Introduction
The epidemic of HIV-1 infection in China is growing increasingly serious. By the end of 2007, there were an estimated 700 000 cases in China. Among HIV risk behaviors, intravenous drug use accounts for the most of total infections, or 44.3%, while infection through sexual contact accounts for 19.6% and infection from past commercial blood sales represents 10.7% [
1]. Patients infected through the commercial sale of blood in China, specifically former plasma donors (FPDs), represent a unique patient population compared to those infected through sexual contact or intravenous drug use in other countries in that the majority of these patients were infected during a relatively narrow time period. The first HIV infection among FPDs was reported in 1994, and the epidemiological survey subsequently conducted in villages in Henan, Shanxi, Anhui, Shandong, and Hubei provinces revealed that the HIV prevalence rate among FPDs was 0.2%-56.1% [
2-
5]. While extensive studies conducted in Europe, North America, and Africa on the natural history of HIV infection have established definitive baselines on the progression of infections transmitted via intravenous drug use and heterosexual and homosexual contact, HIV research and its control and prevention initiatives are relatively recent in China, however. Whether the FPD population’s unique mode of transmission has any impact on the natural history of HIV infection remains unknown.
Previous studies on the natural history of infected patients in China were mostly based on the analysis of small samples, which did not adequately reflect the overall status of this population [
6,
7]. Herein, we have conducted a natural history study based on 5484 HIV-1 infected FPDs in China. We believe this is the first large-scale retrospective study on FPDs and represents more closely the natural progression of infected patients to AIDS in this unique population.
Materials and methods
Study population
Patients were identified and selected through a national epidemiological database which is part of the national surveillance system used by the China Center for Disease Control and Prevention (CDC). Since the China CDC National Surveillance System was built up in 2002, the database of these patients from 1995 to 2003 was empty. Included in this database are demographics, route of infection, date and method of diagnosis, date of treatment, and date of death. All samples studied in this work were collected from Zhumadian city and Shangcai county in Henan province. Shangcai was one of the most severely affected counties during the illegal blood selling and collection practices of the 1990s. The majority of patients currently living were infected during the same period that serves as an important reference for our natural history study. A total of 5484 patients were included in this study. None of the patients was involved in other known risk behaviors such as intravenous drug use, or sexual contact, nor had any of the subjects received antiretroviral therapy. The final time point in the study was Oct 1, 2006, and survival curves represented survival up until this date.
In 1994, the first case infected through unsafe blood selling was discovered [
2]. The commercial plasma donation practices leading to large-scale HIV infection occurred during 1994-1996, with peak activity around 1995. In 1996, the “Regulations on the Management of Blood Products” were implemented to combat illegal blood collection and supply by prohibiting and closing illegal blood collection centers, consequently halting the spread of HIV infection [
8]. We had records for each one as to when they donated. The mean time of commercial plasma donation of the 5484 patients was years (1995±1.2).
Statistical analysis
Kaplan-Meier analysis was used to estimate the distribution pattern of the survival period from the time of HIV infection to the onset of AIDS, and from the onset of AIDS to the time of death. For natural progression from HIV infection to the development of AIDS, confirmation of AIDS serves as the endpoint event. The time elapsed between the date of HIV infection and AIDS diagnosis was considered as the phase of asymptomatic AIDS (in years). For untreated survival time, AIDS-associated mortality served as the endpoint event. The time elapsed between the dates of AIDS diagnosis and of death was considered the patient survival duration (in months). SPSS 13.0 software was used for statistical analysis.
Results
Demographic characteristics of the FPDs cohort
A total of 5484 HIV-1 infected individuals were included in this study, all of whom came from the Shangcai county in Henan province. The majority of the patients (5118/5484, 93.3%) fell within the age range of 25 to 55. Approximately 87.2% (4782/5484) of the patients were married at the time of study. Their education levels were quite limited, with 2536 (46.2%) having graduated from primary school and 2143 (39.1%) from junior high school. Only 13 (0.2%) finished senior high school, and 778 (14.2%) were completely illiterate. An overwhelming proportion of the patients were farmers (5442/5484, 99.2%) and belonged to the Han ethnic majority (5472/5484, 99.8%). Of the 5484 enrolled, 4691 patients had received highly active antiretroviral therapy (HAART) after progression to AIDS and remained living at the end of the study in 2006, and the remaining 793 patients died from AIDS complications, including 312 who died before receiving HAART. The diagnosis of AIDS was based on the national standards described in the “Guidelines for Diagnosis and Treatment of HIV/AIDS in China (2005)” of the People’s Republic of China (CD4+ count<200/mm3 or upon diagnosis with any AIDS-associated opportunistic infections).
