The full spectrum of clinical manifestations of HIV-1 disease for children with perinatal infection is still being described [1,2]. It is estimated that 20–40% of HIV-1-infected children are at high risk for rapid disease progression and will develop AIDS or die within the first years of life [1,3,4]. The majority of children, however, manifest less severe symptoms, and many are surviving into adolescence and young adulthood [2,5,6].
While improvements in care, especially the introduction of potent antiretroviral therapies and prophylaxis against opportunistic infections, have contributed to this longevity [7,8], a number of other factors are thought to influence the rate of perinatal disease progression. Timing of perinatal transmission , genetic susceptibility [10,11], infant HIV RNA viral load [12–14], neonatal thymic function , exposure to perinatal zidovudine [16,17], and characteristics of the virus [18,19] have been independently associated with more rapid progression in children.
Maternal health status is also thought to influence the course of pediatric infection. Blanche et al.  described more rapid HIV-1 progression for infants born to mothers with advanced clinical disease, low CD4 cell counts and high levels of p24 antigenemia. Lambert et al.  correlated poor infant outcome with maternal AIDS, low CD4 cell count and high HIV-1 RNA viral burden. Similarly, Tovo et al.  linked pediatric risk of AIDS to the velocity of maternal disease progression and Chearskul et al.  recently identified advanced maternal disease as a predictor of infant progression for Thai children with HIV-1 infection.
We examined the influence of maternal characteristics upon the pattern of disease expression in a large multicenter cohort of 360 HIV-1 infected children. We also investigated the independent multivariate associations of year of birth, pediatric treatment pattern, maternal health characteristics, and infant outcome and studied whether early initiation of potent antiretroviral therapy independently affected the likelihood of rapid disease progression.
Between April 1986 and September 1998, women at risk for HIV-1 infection were enrolled in the Perinatal AIDS Collaborative Transmission Study (PACTS), a longitudinal prospective study of perinatal HIV-1 transmission and the natural history of pediatric HIV-1 disease. The study was conducted at health care centers in Newark, New Jersey, Baltimore, Maryland, Atlanta, Georgia, and New York City, New York and funded by the Centers for Disease Control and Prevention (CDC). Evaluations of women and infants were carried out at regular intervals during the period of observations and included questionnaires, medical record abstraction, disease staging and phlebotomy.
This study was reviewed and approved by Institutional Review Boards at each participating center and the CDC.
During the period of enrollment, 2656 HIV-1 positive mother–infant pairs were enrolled and 360 children were determined to be HIV-1 infected according to criteria established by the CDC in 1994 . Children were defined as having met a study endpoint if, within the first 24 months of life, they were diagnosed with a Category C illness or died secondary to HIV-1 infection prior to the onset of AIDS . Physicians at participating centers categorized all deaths, with the exception of a motor vehicle accident, as HIV-1-related. Presumed intrauterine infection was defined by a positive PCR or viral culture within 2 days of birth. Intrapartum infection was presumed if results were negative within this interval . Using historical and prospectively collected clinical data, women were categorized as meeting criteria for Class C disease as established by the CDC in 1992 .
Four treatment categories were established based on antiretroviral therapy received prior to 24 months of age or prior to an endpoint diagnosis. Therapy had to begin 30 days prior to the endpoint diagnosis to meet criteria for the category, thus allowing adequate treatment time for a therapeutic effect. The categories used were: no treatment; monotherapy with a single nucleoside reverse transcriptase inhibitor (NRTI); dual therapy with two NRTI; and treatment with three or more drugs including a protease inhibitor (PI) and/or non-nucleoside reverse transcriptase inhibitor (NNRTI). All but two children in the PI/NNRTI category received PI therapy. Once children were placed in a treatment category, they remained within this category continuously until they were treated with a more complex regimen.
Three time intervals were established to examine effect of birth year on outcome variables: 1986–1991; 1992–1994; 1995–1999. Time intervals were chosen to reflect epidemiologic and clinical advances likely to impact on study enrollment and medical management.
Maternal CD4 cell counts and HIV-1 RNA levels were included in the analysis if they were drawn within 90 days prior to delivery through 30 days postpartum. Prenatal samples closest to the time of delivery were selected preferentially over postpartum samples. Lymphocyte subsets were determined by flow cytometry on fresh whole blood samples. Results were available for 269 of 360 women (75%), 170 (63%) drawn at a median of 23 days prior to delivery and 99 (37%) drawn at a median of 4 days postpartum. DNA PCR results within the first 48 h of life were available for 109 (30%) of 360 infants.
