Survival of blood donors and their spouses with HIV-1 subtype E (CRF01 A_E) infection in northern Thailand, 1992–2007
Nelson, Kenrad Ea; Costello, Carolineb,d; Suriyanon, Vinaic; Sennun, Supalukc; Duerr, Annb,e
From the aJohns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA
bCenters for Disease Control and Prevention, Atlanta, Georgia, USA
cResearch Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand
dCurrent addresses: UCLA School of Public Health, Los Angeles, California, USA
eHIV Vaccine Trials Center, Fred Hutchinson Cancer Center, University of Washington, Seattle, Washington, USA.
Correspondence to Kenrad E. Nelson, Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, 615N. Wolfe Street, Baltimore, Maryland 21205, USA. E-mail: firstname.lastname@example.org
Objectives: To evaluate the survival patterns among adults in Thailand 8–14 years after HIV-1 subtype E (CRF01 A_E) infection.
Design: Follow-up for the current vital status of adults who were estimated to have had incident HIV-1 subtype E infection 8–14 years previously.
Methods: Data on the survival of a population of HIV-1-infected male blood donors and their seropositive wives was obtained during March–April 2007. These subjects were identified from a subpopulation of 150 individuals whose seroconversion interval was estimated to be less than 2 years and who were enrolled in 1992–1997. National registration, vital records, and death certificates, as appropriate, were obtained and Kaplan–Meier survival curves were constructed for the entire population, for males and females, and for individuals above and equal to or below the median age at infection.
Results: The vital status was obtained for 138 of 150 subjects (92%). The overall median survival was 8.2 [95% confidence interval (CI) 7.1–9.4] years. The median survival did not differ significantly between men and women or in those above or below the median age.
Conclusion: The median survival of 8.2 years in this population of young adults in Thailand was significantly less than that reported among persons of similar age in high-income countries or in eastern or southern Africa. The survival among individuals in Thailand infected with HIV-1 subtype E appears to be similar to that reported among individuals in Africa infected with HIV-1 subtype D.
AIDS is a major cause of mortality in developing countries in sub-Saharan Africa and Asia . Nevertheless, data on the rate of progression and the length of survival after infection among HIV-infected individuals in these regions are sparse. Accurate information on the natural history of HIV in low to medium-income country populations has become increasingly important recently. Such data would be useful for estimating the number of infected people needing treatment and for measuring the effectiveness of antiretroviral therapy and other interventions in preventing or delaying progression and mortality.
The rate of progression after HIV infection has been reported from several populations in east and southern Africa [2–12]. Not all of the African studies used regular follow-up intervals or enhanced subject tracing to avoid loss to follow-up, and a few have included cases for which a precisely documented seroconversion interval was not available. Nevertheless, such studies are useful to estimate the rate of progression after infection among African populations in low to middle-income countries. In general, the rate of progression after infection in these African individuals appears to be similar or somewhat more rapid than carefully studied cohorts in high-income countries [3,5,7]. Several studies have, however, reported more rapid progression associated with infection with HIV-1 genotype D than genotype A viruses in Africa [4,12–15].
Even fewer data are available from HIV-infected populations in Asia. In contrast with the estimated rates of progression in African populations, however, the data reported from southeastern Asian populations suggest that the rate of progression to AIDS and death has been more rapid among Asian populations than among those in high-income countries and Africa [16–18]. In this paper we report data on survival 8–14 years after HIV infection among male blood donors and their wives in Chiang Mai, Thailand.
In this study we contacted men who were found to be HIV positive when they were screened between 1989 and 1997 as possible blood donors at the blood banks of the Thai Red Cross, the Chiang Mai University hospital or the Lampang Provincial hospital in northern Thailand. If the men were married and their female spouse agreed to be screened for HIV and counseled at the study site at Chiang Mai University, the couple was offered enrollment after the study was explained and they gave their informed consent.
