDC-B) and WHO Stage 3 (WHO-3) Events
Incidence of Mortality and First Occurrence of Centers for Disease Control and Prevention (CDC) Stage C (CDC-C) and World Health Organization (WHO) Stage 4 (WHO-4) and CDC Stage B (CDC-B) and WHO Stage 3 (WHO-3) Events

Person-time in the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol and International Maternal Pediatric Adolescent AIDS Clinical Trials P1074 Study was stratified by CD4 cell count, viral load and antiretroviral (ARV) status, and age. Error bars indicate exact Poisson 95% CIs. cART indicates combination ARV therapy.

Figure 2.  Incidence of Mortality and First Occurrence of All Clinical Outcomes in the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol and International Maternal Pediatric Adolescent AIDS Clinical Trials P1074
Incidence of Mortality and First Occurrence of All Clinical Outcomes in the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol and International Maternal Pediatric Adolescent AIDS Clinical Trials P1074

Error bars indicate exact Poisson 95% CIs. ND indicates neurodevelopmental; PID, pelvic inflammatory disease; and STI, sexually transmitted infection.

Table 1.  Characteristics of PHACS AMP and IMPAACT P1074 Participants at Baseline and During Follow-up
Characteristics of PHACS AMP and IMPAACT P1074 Participants at Baseline and During Follow-up
Table 2.  Distribution of Person-time Stratified by Age, CD4 Cell Count, and Viral Load and ARV Status
Distribution of Person-time Stratified by Age, CD4 Cell Count, and Viral Load and ARV Status
Table 3.  Association Between Person-time and Age, CD4 Cell Count, and Viral Load and ARV Status
Association Between Person-time and Age, CD4 Cell Count, and Viral Load and ARV Status
Supplement.

eMethods. MedDRA Diagnosis Codes of Outcome Categories

eTable 1. Event Rates of First Occurrence During Follow-up by Age

eTable 2. Event Rates of First Occurrence During Follow-up by CD4 Count

eTable 3. Event Rates of First Occurrence During Follow-up by Viral Load and Antiretroviral Status

eTable 4. Stratum-Specific Incidence Rates for Mortality

eTable 5. Stratum-Specific Incidence Rates for First CDC-C/WHO-4 Event

eTable 6. Stratum-Specific Incidence Rates for First CDC-B/WHO-3 Event (Excluding Peripheral Neuropathy)

eTable 7. Stratum-Specific Incidence Rates for First Bacterial Pneumonia (CDC-B/WHO-3 Event)

eTable 8. Stratum-Specific Incidence Rates for First Serious Bacterial Infection (Excluding CDC-B/WHO-3 Event)

eTable 9. Stratum-Specific Incidence Rates for First Presumptive Pelvic Inflammatory Disease (CDC-B/WHO-3 Event)

eTable 10. Stratum-Specific Incidence Rates for First Sexually Transmitted Infection, Among Females Only (Excluding Presumptive Pelvic Inflammatory Disease)

eTable 11. Stratum-Specific Incidence Rates for First Pregnancy

eTable 12. Stratum-Specific Incidence Rates for First Sexually Transmitted Infection, Among Males Only

eTable 13. Stratum-Specific Incidence Rates for First Mental Health or Neurodevelopmental Condition

eTable 14. Stratum-Specific Incidence Rates for First Asthma, Atopy or Allergy Condition

eTable 15. Stratum-Specific Incidence Rates for First Gastrointestinal Condition (Excluding CDC-B/WHO-3 Event, CDC-C/WHO-4 Event, and Bacterial Gastrointestinal Infection)

eTable 16. Stratum-Specific Incidence Rates for First Cardiac Condition (Excluding CDC-C/WHO-4 Event)

eTable 17. Stratum-Specific Incidence Rates for First Anemia

eTable 18. Stratum-Specific Incidence Rates for First Pancreatitis or Hepatitis

eTable 19. Stratum-Specific Incidence Rates for First Peripheral Neuropathy

eTable 20. Stratum-Specific Incidence Rates for First Metabolic or Bone Abnormality, Including Renal Condition

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Original Investigation
May 2017

Association of Risk of Viremia, Immunosuppression, Serious Clinical Events, and Mortality With Increasing Age in Perinatally Human Immunodeficiency Virus–Infected Youth

Author Affiliations
  • 1Division of Infectious Diseases and the Medical Practice Evaluation Center, Massachusetts General Hospital, Boston
  • 2Department of Pediatrics, Massachusetts General Hospital, Boston
  • 3Harvard Medical School, Harvard University, Boston, Massachusetts
  • 4Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 5Center for Biostatistics in AIDS Research, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 6Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana
  • 7Department of Pediatrics (Infectious Diseases), University of Colorado School of Medicine and Children’s Hospital, Aurora
  • 8Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 9Bronx-Lebanon Hospital Center, Icahn School of Medicine at Mt. Sinai, New York, New York
  • 10Division of Pediatric Allergy, Immunology and Infectious Diseases, New Jersey Medical School at Rutgers, Newark
  • 11Infectious Diseases, Boston Children’s Hospital, Boston, Massachusetts
  • 12Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, New York
JAMA Pediatr. 2017;171(5):450-460. doi:10.1001/jamapediatrics.2017.0141
Key Points

Question  What is the association of age, CD4 cell count, viral load, and antiretroviral drug use with key clinical events and mortality as perinatally human immunodeficiency virus–infected youth age?

Findings  Event rates stratified by age, CD4 cell count, and a combined measure of viral load and antiretroviral therapy status were estimated in 1446 perinatally human immunodeficiency virus–infected youth aged 7 to 30 years from 2 cohort studies. Higher incidences of Centers for Disease Control and Prevention stage B and C events and mortality were observed as participants aged, and mortality among older perinatally human immunodeficiency virus–infected youth was 6 to 12 times that among the general US population.

Meaning  Older perinatally human immunodeficiency virus infected–youth were at increased risk of viremia, immunosuppression, Centers for Disease Control and Prevention stage B and C events, and mortality.