Maternal plasma samples were stored and later tested with quantitative HIV-1 RNA assays. Results for 219 women, 102 (47%) drawn prior to delivery at a median of 19 days and 117 (53%) drawn postpartum at a median of 3 days, were included in this analysis. The majority of samples were tested using the NASBA HIV-1 RNA quantitation kit (Organon-Teknika, Durham, North Carolina, USA), lower limit of detection of 400 copies/ml.
An initial description of the cohort was performed by computing frequencies of AIDS or death separately for the first and second years of life, and for each maternal risk factor. Maternal CD4 cell count and maternal HIV-1 RNA were each divided into three categories.
To describe progression to AIDS or death within the first 2 years of life by maternal risk factors, Kaplan–Meier estimated survival functions were plotted for each factor level. For ease of interpreting the survival functions, time to AIDS or death was calculated in months. Extended medical record reviews were conducted for each child, so censoring before 2 years of age was caused by losses to follow-up rather than lack of follow-up time. Log-rank tests were used to determine whether observed differences in the estimated survival functions were statistically significant . Kaplan–Meier analyses were also performed by presumed timing of infection, infant gestational age, birth weight, Pneumocystis carinii pneumonia (PCP) prophylaxis to the infant, maternal hematologic parameters, country of origin, race, age, parity, syphilis during pregnancy, mode of delivery, history of stillbirths, chorioamnionitis, duration of ruptured membranes, tobacco, cocaine, heroin, and alcohol use during pregnancy, and perinatal zidovudine (ZDV) prophylaxis to mother and/or child to check for any significant associations with progression.
Kaplan–Meier estimates with 95% confidence intervals (CI) for the probability of AIDS or death before 2 years of age were calculated for each maternal risk factor by three birth year intervals: 1986–1991, 1992–1994, and 1995–1999.
Multivariate analysis of progression to AIDS or death was achieved by fitting a Cox proportional hazards model. The model was fit by maximizing the partial likelihood function. Tied survival times were handled using the Efron approximation method . All maternal factors from the initial analyses were considered for covariates in the model, as well as pediatric antiretroviral treatment, gestational age, birth weight, perinatal zidovudine prophylaxis to the mother and neonatally to the infant, infant PCP prophylaxis, and year of birth. The model was stratified by study site when significant differences between the sites could not be accounted for by the other covariates. Covariates were eliminated from the model if a partial likelihood ratio test was not significant at α = 0.05. Pediatric antiretroviral treatment was used as a time-dependent covariate because treatment regimens changed throughout the study period. This was accomplished by dividing the study period into 6-month intervals, and describing the treatment regimen separately within each interval to estimate the hazard function.
Once a final model was produced, the validity of the proportional hazards assumption was assessed for each covariate by computing a Wald chi-square test for the interaction of the covariate with log time . Hazard ratios and 95% CI were calculated for the final model.
Of 360 HIV-1-infected infants, 116 were diagnosed with AIDS and 13 died of HIV-1-related causes prior to an AIDS diagnosis in the first 2 years of life; 101 of these outcomes occurred during the first year of life (Table 1). Twenty-four children (6.7%) were lost to follow-up within 2 years of life at a median of 12.5 months.
The proportion of AIDS diagnoses and deaths occurring during the first 24 months of life was largest when maternal HIV-1 Class C disease was present, in the lowest category of maternal CD4 cell count (< 200 × 106/l), and in the highest category of maternal HIV-1 RNA (> 100 000 copies/ml) (Table 1). This proportional relationship for all three factors was similar in the first and second years of life, but was only statistically significant in the first year. This may be attributable to the higher number of outcomes in the first year. The proportion of children meeting endpoint in the first year was also significantly higher with a maternal history of injecting drug use (IDU). The proportion of children progressing was not significantly different for children with presumed intrauterine compared with presumed intrapartum infection (Table 1).
Children of mothers with Class C disease progressed to AIDS or death more rapidly than those born to women with less advanced disease, as demonstrated by the Kaplan–Meier survival curves stratified by maternal HIV-1 classification (P = 0.005) (Fig. 1a). This association between maternal Class C disease and infant disease progression became progressively stronger in later birth year intervals (Table 2).
