Introduction
Whether cART initiation, or at least transient treatment, during primary HIV-1 infection (PHI) could have a long-lasting beneficial effect is unknown. The effects of cART initiated soon after seroconversion [1–4] on CD4 cell count and plasma HIV-RNA appear to be similar to, or even more pronounced than, those seen in chronically infected individuals [5–7]. Moreover, successful early treatment of HIV-1 infection leads to augmented HIV-specific immune responses and a more complete [4,7–11] recovery of the various CD4 T cell subpopulations [7,12]. Although the ‘hit early, hit hard’ strategy [13] has been replaced by a more conservative CD4 cell-guided approach for chronically infected patients, current treatment guidelines suggest that individuals identified in acute infection may form a group with different characteristics in whom immediate treatment may be justified [14,15].
However, evidence regarding long-term effects of antiretroviral treatment during primary infection is extensive but inconclusive. Some early studies on newly infected individuals reported promising results of reduced rates of CD4 cell count decline and controlled viremia after transient antiretroviral treatment were initiated in PHI, suggesting that progression rates may also have been reduced [4,7–11]. Conversely, more recent studies have reported that transient cART during PHI does not lower the viral load set point, and durable viral control occurs infrequently [16,17]. Because long-term exposure to cART is associated with various clinical disorders [18–21] and adherence problems [22,23], the initiation of fixed duration therapy in primary infection has emerged as an alternative. The choice for the optimal length of such treatment appears to be based, however, on a small number of patients, or is seemingly arbitrary [24,25].
In this study, we use data from a large collaboration and select individuals identified during PHI. We compare CD4 cell, HIV-RNA and clinical disease rates in those who initiated ‘early’ cART of different durations, during the first 6 months after seroconversion, with those who ‘deferred’ treatment for at least 6 months following seroconversion.
Methods
The study population was derived from Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE), a collaboration between the investigators of 23 cohorts in Europe, Australia and Canada of individuals with well estimated dates of HIV seroconversion. CASCADE has been described in detail elsewhere [26]. The date of seroconversion is estimated by various methods, most frequently as the midpoint between the last negative and the first positive HIV antibody test dates with the maximum time between these dates being 3 years. Data were pooled in September 2006 comprising a total of 17 240 HIV individuals, but data from one large cohort (n = 7430) were excluded from analyses due to lack of information on treatment changes following its initiation. The inclusion criteria for this study are estimated seroconversion following 1st January 1996; age of at least 15 years at seroconversion; seroconversion interval (interval between last negative and first positive antibody test dates) of less than 6 months or laboratory evidence of acute infection (e.g., PCR positivity in the absence of antibody, evolving antibody response or indeterminate result); follow-up (with known cART status) of at least 6 months; and availability of at least 2 CD4 cell and at least 2 HIV-RNA measurements during follow-up. Individuals with at least 2 CD4 cell measurements less than 350 cells/μl or who developed clinical AIDS within 6 months of estimated seroconversion were excluded as they most likely consist of a special subgroup more likely to initiate cART.
The resulting study population was divided into two groups: ‘early treatment’ group, who started cART within the first 6 months of seroconversion and remained on it for at least 30 days, and a ‘deferred treatment’ group of all remaining individuals. Comparisons of CD4 cell and HIV-RNA measurements between ‘early’ and ‘deferred’ treatment groups were restricted to the period from treatment cessation to any cART reinitiation and to the cART-free period, respectively. Viral load ‘set point’ refers to the HIV-RNA level's equilibrium, observed over long intervals, which is reached after the first year of infection in the absence of any treatment. Comparisons of clinical event rates are based on either the same periods or the total follow-up time. cART was defined as a combination regimen containing at least three drugs from two classes [nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors or nucleoside reverse transcriptase inhibitors (NRTI)], or three NRTIs one of which was abacavir. A treatment cessation was defined as the discontinuation of all antiretroviral drugs for at least 30 days.
CD4 cell count was measured by flow cytometry and plasma viral load by the assay(s) available in each collaborating cohort. The assays used were mostly based on branched DNA (bDNA), nucleic acid sequence-based amplification (NASBA) or reverse transcriptase-polymerase chain reaction (RT-PCR) techniques.
