HIV-RNA Viral load
0 .511.52 2.53
Time since seroconversion (years)
of ART initiation or CD4<350 cells/ml
Time from seroconversion(years)
Sarah Fidler1, Giota Touloumi2, Julie, Fox1, Nikos Pantazis2, Kholoud Porter3, Abdel Babiker3, Jonathan Weber1an the CASCADE Collaboration
Department GUM, Wright Fleming Institute, Imperial College, London, UK1~ Athens University Medical School, Greece2 ~ MRC Clinical Trials Unit, London, UK3
Department of GUM and HIV
Treated population- SMH : 89/105 volunteers with defined PHI were recruited between 2000-2004 into an
observational study at St Mary’s Hospital (SMH) in London where they chose to take a 3-month course of HAART
at HIV seroconversion. PHI was defined as: previous antibody negative test < 6 months (n=73); an evolving HIV-1
antibody titre as defined by an initial low level/equivocal OD value with a subsequent increased antibody titre,
(n=26); or an ‘incident’ test on the detuned antibody assay (OD<0.6) (n=6).
Untreated population- CASCADE: from the total population of 8908 participants within the CASCADE dataset
(an EU-funded collaboration of investigators from 22 cohorts of persons with well-estimated dates of HIV
seroconversion (seroconverters), pooled in December 2004, a selected population of 179 individuals were
identified on the basis of frequency matching with the SMH cohort for age, sex, HIV risk group (sex between men,
sex between men and women), year of estimated seroconversion (2000 or later), and a seroconversion window
interval of less than 6 months as these factors are known to influence CD4 and viral load levels and rates of
Seroconversion date was estimated as the midpoint between negative and positive test dates for 66% and 62% of
SMH and CASCADE participants respectively whereas, for the remaining subjects, the results of antibody
negative to positive laboratory data was used.
Plasma viral load for SMH participants was quantified using the Chiron 3.0 branched DNA (bDNA) assay (Chiron
UK Ltd, Southam, Warwickshire, UK.) with a detection range of 50 to > 500 000 copies/ml. A number of assays
were used within the CASCADE cohorts: Amplicor Monitor (RT-PCR) for 19%, Quantiplex (bDNA) (35%),
Nuclisens (QT)(8%), and assay not recorded for 38%.
CD4+ T-cell subsets were performed using standard fluorescence-activated cell sorter (FACS) analysis.
Objective: to investigate whether a 3-month course of ART during Primary HIV infection (PHI) influences the rate
of CD4+ and viral load change over time.
The initial high level unchecked viral replication associated with primary HIV infection (PHI) induces massive
irreversible CD4+ T-cell destruction that fails to regenerate subsequently. It has been hypothesised that
intervention with HAART in PHI may help to preserve CD4+ HIV-specific immune responses and so potentially
delay disease progression. This has been explored by many groups but the size of the treated populations and
long-term clinical follow-up remains limited.
Receiving a new diagnosis of HIV infection is often not the optimal time to introduce further anxieties associated
with adherence to complex HAART regimens, and risks of development of drug toxicities in the absence of clear
long-term clinical benefits.
The use of a short course of HAART (SCART) in PHI has the appeal of limiting potential drug toxicity and the
development of drug resistance with the aim of delaying the rate of disease progression.
In the absence of results from a RCT of HAART in PHI we present a comparison of the two main surrogate
markers of HIV-1 disease progression, CD4+ T-cell count and HIV RNA, between two separate observational
cohorts of persons identified during PHI.
• All available CD4 and viral load measurements for both groups were included after transformation on the
square root and log10scales respectively. Furthermore, all marker data were excluded from analyses once ART
was initiated due to disease progression in both groups.
• We crudely estimated the mean viral load set-point for both populations by taking the viral load measurement
closest to 1.5 years after seroconversion provided that subjects were not on any ART.
• Measurements from SMH individuals were censored until at least 6 months after the end of SCART.
• Viral load was modelled using two separate models for CASCADE and SMH individuals: a) a nonlinear random
effects model with random intercept and random slope allowing for an initial exponential decay to model viral load
data of CASCADE individuals and b) a similar model allowing for an exponential increase in order to capture the
rise of viral load levels after the end of SCART for the SMH individuals.
• We also analysed time to CD4 drop below 350 cells/µl was or the initiation of clinically indicated ART.
Demographic and clinical characteristics of study population
The distribution of demographic and clinical characteristics are similar between the two groups except for follow-
up time, the number of CD4 and viral load measurements and their frequencies which was significantly longer in
the SMH group.
CD4 cell count (cells/µ µl)
0.51 1.52 2.53
Time since seroconversion (years)
The rate of CD4 decline appears steeper for the untreated CASCADE group compared to the treated SMH
group (p=0.011) (Figure 1). This corresponds to a mean loss of 51 cells/µl (95% confidence intervals= 32-
69) per year in SMH and 77 cells/µl (65- 89) per year in CASCADE participants at 3 years after
seroconversion. This finding persisted even after adjustment for potential confounding effects of sex, risk
group or age at seroconversion.