During this period approximately 25 000 individuals donated blood at one of these sites each year, around 80% of whom were men. The Thai Red Cross only accepted volunteer donors and the Chiang Mai University only accepted volunteer or replacement donors after 1992. The first positive blood donors were detected in 1989 . Screening at the government sexually transmitted disease clinic began in 1988; however, the first positive tests were reported among female sex workers in July 1988 (C. Natpratan, personal communication). On the basis of these data, we assumed that a significant risk of HIV-1 infection among blood donors existed after January 1989.
The blood banks in Chiang Mai identified 4594 HIV-1-positive male donors between 1989 and 1997 . When we attempted to contact these men and invite them to return to the blood bank for notification and counseling, approximately 50% responded and returned. When interviewed, approximately 40% of the men who returned were married. We enrolled a total of 633 men and their wives, i.e. 1266 subjects, in our couples study to evaluate the heterosexual transmission of HIV-1 (Fig. 1). There were no differences in the age, place of residence or other demographic factors between those men who enrolled in the study and those who did not. Couples were excluded if the woman had a history of another possible HIV exposure in addition to sex with her HIV-positive husband. After the initial interview, we excluded 34 couples from enrollment because the women reported other HIV-1 risk factors, i.e. a history of having had other sex partners, injection drug use or a blood transfusion. The subjects were interviewed separately by same-sex interviewers and two follow-up interviews after their enrollment, and subsequently at 6, 12 and 18 months. In addition to a standard HIV risk factor questionnaire detailing sexual, parenteral and medical history, the women were administered a detailed month by month contraceptive and sexual history for the past 5 years in order to evaluate the possible role of hormonal contraceptives as a risk factor for HIV-1 transmission. During these interviews, an additional 13 women were identified who had a history of sex with men other than their HIV-1-positive husband. These couples were also excluded from the study, which together with the 34 couples excluded earlier meant that a total of 47 couples from the original population were excluded.
The study was approved by the institutional review boards of the Bloomberg School of Public Health of Johns Hopkins University, the Centers for Disease Control and Prevention in the United States and the Research Institute for Health Sciences of Chiang Mai University. The enrollment began in 1992 and was completed in 1997, at which time 590 couples had been enrolled. At baseline, 276 (46.8%) of the female partners were HIV positive. The HIV-negative women were followed at 6-month intervals for 18 months after enrollment.
First follow-up survival survey (1999)
We used an HIV-1 envelope peptide enzyme immunoassay to determine the subtype of virus that had infected the 866 HIV-positive subjects . Thailand has had two circulating viruses with narrow genetic diversity, a subtype E and B virus since early in the epidemic . Since 839 (96.9%) of the subjects were seroreactive with subtype E (CRF01 A_E) viruses, survival analyses were limited to the subjects who were found to be infected with this viral subtype. Between March 1998 and December 1999 the vital status and dates of death in those who had died since enrollment were obtained by contacting the subjects, their next of kin, and care providers, and surveying government vital records and death certificates. Follow-up data on their vital status were obtained from 96.7% (811/839) of the subjects at that time. The 28 subjects who were lost to follow-up were censored at the time of their last contact. Most had been seen on several occasions before being lost to follow-up.
We have published the results of a survival analysis after infection from the subjects included in the first follow-up in 1999 . We were able to estimate the time of HIV seroconversion with a 2-year window for 150 subjects. Precisely documented seroconversion intervals were obtained for men with an HIV-negative followed by an HIV-positive blood donation, which was less than 2 years apart (n = 21) and wives who were found to seroconvert after enrollment in the study (n = 12). Credible estimates of similarly narrow seroconversion intervals were obtained for the following additional categories: wives who were HIV positive at baseline and had sexual contact with their husband for 2 years or less and no other HIV risk exposure (n = 46); men who donated HIV-positive blood in 1989–1990, less than 2 years after the onset of the heterosexual HIV-1 epidemic in Thailand (n = 71). We used the midpoint of these estimated seroconversion intervals as the infection date, and the starting point for exposure to risk of dying in this cohort. When similar criteria were used with a 3-year window period to estimate the date of seroconversion, a total of 255 subjects, 164 men and 91 women, could be identified.
