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The Diagnosis and Treatment of HIV-Infected Children in China: Challenges and Opportunities

Zhang, Fujie MD*; Au, Maria C MMS, MPH*; Bouey, Paul D PhD, MPH; Zhao, Yan MD*; Huang, Zhihuan Jennifer MB, PhD, MPH; Dou, Zhihui MS*; Li, Zaicun MD*; Haberer, Jessica MD, MS; Chen, Ray Y MD, MSPH; Yu, Lan MS*

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 1st, 2007 - Volume 44 - Issue 4 - p 429-434
doi: 10.1097/QAI.0b013e31803133ac
Clinical Science

Background: HIV-infected children in China have not been well studied. This national survey describes the demographic characteristics and the associated diagnostic and antiretroviral treatment (ART) efforts directed toward surviving HIV-infected children.

Methods: A cross-sectional study was conducted in the 6 provinces with the highest HIV prevalence: 4 former plasma donation (FPD) provinces and 2 intravenous drug use (IDU) provinces. A survey on demographics and treatment-related issues was distributed to the parents or guardians of all living HIV-infected children identified through the national case reporting system. Descriptive and bivariate analyses were performed on completed surveys.

Results: Six hundred ninety-two (62.4%) of the total 1108 surveys were returned, and 650 were eligible for analysis. The average age in FPD provinces (mean ± SD: 8.1 ± 3.2 years) was significantly older than in IDU provinces (mean ± SD: 5.4 ± 2.2 years; P < 0.001). The average lag time from the probable date of transmission to a diagnosis for patients with mother-to-child transmission (MTCT) was 6.7 ± 3.1 years in the FPD provinces and 4.7 ± 1.9 years in the IDU provinces (P < 0.001). On the basis of the CD4 cell count or World Health Organization staging, 29.8% (144 of 484) of children from all 6 provinces who were not on ART needed it.

Conclusions: This first national pediatric survey indicates that the age and time required for diagnosis were greater in HIV-infected children from FPD provinces compared with those from IDU provinces. In addition, this survey highlights the prolonged delay in the diagnosis and initiation of ART for children in China. Aggressive efforts to identify HIV-positive pregnant women, scale up prevention of MTCT activities, and expand early diagnosis and treatment are urgently needed.

HIV-1 was first reported in China in 1985.1 The prevalence remained extremely low until the early 1990s, when unsanitary blood and plasma selling flourished in Henan and other central provinces, such as Hubei, Anhui, and Shanxi, causing a large wave of HIV infection in this region.2,3 Since most blood selling practices ceased in 1996, the epidemic in the former plasma donation (FPD) region has been largely contained.3 By the early 2000s, however, increasing numbers of HIV-infected persons from the FPD region were developing AIDS. In response, the government implemented aggressive surveillance programs based on blood donation registries in the central provinces with a high prevalence of FPD. As a result of this effort, tens of thousands of patients were identified and brought into care.

In the late 1990s, a new phase of the HIV epidemic emerged among injection drug users (IDUs), particularly in the southern and western provinces, such as Yunnan, Guangxi, and Xinjiang. Case finding efforts in these provinces have largely relied on voluntary counseling and testing (VCT), resulting in many fewer HIV-infected individuals being identified. Some active surveillance has taken place in institutional settings, such as drug detention centers. In addition, in 2004, Yunnan province conducted an active screening campaign of known IDUs, pregnant women, and children <10 years old with HIV-positive mothers.4,5 These surveillance efforts are still inchoate, however, and the migratory nature, chaotic social circumstances, and stigma typical of the IDU population make case finding efforts challenging.

In recent years, the annual rate of increase in reported HIV infections across China has been around 30%, with a clear increase among IDUs.6-8 Currently, IDUs account for 44.3% of the total number of estimated cases, with a reported HIV prevalence male-to-female ratio of 8.4:1, whereas FPDs constitute 10.7% of all estimated cases, with a 1.3:1 male-to-female ratio.9,10 Mother-to-child transmission (MTCT) continues to rise, with an estimated increase from 0.1% in 1997 to 1.4% in 2005, most of which occurred in the IDU provinces.11,12 In 2005 alone, an estimated 9000 cases of MTCT have occurred.11 Despite this increase, little is known about the actual characteristics of this vulnerable pediatric population.

Although HIV-positive adults began receiving free antiretroviral treatment (ART) in China in 2003 through the national “Four Frees and One Care” policy, pediatric formulations did not become available until July 2005 through a donation from the Clinton Foundation HIV/AIDS Initiative. Children treated before this time used adult formulations, but the treatment needs of pediatric and adult patients differ significantly. A better understanding of the characteristics of HIV-infected pediatric patients is needed to create effective strategies for pediatric diagnosis, treatment, and rapid program expansion. This study provides an overview of the current HIV-infected pediatric population in China and evaluates differences in demographic characteristics and in diagnostic and treatment efforts between the predominantly FPD and IDU provinces.

