Although information on the duration of the period from infection with HIV to the onset of AIDS [1–15], continues to be updated [16–25], the current estimates of HIV progression, based largely on individuals infected in the 1980s, may become less relevant to individuals infected more recently. Whereas many HIV-infected persons are now known to remain AIDS-free for over 10 years, data about the rate of progression to AIDS during the first 2–3 years after infection remain limited due to few individuals under follow-up during this initial period.
Results from a number of clinical trials suggest that the introduction of combinations of antiretroviral drugs and of prophylaxis specific to some AIDS-defining opportunistic infections may have played a part in lengthening the incubation time to AIDS, improving survival and changing the profile of AIDS-defining conditions over time [26–28]. The interpretation of estimates of the incubation period over time has been further complicated by changes in the AIDS case definition.
Although a number of studies suggest that age at infection has a major influence on progression rate [5,13,16,19,29–36], the mode of acquiring HIV infection may also influence progression independently of age [37–38]. Few studies, however, include individuals from more than one exposure group.
As the demand for information to assist health-care planning, in terms of changes in HIV progression rates, has intensified, a national register of HIV seroconverters was set up in the UK in October 1994. This is a register, with continuing recruitment, of HIV-infected persons with a history of a negative HIV antibody test within 3 years of the first positive antibody test who are then followed up on an annual basis. Details of the methodology of data collection and follow-up for the Register have already been reported elsewhere . Its main objective is to monitor the variability in the incubation period over time and to evaluate factors which may influence it. This report provides the first analyses from this cohort identified retrospectively and prospectively.
A seroconverter was defined as an HIV-positive individual aged 16 years or over with a history of a negative HIV antibody test within 3 years of the first positive test. The date of seroconversion is estimated as the midpoint between the last negative and first positive test dates. Persons identified during the acute infection stage, namely when infection has occurred but before full seroconversion, are also included in the study, in the absence of a negative result; strictly defined laboratory evidence for acute infection is required .
Clinicians from genito-urinary medicine, infectious disease and other specialities from centres in the UK taking part in the Medical Research Council (MRC) clinical trials in HIV infection were invited to participate by providing information on patients who meet the definition of a seroconverter. Additionally, clinicians from centres not taking part in the MRC trials but which had reported a total of 10 or more AIDS cases to the Public Health Laboratory Service AIDS Centre at the Communicable Disease Surveillance Centre (CDSC - in England and Wales, including reports sent from the Department of Health and Social Services for Northern Ireland) or the Scottish Centre for Infection and Environmental Health (SCIEH – in Scotland) were also invited to participate.
Laboratory directors and medical microbiologists were also contacted by letter and telephone and asked to participate by helping to identify eligible subjects. These include National Health Service, public health and private laboratories, as well as regional blood transfusion centres.
Of 142 clinical centres and 136 laboratories contacted, 131 (92%) and 103 (76%), respectively, have agreed to participate, representing 91% of AIDS case reports and 97% of HIV infection reports in the UK.
To date, one annual follow-up of individuals reported to the Register has been completed through the clinical centres and a second follow-up initiated. This provided information up to August 1996 on enrolled seroconverters. Information on patients lost to follow-up through the clinical centre was sought by cross-checking with the national AIDS surveillance databases at CDSC and SCIEH. This was done confidentially through the use of the Soundex code (an alphanumeric code, based on the patient's surname, consisting of a letter followed by three digits) and date of birth. Cross-checks were also made against CD4 surveillance data (reported to CDSC and SCIEH directly from immunology laboratories) and data available from the ‘Survey of Prevalent HIV Infections that are Diagnosed’ (SOPHID) at CDSC . Further matching was done against records of deaths in persons aged 16–55 years in 1993 and 1994 in England and Wales through the Office for National Statistics (ONS), the central registry for birth, marriage, and death in England and Wales.