Second survival survey (2007)
Another follow-up of the population was performed in March–April 2007. During this follow-up, the vital status of subjects was traced using government population registries and death certificates to identify the deceased since the first follow-up. This follow-up successfully obtained the vital status and the death certificates of 138 (92%)of the original 150 individuals in the seroconverter population. Subjects who died from non-HIV-related causes were included in the survival analysis, with their survival censored at the date of their death. Follow-up of the cohort was censored on 31 December 2004 because of the wider availability of HAART after that date.
Analysis time for all subjects was left truncated at the date of the positive test. The survival by sex and age was evaluated for the cohort of 150, with the 12 who were lost to follow-up right censored at the time of their last contact. We analysed the survival by age at seroconversion using those above and below the median age at which they seroconverted, i.e. 24 years. We used Kaplan–Meier curves to estimate the median survival time after infection. Differences in survival after infection between groups were evaluated using the log-rank test.
At the time of enrollment between 1992 and 1997, 46% of the women were HIV-1 positive . The median age was 29 years (range 18–56) for men and 26 years (range 15–52) for women. Most subjects were asymptomatic and all were antiretroviral naive at enrollment. None of the men were aware of their HIV-positive status at the time of their blood donation. The women were also unaware of their own and their husband's status at enrollment. Although 24% of the study subjects with an estimated 2 or 3-year seroconversion window had CD4 cell counts less than 200 cells/μl at enrollment (Table 1), these data included donors who were found to be HIV positive very early in the epidemic, i.e. 1989–1999. These men had been infected for several years before their enrollment in the study.
At the first follow-up in 1999, 49.4% of the men and 25.7% of the women had died. In 1999 we evaluated the survival after infection among 150 subjects with an estimated less than 2-year seroconversion window period. In this group, 75% had survived 5.8 years (95% CI 5.2–6.3) and the 50% survival was estimated to be 7.8 years (95% CI 7.0–9.1).
Between February and April 2007 we attempted to determine the status of the 150 subjects with an estimated less than 2-year seroconversion window. We successfully followed 138 (92%) of this cohort and 12 (8%) were lost to follow-up. At the time of this second follow-up, 16 (17.4%) of the men and 16 (27.6%) of the women were still alive. The 12 who were lost to follow-up were censored at the time of their last follow-up and included in the survival analysis. The median survival in this cohort was 8.2 (95% CI 7.1–9.4) years (Fig. 2, Table 2). The median survival in the 255 individuals with an estimated less than 3-year seroconversion window was 7.2 (95% CI 6.5–8.5) years (Table 2).
The median survival among women was somewhat longer (9.6 years; 95% CI 6.2–12.0) than among men (7.8 years; 95% CI 6.9–9.1). This difference was not, however, significant. The median survival among younger subjects at the time of their estimated seroconversion was longer than that of older subjects among both men and women, although this difference was not significant. Among 76 subjects who were 24 years of age or less when they were estimated to have seroconverted the median survival was 8.2 (95% 7.2–12.0) years compared with a median survival of 7.8 (95% CI 6.1–9.4) years among those older than 24 years when they seroconverted. The Kaplan–Meier survival curves by age and sex are shown in Figure 3.
The 75% and median survival for the three groups of subjects comprising the population of 150 with an estimated survival of less than 2 years were analysed separately from the entire group. Among the 33 subjects with an HIV-negative test followed by a positive test less than 2 years later, 11 of the 21 men in this group and three of the 12 women had died. Among the 21 men, the 75% survival was 6.0 (95% CI 5.5–9.1) years and the median survival was 9.1 (95% CI 6.4–unbounded) years. Among the 12 women the 75% survival was 6.0 (95% CI 4.5–unbounded) years.