Abstract

Importance  As perinatally human immunodeficiency virus–infected youth (PHIVY) in the United States grow older and more treatment experienced, clinicians need updated information about the association of age, CD4 cell count, viral load (VL), and antiretroviral (ARV) drug use with risk of opportunistic infections, key clinical events, and mortality to understand patient risks and improve care.

Objective  To examine the incidence or first occurrence during follow-up of key clinical events (including Centers for Disease Control and Prevention stage B [CDC-B] and stage C [CDC-C] events) and mortality among PHIVY stratified by age, CD4 cell count, and VL and ARV status.

Design, Setting, and Participants  Combining data from the Pediatric HIV/AIDS Cohort Study (PHACS) Adolescent Master Protocol and International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1074 multicenter cohort studies (March 2007 through April 2015), we estimated event rates during person-time spent in key strata of age (7-12, 13-17, and 18-30 years), CD4 cell count (<200, 200-499, and ≥500/μL), and a combined measure of VL and ARV status (VL <400 or ≥400 copies/mL; ARV therapy or no ARV therapy). A total of 1562 participants in the PHACS Adolescent Master Protocol and IMPAACT P1074 were eligible, and 1446 PHIVY from 41 ambulatory sites in the 12 US states, including Puerto Rico were enrolled. The dates of analysis were March 2015 through January 2017.

Main Outcomes and Measures  Clinical event rates stratified by person-time in age, CD4 cell count, and VL and ARV categories.

Results  A total of 1446 PHIVY participated in the study (mean [SD] age, 14.6 [4.6] years; 759 female [52.5%]; 953 black [65.9%]). During a mean (SD) follow-up of 4.9 (1.3) years, higher incidences of CDC-B events, CDC-C events, and mortality were observed as participants aged. Older PHIVY (aged 13-17 and 18-30 years) spent more time with a VL of 400 copies/mL or more and with a CD4 cell count of less than 200/µL compared with 7- to 12-year-old participants (30% and 44% vs 22% of person-time with a VL≥400 copies/mL; 5% and 18% vs 2% of person-time with CD4 cell count <200/µL; P < .001 for each comparison). We observed higher rates of CDC-B events, CDC-C events, bacterial infections, and mortality at lower CD4 cell counts, as expected. The mortality rate among older PHIVY was 6 to 12 times that among the general US population. Higher rates of sexually transmitted infections were also observed at lower CD4 cell counts after adjusting for age.

Conclusions and Relevance  Older PHIVY were at increased risk of viremia, immunosuppression, CDC-B events, CDC-C events, and mortality. Interventions to improve ARV therapy adherence and optimize models of care for PHIVY as they age are urgently needed to improve long-term outcomes among PHIVY.

Introduction

Effective interventions to prevent mother-to-child human immunodeficiency virus (HIV) transmission and treat HIV-infected infants and children have shifted the US pediatric HIV epidemic; youth 13 years or older now represent the majority of perinatally HIV-infected youth (PHIVY) in the United States.1-3 Rates of viremia and immunosuppression have decreased among PHIVY in the United States since the implementation of effective combination antiretroviral therapy (cART) but may remain higher for older PHIVY.4,5 Compared with adults, PHIVY experience lower rates of HIV RNA viral load (VL) suppression and higher rates of loss to follow-up.6-8 As youth age and transition to adult care, their risks of opportunistic infections (OIs), other serious clinical events, and mortality are not well described.9-14

Understanding the frequency of important clinical events for PHIVY, as well as the consequences of being prescribed cART without a suppressed VL, will provide critical information to design interventions for this group, who are at risk for severe illness, accumulation of drug-resistance mutations, and secondary transmission.15,16 Our objectives were to determine the frequency of viremia and immunosuppression among PHIVY and young adults aged 7 to 30 years engaged in care in 2 large national cohort studies and to analyze associations among age, CD4 cell count, viremia, antiretroviral (ARV) drug use, and risks of significant clinical events and mortality.

Methods
Study Population

We evaluated participants in the Pediatric HIV/AIDS Cohort Study (PHACS) Adolescent Master Protocol (AMP) and the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1074 cohort studies. PHACS AMP enrolled 451 PHIVY aged 7 to 16 years from March 2007 through November 2009 at 15 US sites; follow-up is ongoing.2 The IMPAACT P1074 study enrolled 1201 participants (87% PHIVY) with a mean (SD) age of 17.4 (5.4) years from April 2009 through June 2013 at 40 US sites; follow-up was completed in June 2014.17 For this analysis, PHACS AMP participants were eligible if they had 1 or more visits from March 2007, through April 2015, and 1 or more CD4 cell count and VL measurements recorded after baseline. IMPAACT P1074 participants were eligible if they were PHIVY and had 1 or more medical record abstractions with CD4 cell count and VL data recorded after baseline. The PHACS AMP baseline was defined as date of study entry; the IMPAACT P1074 baseline was defined as 1 year before study entry. Simultaneous coenrollment in PHACS AMP and IMPAACT P1074 was not permitted. On the basis of guidelines, practice patterns, and trial data, we defined cART regimens as 1 of 3 mutually exclusive types expected to be suppressive: (1) 3 or more drugs from 2 or more classes, (2) a protease inhibitor (excluding ritonavir alone) plus 1 drug from another class, or (3) 3 or more nucleos(t)ide reverse transcriptase inhibitors.2,18-22 We excluded person-time when patients had VLs of less than 400 copies/mL and were not prescribed ARV drugs and when patients had VLs of 400 copies/mL or higher while being prescribed an ARV regimen other than cART. Although individual patient circumstances may have warranted these approaches, they are not expected to suppress VL and were not standard of care during the study period.2,18-22 Loss to follow-up was defined as stopping data collection for any reason other than death, study completion, or site closure. The study protocols for PHACS AMP and IMPAACT P1074 were approved by the institutional review board of each participating site. The Harvard T.H. Chan School of Public Health (Boston, Massachusetts) Institutional Review Board also approved the PHACS AMP study protocol and all work undertaken by the IMPAACT Network. For both studies, written informed consent was obtained from all participants and/or families, with written assent obtained for minors according to local institutional review board guidelines. For analysis, data were deidentified.

