The natural history of HIV-1 subtype E infection in young men in Thailand with up to 14 years of follow-up
Rangsin, Rama; Piyaraj, Phunlerdb; Sirisanthana, Thirac; Sirisopana, Narongridd; Short, Onsric; Nelson, Kenrad Ee
From the aDepartments of Community and Military Medicine, Thailand
bParasitology, Phramongkutklao College of Medicine, Bangkok, Thailand
cResearch Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand
dArmed Forces Institute of Medical Sciences, The Royal Thai Army, Bangkok, Thailand
eDepartment of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA.
Correspondence to Ram Rangsin, Department of Military and Community Medicine, Phramongkutklao College of Medicine, 315 Ratchavithi Road, Ratchathewee, Bangkok 10400, Thailand. E-mail: firstname.lastname@example.org
Objective: We evaluated the progression to AIDS and death among 228 men who seroconverted within a 6-month window when in the Royal Thai Army between 1991 and 1995.
Design and methods: Men (N = 228) who seroconverted to HIV at 21–23 years of age between 1991 and 1995 were evaluated up to 14 years after HIV seroconversion. The seroconverters were matched with men who were seronegative when they were discharged from the military. In 2005–2006, the vital status was determined through the national mortality database and survivors were contacted for follow-up clinical and immunological assessment. Death certificates, medical records and next of kin interviews were used to evaluate the causes of death.
Results: As of March 2006, among 228 seroconverters, 56 (24.6%) were alive, 171 (75.0%) had died and one (0.4%) had undetermined status. Among 255 HIV-seronegative individuals at baseline, 15 (5.9%) had died. The median time from HIV seroconversion to death was 7.8 years. The median time to AIDS death was 8.4 years. The median times from seroconversion to clinical AIDS and a CD4 cell count less than 200 cells/μl were 7.2 years and 6.5 years, respectively. The median time from seroconversion to World Health Organization criteria for antiretroviral therapy was 6.3 years.
Conclusion: Our data indicate a more rapid progression to AIDS and death after HIV-1 infection among young Thai men than has been reported in similar aged men who were HAART-naive in western high income countries.
AIDS is a major public health problem in Thailand . Knowledge of the natural history and survival after HIV-1 infection among various populations is crucial in order to estimate the extent of the epidemic, the number of individuals who need treatment and to evaluate interventions. Also, a more complete knowledge of the pattern of disease progression will facilitate a better understanding of the interaction between the human host, the virus, and other factors related to the pathogenesis of the disease. Populations with known dates of seroconversion and successful long-term follow-up are essential to understand the natural history of HIV-1.
Knowledge of the rate of disease progression after HIV-1 infection is still incomplete in low and middle income countries. Several studies of sub-Saharan African populations have reported that the progression is not significantly different from that in high income countries . The rate of disease progression is not homogenous in all African populations, because there is evidence of more rapid progression among individuals infected with different subtypes. Individuals infected with HIV-1 subtype D have been reported to progress more rapidly than those infected with subtype A [3–5].
Another reason for the conflicting reports on the rate of disease progression may be the insufficient length of follow-up of some cohorts in low and middle income countries. Some studies report the results of survival after only 3–7 years. The estimate of the median time to death from such short follow-up times may be imprecise. A few cohorts in low and middle income countries, including our study, have long observation periods and a high rate of follow-up from which it is possible to make a more precise estimate of the natural history.
In Thailand, the major HIV-1 virus that is circulating is subtype E (CRF01 A_E) [6–11]. We have evaluated disease progression among a population of seroconverters identified in 1991–1995 among male military conscripts in the Royal Thai Army. This group of HIV-1-infected young men with a documented date of infection within a 6-month window between a seronegative and their first seropositive test has been followed successfully for up to 14 years. The information regarding the natural history of HIV-1 infection from these seroconverters will supplement the knowledge of HIV-1 disease progression from low and middle income countries before the wide availability of combined effective antiretroviral therapy (ART).