Statistical analysis
Repeated measurements of CD4 cell count were analyzed through piecewise linear mixed models in order to take into account the correlation of multiple measurements from the same individual [27]. The model allowed for a simple linear increase from seroconversion until ‘early’ cART interruption and a biphasic decrease thereafter with a ‘change-point’ at 6 months after cART cessation. A simple linear trend was adequate to capture the natural history CD4 cell evolution of the ‘deferred treatment’ group. CD4 cell count and HIV-RNA measurements have been square root and log10 transformed, respectively [28,29]. All HIV-RNA measurements below detection limit were replaced by half of the assay's cutoff value. In order to estimate CD4 cell count levels at cART initiation, for the ‘deferred treatment’ group or reinitiation for the ‘early treatment’ group using all available information, modified Kaplan–Meier techniques were used in which the time scale was replaced by a reversed CD4 cell scale [30]. Data on time to clinical AIDS or death were analysed through Cox proportional hazards models and log-rank tests.
Sensitivity analysis
We repeated analysis of CD4 cell count data using two stricter definitions of ‘early’ treatment: HIV test interval within 3 months with cART initiated within 3 months, and a test interval of 1 month and cART initiation within 1 month. To investigate the potential differential effect of presence of seroconversion illness on CD4 cell temporal trends, we reanalyzed longitudinal CD4 cell data separately for persons with or without symptoms of seroconversion illness.
Results
Of 9742 individuals aged at least 15 years at seroconversion, 3572 individuals seroconverted following 1st January 1996, of whom 1755 were diagnosed within 6 months of estimated seroconversion. Of these individuals, 732 were excluded from analyses because follow-up was of less than 6 months (n = 400), duration of cART within 6 months of seroconversion was less than 1 month (n = 21), clinical AIDS was diagnosed within 6 months (n = 21), at least 2 CD4 cell count measurements less than 350 cells/μl were recorded within 6 months following seroconversion (n = 97) or less than 2 CD4 cell counts or HIV-RNA measurements were available (n = 193).
Of 1023 individuals in analyses, 348 (34%) formed the ‘early treatment’ group and initiated cART [median calendar year of initiation, interquartile range (IQR): 2000, 1998–2002] within the first 6 months after seroconversion. The remaining 675 (66%) formed the ‘deferred treatment’ group, of whom 226 (34%) initiated cART during chronic infection (median time from seroconverion to ART initiation: 2.02 years; IQR: 1.13–3.54 years). Descriptive characteristics of the study population are presented in Table 1.
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Table 1: Demographic and clinical characteristics of the study population.
Of the 348 ‘early treated’ individuals, 147 (43%) stopped all cART drugs. Of these, 38 individuals had been treated for 6 months or less (median and IQR duration of cART 3.0; 1.7–4.5 months), 40 individuals for more than 6–12 months (9.1; 7.2–10.9) and 69 for more than 12 months (22.4; 16.3–38.3). Median follow-up after treatment cessation was 15.2, 9.1 and 11.2 months, respectively.
Longitudinal evolution of CD4 cell count
Figure 1 a shows cross-sectional median levels of CD4 cell count for ‘early’ and ‘deferred’ groups. CD4 cell counts of ‘early treated’ individuals are presented in two subplots according to their cART status: based on measurements taken while they were still on their first cART regimen, and following treatment cessation. The significant increase in CD4 cell counts among individuals who initiated cART early is evident and biphasic with a steeper increase during the first 6 months of cART initiation (Fig. 1a). Figure 1b suggests that CD4 cell levels of ‘early treated’ individuals decline at a fast rate once cART is stopped, and this decline is more pronounced during the first 6 months of treatment cessation. Compared with the ‘deferred treatment’ group, individuals among the ‘early treated’ stopping all cART also appear to retain slightly higher levels during treatment cessation, but the rate of decline does not seem to differ between these two groups.
Fig. 1: Cross-sectional median CD4 cell levels by (a) time since seroconversion – stratified by group and ART period [during first combination antiretroviral therapy and following its cessation (treatment interruption) for ‘early treated’ individuals] and (b) time since first combination antiretroviral therapy cessation (only for ‘early treated’ individuals interrupting their first combination antiretroviral therapy, cART). Numbers indicate individuals contributing measurements at each time point. cART, combination antiretroviral therapy.