Clinical and Laboratory Data

Data collection methods have been described previously for both studies.2,17 CD4 cell counts, VLs, ARV drug use, and clinical events were abstracted from medical records, and clinical events were coded using the Medical Dictionary for Regulatory Activities, version 18, by the Frontier Science Technology and Research Foundation (eMethods in the Supplement).23

Outcome Measures

Primary outcomes included mortality and first occurrence of Centers for Disease Control and Prevention (CDC) stage C (CDC-C) and World Health Organization (WHO) stage 4 (WHO-4) or CDC stage B (CDC-B) and WHO stage 3 (WHO-3) events during follow-up.24-27 Secondary outcomes included the following: bacterial pneumonia; serious bacterial infections; presumptive pelvic inflammatory disease (PID); other sexually transmitted infections (STIs); pregnancy; mental health and neurodevelopmental conditions; asthma, atopy, or allergy conditions; gastrointestinal tract conditions; cardiac conditions; anemia; pancreatitis or hepatitis; peripheral neuropathy; and metabolic or bone abnormalities, including renal conditions. Presumptive PID and pregnancy were limited to females 13 years or older; other STIs were limited to age 13 years or older and stratified by sex due to sex-specific screening practices. Each Medical Dictionary for Regulatory Activities term was assigned a single diagnostic category except for bacterial pneumonia and PID, which were included in CDC-B and WHO-3 events and examined separately.

Statistical Analysis

We estimated incidence rates of key clinical events, stratified by the combination of time-varying age (7-12, 13-17, and 18-30 years), CD4 cell count (<200, 200-499, and ≥500/µL), and VL and ARV status. The VL and ARV status was categorized as (1) suppressive ARV therapy: VL less than 400 copies/mL and prescribed any ARV drug; (2) nonsuppressive cART: VL of 400 copies/mL or more and prescribed cART; and (3) no ARV therapy: VL of 400 copies/mL or more and not prescribed any ARV drugs. The dates of analysis were March 2015, through January 2017.

We estimated incidence rates and assessed trends by age, CD4 cell count, and VL and ARV categories using Poisson regression models, accounting for within-subject correlation with robust standard variance estimators. For selected individual events (STIs, pregnancy, and cardiac events), incidence rates by CD4 cell counts were adjusted for age using inverse probability weighting because person-time contributing to each age category was unevenly distributed by CD4 cell count category.28-33 Only the first occurrence of each event after baseline for each participant was included.

To assign participants to baseline strata and calculate the total person-time contributed by all participants to each stratum, we used linear interpolation between adjacent CD4 cell count and log10-transformed VL readings and estimated dates when strata thresholds were crossed. The nearest CD4 cell count and VL readings before baseline were used when available for interpolation, and the last available CD4 cell count and VL were carried forward until the end of follow-up.

We used weighted repeated-measures generalized estimating equation models with an independence working correlation, identity link, normal distribution, and robust variance estimators to determine the association between age and person-time with VL of 400 copies/mL or more, age and person-time with CD4 cell count less than 200/µL, and VL and ARV status and person-time with CD4 cell count less than 200/µL. For these generalized estimating equation analyses, we additionally subdivided the older age stratum into 18 to 21, 22 to 25, and 26 to 30 years.

To compare mortality rates between PHIVY and youth in the general US population, we calculated mortality ratios standardized to CDC age, sex, and race distributions.34 The CIs for the standardized mortality ratios were calculated using the Boice-Monson method.

Results
Characteristics of the Study Population

A total of 1446 PHIVY participated in the study (mean [SD] age, 14.6 [4.6] years; 759 female [52.5%]; 953 black [65.9%]). Of the initial 1467 PHIVY in PHACS AMP and/or IMPAACT P1074, we excluded 18 who did not have the combination of ARV, CD4 cell count, and VL data at any point during follow-up; 1 who spent his or her entire person-time in the study with a VL of 400 copies/mL or higher while prescribed a regimen other than cART; and 2 who spent their entire person-time with a VL less than 400 copies/mL while not prescribed ARV drugs. We excluded 92.3 person-years (1.4% of overall person-time) while participants were viremic and prescribed a regimen other than cART and 59.4 person-years (0.9% of overall person-time) while participants had a VL less than 400 copies/mL while not prescribed ARV drugs, from a total of 247 participants. Table 1 reports additional baseline and follow-up characteristics. Of note, patients who were lost to follow-up differed significantly from retained patients only in baseline age (15.8 vs 14.4 years).

Distribution of Person-time

Participants contributed 19% of person-time between the ages of 7 and 12 years, 38% between the age of 13 and 17 years, and 43% between the ages of 18 and 30 years; only 2% of total person-time was between the ages of 26 and 30 years (Table 2). Most person-time was spent with CD4 cell counts of 500/µL or more (65% of person-time compared with 24% at CD4 cell counts of 200-499/µL and 10% at CD4 cells counts <200/µL) and prescribed suppressive ARV therapy (66% of person-time compared with 28% in those prescribed nonsuppressive cART and 7% in those taking no ARV drugs). Person-years spent in older age strata (13-17 and 18-30 years) compared with ages 7 to 12 years were more likely to be spent with CD4 cell counts of less than 200/µL (5% and 18% vs 2%; P < .001 for each pairwise comparison). For older PHIVY (aged 13-17 and 18-30 years), more person-time was also spent with a VL of 400 copies/mL or more (nonsuppressive cART or no ARVs drug use, 30% for those 13-17 years old and 44% for those 18-30 years old vs 22% for PHIVY 7-12 years old; P < .001 for both). When the older age stratum was further divided into 18 to 21, 22 to 25, and 26 to 30 years, the proportions of time spent being viremic and with low CD4 cell counts remained substantially higher for each substratum compared with younger ages (Table 3). Prescription of nonsuppressive cART was not associated with having a CD4 cell count of less than 200/μL compared with use of no ARV drugs (25% vs 24% of person-time; P = .72).