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The Provincial Centers for Disease Control (PCDCs) have reported all known HIV cases to the National Communicable Disease System at the Chinese Center for Disease Control and Prevention (CCDC) since 1985. Cases must meet the HIV diagnostic criteria established by the CCDC to be included in the national count.3 Between 1985 and 2004, 1820 cases in children between the ages of 0 and 17 years were reported in this system. In October 2004, a nationwide survey was conducted by the National Center for AIDS/STD Prevention and Control (NCAIDS) and PCDCs on all living HIV-infected pediatric patients who were 0 to 17 years of age at the time of this survey. All 31 provinces and autonomous regions participated, and 1259 children were identified.13 The 6 highest prevalence provinces (Henan, Yunnan, Hubei, Anhui, Guangxi, and Shanxi), representing 88% (n = 1108) of the overall reported cases, were selected for the HIV Pediatric Baseline Survey. This subset of provinces was chosen because it constitutes the first sites of the national pediatric treatment program. From January 12, 2005 to May 25, 2005, 1108 surveys were distributed to the PCDCs of these 6 provinces. After obtaining informed consent, patients and guardians willing to participate were asked to complete the demographic information, with their health care provider completing the clinical components.

Demographic characteristics, including gender, date of birth, and province of residence, were examined. Age was calculated from the date of birth for each participant to March 15, 2005. In these analyses, provinces were divided into 2 categories depending on the predominant mode of HIV transmission in each province. In 2005, the central provinces of Henan, Hubei, Anhui, Hebei, and Shanxi accounted for 80.4% of all infections among the FPD population, whereas Yunnan, Guangxi, Guangdong, Guizhou, Sichuan, Hunan, and Xinjiang accounted for 89.5% of HIV/AIDS cases among IDUs.11 Based on these data and on the fact that at least 2 different epidemics caused HIV infection in these provinces, Henan, Hubei, Anhui, and Shanxi were categorized as FPD provinces, whereas Guangxi and Yunnan were categorized as IDU provinces.

The child's route of HIV transmission, mother's HIV status, and probable date of transmission were self-reported or reported by a guardian. The route of transmission was considered to be MTCT if a subject had a probable date of transmission between 9 months before and 24 months after the date of birth to capture antepartum, intrapartum, and postpartum (via breast-feeding) transmission.14 Reports have shown that more than 80% of all children in rural parts of China are breast-fed15 and that more than 11% are still breast-fed after the age of 2 years.16 The estimated lag time from transmission to diagnosis was calculated as the difference between the probable date of transmission and the date of confirmed HIV diagnosis by Western blot analysis.

Although the new 2005 World Health Organization (WHO) pediatric guideline is currently the “gold standard” for HIV pediatric care, the current treatment classification in China is determined by the Chinese National Free Antiretroviral Therapy Manual,17 which is based on the WHO 2004 pediatric guidelines.18 Therefore, treatment is warranted for children with a CD4 count of <500 cells/mm3 for children aged 1 to 5 years and for children with a CD count of <200 cells/mm3 for children older than 5 years of age, which corresponds to a CD4 cell count <15% or those with WHO pediatric stage III disease, irrespective of CD4 count. Individuals not on treatment but who need treatment or do not need treatment are defined as those who meet or do not meet, respectively, the previous CD4 cell count or WHO criteria. Those with missing data such that a treatment determination cannot be made are categorized as not sure/missing. Descriptive and bivariate analyses were performed with SAS 9.0 (SAS Institute, Cary, NC). Student t tests were used to provide the mean and SD for continuous variables, whereas χ2 and Fisher exact tests were used for categoric variables where appropriate.

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Of the 1108 surveys distributed to the 6 provinces, 692 (62.4%) were returned. Reasons for nonresponse to the survey included a guardian's unwillingness to participate, change of residence, patient deceased, or patient lost to follow-up. Of the 692 surveys received, 10 were excluded in all analyses because of missing date of birth, 6 because of missing date of diagnosis or confirmation, 4 because of date of diagnosis before 1.5 years of age, and 22 because of inconsistencies in their data. Overall, 650 surveys were included in the final analysis.