It should be noted, however, that all figures based on cross-sectional medians of CD4 cell count are subject to selection bias, as individuals with the lowest values will tend to be selected for therapy initiation (for the ‘deferred’ group) or reinitiation (for the ‘early treatment’ group), which may result in an overoptimistic picture regarding CD4 cell evolution in both groups, and caution is needed when interpreting such figures. The same argument holds for the corresponding figures for HIV-RNA.
Average predicted trends based on estimates from the linear mixed model are presented in Fig. 2a. Trends presented in Fig. 2b are based on a similar model that, additionally, allowed for different trends according to treatment duration of ‘early’ cART. The biphasic nature of the cART-induced CD4 cell count increase in the ‘early treatment’ group was not captured by our model, but this was intentional as we avoided using a more complex model given that our focus is on CD4 cell count trends after the cessation of ‘early’ cART. The initial fast decrease following cART cessation is followed by a less steep slope that appears to be comparable to that of the ‘deferred treatment’ group. The estimated slopes for both groups are presented in Table 2. As shown in this table, the average estimated final slope (beyond the first 6 months) of the ‘early treatment’ group is slightly steeper compared with that of the ‘deferred treatment’ group, but differences are not significant. Individuals receiving ‘early’ cART for up to 12 months appear to reach comparable CD4 cell levels as those still untreated within approximately 6 months of stopping treatment. Individuals treated for longer than 12 months, however, appear to maintain higher CD4 cell levels after treatment cessation compared with untreated individuals. For illustration, ‘typical’ individuals (with median ‘early’ cART duration in each subgroup), with a CD4 cell count of 550 (700) cells/μl at seroconversion, could expect an estimated CD4 cell count 5 years after seroconversion of 234 (335) CD4 cells/μl if they had deferred treatment, and 241 (343), 304 (418) and 430 (564) CD4 cells/μl had they received ‘early’ treatment for 6 months or less, 6–12 and more than 12 months, respectively. The differences in CD4 cell counts between the ‘deferred’ group and the ‘early’ treated groups for 6 months or less or for 6–12 months were not statistically significant. However, for the more than 12 months subgroup, available follow-up time after treatment cessation is short (median 11.2 months) relative to treatment duration (median 22.4 months), thus, proper inference is not possible.
Fig. 2: Predicted average CD4 cell count trends by (a) group (‘early’ and ‘deferred’ treatment) and (b) group (‘early’ and ‘deferred’ treatment) and duration of first cART. cART, combination antiretroviral therapy.
Table 2: Estimated CD4 cell slopes [square root (cells/μl)/year] by group and duration of ‘early’ combination antiretroviral therapy.
Longitudinal evolution of HIV-RNA: viral load ‘set point’
Figure 3a and b shows cross-sectional medians of HIV-RNA levels (on log10 scale) for ‘early’ and ‘deferred’ treatment groups. After initiation of cART, a rapid decrease in viral load is observed followed by a rapid increase following cART cessation. Viral load levels of ‘early treated’ individuals while off cART appear to be comparable to the corresponding levels of untreated individuals in the ‘deferred treatment’ group.
Fig. 3: Cross-sectional median HIV-RNA levels by (a) time since seroconversion – stratified by group and antiretroviral therapy period [during first combination antiretroviral therapy and during its cessation (treatment interruption) for ‘early treated’ individuals] and (b) time since first combination antiretroviral therapy cessation (only for ‘early treated’ individuals interrupting their first combination antiretroviral therapy). Numbers indicate individuals contributing measurements at each time point. Horizontal dashed black line indicates the 500 copies/ml threshold. cART, combination antiretroviral therapy.
Viral load ‘set point’ levels were estimated by taking the average of all HIV-RNA measurements per individual, provided that individuals in the ‘deferred treatment’ group were still ART naïve, and individuals in the ‘early treated’ group had stopped cART for at least 6 months. All measurements taken within the first year after seroconversion were excluded. The estimated mean [95% confidence interval (CI)] ‘set point’ levels were similar at 4.30 (4.14, 4.46) for those who deferred treatment, and at 4.37 (4.01, 4.73), 4.09 (3.68, 4.50) and 4.18 (3.87, 4.48) log10 copies/ml for individuals in the ‘early’ group, respectively, treated for up to 6 months, 6–12 months or more than 12 months and individuals (P = 0.57).