The criteria for identifying seroconverters from each centre were carefully documented as these have implications for the statistical analysis. For example, it was important to know whether an individual's inclusion was potentially dependent on their vital status, i.e., whether individuals were more likely to be included if they were alive and attending the clinic at a particular point in time. Complete ascertainment of all eligible seroconverters was sought (including those who had died, transferred to other centres or become lost to follow-up). Seroconverters from centres where this was possible enter the ‘risk set’ for analysis at the estimated date of seroconversion. If complete ascertainment was not possible, seroconverters from such centres were treated as ‘late entry’ subjects to avoid bias , entering the risk set at (h–date of seroconversion), where h is the date from which ascertainment is considered to be complete at that centre. For example, in a clinic in which only the records of persons attending from 1 January 1990 were available, a person who seroconverted on 1 January 1987 enters the ‘risk set’, at 3 years (1 January 1990 1 – January 1987) because their inclusion in the dataset was dependent on survival until January 1990.
For each seroconverter we also documented how we first became aware of their eligibility to be included on the Register, whether this was through the laboratory performing the HIV tests or through the clinical centre. We reasoned that laboratory data, independent of whether or not the attender is asymptomatic or whether they continue to be seen at that clinic, may be less subject to bias towards the preferential inclusion of persons who progressed rapidly, to those who seroconverted more recently, or to those still attending at their original clinical centre.
Non-parametric estimates of time from HIV serocon-version to AIDS and to death are given by Kaplan-Meier estimates, allowing for late entry. The association of the following variables with these times were tested using log-rank methods and in Cox proportional hazards models: sex (M or F); exposure category [homosexual/bisexual men, injecting drug users (IDU), other]; age (years) at seroconversion; year of serocon-version (1983–1994); how identified (through the clinic, through the laboratory); HIV test interval (months), the time between the last negative and first positive test dates (within the same month, 1 month or more). The year of seroconversion was estimated as the midpoint between the last negative and first positive antibody test dates unless a date was available indicating laboratory evidence of acute infection, in which case the midpoint between that date and the first positive antibody test date was used. Seroconverters identified through both the clinic and the laboratory are included under ‘laboratory’ as this method of ascertainment was thought a priori to be less prone to bias.
The data presented are for subjects with a documented negative antibody test or documented acute infection (i.e., subjects for whom a previous negative test could not be verified by the time the analysis was carried out are excluded) and reported to the Register between October 1994–January 1997. Follow-up was censored at 31 December 1994, with those reported without AIDS earlier than this date assumed to be alive and AIDS-free at 31 December 1994. The rationale for this is that, of AIDS cases reported to CDSC and SCIEH, 95% are estimated to be reported within 24 months of AIDS diagnosis (A.R. Brady, personal communication, 1997). As the matching against the CDSC and SCIEH databases (both estimated to be 87% complete) was done in December 1996, we assumed that if AIDS had been diagnosed in seroconverters on the Register by December 1994 these would have probably been reported by then.
For the analysis of time to AIDS, attenders who died without an AIDS diagnosis were censored at the date of death. The US Centers for Disease Control and Prevention (CDC) and World Health Organization AIDS case definition was used and expanded on 1 January 1993 to include three clinical manifestations that were included in the 1993 CDC definition: invasive cervical carcinoma, recurrent pneumonia in a 12-month period, and pulmonary tuberculosis [42,43].
Between October 1994 and January 1997, 1588 sero-converters were reported to the Register. For 555 of these we have so far not been able to verify a previous negative antibody test, leaving 1033 documented sero-converters, of whom 961 were included in the analyses censored at 31 December 1994 (i.e., 72 persons seroconverted after that date). For 432 of these (45%) follow-up was included from seroconversion, and 529 were analysed as ‘late entry’ subjects entering the risk set between 14 days and 11.1 years following serocon-version.
Of the 961 in the analysis 847 (88%) were male, 727 of whom were infected through sex between men. The median age at seroconversion overall was 28 years (range, 16–70 years), with homosexual and bisexual men (median age, 29 years) being generally older than IDU (median age, 23 years; Table 1). For 558 persons (58%) seroconversion was estimated to within ± 6 months (49 of whom within the same calendar month), for 260 persons the interval between the last negative and first positive antibody tests was 13–24 months, and for 143 this interval was 25–36 months. The presence of a seroconversion illness was not always documented, with 158 reporting an illness, 335 reporting no illness, and with no information for 468. We therefore did not include the presence of a seroconversion illness as a cofactor in the analysis.