Mortality

Overall, there were 29 deaths (0.4 per 100 person-years) (eTables 1-4 in the Supplement). A total of 23 deaths (79.3%) occurred at CD4 cell counts of less than 200/µL (3.5 per 100 person-years). A total of 24 deaths (82.3%) occurred while VL was 400 copies/mL or higher, with mortality rates of 0.9 per 100 person-years for nonsuppressive cART and 1.6 per 100 person-years for no ARV drug use (P < .001 for trend). All but 1 death (96.6%) occurred in 18- to 30-year-old participants (1.0 per 100 person-years; P < .001 for trend). Mortality rates were 5.6-fold (95% CI, 2.8-11.1) higher among those aged 15 through 19 years and 12.3-fold (95% CI, 8.0-18.9) higher among those aged 20 through 29 years than youth of the same age in the US general population.34

First Events During Follow-up
CDC-C and WHO-4 Events

There were 86 CDC-C and WHO-4 events (1.4 per 100 person-years) (eTable 5 in the Supplement). Higher rates of CDC-C and WHO-4 events were observed at lower CD4 cell counts (<200/µL: 9.6 per 100 person-years; 200-499/µL: 1.0 per 100 person-years; ≥500/µL: 0.4 per 100 person-years; P < .001 for trend). Of 17 events that occurred at CD4 cell counts of 500/µL or less (20% of total), only 2 were OIs (pulmonary tuberculosis and ocular toxoplasmosis); others were HIV-related kidney and cardiac diseases. Higher rates of CDC-C and WHO-4 events occurred with higher VL (suppressive ARV therapy: 0.6 per 100 person-years; nonsuppressive cART: 3.0 per 100 person-years; no ARV therapy: 2.4 per 100 person-years; P < .001 for trend). Higher rates of CDC-C and WHO-4 events were also observed with older age (7-12 years of age: 0.7 per 100 person-years; 13-17 years of age: 0.9 per 100 person-years; 18-30 years of age: 2.1 per 100 person-years; P < .001 for trend).

CDC-B and WHO-3 Events

There were 193 CDC-B and WHO-3 events (3.2 per 100 person-years) (Figure 1, Figure 2, and eTable 6 in the Supplement). Higher rates of CDC-B and WHO-3 events were observed at lower CD4 cell counts (<200/µL: 12.5 per 100 person-years; 200-499/µL: 3.8 per 100 person-years; ≥500/µL: 1.8 per 100 person-years; P < .001 for trend). The CDC-B and WHO-3 events were also more common at higher VL (suppressive ARV therapy: 2.0 per 100 person-years; nonsuppressive cART: 5.5 per 100 person-years; no ARV therapy: 7.1 per 100 person-years; P < .001 for trend). These event rates also increased as participants aged (7-12 years old: 2.4 per 100 person-years; 13-17 years old: 2.9 per 100 person-years; 18-30 years old: 3.9 per 100 person-years; P = .01 for trend). For bacterial pneumonia (CDC-B and WHO-3 event) and serious bacterial infections, higher event rates were also observed at lower CD4 cell counts and higher VLs, but no trends were observed by age (eTable 7 and eTable 8 in the Supplement).

Reproductive System Events

In female participants, higher rates of presumptive PID, other STIs, and pregnancies were observed with older age and with VLs higher than 400 copies/mL (eTables 9-11 in the Supplement); higher rates of STIs (not including PID) and pregnancy were observed with lower CD4 cell counts. After adjusting for age, the association between increasing rates of pregnancies and lower CD4 cell counts was not statistically significant (<200/µL: 4.5 per 100 person-years; 200-499/µL: 4.8 per 100 person-years; ≥500/µL: 2.8 per 100 person-years; P = .18); however, the trend of increased rates of first female STI at lower CD4 cell counts remained significant (<200/µL: 8.1 per 100 person-years; 200-499/µL: 5.9 per 100 person-years; ≥500/µL: 3.1 per 100 person-years; P < .001). First STIs were infrequently reported in males (eTable 12 in the Supplement).

Other Clinical Events

Mental health and neurodevelopmental conditions were among the most frequent conditions (4.0 per 100 person-years); no trends were observed by age, CD4 cell count, or VL and ARV status (eTable 13 in the Supplement). For asthma, atopy, or allergy conditions, no trends were observed by age, CD4 cell count, or VL and ARV status (eTable 14 in the Supplement). For gastrointestinal tract conditions, rates increased with lower CD4 cell counts (P < .001); however, no trends were observed by age or VL and ARV status (eTable 15 in the Supplement). Higher rates of first non–AIDS-defining cardiac events were observed at lower CD4 cell counts (eTable 16 in the Supplement), although this trend was no longer significant after adjusting for age (<200/µL: 2.1 per 100 person-years; 200-499/µL: 1.0 per 100 person-years; ≥500/µL: 0.7 per 100 person-years; P = .08). Events potentially attributed to antiretroviral toxicity, such as anemia (0.0 per 100 person-years), pancreatitis or hepatitis (0.4 per 100 person-years), and peripheral neuropathy (0.2 per 100 person-years) were among the least frequently reported events (eTables 17-19 in the Supplement). Rates of first metabolic or bone abnormalities (1.5 per 100 person-years) revealed no difference by age or CD4 cell count, but there was a trend of lower rates in patients with VLs greater than 400 copies/mL (suppressive ARVs: 1.7 per 100 person-years; nonsuppressive cART: 1 1.1 per 100 person-years; no ARVs: 0.7 per 100 person-years; P = .04) (eTable 20 in the Supplement).