Combination antiretroviral therapy (re)initiation
Of 147 individuals who interrupted cART, 90 patients (61%) reinitiated therapy. Of the 675 individuals in the ‘deferred treatment’ group, 226 (34%) initiated a cART regimen during the available follow-up. The 25th (95% CI) percentiles of time to cART (re)initiation were 3.5 (2.8–4.3) and 2.3 (2.0–2.6) years after seroconversion for the ‘early’ and ‘deferred’ treatment groups, respectively, corresponding to a hazard ratio (95% CI) of 0.65 (0.51, 0.83), suggesting a lower rate of cART (re)initiation among the ‘early’ treatment group. However, taking into account the time interval that the ‘early treated’ individuals spent on cART initially, and using the appropriate ‘late entry’ adjustment the hazard ratio (95% CI) became 2.63 (2.05, 3.37) indicating a significantly higher rate of cART reinitiation in the ‘early treatment’ group compared with the ‘deferred treatment’ group. Investigating the issue of cART (re)initiation further, we excluded from analysis individuals in the ‘early treatment’ group who did not interrupt their first cART during follow-up and using a modified Kaplan–Meier technique [30], we estimated the median (95% CI) CD4 cell count at cART (re)initiation to be 351 (303, 421) and 278 (261, 292) cells/μl (P < 0.001) for ‘early’ and ‘deferred’ treatment groups. Thus, ‘early treated’ individuals tend to reinitiate cART at approximately 80 cells/μl higher CD4 cell levels compared with individuals in the ‘deferred treatment’ group. Differences remained practically unchanged even after adjustment for presence of seroconversion illness.
Clinical events
There were no deaths during either the cART-free period, for the ‘deferred treatment’ group, or following reinitiation, for the ‘early treatment’ group. Of the 348 ‘early treated’ individuals and 664 in the ‘deferred’ group, six (1.7%) and 11 (1.6%) developed clinical AIDS, respectively (P = 0.776). Four of the six AIDS events in the ‘early’ treatment group were observed during treatment interruption. Considering the whole available follow-up time, the numbers of AIDS events were also similar at 13 (3.7%) and 20 (3%) in the ‘early’ and ‘deferred’ treatment groups, respectively (P = 0.95). Two (0.6%) and 12 (1.8%) individuals in the ‘early’ and ‘deferred’ treatment groups, respectively, died during the whole follow-up period. This difference was marginally statistically significant (P = 0.05), but it should be noted that the majority of deaths (nine out of 12) in the ‘deferred treatment’ group were not AIDS defining, three of which may have been HIV related (one bacterial infection, one respiratory disease, one malignancy, two drug overdoses, one suicide and three cases with unknown cause of death). The corresponding proportion of non-AIDS deaths among ‘early treated’ individuals was 1/2 (drug overdose).
Sensitivity analysis
Results from analyses using stricter definitions of ‘early’ treatment were consistent with those reported in the main analysis (data not shown). Results from individuals without symptoms of seroconversion illnesses were similar to those reported in the main analysis. However, as expected, individuals who had symptoms of seroconversion illnesses and deferred treatment had, in general, lower CD4 cell counts than those without symptoms making differences between the ‘early’ and ‘deferred’ groups slightly more pronounced compared with the main analysis (data not shown).
Discussion
Our findings suggest that any early immunologic gain from initiating cART within the 6 months following HIV seroconversion is unlikely to be sustained, with the possible exception of cART administered for longer than 1 year. Although there is some evidence that the initial CD4 cell gain, in those treated for longer than 1 year during early HIV-1 infection, may persist for at least some years after interruption, available follow-up data in the present study limit any firm conclusions. The question still remains, therefore, as to whether it is beneficial to initiate cART in primary infection and, more crucially, for how long. Although we are not able to address these questions through this study, given the dangers of inferring treatment efficacy from observational data [31,32], our study, nonetheless, is the largest to date to report on CD4 cell, HIV-RNA and clinical events of persons treated during primary HIV infection.
We found no evidence for a difference in the average estimated slope beyond the first 6 months following treatment cessation between the ‘early’ and ‘deferred’ treatment groups. Furthermore, HIV-RNA levels of ‘early treated’ individuals while off cART appear to be comparable to the corresponding levels of untreated individuals in the ‘deferred’ group. This is confirmed by a number of other studies [16,17] but refuted by others [7–10] though the length of follow-up reported in most studies is typically limited.