Among the 71 men with an HIV-positive blood donation within 2 years of the onset of the Thai epidemic, the 75% survival was 5.6 (95% CI 5.2–6.5) years and the median survival was 7.8 (95% CI 6.7–9.1) years. Among the 46 women with probable sexual transmission of HIV within the 2 years before their known seropositivity, the 75% survival was 5.4 (95% CI 4.6–6.3) years and the median survival was 8.1 (95% CI 6.2–11.7) years. Although survival did not differ significantly by seroconversion interval, median survival was somewhat longer for those with a seroconversion interval of less than 2 years (Table 3). The Kaplan–Meier survival curves for the 150 individuals with a seroconversion interval of less than 2 years by their method of enrollment are shown in Figure 4.
Equation (Uncited)Image Tools
Our data suggest that the survival after HIV-1 subtype E (CRF01 A_E) viruses among young adults in Thailand is shorter than has been reported from similar aged cohorts in high-income countries in the CASCADE study . The median survival among HIV-1-positive individuals 25–34 years of age in the CASCADE cohorts was 11.0 (95% CI 10.6–11.3) years. The estimated median survival in our cohort was similar to that reported among two other cohorts of seroconverters from Thailand [16,17] Among 21–23-year-old men who seroconverted while in the Royal Thai Army, the median survival was 7.8 (95% CI 7.3–8.5) years [16,24]. A follow-up study of female sex workers in Chiang Rai, Thailand, found the time to 25% mortality to be 6 years, which was similar to the rate of early disease progression among the Royal Thai Army conscripts  and the blood donors and their wives , but more rapid than reported in the CASCADE cohorts from high-income countries, who reached 25% mortality in approximately 8.0 years .
Equation (Uncited)Image Tools
In contrast to these survival data among individuals infected with HIV-1 subtype E (CRF01 A_E) viruses in Thailand, several follow-up studies of populations in low and middle-income countries in Africa have reported survival rates after HIV-1 infection to be similar to those reported among the CASCADE population from high-income countries [3,5–8,10,11]. Survival between populations in different cohorts can be difficult to evaluate unless the age differences between cohorts are taken into account. Nevertheless, the difference in survival between the Thai and African cohorts increased when adjusted for age . In addition, several investigators have reported that individuals infected with HIV-1 subtype D viruses in African low-income countries have progressed more rapidly than those infected with subtype A viruses [4,12–15].
Equation (Uncited)Image Tools
The viral load among individuals infected with HIV-1 subtype E during the first 18 months after infection has been reported to be significantly higher than among individuals in Thailand infected with subtype B viruses . In addition, one study found higher rates of heterosexual transmission of subtype E viruses than subtype B viruses in Thailand . It is possible that the higher viral load early after infection with subtype E viruses could be responsible for both the higher rates of sexual transmission and more rapid progression [24,25–27].
Aside from the possibility that HIV-1 subtype E viruses are associated with increased virulence, other explanations for the more rapid progression of HIV-1 infections in Thailand are possible. Chronic infection with other pathogens, such as tuberculosis, hepatitis B or C, herpes simplex virus 2 or other agents has been reported to accelerate the progression of HIV infection. These chronic infections are, however, also quite common in middle and low-income countries in Africa and some HIV-infected populations in high-income countries.
The progression of HIV-1 infection has been found to be affected by host genetic constitution, including human leukocyte antigen (HLA) alleles, co-receptors on CD4 positive cells and other host genetic factors . A number of HLA alleles have been found to be associated with HIV disease course; HLA B27, B57 and B58 have been associated with slower disease progression, whereas B18 and B35 have been associated with faster progression [28–30]. The small differences in the frequency of these HLA haplotypes between western and Thai populations do not appear to explain the decreased survival rates seen [31,32]. Heterozygosity for the CCR5 delta 32 mutation has been associated with decreased disease progression in Caucasian populations but is not present among Thai individuals. This mutation is also absent among African populations, however, so its absence in Thai populations is unlikely to explain the lower survival in Thai compared with African individuals. No genetic hypothesis or data published to date in populations in northern Thailand and those in the United States or eastern or southern Africa, explain the differences in the progression of HIV-1 infection. Another consideration is that the virulence of HIV-1 attenuates over time as it circulates in a human population. As the epidemic in Thailand had developed recently, in comparison with that in Africa, when the subjects in our study were enrolled, subjects in Thailand and Africa were studied at different stages of the epidemic. The data reported from the CASCADE collaboration found no evidence that the natural history of HIV-1 has changed over time .