Discussion

We analyzed rates of clinical events and mortality during 6548 person-years of follow-up from 1446 PHIVY aged 7 to 30 years in PHACS AMP and IMPAACT P1074 cohort studies, stratified by time-updated age, CD4 cell count, and VL and ARV status. There were 3 key findings from this work. First, older youth were at highest risk for viremia, low CD4 cell counts, and serious clinical events, including mortality, CDC-C and WHO-4 events, and CDC-B and WHO-3 events. Monitoring of VL remained consistent across age ranges, suggesting ongoing engagement in care; thus, high overall rates of viremia among participants aged 18 to 30 years are likely attributable to suboptimal medication adherence or acceptance or accumulated viral resistance. Older PHIVY had greater early exposure to monoregimens or dual regimens compared with younger PHIVY; the lack of viral suppression among those PHIVY prescribed cART is more likely related to poor medication adherence or acceptance because resistance to newer ARV drugs, such as integrase inhibitors, is uncommon.35 Older youth also spent more time with CD4 cell counts less than 200/µL. Data from PHIVY aged 6 to 17 years suggest that having a CD4 cell count less than 200/µL is associated with lower quality of life, psychiatric symptoms, and poor cognitive, academic, and social functioning, and data from adults suggest high risks of OIs and death.36,37 Our findings are consistent with increasing literature that outlines the challenges to adhering to medications for PHIVY in adolescence, which intensify as PHIVY reach early adulthood.38-43

Second, we observed relatively few clinical events and deaths during the follow-up period, during which cART was standard of care. These results add to prior reports1,17 of clinical events in PHACS AMP and IMPAACT P1074 by stratifying clinical event rates by time-updated age, CD4 cell count, and VL and ARV status. Our results are similar to other cohort studies9,13,44 of PHIVY in the United States, United Kingdom, and Ireland. For example, our observed incidence rates of mortality (0.4 per 100 person-years), CDC-C and WHO-4 events (1.4 per 100 person-years), CDC-B and WHO-3 events (3.2 per 100 person-years), and bacterial pneumonia (1.4 per 100 person-years) were comparable to those reported in the Pediatric AIDS Clinical Trials Group 219c cohort in 2006, 10 years into the cART era (mortality: 0.5-0.8 per 100 person-years; CDC-C events: 1.5 per 100 person-years; CDC-B events: 5.0 per 100 person-years; bacterial pneumonia: 2.2 per 100 person-years).5,12,44 However, the mortality rate in older adolescent PHIVY (aged 15-19 years) remained 6 times and in young adult PHIVY (aged 20-29 years) remained 12 times that of the US general population, after accounting for age, sex, and race. The STIs among female participants and mental health and neurodevelopmental diagnoses were among the most commonly documented conditions. Higher STI rates (excluding PID) among female participants were associated with lower CD4 cell counts after adjusting for age. This finding and the association of lower CD4 cell count with herpes simplex virus reactivation and lack of human papillomavirus clearance have been previously reported.28-30,45-49 These data suggest a potential biological effect of immunosuppression; in addition, more frequent risk behavior among patients incompletely adherent to cART may contribute to higher STI rates.8,30 Pregnancy rates overall (3.5 per 100 person-years) and at older ages (13-17 years: 2.0 per 100 person-years; 18-30 years: 4.9 per 100 person-years) were similar to those in the general population (range for 15-29 years: 3.95-16.30 per 100 person-years).50 Pregnancy rates were higher among those with lower CD4 cell counts, although the strength of this association decreased after age adjustment. Complications potentially related to long-term ARV therapy, including anemia, pancreatitis, hepatitis, peripheral neuropathy, and metabolic and bone abnormalities, were documented infrequently, likely reflecting use of less toxic ARV drugs over time.35,51

Third, our person-time results add a valuable dimension to the literature base of cross-sectional and longitudinal studies on viremia in PHIVY. In PHACS AMP and IMPAACT P1074 cohorts described here, 66% of person-time was spent with VLs less than 400 copies/mL, similar to that observed in the HIV Research Network (63% of PHIVY aged 12-21 years with VLs less than 400 copies/mL during 2009-2012). However, viral suppression is higher than that reported in the Adolescent Trials Network (37% of PHIVY with VLs below the lower level of detection) and in a recent meta-analysis (pooled North America estimate of youth with suppressed VLs: 53% [range, 28%-75%] of youth aged 12-24 years during 1990-2013).4,8,52 Although lower suppression rates in the meta-analysis cohorts may reflect the inclusion of non-PHIVY, lower suppression rates for PHIVY in the Adolescent Trials Network cohort may reflect older age in that cohort (mean age, 17.9 vs 14.6 years for the Adolescent Trials Network cohort vs our combined cohorts). In contrast to data from adults, we found that having VLs of 400 copies/mL or higher while being prescribed cART did not improve immunosuppression compared with having VLs of 400 copies/mL or higher while taking no ARVs at all.53-61 The 35% of person-time spent with VLs of 400 copies/mL or higher in our study raises critical concerns not only for individual patient outcomes but also for the HIV epidemic among US youth.30,35,62 Youth who are viremic despite being engaged in care are more likely to have drug-resistant virus and to report lower condom use than nonviremic youth and thus are at risk of secondary horizontal or vertical transmission.63-65

Limitations

This analysis of PHIVY in 2 large cohort studies had several limitations. First, the smallest proportion of person-time (19%) was spent at ages 7 to 12 years of age; nevertheless, we had adequate power for all statistical comparisons. Second, data collection protocols in the 2 cohorts may have affected incidence rate estimates for specific events because: (1) we analyzed first events, we could not identify recurrent bacterial pneumonia, potentially underestimating CDC-C events; (2) STI screening was not performed at study-specific intervals but per local care practice; and (3) care sought by participants at nonstudy health care facilities was recorded only if reported to study staff. In addition, IMPAACT P1074 recorded only events deemed to be clinically significant by health care professionals, whereas PHACS AMP recorded all events; we addressed this limitation by including only events that met the reporting threshold for both studies (eg, laboratory-value diagnoses were excluded). Furthermore, PHIVY least engaged in care and at highest risk for adverse outcomes may not have been included. Conversely, to permit consistent coding of events between PHACS AMP and IMPAACT P1074 studies, we excluded events before baseline, which may have led to overestimation of some first event rates. Finally, adherence data were not included in the analysis because adherence measures were collected only in 1 study (PHACS AMP). Despite these counterbalancing possibilities, to our knowledge, this analysis provides the most recent, detailed data available about clinical risks in US PHIVY over time. This information will be critical information for US policy makers as research and programmatic funding shifts for pediatric HIV infection in the United States.66

Conclusions

We found that serious clinical events, including OIs and death, are rare in PHIVY receiving suppressive ART, but viremia, lower CD4 cell counts, and rates of serious clinical events and mortality increase throughout adolescence and young adulthood. Interventions to improve ART adherence and optimize models of care as PHIVY age are urgently needed to improve long-term outcomes among this increasing and vulnerable population.