A retrospective cohort study was conducted among former military conscripts. In 1997, we identified 249 men who had seroconverted when they were in the Royal Thai Army between 1991 and 1995 [6,12] and lived in provinces with at least five seroconverters. These men were identified from studies of seven cohorts of military conscripts who had been enrolled in HIV incidence studies. The men were HIV-1 seronegative when they were inducted into the military but seroconverted during their 2 years of military service. Most men had been tested at 6 month intervals [6–9]. During the first follow-up survey, 14 men had been enrolled into the study and were found to be HIV-1 negative. The total number of HIV-1 seroconverters in the previous round of follow-up was 235 men (Fig. 1). The seropositive men were matched by the date of induction and district of residence with men who had been seronegative on discharge from the military. The seronegative men were selected in order to maintain the confidentiality of the seropositive men, to provide clinical and laboratory data for comparison with the seropositive men, and to estimate non-AIDS mortality in the population. Our study had two follow-up surveys. The first survey was from November 1998 to September 1999 and the second survey was from July 2005 to March 2006. Eligible participants were contacted, based on their last known address provided by the district Veterans' Affairs Office. All of the seroconverters and their matched seronegative controls were invited to participate in the first survey. During the second survey only the seroconverters who survived up to the first survey and their matched seronegative controls were invited to participate. Individuals who were located and were willing to participate were given an appointment to report to a nearby district hospital where they were evaluated for their clinical signs and symptoms, virological and immunological status, antiretroviral treatment or prophylaxis of opportunistic infections and behavioral characteristics. The vital status of all of the original subjects in the study was determined by contacting the subjects, their families or official records.
Men who gave informed consent to participate had a physical examination, phlebotomy, and interview for demographic factors and a risk behavior history. Structured questions regarding HIV-associated symptoms (e.g. fever, night sweats, unexplained weight loss, etc.) along with any medical conditions that required treatment since discharge, were asked of all volunteers. The latter formed the basis for a medical record review. Blood specimen collection, interviews and physical examinations from both HIV-1 seroconverters and men who had been seronegative at military discharge were performed by study personnel who were blinded to the men's HIV-1 serostatus. Blood was processed within 24 h of collection and was analysed in the laboratory of the Research Institute for Health Sciences at Chiang Mai University or the Armed Forces Institute of Medical Sciences in Bangkok, depending on the enrollment site. For those who died, their next of kin were interviewed using a standard form modified from INDEPTH DSS Standard Verbal Autopsy Instruments  to collect information regarding their symptoms in order to determine their primary and underlying causes of death. Death certificates and medical records were obtained and reviewed.
Laboratory tests for the 1998–1999 follow-up included HIV antibody testing by enzyme-linked immunosorbent assay (ELISA; Organon Teknika, Durham, North Carolina, USA) with Western blot confirmation of ELISA-positive sera (Diagnostics Biotechnology, Singapore, for Research Institute for Health Sciences; New LAV-Blot1; Sanofi Diagnostics Pasteur, France, for Armed Forces Institute of Medical Sciences); for the 2005/2006 follow-up; HIV antibody testing by the IMx System (IMx System HIV-1/HIV-2 III Plus; Abbott Laboratories, Abbott Park, Illinois, USA) and ELISA-GPA (Serodia-HIV1; Fujirebio Inc., Tokyo, Japan) with Western blot confirmation of ELISA-positive sera (HIV Blot 2.2; Genelabs Diagnostics, Singapore); complete blood count included an automated count of 10 000 white blood cells, and CD4 cell count determined by flow cytometry. Serotyping with an HIV-1 V3 loop peptide enzyme immunoassay designed to differentiate HIV-1 subtype E and B viruses  was performed on the sera collected after HIV-1 seroconversion.
Medical conditions review
Information regarding the medical condition of both the seroconverters and the seronegative participants was obtained by reviewing medical (hospital and autopsy) records or death certificates. Physical examination was completed and self-reported histories of medical conditions were collected from survivors who attended the follow-up clinics. Clinical information about symptomatic HIV infections and AIDS-related events was extracted from the medical records and categorized according to the clinical criteria used in the 1993 Thai AIDS case definition, which is a modification of the 1993 Center for Disease Control and Prevention AIDS definition  that includes Penicillium maneffei infection as an AIDS-defining illness.