Five hundred and eighty-one seroconverters were documented as having been ascertained through the clinical centre, 293 through the laboratory, and 87 through both. For subsequent analyses, the 87 subjects ascertained through both the laboratory and the clinical centre were included with the 293 ascertained through the laboratory.
As the cross-checks with national death data through the ONS applied only to persons who died in England and Wales, follow-up for 16 seroconverters from Scottish centres, who were last seen prior to the end of 1994, and five persons who were reported to have left the UK, was censored at the date last seen. For 48 other persons last seen in clinical centres in England and Wales prior to the end of 1994, we assumed that they were alive and AIDS-free at the end of 1994. No cases were lost to follow-up in Northern Ireland.
One hundred and eighty-nine persons (19.7%) had developed AIDS by December 1994 (exposure category: 139, sex between men; 37, injecting drug use; 10, sex between men and women; three, other) and 129 (13.4%) had died (Table 2). Of the 129 who died, 26 had not been diagnosed with AIDS (risk behaviour: 21, injecting drug use; five, homosexual transmission). The causes of death given for these persons were: drug/alcohol use (nine), liver disease (three), concussion (two), meningitis (one), bronchopneumonia (one), hepatitis B (one), and suicide/accidental death (two). For the remaining seven, the cause of death was not reported.
Time from HIV seroconversion to AIDS
The probabilities of progression to AIDS at 5, 10, and 11 years following HIV seroconversion were estimated to be 18.0% [95% confidence interval (CI), 13.9–22.2], 60.2% (95% CI, 52.1–68.3), and 65.9% (95% CI, 56.7–75.0), respectively, with a median time to AIDS of 8.83 years (95% CI, 7.67–9.75). Estimates of the cumulative probabilities for the diagnosis of AIDS and death are given in Fig 1.
There is strong evidence that older age at seroconversion (P = 0.008) is independently associated with rapid progression to AIDS (Table 3). We estimate cumulative progression to AIDS 5 years after HIV seroconversion to be 4.2, 16.9, 20.6, 31.5 and 36.2% for persons aged 16–19, 20–29, 30–39, 40–49 and 50 years or more at seroconversion, respectively.
Persons with 1–36 months between antibody test dates appeared to progress much more slowly than the 49 persons for whom seroconversion was estimated within the same calendar month [relative risk (RR), 0.46; 95% CI, 0.25–0.82]. To examine this finding further, we fitted a series of models to examine whether this effect persisted throughout the time of follow-up. The finding appeared to be almost entirely due to three cases who presented with an AIDS-defining disease within 3 months of HIV seroconversion and for whom serocon-version was estimated within 1 calendar month. Exclusion of these three persons from analyses did not affect overall progression estimates from seroconversion to AIDS.
Whereas IDU appeared to progress more slowly than homosexual men on univariate analysis (RR, 0.40; 95% CI, 0.25–0.63), this association was not significant after adjusting for age at seroconversion and sex (RR, 0.59; 95% CI, 0.33–1.04).
Time from HIV seroconversion to death
The probabilities of death from any cause at 5, 10, and 11 years following HIV seroconversion were estimated to be 9.8% (95% CI, 1.8–17.8), 48.1% (95% CI, 40.1–56.1), and 58.9% (95% CI, 49.2–68.7), respectively, with a median survival of 10.25 years (95% CI, 8.98–10.90).
Age was found to be independently associated with survival following HIV seroconversion (RR of death per 1 year increase in age, 1.04; 95% CI, 1.02–1.07; Table 4). Five years after seroconversion we estimate that 8.0% of persons aged 40 years or younger at seroconversion will have died (95% CI, 4.9–11.2) compared with 24.0% (95% CI, 9.9–38.0) of persons aged 40 years or over.
Models using quadratic and cubic terms for age did not improve the fit. Fitting the year of seroconversion as a categorical variable did not result in an improvement nor did it suggest that transformation of the covariate was appropriate.