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Article Information

Corresponding Author: Anne M. Neilan, MD, MPH, Division of Infectious Diseases, Massachusetts General Hospital, 50 Staniford St, Boston, MA 02114 (aneilan@partners.org).

Accepted for Publication: January 19, 2017.

Published Online: March 27, 2017. doi:10.1001/jamapediatrics.2017.0141

Author Contributions: Dr Patel and Mr Karalius had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Neilan, Karalius, Patel, Van Dyke, Agwu, Seage, Ciaranello.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Neilan, Karalius, Patel, Ciaranello.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Neilan, Karalius, Patel, Williams, Chernoff, Seage.

Obtained funding: Neilan, Van Dyke, Seage, Ciaranello.

Administrative, technical, or material support: Neilan, Karalius, Patel, Van Dyke, Seage, Ciaranello.

Study supervision: Patel, Agwu, Seage, Ciaranello.

Conflict of Interest Disclosures: None reported.

Funding/Support: The Pediatric HIV/AIDS Cohort Study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with cofunding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism through cooperative agreements HD052102 with the Harvard T. H. Chan School of Public Health and HD052104 with the Tulane University School of Medicine. Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) group was provided by grants UM1AI068632 (IMPAACT Leadership and Operations Center), UM1AI068616 (IMPAACT Statistical and Data Management Center), and UM1AI106716 (IMPAACT Laboratory Center) from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health. This research was also funded by grants T32 AI007433 (Dr Neilan) from the National Institute of Allergy and Infectious Diseases, grant R01 HD079214 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Drs Patel, Seage, Ciaranello), and the Charles Hood Foundation Child Health Research Award (Drs Neilan, Patel, and Ciaranello).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