A number of factors are likely to influence findings and make between-study comparisons difficult. First, the time interval between seroconversion and cART initiation maybe an important determinant in the enduring effect of transient cART. Following HIV seroconversion, massive unchecked viral replication and permanent damage of CD4 cell-mediated immune functions [33] typically occur within a period of weeks, rather than months, and initiation of cART at 6 months may fall short of preventing permanent distortion of immune function. A small study [34] setup to investigate the effects of timing of cART initiation during PHI showed a greater benefit when cART was initiated within 2 weeks of seroconversion compared with between 2 weeks and 6 months. However, in our sensitivity analyses, we did not observe any trend for slower long-term CD4 cell count declines when we used stricter definitions of ‘early’ treated.
Second, duration of transient cART may also play a part though cART appears to be given for a few months, rather than years, in most of these studies. To our knowledge, however, this is the only published study to consider the effect of different durations of cART on these outcomes. We found that individuals receiving ‘early’ cART for less than 1 year appear to reach comparable CD4 cell levels within approximately 6 months of stopping treatment as those still untreated. Our findings indicate that prolonged cART for more than 1 year may lead to a CD4 cell count benefit compared with a strategy of deferred cART. However, whether this initial benefit persists over several years remains to be seen as longer follow-up time is needed.
Third, the large number of different drug combinations used in this population makes comparison difficult. A total of 64 treatment combinations were used by the 147 individuals who initiated treatment early and subsequently stopped therapy. The most common combinations were zidovudine, lamivudine and boosted lopinavir (25, 10.6%) and zidovudine, lamivudine and nevirarpine (20, 8.5%). Of note, for 73 individuals (49.7%), the first regimen contained a nonboosted protease inhibitor. This explains in part the seeming discrepancy with our earlier finding of significantly improved CD4 cell slope for individuals treated for 12 weeks at one clinical center where no patient received a nonboosted protease inhibitor [35]. In general, when interpreting the results of our study, one should take into account that it partly includes individuals who started therapy during the early years of cART and that therapies which became available in later years, particularly after 1999, are better at maximizing patient outcomes and reducing therapeutic failures. When we reanalyzed CD4 cell count data, restricting the study population to those who seroconverted on or after 1999, we observed a slightly better discrimination between treatment groups (data not shown), which is probably an indication that we may have underestimated any beneficial effects of transient therapy less than 12-month duration.
Finally, levels of adherence may differ among study populations, though this is generally not reported.
When we accounted for the total time spent on cART, individuals in the ‘early’ group compared with the ‘deferred’ group were twice as likely to reinitiate cART and tended to reinitiate it at higher median CD4 cell count. The reason for this is not clear, in particular, when we consider that the rates of clinical events and CD4 cell loss during the cART-free period were similar in both groups. It maybe that, for clinicians and patients, once the decision is made to begin treatment in primary infection, an aggressive approach is taken to subsequent management.
As with all observational studies, there are a number of limitations to consider. First, we do not have information on the reasons for initiation of therapy during PHI or for stopping it. Patients with seroconversion illness are overrepresented in the ‘early’ group and, given that they will have, in general, worse prognosis compared to those without it, this imbalance could have resulted in diluting the potential beneficial effect of early treatment. However, results from separate analysis for participants without symptoms of seroconversion illnesses were consistent with those reported in the main analysis; thus, do not support this hypothesis. On the contrary, results from the analysis of individuals with symptoms of seroconversion illnesses showed that, while those who deferred treatment had a similar rate of CD4 cell decline to those who received ‘early’ transient cART, they had constantly lower CD4 cell count levels. This finding is consistent with the current treatment guidelines that suggest that early therapy should be considered in cases with symptoms of acute retroviral syndrome [14].
Second, interlaboratory variability in HIV-RNA and CD4 T-cell quantification and the lower frequency of those two measurements among the ‘deferred treatment’ group may have diluted differences between the early treated and deferred groups.
Finally, our negative findings regarding differences in HIV-RNA set point and long-term CD4 cell count evolution between those treated for less than 12 months and those who deferred treatment should be judged considering also the higher non-AIDS death rates among the deferred group and the higher AIDS rates observed following treatment cessation compared with rates during the transient cART period among ‘early treated’ groups.