The difference in estimated survival curves was also strongly significant for differing levels of maternal CD4 cell count (P = 0.003), with children born to women with CD4 cell counts < 200 × 106/l progressing much faster than children born to women with less evidence of immune suppression (Fig. 1b). This difference was relatively weak in the 1986–1991 birth year interval, but became more pronounced for children born after 1991(Table 2).
The influence of maternal HIV-1 RNA did not become apparent until after the first 5 months of life, when higher maternal HIV-1 RNA was associated with more rapid pediatric disease progression (P = 0.049) (Fig. 1c). The differences in Kaplan–Meier probability estimates by maternal HIV-1 RNA also became stronger in later birth year intervals (Table 2).
There was no significant difference in disease progression between infants with available maternal viral load results (n = 219) and those without (n = 141) (log-rank, P = 0.548). Availability of maternal viral loads was evenly distributed across levels of the other maternal risk factors, but those with missing values for maternal CD4 cell count, HIV-1 disease class, or IDU history tended to have unavailable viral loads.
Kaplan–Meier survival curves also revealed a significantly faster rate of disease progression for infants born to women with a history of IDU (P = 0.015) (Fig. 1d). This difference seemed to be strongest during 1986–1991, which was probably the result of higher enrollment of injecting drug users early in the study at several study sites (Table 2). Though a greater proportion of infants with presumed intrauterine infection progressed compared with those with presumed intrapartum infection during two of the time periods (Table 2), a log-rank test did not demonstrate a statistically significant difference (P = 0.285). Maternal zidovudine use during pregnancy did not appear to influence infant outcome (Table 2). Few women who transmitted HIV to their infants received dual NRTI, NNRTI or PI therapy.
PCP accounted for 39 of 116 (33%) AIDS-defining illnesses. Kaplan–Meier survival curves did not demonstrate a statistically significant difference in the rate of disease progression for children who began PCP prophylaxis within 6 months of birth compared with those untreated. To further explore the potential impact of PCP prophylaxis, Kaplan–Meier estimates were calculated for each maternal risk factor after excluding PCP diagnoses as a pediatric endpoint. The relationships between maternal CD4 cell count, HIV-1 RNA, Class C disease, history of IDU with progression to AIDS or death remained statistically significant. No additional variables examined using Kaplan–Meier analyses had a statistically significant association with infant outcome.
The final Cox proportional hazards model included maternal HIV-1 Class C disease, maternal HIV-1 RNA, infant year of birth, and pediatric antiretroviral therapy as predictors (Table 3). Using the time-dependent pediatric treatment covariate, the proportion of untreated infants decreased as the 6-month age interval increased, from 80.6% in months 0–6 to 34.6% in months 18–24 (Table 4). Similarly, the proportion of treated infants in the three antiretroviral categories increased as the children aged (Table 4).
Maternal CD4 cell subset count was not significant in the Cox model when maternal HIV-1 class and HIV-1 RNA were both included, indicating some overlap in the effect of these variables. Maternal history of IDU was not significant in the model when year of birth was included.
The model results indicated that the instantaneous risk of a child developing AIDS or dying from an HIV-1-related illness at any time point during the first 2 years of life was 1.7 times higher (95% CI, 1.05–2.7) when the mother had HIV-1 class C disease, adjusted for maternal viral load, pediatric treatment, and year of birth (Table 3). Similarly, the adjusted increase in instantaneous risk of a child meeting endpoint when the mother had HIV-1 RNA > 100 000 copies/ml was 2.4 times greater (95% CI, 1.2–4.6) compared with the mother having an HIV-1 RNA < 25 000 copies/ml. Children who received treatment with a PI were significantly less likely to progress to AIDS or death compared with those not receiving therapy (P = 0.03) when adjusted for the maternal disease factors and year of birth. Dual therapy also showed a protective effect, less so than PI treatment, but the finding was not statistically significant. Monotherapy with an NRTI monotherapy failed to have any demonstrable protective effect. There was also a significant decrease in risk of AIDS or HIV-1-related death for each 1-year increase in year of birth (P = 0.006).