Analyses were performed using Stata for Windows version 9.2 (Stata Corp., College Station, Texas, USA). The date of seroconversion of the HIV-1-positive cases was defined as the midpoint between the date of the last negative and the first positive HIV-1 ELISA.
In order to estimate the time to death from all causes, the primary endpoint in this analysis was death. We searched the National Registration Database System and the Central Population Database of the Ministry of the Interior in October 1999 and January 2006. Those who were reported to be alive after the second follow-up were right-censored on 1 June 2005. The HIV-1 seroconverters who received HAART were right-censored on the starting date of the treatment. The three men who were seronegative at discharge from the military but later had an HIV infection and died from AIDS were right-censored on the date of their death.
To estimate the time to clinical AIDS, the endpoint was the first clinical AIDS diagnosis. Those who had information indicating that they had clinical AIDS from the medical records or relative interviews were right-censored on the date of their first diagnosis. Among those who died from AIDS without any clinical information before their death, the dates of AIDS diagnosis were imputed using the median time between AIDS onset and death from those with a known date of AIDS onset. Those who died from other causes were right-censored on the dates of death. Those who were alive and enrolled into either the first or the second follow-up visit or both and did not have a history of AIDS were right-censored as AIDS-free one year after their last visit. Those who were alive but did not enroll into the study were right-censored on 1 June 2005.
To estimate the time to a CD4 cell count less than 200 cells/μl, the endpoint was the first CD4 cell count less than 200 cells/μl. For those who had CD4 cell counts either when they were seen at the follow-up visits or recorded in their medical record, the dates on which the threshold of a CD4 cell count less than 200 cells/μl was passed was computed using the rate of CD4 cell decline in those with multiple counts on the assumption that the CD4 cell decline is approximately linear after an initial steep decline. Among those who died from AIDS without any CD4 cell count information before their deaths, the dates of a CD4 cell count less than 200 cells/μl were imputed using the median time between the onset of a CD4 cell count less than 200 cells/μl and death from those who had the date of a CD4 cell count less than 200 cells/μl recorded. Those who were alive and enrolled into either the first or the second follow-up visit and did not have a history of a CD4 cell count less than 200 cells/μl were right-censored as event-free one year after their last visit. Those who were alive but were not seen in the follow-up study were right-censored on 1 June 2005.
In order to estimate the time from seroconversion to the WHO criteria for ART, we gathered the available information from medical record reviews, physical examinations and the CD4 cell count at the follow-up survey to assess whether the subjects reached this endpoint, that is WHO stage IV, WHO stage III with CD4 cell counts less than 350 cells/μl, or CD4 cell counts less than 200 cells/μl irrespective of clinical stage. The same imputation methods and censoring strategies used in the clinical AIDS and CD4 cell count less than 200 cells/μl endpoints were used for this estimation.
Survival analysis was evaluated using the Kaplan–Meier method. Overall survival estimates and 95% confidence intervals (CI) were calculated for the seroconverters and seronegative men.
This research was reviewed and approved by the Institutional Review Boards of the Thailand Ministry of Public Health, the Royal Thai Army Medical Department, and the Chiang Mai University Research Institute for Health Sciences.
The baseline information of the HIV-1 seroconverters has been reported for the first follow-up survey in 1998–1999, 5–7 years after seroconversion . In brief, 99% of the seroconversions occurred when the men were between 21 and 23 years of age and 96% of them occurred during 1991–1993. Approximately 80% of the seroconverters had resided in the upper northern region of Thailand before their military service; 97.8% were infected with subtype E (CRF01_AE), and four (2.2%) were infected with subtype B. The viral stubype was determined by genotype-specific peptide ELISA of available serum samples from 185 men. This assay has been found to have high specificity in classifying HIV-1 subtype E viruses in Thailand .