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Demographic Characteristics

The distribution of patients by province was dominated by Henan at 87.7%. Summary data from the Pediatric Baseline Survey (Table 1) demonstrate that boys accounted for 62.3% of the cases, consistent with the national adult HIV case reporting average of 61.0%.9 The average age was 7.9 years (mean ± SD: 7.9 ± 3.2 years). The average age for the FPD provinces was 2.7 years older than that for the IDU provinces (mean ± SD: 8.1 ± 3.2 years and 5.4 ± 2.2 years, respectively; P < 0.001).



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Transmission, Diagnosis, and Treatment

MTCT was the predominant mode of transmission in this study (Table 2), accounting for 75.5% of all cases, followed by blood products-related cases at 15.7%. Among the blood products-related cases, most (69.4%) children were infected between 1992 and 1996 when blood selling activities were most intense (data not shown). Overall, nearly 80% of pediatric cases were identified in surveillance sites rather than in hospitals or VCT clinics. Although the active surveillance site was the primary site for diagnosis in the FPD regions, VCT clinics constituted most (59.1%) of the case finding efforts in the IDU provinces. Time to diagnosis in all cases was less within the MTCT group (mean ± SD: 6.6 ± 3.1 years) than in the “others” group (mean ± SD: 8.1 ± 2.8 years), with time to diagnosis in the IDU provinces being less than in the FPD provinces (mean ± SD: 4.7 ± 1.9 years and 6.7 ± 3.1 years, respectively; P < 0.001).



Patients not on treatment were categorized according to their demonstrated need for treatment (Table 3). Among all cases, 29.8% met the treatment criteria, 46.5% did not, and 23.8% were unknown. A similar pattern was seen in the FPD group. In the IDU group, however, the unsure/missing category was dominant (79.5%), followed by do not need (14.7%) and need (5.9%) categories.



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This cross-sectional survey of the surviving pediatric HIV-infected cohort in China is the first national study of its kind and identifies several interesting and concerning characteristics. More than 90% of the known surviving HIV-infected children are in the FPD provinces and over 75% of all children were infected through maternal transmission, whether antepartum, peripartum, or breast-feeding. Most cases in FDP provinces were identified through active surveillance compared with identification through passive VCT clinics in the IDU provinces. Children were generally between 6 and 8 years old at the time of diagnosis. In addition, almost 30% of the children not currently on therapy met the treatment criteria for therapy. A follow-up survey should be conducted to assess the treatment situation now that a national pediatric ART program has been initiated. Data collected in conjunction with expansion of the national pediatric ART treatment programs should permit this type of work.

These data are heavily weighted toward the FPD population, because that cohort is where the most active surveillance in China has been done thus far. Despite this, several concerning trends are consistent across both populations. The first issue is that more than 75% of children were infected through maternal transmission. Despite the known benefits of maternal antiretroviral prophylaxis in pregnancy,19 only 1 mother of the 491 children infected by MTCT reported the use of ART during pregnancy (data not shown). Although the first prevention of mother-to-child transmission (PMTCT) program began in 2002 with single-dose nevirapine, MTCT rates continue to rise.8 This is partly attributable to the challenges and difficulties encountered in the coordinating efforts between the Maternal and Child Health Department (MCH) and the CDC system in linking such programs, in addition to the lack of consistent implementation of national policy at the provincial and county levels. The government recognizes this problem and is working to improve the collaboration between these 2 separate government entities and to expand PMTCT sites with the use of triple therapy and early diagnosis in high-risk pregnant women in various pilot programs.11 Additionally, the government is launching a family-centered HIV treatment and care pilot project (Family Care Pilot Project) in Guangxi this year, which should link services and comprehensive care to pregnant women and their partners for HIV screening, PMTCT with the use of triple therapy, and polymerase chain reaction (PCR)-based diagnostics for infants born to HIV-positive mothers.

The issue of early diagnosis of infants has also been of concern in China thus far. The findings of this survey highlight the overall prolonged delay in diagnosis and treatment of the entire pediatric population. Although no study has been conducted on the mortality rate of HIV-infected pediatric patients in China, data from many developing settings in Africa have shown that without ART, most HIV-infected children do not survive to the age of 5 years,20,21 with approximately half dying before the age of 2 years. Currently, the free HIV antibody testing available through the Chinese government only confirms the diagnosis of HIV after 18 months of age. It is plausible that a significant proportion of Chinese infants have already died without the benefit of HIV treatment by that time. HIV DNA testing is available only as a research tool, and HIV RNA testing remains too expensive to be used routinely, because families would have to bear this cost. The addition of these PCR-based diagnostics in the Family Care Pilot Project in Guangxi is a step forward; however, until these tests are much more widely available and affordable, the prolonged delay in diagnosis of children is not likely to be reduced significantly.