Ascertainment of seroconverters through the laboratory was found to be independently associated with faster progression to death following HIV seroconversion (RR, 1.84; 95% CI, 1.10–3.06).
Restriction of analysis to persons with a 24-month HIV test interval, or to persons with a 12-month interval had very little influence on progression estimates.
A national register of seroconverters has been established in the UK and is now one of the largest cohorts capable of monitoring the times from HIV seroconversion to AIDS and to death, and the factors which may influence them.
One of the major concerns in analysing data from retrospectively identified cohorts is that persons who die shortly following seroconversion may have been omitted. Such an analysis would result in lower progression time to AIDS and to death. To correct for this potentially serious source of bias we treated seroconverters in the life table analysis as ‘late entry’ subjects unless we were satisfied that all seroconverters, including those who have died, moved or become lost to follow-up from that centre, were included. Although such an approach to analysis overcomes this bias, it may result in greater uncertainty in the estimates of progression rates within the first few years following serocon-version as it reduces the number of subjects followed up from seroconversion. Complete ascertainment of all seroconverters retrospectively wherever possible, as well as the ongoing recruitment of new seroconverters is, therefore, desirable. This will result in overall estimates which are not subject to ascertainment bias as well as more reliable estimates of progression within the first few years following seroconversion.
A further possible source of bias concerns the representativeness of seroconverters who have undergone repeat testing for HIV as a subset of HIV-infected persons. Persons acquiring infection through sex between men and women, for example, often have not previously perceived themselves to be at risk of HIV infection and so tend not to have had previous negative tests for HIV and, therefore, are under-represented among seroconverters. Ideally, HIV-negative cohorts need to be regularly followed up so that the detection of a positive test is not dependent on a person's reason to seek the test. Because of the selectivity of persons enrolled in these cohorts, however, results from these studies are not generalizable to the population. This is true for both retrospectively and prospectively ascertained cohorts. We have not attempted to deal with this potential source of bias in the present study.
The probabilities of progression to AIDS found here are in general agreement with those from other studies of similar population structure, i.e., predominantly homosexual and bisexual men (Table 5). IDU appear to progress significantly more slowly than homosexual and bisexual men in the univariate analysis. However, first, after correcting for the possible influence of age as well as sex we found no evidence of a difference in progression rates between the two groups (Table 3). Secondly, as a higher proportion of IDU die before AIDS, and are therefore censored at death, AIDS events will appear much lower in this group. Of the 44 IDU who died, 21 (48%) had not been diagnosed with AIDS, compared with five of 76 (7%) of homosexual and bisexual men who had died. A separate analysis of progression to either an AIDS diagnosis or death found no evidence of a difference in progression rates between the two groups (RR, 0.91; 95% CI, 0.59–1.41 for IDU compared with homosexual men) after adjusting for the effects of age and sex.
Thirdly, homosexual men may appear to have faster progression to AIDS relative to other groups because the incidence of Kaposi's sarcoma (KS) is higher than in other exposure groups  and tends to present at higher CD4 cell counts . In this data set, 20 AIDS cases were diagnosed with KS as the first AIDS disease (all homosexual and bisexual men). An analysis of progression to AIDS, censoring those diagnosed with KS gave a RR of 0.68 for IDU compared with homosexual and bisexual men (95% CI, 0.40–1.16) after correcting for the possible influence of age and sex.
Faster progression to AIDS with increasing age at sero-conversion has been observed in a number of published studies and gives credence to the likely importance of age as a cofactor for progression. A number of studies of homosexual and bisexual men have not observed this effect [3,7,12,25,44–49], and this may be due to a lack of heterogeneity in the age structure of the populations studied. The increase in risk for the development of AIDS in the present study is estimated to be 4% for each year of age, equivalent to 42% for each 10-year age group (95% CI, 15–74%). This is comparable to the findings from other cohort studies (Table 6). The increase in risk of progression to death for each 10-year increase in age is estimated to be 51% (95% CI, 19–93%).
The finding that seroconverters identified through the laboratories appear to progress to death faster than those identified through the clinical centres is difficult to interpret. It may not be feasible to disentangle the method of ascertainment as laboratory information on the presence of a previous negative antibody test may have come via the clinical centre when the request (for the positive test) was made. It may be impossible to determine which is the primary source of information, therefore, and the finding may be spurious.