Group Members: The following institutions, clinical site investigators, and staff participated in conducting the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol (AMP) and AMP Up in 2015, in alphabetical order: Ann & Robert H. Lurie Children’s Hospital of Chicago: Ram Yogev, MD, Margaret Ann Sanders, PhD, Kathleen Malee, PhD, Scott Hunter, PhD; Baylor College of Medicine: William Shearer, MD, PhD, Mary Paul, MD, Norma Cooper, MA, Lynnette Harris, PhD; Bronx-Lebanon Hospital Center: Murli Purswani, MD, Mahboobullah Baig, MBBS, Anna Cintron, MS; Children's Diagnostic & Treatment Center: Ana Puga, MD, Sandra Navarro, BA, Patricia A. Garvie, PhD, James Blood, MSW; Boston Children’s Hospital: Sandra K. Burchett, MD, MSc, Nancy Karthas, NP, Betsy Kammerer, PhD; Jacobi Medical Center: Andrew Wiznia, MD, Marlene Burey, RN, Molly Nozyce, PhD; Rutgers - New Jersey Medical School: Arry Dieudonne, MD, Linda Bettica, Rn, James Oleske, MD; St. Christopher’s Hospital for Children: Janet S. Chen, MD, Maria Garcia Bulkley, PA-C, Latreaca Ivey, MPH, Mitzie Grant, PhD; St. Jude Children's Research Hospital: Katherine Knapp, MD, Kim Allison, BSN, Megan Wilkins, PhD; San Juan Hospital/Department of Pediatrics: Midnela Acevedo-Flores, MD, Heida Rios, MS, Vivian Olivera, PhD; Tulane University School of Medicine: Margarita Silio, MD, Medea Gabriel, RN, Patricia Sirois, PhD; University of California, San Diego: Stephen A. Spector, MD, Kim Norris, RN, Sharon Nichols, PhD; University of Colorado Denver Health Sciences Center: Elizabeth McFarland, MD, Juliana Darrow, MPH, Emily Barr, CPNP-PC, Paul Harding, MS; University of Miami: Gwendolyn Scott, MD, Grace Alvarez, BA, Anai Cuadra, PhD. The following individuals and institutions were involved in the conduct of International Maternal Pediatric Adolescent AIDS Clinical Trials P1074: New Jersey Medical School: Arry Dieudonne, MD, Linda Bettica, LPN, Anthony Scolpino, BA, James Oleske MD, MPH; UCLA–Los Angeles/Brazil AIDS Consortium: Yvonne Bryson, MD, Michele Carter, RN, Jaime Deville, MD, Karin Nielsen, MD; Texas Children’s Hospital: Michelle Del Rey, RN, Chivon McMullen-Jackson, BSN, RN, ADN, William Shearer, MD, PhD, Mary Paul, MD; Ann & Robert H.Lurie Children’s Hospital of Chicago: Ram Yogev, MD, Margaret Ann Sanders, MPH, Ruth Williams, RN, Lynn Heald, PNP; Columbia University Medical Center (staff not specified); University of Miami Pediatric Perinatal HIV/AIDS: Gwendolyn Scott, MD, Charles Mitchell, MD, Claudia Florez, MD, Grace Alvarez, MD; University of California, San Diego, Mother-Child-Adolescent Program: Stephen Spector, MD, Rolando Viani, MD, MTP, Kimberly Norris, RN, BSN, Lisa Stangl, RN, NP; Duke University Medical Center: John Swetnam, Margaret Donnelly, PA-C, Joan Wilson, RN, MSN, Sunita Patil, PhD; Metropolitan Hospital: Mahrukh Bamji, MD, Indu Pathak, MD, Savita Manwanim, MD, Ekta Patel, MD; Boston Children’s Hospital: Sandra Burchett, MD, MS, Nancy Karthas, RN, MS, CPNP, Catherine Kneut, RN, MS, CPNP, Charlotte Mao, MD, MPH; Boston Medical Center Pediatric HIV Program: Ellen Cooper, MD, Diana Clarke, PharmD, Debra McLaud, RN, Pablo Leitz, MPH; New York University, New York: Aditya Kaul, MD, Nagamah Deygoo, MS, William Borkowsky, MD, Siham Akleh, RN; Jacobi Medical Center, Bronx: Michael Rosenberg, MD, Joanna Dobroszycki, MD, Karen Kassen, RN, BSN, Marlene Burey, NP; Children’s National Medical Center, Washington, DC: Steven Zeichner, MD, PhD, Connie Trexler, RN; Seattle Children’s Hospital: Ann Melvin, MD, MPH, Gloria Bowen, MA, Amanda Robson Nuss, BS, Carrie Pettler, MPH; University of South Florida–Tampa: Carina Rodriguez, MD, Patricia Emmanuel, MD, Denise Casey, RN, Alicia Marion, ARNP; San Juan City Hospital: Nicolas Rosario-Matos, MD, Wanda Marrero-Figueroa, BSN-RN, Carlos Ortega, BA, Lizbeth Fabregas, BS, MS; SUNY Stony Brook: Sharon Nachman, MD, Denise Ferraro, FNP, Erin Infanzon, Michele Kelly, NP; Children’s Hospital of Michigan: Chokechai Rongkavilit, MD, Ayanna Walters, RN, Eric McGrath, MD; Howard University, Washington DC: Sohail Rana, MD, Chandni Parikh, PNP, Caroline Reed, FNP, Patricia Houston, MS; Harbor UCLA Medical Center: Margaret Keller, MD, Michael Bolaris, MD, Judy Hayes, RN, Yolanda Gonzalez, RN; University of Southern California School of Medicine–Los Angeles County: Eva Operskalski, PhD, MBA, James Homans, MD, MPH, LaShonda Spencer, MD, Andrea Kovacs, MD; University of Florida Health Science Center: Mobeen Rathore, MD, Nizar Maraqa, MD, Saniyyah Mahmoudi, MSN, ARNP, Tabetha Gayton, PhD, ARNP; University of Colorado Denver: Hannah Bernath, MPH, Kerry Hahn, CCRP, Jennifer Dunn, MS, RN, FNP, Jennifer Englund, BS; South Florida Children’s Diagnostic and Treatment Center Fort Lauderdale: Ana Puga, MD, Amy Inman, Zulma Eysallenne, RN, James Blood, MSW; Strong Memorial Hospital, University of Rochester Medical Center: Geoffrey Weinberg, MD, Barbra Murante, MS, RN, PNP; Rush University Cook County Hospital, Chicago: Kenneth Boyer, MD, Jamie Martinez, MD, James McAuley, MD, Maureen Haak; Children’s Hospital of Los Angeles: Nancy Flores, Diane Tucker, MSN, Julie McAvoy, MPH, Marvin Belzer, MD; University of California San Francisco: Diane Wara, MD, Theodore Ruel, MD, Mica Muskat, NP, Nicole Tilton, NP; Johns Hopkins University Baltimore: Allison Agwu, MD, ScM, Thuy Anderson, RN, BSN, Aleisha Collinson-Streng, RN, BSN, ACRN, Kaye Park, MPH; Miller Children’s Hospital: Audra Deveikis, MD, Jagmohan Batra, MD, Tempe Chen, MD, David Michalik, DO; University of Maryland Baltimore: Douglas Watson, MD, Maria Johnson, DDS, Susan Lovelace, MSN, Corinda Hilyard; Tulane University New Orleans: Russell Van Dyke, MD, Margarita Silio, MD, Thomas Alchediak, MD, Sheila Bradford, RN; University of Alabama, Birmingham: Dorothy Shaw, BA, Sharan Robbins, BA, MAE, Newana Beatty, CCRC, Marilyn Crain, MD, MPH; The Children’s Hospital of Philadelphia: Carol Vincent, PhD, CRNP, Richard Rutstein, MD, Steven Douglas, MD, Sheri McDougall, MSHed, CCRC; Bronx-Lebanon Hospital: Anna Marie Emeh, MD, Mary Elizabeth Vachon, MPH, Levi Cherian, Murli Purswani, MD, FAAP; St Jude’s Children’s Hospital: Katherine Knapp, MD, Patricia Flynn, MD, Judy Glenn, LPN, Thomas Wride, MS; University of Puerto Rico Pediatric HIV/AIDS Research Program: Irma Febo, MD, Ruth Santos-Otero, RN, MPH, Maritza Cruz-Rodriguez, BA; Western New England Maternal Pediatric Adolescent AIDS: Katherine