Once children are diagnosed as positive, entrance into care and possible treatment initiation are necessary. In this survey, almost 30% of children who met the treatment criteria were not currently receiving treatment. The reasons for this low rate of treatment are not clear from this cross-sectional survey but likely include a complicated mix of factors: the lack of appropriate pediatric formulations; patients previously treated but with treatment now discontinued because of intolerance, poor adherence, or treatment failure; a shortage of experienced health care professionals in pediatric HIV; and the absence of clear national policies for HIV-infected children at the time of the survey. The particularly high rate of unsure/missing treatment data for IDU cohort patients not on treatment argues strongly for the need for increased physician education and better dissemination of the national treatment guidelines. These circumstances are changing, however. National pediatric HIV training is currently underway, because the government plans to expand the pediatric ART program to include 500 children nationwide in 2006.

The differences identified between the FPD and IDU cohorts are reasonable, given our understanding of the epidemic in China. The FPD cohort being an older population quite possibly reflects the fact that HIV entered that population earlier. In addition, without ongoing infections in that cohort and families generally being limited to 1 child, few new infections are likely to occur to bring down the mean age. In contrast, the IDU cohort continues to have new infections, which is likely to lead to new pediatric infections through maternal transmission.11 The longer time to diagnosis in the FPD group may be a reflection of the age of the epidemic as well, with increased emphasis in recent years on testing and ongoing new infections in the IDU cohort.

One relatively subtle point of the survey that has significant ramifications in China is that almost 80% of HIV diagnoses were attributable to active surveillance rather than to passive VCT clinics or hospital admissions (see Table 2). Significant stigma against HIV still exists in China, with relatively few people getting tested voluntarily. The skewing of our data toward the FPD population may be attributable to the government's active surveillance in FPD regions rather than a true reflection of the pediatric epidemic in China. Although 60% of all IDU cases were found through passive VCT clinics in this survey, the small number of total cases identified through this passive method argues strongly for more active surveillance in the IDU population to increase case finding in the region, similar to the FPD region. Moreover, some evidence suggests that stigma and fear of testing may be lower in the FPD areas in comparison to the IDU areas because of the higher prevalence of HIV infection and less social marginalization of the infected population.22,23 The increasing incidence of infection in IDUs and other populations highlights the importance of PMTCT programs and the need to expand education, stigma reduction, and active surveillance to identify infected children, especially within this population.

Because this study is cross-sectional and relies on self-reported data, there are several limitations to be noted. First, a survival bias exists, because the population studied consisted of the slower progressing surviving pediatric cohort. This limitation, however, is a reflection of the reality of pediatric HIV diagnosis and treatment in China. Second, information was not available on the 567 nonresponding HIV-infected patients. A high level of social stigma regarding HIV continues to persist in China, which, in turn, may adversely affect respondents' willingness to complete the surveys. Although we cannot know for sure if there are differences between the responders and nonresponders, it is encouraging that the response rate was 62%. Third, although self- or guardian-reported information may have allowed for many inconsistencies in the data, most of our questions are based strictly on basic facts. Fourth, even though some information, such as laboratory data, was missing in many surveys, this does not affect the main points about how children were infected and the prolonged time to diagnosis. Finally, the smaller sample size and less intense case finding efforts in the IDU regions may make the findings for that cohort less generalizable. Given the large number of FPD participants in the survey and the intensity of surveillance conducted in those regions, however, these findings are most likely generalizable to other FPD regions. Despite these limitations, this study identified important and concerning trends in the current pediatric HIV situation in China.

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The results of this survey, particularly the route of infection, how children are diagnosed, the time to diagnosis, and the proportion of patients on treatment, are all important indicators from which the national treatment program can measure improvements in the health care delivery of HIV-infected children. The Chinese government is beginning to recognize these issues and is initiating pilot comprehensive PMTCT projects in response. Much work remains, however, and the national pediatric HIV treatment program must strengthen itself in several capacities. Analysis of these data has demonstrated the critical need to improve routine surveillance of children at risk and to incorporate early diagnostic testing methods. Additionally, educational programs are needed to support health care providers in diagnosing and treating pediatric HIV infection. Greater effort is needed to expand pediatric formulation and treatment availability and to enroll more children into ART programs. Most importantly, given the lack of a comprehensive PMTCT program in this country, a more aggressive approach to expanding the screening and treatment of pregnant women is needed to reduce the incidence of vertical transmission. The Chinese government has taken significant steps in recent years to control the overall HIV epidemic in China, with the goal now being to contain the overall infected population to less than 1.5 million by 2010.11 Comprehensive prevention and treatment of pediatric HIV infection are important components of this overall strategy and must move quickly beyond pilot programs to be scaled up nationally.

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China; diagnosis; highly active antiretroviral therapy; HIV; pediatrics

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