Encouraging results from clinical trials suggest that the use of combination antiretroviral therapy in the mid-1990s is likely to prolong survival and, depending on uptake rate, this would be expected to lead to an observation of better prognosis in the more recent time periods. Further improvements are anticipated with increasing use of drug regimens that include two nucleoside analogues and a protease inhibitor. A study from Amsterdam, The Netherlands, has reported a slight lengthening of survival among homosexual men sero-converting between 1985 and 1993 . We have not seen any lengthening but, and as the majority of subjects on therapy included in this analysis are likely to have received monotherapy, it may be too early for the benefits of combination therapy to be observed in this study. A recent study from Turin has reported on a possible increase in the rate of progression to CD4 cell counts of 500, 400, 200 × 106/l and AIDS in persons seroconverting between 1992 and 1995 . This highlights the importance of continuing to monitor the survival of seroconverters closely, as well as examine the likely contribution of drug regimens to any changes observed over time.
These are preliminary findings from the Register which need to be interpreted with caution. Since more than one-half of subjects included in these analysis seroconverted in the 1990s statistical power is limited in providing more precise estimates of progression rates beyond 10 years after seroconversion. Further, because we have allowed for late entry, progression estimates in the first few years following seroconversion are, at the present time, limited. The Register, however, has established a high level of long-term follow-up through matching against a number of national databases of HIV-infected persons and of all deaths. The number of prospectively identified seroconverters reported to the Register will increase as the recruitment of newly infected individuals continues, allowing essential questions on the evolution of the clinical course of HIV disease to be addressed in a timely way in the future.
The help of staff at CDSC (M. Wright, R. Shoemaker, K. Davison, D. Howitt, A. Molesworth, R. Gilbert), SCIEH (G. Codere, G. Burns) and the Clinical Trials Centre (C. Duff, J. Gillett, P. Kelleher, S. Sellars, R. Manning) is gratefully acknowledged.
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The UK Register of HIV Seroconverters Steering Committee
Valerie Beral (Imperial Cancer Research Fund Cancer Epidemiology Unit, Oxford; Chairperson), Abdel Babiker [Medical Research Council (MRC) HIV Clinical Trials Centre, University College London Medical School (UCLMS), London]†, Ray Brettle (City Hospital, Edinburgh), Chris Carne (Addenbrooke's Hospital, Cambridge), Janet H. Darbyshire (MRC HIV Clinical Trials Centre, UCLMS, London)†, Barry G. Evans†, O. Noel Gill [Public Health Laboratory Service (PHLS) Communicable Disease Surveillance Centre, London]†, Richard J.C. Gilson (Department of Sexually Transmitted Diseases, UCLMS, London), David Goldberg (Scottish Centre for Infection and Environmental Health, Glasgow), David A. Hawkins (Chelsea & Westminster Hospital, London), Don Jeffries (St Bartholomew's Hospital, London), Anne M. Johnson (MRC UK HIV Epidemiology Co-ordinating Centre, UCLMS, London)†, Margaret A. Johnson (Royal Free Hospital School of Medicine, London), Andrew J. McMichael (Institute of Molecular Medicine, Oxford), Philip P. Mortimer (PHLS Central Public Health Laboratory, London), Andrew N. Phillips (Royal Free Hospital School of Medicine, London)†, Kholoud Porter (MRC HIV Clinical Trials Centre, UCLMS, London; Project Co-ordinator), Anton Pozniak (King's College Hospital, London), Jonathan Weber (St Mary's Hospital, London), Sally Wellsteed (Department of Health, London).