Of 235 seroconverters, 171 men (72.8%) had died and 63 men (26.8%) were alive at the time of the 2005/2006 follow-up. We could not determine the vital status of one man (0.4%). Among 63 men who were alive, 51 were evaluated in the second follow-up survey with an interview, examination and blood test. We found that seven of these men had a negative HIV-1 enzyme immunoassay. These seven men who did not participate in the first follow-up survey in 1998–1999 were then excluded from the survival analysis. Therefore, the final number of seroconverters in our analysis is 228. Among 255 seronegative subjects, 237 (92.9%) were alive, and 15 (5.9%) had died. We could not identify the vital status of three of them (1.7%; Table 1, Fig. 1).
Among the 228 seroconverters, death certificates were obtained for 168 of the 171 men who had died (98.2%). After evaluating the probable causes of death using information from death certificates, medical records and relative interviews, 142 men (83.0%) were judged to meet the clinical criteria of AIDS as the primary cause of death. The other causes of death included suicide (4%), motor vehicle accident (2.9%), heart failure (2.3%), cancer (1.8%), drowning (1.2%), drug overdose (0.6%) and other conditions (2.3%). Three deaths (1.8%) could not be evaluated because we could not obtain either a medical record or a relative interview. Among the HIV-1-seronegative controls, we found that four men had seroconverted before the first follow-up and five men seroconverted before the second follow-up survey. There were 15 deaths among the 255 seronegative men. The cause of death included motor vehicle accident (33.3%), AIDS (20%), suicide (13.3%), respiratory failure (13.3%), cancer (13.3%), and electrical shock (6.7%). The seroconverters provided 1841.0 person-years of exposure, whereas the seronegative men provided 2839.6 person-years of exposure. The mortality rate among seroconverters and HIV-1-negative men were 91.2 and 4.2 deaths per 1000 person-years (after excluding three AIDS deaths from the group who were seronegative at discharge), respectively. The rate ratio of deaths between HIV-1 seroconverters and seronegative men was 22.0 (95% CI 12.3–43.4).
Figure 2 shows the Kaplan–Meier survival curve of deaths for all causes after HIV-1 infection for seroconverters and since the last HIV-1-negative test during military service for the seronegative men. The median time from seroconversion to death by all causes was 7.8 years (95% CI 7.3–8.5). When only deaths directly caused by AIDS were considered, the median time to AIDS death was 8.4 years (95% CI 7.5–9.1).
Overall, 43 seroconverters were enrolled and completed physical and laboratory evaluations at the second follow-up. Seventeen men were asymptomatic and three men had clinical AIDS. The other 23 were symptomatic but did not have AIDS. Twenty men had CD4 cell counts less than 200 cells/μl, and 23 had CD4 counts of 200 cells/μl or greater.
The median time from seroconversion to clinical AIDS was 7.2 years (95% CI 6.6–8.0). The median time since seroconversion to a CD4 cell count less than 200 cells/μl was 6.5 years (95% CI 6.2–7.0). The median time from seroconversion to reach the WHO criteria for ART was 6.3 years (95% CI 5.9–6.8).
HIV-1-RNA levels at the second follow-up ranged from less than 400 copies/ml to more than 750 000 copies/ml. Mean and median HIV-1-RNA values were 94 691 (5.0 log) and 12 923 (4.1 log) copies/ml, respectively, for those with detectable HIV-1 RNA.
At the first follow-up, two subjects had received ART (zidovudine monotherapy) and two subjects had received Pneumocystis carinii pneumonia prophylaxis. At the second follow-up, 16 subjects had received ART (combination ART) and 46 subjects had received Pneumocystis carinii pneumonia prophylaxis.