Kaplan-Meier analysis of asymptomatic phase and time to death after onset of symptoms
Based on Kaplan-Meier analysis of 5484 patients over an 11-year period, the cumulative probability of developing AIDS between years 1 and 5 was 0.00 to 0.02; between years 6 and 8, 0.045 to 0.38; and between years 9 and 11, 0.96 to 0.99. The estimated median asymptomatic period for this population was about 9.21 years (Fig. 1; Table 1).
The survival rate from the onset of AIDS symptoms to death was also estimated for the 312 AIDS patients who did not receive antiretroviral (ARV) treatment. The cumulative survival rate between months 0 and 4 following the onset of AIDS ranged from 1.00 to 0.60; between months 4 and 12, it ranged from 0.60 to 0.27; and between months 12 and 24, it ranged from 0.27 to 0.06. All symptomatic patients who did not receive ART died within 48 months after the onset of AIDS. The estimated median survival duration for AIDS patients was about 9.91 months (Fig. 2; Tables 2 and 3).
Discussion
Infected FPDs in China represent a unique patient population, composed mostly of young, married farmers with low education and income levels and stable places of residence. The large majority of these patients were infected during the same period, from 1994 through 1996, with no newly identified infected HIV+ patients. The FPDs cohort is distinct from other HIV-infected populations in Europe, North America, Africa and Southeast Asia, whose sources of infection were largely due to sexual transmission and intravenous drug use. Globally, there is no similarly infected HIV-1 population on the same scale. Our current study represents the first large-scale study on the natural history of infected FPD patients in China.
The natural progression to symptomatic AIDS differs for infected populations across various geographic locations and routes of transmission. Studies conducted among homosexual populations in Holland, the United States, Australia, and Canada revealed that the median period of asymptomatic infection was 8.3 years [
9]. For intravenous drug users in Edinburgh, United Kingdom, who were infected between 1983 and 1985, the median asymptomatic period was 11.6 years [
10]. The United Nations AIDS Scheme (UNAIDS) reported that the median period of asymptomatic infection for HIV-infected individuals who did not receive antiviral treatment in developing countries was 9.5 years [
11]. Our findings showed that the median asymptomatic phase in Chinese FPDs was about 9.21 years (95% CI: 8.96-9.04), which is similar to figures reported in developing countries in Africa. In this study, the FPDs were infected around 1995, which might underestimate the actual median period of asymptomatic infection since some of the patients may have been infected prior to 1994. In addition, this study excluded about 212 individuals who had not progressed AIDS when the study was closed. Our estimates, therefore, represented the natural history of typical progressors.
Our finding of a 9.21-year median asymptomatic phase duration in FPDs closely matches the natural history of AIDS progression observed in developing countries as described in the UNAIDS report. However, the cumulative incidence in the first 8 years is lower than that noted in the UNAIDS report for the same period, while cumulative incidence in the 9th and 10th years is higher. These observed differences may be due to the lack of relevant epidemiological data prior to 2003. No records were found for HIV-infected individuals who died of AIDS complications during that period, consequently leading to the low cumulative incidence in the first 8 years and the considerably elevated incidence in the 9th and 10th years after 2003.
The cumulative death rate in the first, second, and third year after onset of AIDS in adult patients in African developing countries was 25%, 95%, and 100%, respectively, with the mean survival duration following the onset of AIDS being 16.3 months. Our study revealed the following results: the death rate was 73.4% in the first year, much higher than that reported in the UNAIDS study; the mean survival duration after the onset of AIDS was 9.91 months, much shorter than the UNAIDS result; and the time to death after the onset of AIDS was a half year earlier, close to the 9.3 months reported elsewhere for populations in developing countries in Africa [
11]. Possible explanations for the shorter mean survival duration after the onset of AIDS include: (1) The administration of HAART (76.22% of AIDS patients had already been treated) confers non-natural disease progression. This is unlikely to be the case for our study since those on antiretroviral therapy were excluded from the current study. Thus, the population was limited to untreated deaths and is not representative of all AIDS-associated mortalities; and (2) Due to the study site’s rural setting, healthcare resources for diagnosis and treatment were limited. In general, patients had little awareness of medical care, and many had already entered late-stage AIDS by the time they first sought treatment and were recorded for the national HIV general survey. Consequently, the study found a considerably elevated mortality rate after the onset of symptoms.
In summary, our current study constitutes the first large-scale research on the natural history of HIV-1 infected FPDs in China. Our study has, for the first time, estimated a median asymptomatic phase (of about 9.21 years) and a median life span after the onset of symptoms (of about 9.91 months) for this population. However, our study has certain limitations. Some of the HIV-infected individuals had died before they were identified and included in this cohort study, which may lead to underestimation of median life span after the onset of symptoms. Nevertheless, our research on China’s HIV-1 infected FPDs should serve as an important reference for patient management and care of this significant HIV-positive population.
Higher Education Press and Springer-Verlag Berlin Heidelberg
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