†Members of the Executive Committee
Clinics and laboratories providing information on subjects in the UKRHS
We thank the many colleagues from participating clinics and laboratories who provided information on subjects included in this analysis: City Hospital, Aberdeen, Scotland; Monklands Hospital, Airdrie, Scotland; Ashford Hospital, Ashford, Middlesex; District General Hospital, Barnsley, Yorkshire; District Hospital, Basingstoke, Hampshire; Royal Victoria Hospital, Belfast, Ireland; General Hospital, Heartlands Hospital Birmingham, West Midlands; Victoria Hospital, Blackpool, Lancashire; General Hospital, Bolton, Lancashire; Pilgrim Hospital, Boston, Lincolnshire; General Hospital, Bournemouth, Dorset; Claude Nicol Centre, Brighton, East Sussex; Royal Infirmary, Southmead Hospital, Bristol, Avon; Addenbrooke's Hospital, Cambridge, Cambridgeshire; St Peters Hospital, Chertsey, Surrey; City Hospital, Chester, Cheshire; Chesterfield and North Derbyshire Hospital, Chesterfield, Derbyshire; St Richards Hospital, Chichester, West Sussex; Essex County Hospital, Colchester, Essex; Royal Infirmary, Doncaster, Yorkshire; Royal Infirmary, Dundee, Scotland; Dryburn Hospital, Durham, County Durham; City Hospital, Royal Infirmary, Edinburgh, Scotland; Royal Infirmary, Ruchill Hospital, Southern General Hospital, Glasgow, Scotland; Royal Hospital, Gloucester, Gloucestershire; Farnham Road Hospital, Guildford, Surrey; General Hospital, High Wycombe, Buckinghamshire; Royal Infirmary, Huddersfield, Yorkshire; Raigmore Hospital, Inverness, Scotland; Ayrshire Central Hospital, Irvine, Scotland; Crosshouse Hospital, Kilmarnock, Scotland; General Infirmary, Leeds, Yorkshire; Royal Infirmary, Leicester, Leicestershire; Ambrose King Centre, Archway Clinic, Central Middlesex Hospital, Charing Cross Hospital, Ealing Hospital, FACTS Medical Centre, Greenwich District Hospital, Hammersmith Hospital, King's College Hospital, Kobler Centre, Lewisham Hospital, Mortimer Market Centre, Newham General Hospital, North Middlesex Hospital, Royal Free Hospital, St George's Hospital, St Mary's Hospital, Victoria Sexual Health Clinic, West Middlesex Hospital, Whipps Cross Hospital, Whittington Hospital, London; Luton and Dunstable Hospital, Luton, Bedfordshire; North Manchester General Hospital, Royal Infirmary, Withington Hospital, Manchester; Borders General Hospital, Melrose, Scotland; Middlesborough Hospital, Middlesborough, Cleveland; Milton Keynes Hospital, Milton Keynes, Bedfordshire; General Hospital, Newcastle upon Tyne, Tyne and Wear; General Hospital, Northampton, Northamptonshire; Norwich Hospital, Norwich, Norfolk; City Hospital, Nottingham, Nottinghamshire; Oldham and District General Hospital, Oldham, Lancashire; Freedom Fields Hospital, Plymouth, Devon; St Mary's Hospital, Portsmouth, Hampshire; Royal Hospital Preston, Lancashire; Royal Berkshire Hospital, Reading, Berkshire; New East Surrey Hospital, Redhill, Surrey; Baillie Street Health Centre, Rochdale, Lancashire; Hope Hospital, Salford, Manchester; Royal Hallamshire Hospital, Sheffield, Yorkshire; Upton Park Hospital, Slough, Berkshire; Royal South Hampshire Hospital, Southampton, Hampshire; Conquest Hospital, St Leonards-on-Sea, East Sussex; St Thomas' Hospital, Stockport, Manchester; North Staffordshire Hospital, Stoke-on-Trent, Staffordshire; King's Mill Centre, Sutton-in-Ashfield, Nottinghamshire; Singleton Hospital, Swansea, Wales; Princess Margaret Hospital, Swindon, Wiltshire; Princess Royal Hospital, Telford, Shropshire; Mayday Hospital, Thornton Heath, East Sussex; Torbay Hospital, Torquay, Devon; Manor Hospital, Walsall, West Midlands; Royal Albert Edward Infirmary, Wigan, Lancashire; New Cross Hospital, Wolverhampton, West Midlands; Royal Infirmary, Worcester, Hereford and Worcester.