The majority (71.3%) of AIDS diagnoses and deaths occurred in untreated children. Fewer than 6% of children receiving NRTI only, dual NRTI, or PI therapy during the 0–6 month age period met the endpoint compared with 19.7% of children not receiving treatment (Table 4). During the 6–12 and 12–18 month age intervals, respectively, similar proportions of children in the no treatment (15.1%, 8.6%), NRTI only (15.4%, 12.8%), and dual NRTI (13.8%, 9.4%) categories met the endpoint. In comparison, fewer than 4% of children treated with more complex antiretroviral regimens met the endpoint during these age intervals. Only five children developed AIDS or died during the 18–24-month age interval (Table 4).
This study investigated the association between maternal health factors and pediatric HIV-1 disease progression in a large cohort of children with perinatally acquired infection. Supporting the findings of two cohort studies, we demonstrated that children born to women with more advanced HIV disease, as measured by high HIV RNA, low CD4 cell counts and C category illness, were more likely to develop AIDS or die by 24 months of age compared to those born to healthier mothers [20,21]. In multivariate analyses, HIV RNA was found to be the strongest predictor of infant outcome: those born to women with HIV RNA > 100 000 copies/ml were 2.4 times as likely to progress as children born to women with levels < 25 000 copies/ml. These findings suggest that both clinical markers of more advanced maternal disease and higher viral loads are independently associated with more rapid disease progression among HIV-infected children.
Intuitively, one might expect that sicker mothers will have sicker babies. Several hypotheses can explain these findings. In women with advanced HIV disease, viral mutations escape normal host mediated cytotoxic lymphocyte (CTL) responses leading to inadequate control of viral replication. The same viral strains are probably transmitted to the infant who also inherits maternal immune response genes . The infected infant is at high risk to be a poor immunologic genetic match for the infecting virus resulting in rapid viral replication and subsequent disease progression. High levels of HIV RNA during the first months of life have been associated with rapid disease progression in children [12,13].
In addition to immunologic inadequacies, infants born to mothers with high viral burden and advanced disease may inherit more virulent viral strains. In several small studies, mother-to-child transmission was correlated with ‘rapid/high’ replication of HIV-1 in human cell lines, properties associated with a greater degree of pathogenicity [28,29]. Viral variants with increased growth capacity have been described in adults and children with rapidly progressive disease [30,31]. Therefore, intrinsic characteristics of the virus as well as host ability to provide protection may contribute to more rapid deterioration in children exposed to high levels of maternal HIV RNA. Also, infants born to women receiving antiretroviral therapy may inherit genotypically resistant virus which is less responsive to treatment. However, in an analysis by Palumbo et al. examining the relationship between antiretroviral resistance mutations and perinatal transmission in this cohort, there was no significant association between vertical transmission and the presence of NRTI-associated resistance mutations. Furthermore, resistance mutations were rarely detected in samples of infected neonates and the mutation patterns of the infant differed from those of their mothers .
Timing of mother-to-child transmission has been related to infant disease progression, with intrauterine infection conferring increased risk to the child . While a higher proportion of children with presumed intrauterine infection progressed compared to those with presumed intrapartum exposure, the relationship was not statistically significant. We were unable, however, to examine thoroughly how maternal factors affect this relationship due to a low percentage of children with early viral studies.
The large number of mother–infant pairs available for this analysis enabled us to examine each health factor independently as well as in multivariate analyses. We found that maternal CD4 cell count, while independently associated with infant outcome, was not predictive of disease progression when considered together with clinical status and viral load. This is probably a result of the overlapping clinical meaning of these health variables.
Given more than a decade of enrollment into this cohort, we were also able to consider temporal changes in care and treatment as they affected pediatric disease progression. Each 1-year increase in birth year conferred a significant decrease in the likelihood of developing AIDS or dying by 24 months of age. Several important changes in the care of women and children with HIV-1-infection occurred during the course of the study including the introduction of DNA PCR for early HIV diagnosis in infants , widespread use of prophylaxis against PCP , and the introduction of antiretroviral therapies, including powerful PI for treatment as well as perinatal prevention . We did not find a relationship between maternal zidovudine use and pediatric disease expression. Year of birth, which accounts for improvements in care for both women and children, appears to have the larger effect. This may reflect the relatively limited impact of zidovudine monotherapy on maternal health. Too few women received more complex antiretroviral regimens for them to be considered independently in this analysis.
While PCP was the most common AIDS-defining illness for children, there was not a statistically significant difference in the rate of disease progression for children receiving PCP prophylaxis during infancy compared with those who were untreated. Furthermore, when PCP was excluded as an AIDS-defining illness, clinical markers of more advanced maternal disease and higher maternal viral load remained independently associated with more rapid disease progression among HIV-infected children.