Among the 35 men who were still alive and had either clinical AIDS or CD4 cell counts less than 200 cells/μl, 16 had received HAART in the form of GPO-vir (fixed-dose combinations of stavudine/lamivudine/nevirapine). Most of those who had received HAART began treatment in 2004–2005. All subjects who were alive and were receiving HAART had undetectable HIV-1-RNA levels. The remaining HIV-infected subjects who were not receiving treatment at the time of the second survey were referred to hospitals to participate in the National Access to Antiretroviral Programs for People living with HIV/AIDS. The National Access to Antiretroviral Programs for People living with HIV/AIDS is a Thai governmental programme that provides free antiretroviral drugs to all HIV-1-infected patients who need treatment.
We report the natural history of HIV-1 subtype E (CRF01 A_E) infection among 228 Thai men who seroconverted at age 20–23 after to 12–14 years of follow-up. We were successful in determining the vital status of all but one (0.4%) of the 228 seroconverters at the time of the second follow-up. As the number of seroconverters was relatively large and the study population was homogenous in terms of sex and age at seroconversion, the survival estimates from our study are relatively precise. One limitation of our study is that we only have data on young adult men, however, so the rates of progression of HIV-1 in women or older individuals in Thailand can not be determined from our data. The seroconverters were identified within a 6-month interval. The median survival from all causes of death was 7.8 years (95% CI 7.3–8.5) and the median time to AIDS death was 8.4 years (95% CI 7.5–9.1). The median survival after seroconversion in our Thai cohort was significantly shorter than that reported by the CASCADE study, a meta-analysis of 13 030 HIV seroconverters from 38 cohorts in high income countries. The median survival after seroconversion in the CASCADE study for subjects 15–24 years of age was 12.5 years (95% CI 12.1–12.9) . We found that the median time from seroconversion to clinical AIDS in young Thai men was 7.2 years (95% CI 6.6–8.0), whereas it was 11.0 years (95% CI 6.6–8.1) among subjects 15–24 years of age in the CASCADE study.
The median survival among Thai men in our study is very similar to that reported in another study of HIV-1 subtype E (CRF01 A_E)-infected individuals among blood donors and their spouses in Thailand. That study, in which the follow-up period was 14 years after infection, reported that the median survival time after seroconversion was 8.2 years (95% CI 7.1–9.4) . In addition, a few other studies from low and middle income countries have reported a more rapid progression of HIV-1 and shorter survival than populations in high income countries [17–21]. Another study of HIV-1 among female commercial sex workers in northern Thailand found a survival rate similar to our military cohort after 5–7 years of follow-up . Several studies from sub-Saharan Africa [22–24], however, reported that the disease progression after HIV-1 infection was very similar to that reported from high income countries before the widespread use of HAART. The differences in disease progression among various populations may be the result of differences in the host, the viruses, or the environment. In addition to host differences between individuals in Thailand and sub-Saharan Africa, the viruses circulating in Thailand and sub-Saharan Africa are different. In Thailand the majority of HIV-1 infections are caused by HIV-1 subtype E (CRF01 A_E), whereas several other subtypes are circulating in sub-Saharan Africa, including subtypes A, C, D, G, and other circulating recombinant forms [25–27]. Subtype E is, however, very uncommon in Africa.
Different HIV-1 subtypes may be associated with different rates of disease progression. Several studies from sub-Saharan Africa have reported that individuals infected with subtype A have slower disease progression than those infected with subtype D [3,4,28] or A/D recombinant viruses. In Thailand, where subtype E (CRF01 A_E) has been the predominant subtype of HIV-1 infection, each of the three follow-up studies after seroconversion have reported more rapid progression and shorter median survival than have been reported from high income countries [14,16,19].
The seroconverters in our study had a relatively high viral load in the first year after their infection. The mean and median HIV-1-RNA levels were 74 397 (4.9 log) and 31 906 (4.6 log) copies/ml, respectively, among 65 HIV-1 seroconverters in the first 6–12 months after seroconversion. Hu et al.  found that the viral loads in seroconverters in Thailand who were infected with subtype E (CRF01 A_E) were higher in the first 6–18 months after infection than in Thai individuals infected with subtype B viruses. This suggests the possibility that HIV subtype E strains may be more virulent than subtype B viruses.