In conclusion, in the absence of randomized evidence, and awaiting the results from the Short Pulse HIV Anti Retroviral Treatment at Sero Conversion (SPARTAC) trial (http://www.ctu.mrc.ac.uk/studies/spartac.asp), uncertainty in relation to the long-term clinical benefit of early treatment of early HIV infection persists. Evidence from our data suggests that higher CD4 cell gains may result when early treatment is maintained for at least 12 months. Continued careful monitoring of such individuals, however, will be crucial while on treatment and once it is stopped.
Acknowledgements
CASCADE has been funded through grants from the European Union BMH4-CT97-2550, QLK2-2000-01431, QLRT-2001-01708 and LSHP-CT-2006-018949.
There are no conflicts of interest.
Author contributions: N.P. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Statistical expertise: N.P. and G.T., supervised by G.T., N.P., G.T., P.V., J.G., H.C.B., K.P. were responsible for study concept and design. Analysis and interpretation of data undertaken by N.P., G.T., K.P., who also drafted manuscript with critical revision for important intellectual content undertaken by P.V., J.G., H.C.B.
CASCADE Collaboration consists of the following members:
Steering Committee: Julia Del Amo (Chair), Laurence Meyer (Vice Chair), Heiner C. Bucher, Geneviève Chêne, Deenan Pillay, Maria Prins, Magda Rosinska, Caroline Sabin, Giota Touloumi. Coordinating Centre: Kholoud Porter (Project Leader), Sara Lodi, Sarah Walker, Abdel Babiker, Janet Darbyshire. Clinical Advisory Board: Heiner Bucher, Andrea de Luca, Martin Fisher, Roberto Muga.
Collaborators: Australia, Sydney: AIDS Prospective Study and Sydney Primary HIV Infection cohort (John Kaldor, Tony Kelleher, Tim Ramacciotti, Linda Gelgor, David Cooper, Don Smith); Canada, South Alberta clinic (John Gill); Denmark, Copenhagen: HIV Seroconverter Cohort (Louise Bruun Jørgensen, Claus Nielsen, Court Pedersen); Estonia, Tartu Ülikool (Irja Lutsar); France, Aquitaine cohort (Geneviève Chêne, Francois Dabis, Rodolphe Thiebaut, Bernard Masquelier), French Hospital Database (Dominique Costagliola, Marguerite Guiguet), Lyon Primary Infection cohort (Philippe Vanhems), SEROCO cohort (Laurence Meyer, Faroudy Boufassa); Germany, German cohort (Osamah Hamouda, Claudia Kucherer); Greece, Greek Haemophilia cohort (Giota Touloumi, Nikos Pantazis, Angelos Hatzakis, Dimitrios Paraskevis, Anastasia Karafoulidou); Italy, Italian Seroconversion Study (Giovanni Rezza, Maria Dorrucci, Benedetta Longo, Claudia Balotta); Netherlands, Amsterdam: Cohort Studies among homosexual men and drug users (Maria Prins, Liselotte van Asten, Akke van der Bij, Ronald Geskus, Roel Coutinho); Norway, Oslo and Ulleval Hospital cohorts (Mette Sannes, Oddbjorn Brubakk, Anne Eskild, Johan N Bruun); Poland, National Institute of Hygiene (Magdalena Rosinska); Portugal, Universidade Nova de Lisboa (Ricardo Camacho); Russia, Pasteur Institute (Tatyana Smolskaya); Spain, Badalona IDU hospital cohort (Roberto Muga), Barcelona IDU Cohort (Patricia Garcia de Olalla), Madrid cohort (Julia Del Amo, Jorge del Romero), Valencia IDU cohort (Santiago Pérez-Hoyos, Ildefonso Hernandez Aguado); Switzerland, Swiss HIV Cohort Study (Heiner C. Bucher, Martin Rickenbach, Patrick Francioli); Ukraine, Perinatal Prevention of AIDS Initiative (Ruslan Malyuta); United Kingdom, Edinburgh Hospital cohort (Ray Brettle), Health Protection Agency (Valerie Delpech, Sam Lattimore, Gary Murphy, John Parry, Noel Gill), Royal Free haemophilia cohort (Caroline Sabin, Christine Lee), UK Register of HIV Seroconverters (Kholoud Porter, Anne Johnson, Andrew Phillips, Abdel Babiker, Janet Darbyshire, Valerie Delpech), University College London (Deenan Pillay), University of Oxford (Harold Jaffe).
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