Our study examined the impact of antiretroviral therapy on disease progression during the first 2 years of life. Treatment with combination therapy with a PI significantly decreased the likelihood of rapid progression. It should be noted that PI were initially used for only the sickest children. Widespread use of these therapies in HIV-infected infants did not begin until enrollment of pregnant women into the study had ended. Despite limited use of these treatments in this cohort, when we looked at progression during 6-month age intervals by treatment regimen, we found that only 1 of 17 (5.9%) children met the endpoint during the first 6 months of life. Similarly, less than 4% of children thus treated during the other age intervals developed AIDS or died.
It is interesting to note that only three of 70 (4.2%) children less than 6 months of age who received any therapy progressed to endpoint. No children receiving dual NRTI treatment progressed. However, children receiving NRTI therapy in older age intervals had frequencies of disease progression similar to that of the no-treatment group. Furthermore, in multivariate analysis, treatment with dual NRTI therapy offered a modest protective effect, while monotherapy did not. Clinical trials comparing dual NRTI to monotherapy suggest these treatments impact on disease progression and are consistent with our findings that few infants receiving dual therapy progressed [36,37]. Nucleoside reverse transcriptase inhibitor treatment, particularly dual therapy, may have adequate efficacy during the early months after initiation. Over time, therapeutic effect probably wanes, resulting in less effective viral control and subsequent deterioration. It should be noted that dual NRTI therapy is no longer a routinely recommended treatment option for children. The low rate of events in the NRTI categories appears at least partially related to the widespread use of PCP prophylaxis. Fifty percent of the AIDS diagnoses during the first 6-month age interval across all treatment categories were attributed to PCP. Only 41% of children in the no-treatment group were prescribed prophylaxis compared with 86% of those receiving NRTI therapy.
This study has several limitations. Not all women had CD4 cell counts or samples available for HIV RNA studies. Also, only 1% of women with available samples enrolled in the study between 1986 and 1991 had HIV RNA values > 100 000 copies/ml. In light of the high rate of mother-to-child transmission during that period of study, we would expect more women to have had high levels of replicating virus. Viral degradation may have occurred during transport and/or long-term storage of samples. Non-differential misclassification of maternal HIV RNA level in the early years of the study would have resulted in a tendency to underestimate the true association with pediatric HIV disease progression . It is also noteworthy that while viral load degradation may explain why the association with infant outcome is weaker during the earliest years of the study, the same trend is seen for maternal CD4 cell count and clinical status, measures which were not affected by the passage of time.
This large prospective study of HIV-infected women and children further elaborates our understanding of the relationship between maternal health factors and pediatric disease manifestations. Advantages conferred by general advances in pediatric HIV care and the introduction of powerful antiretroviral therapies have significantly improved the prognosis for children with HIV-1 disease.
Sponsorship: Supported by cooperative agreements from the Centers for Disease Control and Prevention.
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Bronx Lebanon Hospital: S. Bakshi, M. Purswani, E. Stuard; Centers for Disease Control and Prevention: A. Bell, J. Ethier-Ives, L. Koenig, M. Glenn Fowler; Emory University School of Medicine: A. Nahmias, M. Sawyer, M. Lindsey; Harlem Hospital Center: S. Champion, J. Floyd, C. Freeland, P. Prince; Jacobi Hospital Center: J. Abadi, J. Dobroszycki, A. Harris, G. Lambert; Metropolitan Hospital Center: M. Bamji, L. Jackson; Medical and Health Research Association of New York City, Inc.: T. Alford, M. A. Chiasson, D. Thea, J. Weedon; Montefiore Medical Center: J. Aronson, M. Mayers, M. Naccarato, V. Nedwin, E. Schoenbaum; University of Medicine and Dentistry of New Jersey: A. Bardeguez, L. Bettica, T. Denny, J. Oleske; University of Maryland School of Medicine: L. Alger, J. Farley, P. Nair, S. Hines
The Center for Comprehensive Health Practice, Bellevue, Lincoln and Mount Sinai Hospitals in New York City participated in data collection during the period 1988–1994.
Keywords:© 2003 Lippincott Williams & Wilkins, Inc.
pediatric AIDS; vertical transmission; pediatric HIV disease; viral load; protease inhibitors; antiretroviral therapy