Luzuriaga, MD, Christina Hermos, MD, Jesica Pagano-Therrien, CPNP, Donna Picard BSN, RN, BC. International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT): We thank the children and families for their participation in IMPAACT P1074 and the individuals and institutions involved in the conduct of IMPAACT P1074, as follows: New Jersey Medical School: New Jersey Medical School: Arry Dieudonne, MD, Linda Bettica, LPN, Anthony Scolpino, BA, James Oleske MD, MPH; UCLA–Los Angeles/Brazil AIDS Consortium: Yvonne Bryson, MD, Michele Carter, RN, Jaime Deville, MD, Karin Nielsen, MD; Texas Children’s Hospital: Michelle Del Rey, RN, Chivon McMullen-Jackson, BSN, RN, ADN, William Shearer, MD, PhD, Mary Paul, MD; Ann & Robert H. Lurie Children’s Hospital of Chicago: Ram Yogev, MD, Margaret Ann Sanders, MPH, Ruth Williams, RN, Lynn Heald, PNP; Columbia University Medical Center (staff not specified); University of Miami Pediatric Perinatal HIV/AIDS: Gwendolyn Scott, MD, Charles Mitchell, MD, Claudia Florez, MD, Grace Alvarez, MD; University of California, San Diego, Mother-Child-Adolescent Program: Stephen Spector, MD, Rolando Viani, MD, MTP, Kimberly Norris, RN, BSN, Lisa Stangl, RN, NP; Duke University Medical Center: John Swetnam, Margaret Donnelly, PA-C, Joan Wilson, RN, MSN, Sunita Patil, PhD; Metropolitan Hospital: Mahrukh Bamji, MD, Indu Pathak, MD, Savita Manwanim, MD, Ekta Patel, MD; Boston Children’s Hospital: Sandra Burchett, MD, MS, Nancy Karthas, RN, MS, CPNP, Catherine Kneut, RN, MS, CPNP, Charlotte Mao, MD, MPH; Boston Medical Center Pediatric HIV Program: Ellen Cooper, MD, Diana Clarke, PharmD, Debra McLaud, RN, Pablo Leitz, MPH; New York University, New York: Aditya Kaul, MD, Nagamah Deygoo, MS, William Borkowsky, MD, Siham Akleh, RN; Jacobi Medical Center, Bronx: Michael Rosenberg, MD, Joanna Dobroszycki, MD, Karen Kassen, RN, BSN, Marlene Burey, NP; Children’s National Medical Center, Washington, DC: Steven Zeichner, MD, PhD, Connie Trexler, RN; Seattle Children’s Hospital: Ann Melvin, MD, MPH, Gloria Bowen, MA, Amanda Robson Nuss, BS, Carrie Pettler, MPH; University of South Florida–Tampa: Carina Rodriguez, MD, Patricia Emmanuel, MD, Denise Casey, RN, Alicia Marion, ARNP; San Juan City Hospital: Nicolas Rosario-Matos, MD, Wanda Marrero-Figueroa, BSN-RN, Carlos Ortega, BA, Lizbeth Fabregas, BS, MS; SUNY Stony Brook: Sharon Nachman, MD, Denise Ferraro, FNP, Erin Infanzon, Michele Kelly, NP; Children’s Hospital of Michigan: Chokechai Rongkavilit, MD, Ayanna Walters, RN, Eric McGrath, MD; Howard University, Washington DC: Sohail Rana, MD, Chandni Parikh, PNP, Caroline Reed, FNP, Patricia Houston, MS; Harbor UCLA Medical Center: Margaret Keller, MD, Michael Bolaris, MD, Judy Hayes, RN, Yolanda Gonzalez, RN; University of Southern California School of Medicine–Los Angeles County: Eva Operskalski, PhD, MBA, James Homans, MD, MPH, LaShonda Spencer, MD, Andrea Kovacs, MD; University of Florida Health Science Center: Mobeen Rathore, MD, Nizar Maraqa, MD, Saniyyah Mahmoudi, MSN, ARNP, Tabetha Gayton, PhD, ARNP; University of Colorado Denver: Hannah Bernath, MPH, Kerry Hahn, CCRP, Jennifer Dunn, MS, RN, FNP, Jennifer Englund, BS; South Florida Children’s Diagnostic and Treatment Center Fort Lauderdale: Ana Puga, MD, Amy Inman, Zulma Eysallenne, RN, James Blood, MSW; Strong Memorial Hospital, University of Rochester Medical Center: Geoffrey Weinberg, MD, Barbra Murante, MS, RN, PNP; Rush University Cook County Hospital, Chicago: Kenneth Boyer, MD, Jamie Martinez, MD, James McAuley, MD, Maureen Haak; Children’s Hospital of Los Angeles: Nancy Flores, Diane Tucker, MSN, Julie McAvoy, MPH, Marvin Belzer, MD; University of California San Francisco: Diane Wara, MD, Theodore Ruel, MD, Mica Muskat, NP, Nicole Tilton, NP; Johns Hopkins University Baltimore: Allison Agwu, MD, ScM, Thuy Anderson, RN, BSN, Aleisha Collinson-Streng, RN, BSN, ACRN, Kaye Park, MPH; Miller Children’s Hospital: Audra Deveikis, MD, Jagmohan Batra, MD, Tempe Chen, MD, David Michalik, DO; University of Maryland Baltimore: Douglas Watson, MD, Maria Johnson, DDS, Susan Lovelace, MSN, Corinda Hilyard; Tulane University New Orleans: Russell Van Dyke, MD, Margarita Silio, MD, Thomas Alchediak, MD, Sheila Bradford, RN; University of Alabama, Birmingham: Dorothy Shaw, BA, Sharan Robbins, BA, MAE, Newana Beatty, CCRC, Marilyn Crain, MD, MPH; The Children’s Hospital of Philadelphia: Carol Vincent, PhD, CRNP, Richard Rutstein, MD, Steven Douglas, MD, Sheri McDougall, MSHed, CCRC; Bronx-Lebanon Hospital: Anna Marie Emeh, MD, Mary Elizabeth Vachon, MPH, Levi Cherian, Murli Purswani, MD, FAAP; St Jude’s Children’s Hospital: Katherine Knapp, MD, Patricia Flynn, MD, Judy Glenn, LPN, Thomas Wride, MS; University of Puerto Rico Pediatric HIV/AIDS Research Program: Irma Febo, MD, Ruth Santos-Otero, RN, MPH, Maritza Cruz-Rodriguez, BA; Western New England Maternal Pediatric Adolescent AIDS: Katherine Luzuriaga, MD, Christina Hermos, MD, Jesica Pagano-Therrien, CPNP, Donna Picard BSN, RN, BC.

Disclaimer: The conclusions and opinions expressed in this article are those of the authors and do not necessarily reflect those of the National Institutes of Health or US Department of Health and Human Services or other funders.

Additional Contributions: We thank the children and families for their participation in the Pediatric HIV/AIDS Cohort Study (PHACS) and the individuals and institutions involved in the conduct of PHACS. We thank the children and families for their participation in International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1074 and the individuals and institutions involved in the conduct of IMPAACT P1074. For PHACS, data management services were provided by Frontier Science and Technology Research Foundation (principal investigator: Suzanne Siminski, MS, MBA), and regulatory services and logistical support were provided by Westat Inc (principal investigator: Julie Davidson, MSN). Simone Frank, BA, and Alex Bulteel, BA, assisted with manuscript preparation and Kenneth Freedberg, MD, MSc, and the Cost-effectiveness of Preventing AIDS Complications pediatric research team in the Medical Practice Evaluation Center at Massachusetts General Hospital provided feedback on study design and interpretation. Simone Frank, Alex Bulteel, and Kenneth Freedberg were compensated for their help.

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