Our study has several limitations. We were able to estimate the time of seroconversion with a less than 2-year window in 150 individuals and obtain follow-up survival data on 138 subjects 8–14 years after their estimated seroconversion. The seroconversion window period was, however, documented by a transition from a negative to a positive HIV serological test in only 33 of those individuals. Among the 21 male blood donors who had documented seroconversion, the median survival was slightly longer than the remainder of the group; however, the differences were not statistically significant. The 12 women who seroconverted after enrollment were followed for a shorter time. Approximately half of this cohort with a less than 2-year window were male blood donors who were HIV-1 positive within 1–2 years of the start of the heterosexual epidemic in Thailand. The time of the onset of the epidemic in Thailand has been quite well documented . We cannot exclude the possibility, however, that uncertainty about the time of seroconversion among those who were not documented to be seronegative and then seropositive within 2 years might have led to an underestimation of the survival time.
Indigenous transmission of HIV-1 began among injection drug users in Bangkok in 1988 . The epidemic in injection drug users was followed soon after by a heterosexually transmitted epidemic. Screening of female sex workers and sexually transmitted disease clinic patients began in Chiang Mai in 1988, and the first HIV-1-seropositive individuals were found in mid-1988. Blood donors were first found to be HIV-1 positive in Chiang Mai in 1989, after which the epidemic in northern Thailand spread rapidly. Before 1988–1989 HIV infections were detected only sporadically, despite the systematic screening of some high-risk populations . Therefore, we believe our estimate that blood donors who tested positive in 1989–1990 were infected within the previous 2 years is reasonable. In order for the median survival to be approximately 11 years after infection, as reported in the CASCADE cohort, these blood donors would had to have acquired their HIV infection in the early 1980s. We believe this to be very unlikely.
The other group in the less than 2-year window cohort were 46 HIV-positive women. They were each interviewed on multiple occasions for their contraceptive calendar and sexual behavior, because we were interested in exploring the association between hormonal contraceptives and sexual HIV acquisition in these women. During these interviews we excluded 47 couples from the study, based upon information that the women had other possible HIV risk histories. Nevertheless, despite these detailed in-depth interviews we cannot be certain that sex with their HIV-infected husband was the reason for their infection in every case. We believe it is the likely source of the infection for most, if not all, of these women.
The study population of blood donors was generally healthy at the time they donated. Soon after the generalized HIV-1 epidemic was recognized in Thailand, first among injection drug users and subsequently among sex workers and sexually transmitted disease patients in Thailand, all government clinics and many private anonymous clinics offered HIV testing. None of the HIV-positive donors in our study donated blood in order to receive the results of an HIV test, nor had any had a previous HIV-positive test. In the first few years of the epidemic notification of test results and counseling of HIV-positive donors was not routinely carried out, so this would not have been a motive for donating blood.
Our study has several strengths. We were able to identify a cohort of asymptomatic HIV-infected individuals early in a rapidly expanding epidemic and follow them for up to 14 years. We could estimate the time of HIV infection with a less than 2-year window in 150 individuals and with less than 3 years in 255 subjects.
Our follow-up of the less than 2-year window cohort was successful in 138 (92%) of the subjects. This is one of the few long-term follow-up studies of HIV-1 subtype E-infected cohorts in Asia. Our data suggest that the median survival is significantly shorter than has been reported among several cohorts from low to medium-income countries in Africa and higher income countries in Europe and North America, but may be similar to that seen after subtype D infections in Africa.
Conflicts of interest: None.
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HIV natural history; low/middle-income countries; survival; Thailand
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