The immunological status of the host might also be a factor in the rate of progression to AIDS and death after HIV-1 infection. In our first follow-up we found that the CD4 cell counts among HIV-1-negative Thai men were relatively low (mean 764 cells/μl) . These CD4 cell counts are significantly lower than HIV-negative homosexual men enrolled in the MACS cohort in the United States . Other investigators have also found lower CD4 cell counts in HIV-negative healthy adult male populations in Thailand than have been reported from similar populations in the United States . Individuals with lower baseline CD4 cell counts before HIV-1 infection might progress more rapidly to a CD4 cell count less than 200 cells/μl and clinical AIDS.
Methodological issues, such as selection bias and censoring methods could explain some of the differences reported in survival after HIV infection in various populations. Seroconverters in our study were identified within a 6-month interval. The median interval between the last seronegative and the first HIV-1 test in the seroconverters was only 31.1 weeks. Therefore, our study is more likely to include fast progressors in the study than those with wider seroconversion intervals and significant rates of out migration . Furthermore, follow-up for 12–14 years for survival in our study was over 99% complete. Different censoring strategies could lead to different estimates of progression and survival times. We analysed our data using different censuring strategies reported by van Benthem et al.  and found very similar survival and progression rates with the different methods. When participants with no known AIDS diagnosis were censored at the date of their last visit, the median time to clinical AIDS was 7.14 years (95% CI 6.5–7.8). When participants with no known AIDS diagnosis were censored as AIDS-free at the date of analysis, the median time to AIDS was 7.16 years (95% CI 6.6–8.0).
Our study found 14 men in the first round of follow-up and seven men in the second round who had negative HIV-1 serological tests. These discrepant antibody test results from the data obtained when the men were in the military and our follow-up results led us to re-evaluate the clerical and testing procedures when these seroconverters were initially identified. This review suggested that the reason for these discrepant data was most likely due to clerical errors or problems in specimen handling or labelling at baseline. Most of these men had only one reported positive serological result on their last semi-annual test before they left the military. In contrast, nearly all of the confirmed positive men, who were followed as true seroconverters, had more than one HIV-1-positive enzyme immunoassay with Western blot confirmation. Therefore we are confident that our final cohort of 228 seroconverters were all HIV-1 infected.
In conclusion, our data indicate a more rapid progression to AIDS and death after HIV-1 seroconversion among ART-naive young Thai men than that reported among similar aged men who were HAART-naive in high income countries.
The authors thank Col Pochaman Watcharapichat, Col Thippawan Chuenchitra, Msg Vanchat Rungruangroj, Msg Bungearn Indhontri, Msg Naluapon Kuttasingkee, Sg Kamonwan Songprasong, Sg Kiatisak Somsri, Lt Col Kunakorn Kana, and Wanlaya Lapwech from the Armed Forces Research Institute of Medical Sciences (Bangkok, Thailand) for help with the laboratory and field studies. They also thank Sriprapa U-ngern, Wichai Inchum, Nakorn Pariwatsakulchai, Songkran Waiyo, Cholticha Ruangyuttigarn, Rassamee Keawvichit, and Kittipong Rungruengthanakit from the Research Institute for Health Sciences (Chiang Mai, Thailand) for help with the laboratory and field studies. They also thank Antika Wongthanee for help with the data management, Dr Lauri E. Markowitz, Dr Joseph Chiu, Dr Chirasak Khamboonruang, Dr Sakol Eiumtrakul, Col Arthur E. Brown, Dr Merlin Robb, Dr Chris Beyrer, and Dr Surinda Kawichai for help with the planning and the implementation of the first follow-up survey. The authors also thank Dr Milly Marston and the ALPHA network for help with Stata analysis and methodology.
Sponsorship: This study was supported by the Office of AIDS Research, the National Institutes of Health, USA, and the Thailand Research Fund. P.P. was partly supported by the AIDS International Research Training Grant from the Fogarty International Center of the National Institutes of Health to Johns Hopkins University.
Conflicts of interest: None.
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