Figure 1. Estimated average trends for CD4 cell count based on a common linear random effects model for
CASCADE and SMH (all measurements until 6 months after stop of SCART censored) data allowing for
group-specific average intercept and slope
Figure 2. Estimated average trends for viral load levels on two separate nonlinear random effects models for
CASCADE and SMH populations (all SMH measurements prior to the end of SCART censored). Nonlinear models
were used to capture the initial drop in viral load levels of untreated CASCADE individuals for the first year after
seroconversion and the fast rise of viral load levels among SMH individuals after the end of SCART
Figure 3. Cumulative probability of the combined event “HAART initiation or CD4<350 cells/µl”, by time since
seroconversion for subjects treated with SCART (SMH) and untreated controls (CASCADE)
This is the first report showing an apparently significant and sustained alteration in the rate of CD4+ T-cell decline up
to 3 years after seroconversion in persons treated with SCART at PHI, when compared with a matched untreated
These findings concur with a recently published observation of the benefits in CD4 counts observed in HAART treated
acute and early individuals with PHI.
Given that the comparison between the two groups was not performed within the context of a randomised clinical trial,
analyses are subject to bias due to unmeasured confounders as well as confounding by indication. These
observational data cannot, therefore, be used to infer treatment efficacy but clearly signal the need for a randomised
SPARTAC is a RCT of HAART in PHI is currently recruiting in 37 international sites and is powered to address this
Slower CD4 cell decline following cessation of a 3
Slower CD4 cell decline following cessation of a 3- -month course of HAART in Primary HIV infectionmonth course of HAART in Primary HIV infection
The estimated hazard ratio for the
combined event “ART initiation or
CD4<350 cells/µl” was 1.447(95% CI:
1.020 – 2.054; p = 0.039). The
untreated CASCADE population
were more likely to reach CD4<350
or initiate HAART
Sex between men
Male sex between men and women
Female sex between men and women
Median age (IQR) at seroconversion
(years)30.89 (27.98 – 35.3) 32.9(27.9 – 38.5)0.224
Calendar year of seroconversion
84 (47%) 0.332
Evidence of seroconversion
Midpoint59 (66%) 111 (62%)0.505
Median seroconversion interval
(months) 3.2(1.9-4.3) 3.1 (2.3-5)0.745
Median follow-up time (years) 2.45 (2.03 – 3.4) 1.20 (0.83 – 1.95) <0.001
There was no significant difference
in viral load between the 2
populations either at set point
(18 months after seroconversion)
Or up to 2 years after SC
Objective: to investigate whether a short course of HAART during primary HIV infection (PHI)
influences rate of CD4+ and viral load change.
Study Design: matched non-randomised comparison of two HIV-1 seroconverter populations.
Methods: using linear and non-linear random effects models, we compared CD4+ and HIV RNA
data following HAART cessation from 89 individuals, seroconverting 1999-2003, who chose to
take a 3-month course of HAART at PHI, with 179 untreated controls in CASCADE. Participants
were frequency matched for age, sex, risk factor, year of seroconversion (SC) and presentation
within the first 6 months of SC. We also compared time to CD4 <350 cells/µl or initiation of
clinically-indicated ART as competing risks.
Results: rate of CD4+ decline following therapy cessation appeared significantly slower among
treated participants compared with untreated controls (losses of 51, 95%CI= 32- 69 and 77, 65-89
cells/µl per year respectively) 3 years after SC; p=0.011. At the same time point viral loads
appeared to differ significantly (4.09 and 4.53 for treated and untreated respectively) although this
was largely based on extrapolated data. At 2 years there was no significant difference in mean
viral load levels (4.31, 4.14-4.48 and 4.47, 4.28-4.66). CASCADE seroconverters were more likely
to reach CD4 <350 cells/µl or initiate clinically indicated ART (HR= 1.45, 95% CI= 1.02-2.05;
Conclusion: a short course of ART at PHI may delay CD4+ decline. However, findings need
confirmation through a randomised clinical trial powered to address definitively the role of ART
intervention in PHI. This is currently underway through SPARTAC.
Steering Committee: Julia Del Amo (Chair), Laurence Meyer (Vice Chair), Heiner Bucher, Geneviève Chêne, Deenan Pillay, Maria Prins, Magda Rosinska, Caroline Sabin, Giota
Co-ordinating Centre: Kholoud Porter (Project Leader), Krishnan Bhaskaran (Scientific Co-ordinator), Sarah Walker, Abdel Babiker, Janet Darbyshire
Clinical Advisory Board: Heiner Bucher, Andrea de Luca, Martin Fisher, Cécile Goujard, Roberto Muga, Court Pedersen
Collaborators: Australia Sydney AIDS Prospective Study and Sydney Primary HIV Infection cohort (John Kaldor, Tony Kelleher, Tim Ramacciotti, David Cooper, Don Smith);
Canada South Alberta clinic (John Gill); Denmark Danish HIV cohort (Niels Obel, Court Pedersen, Louise Bruun Jørgensen, Claus Nielsen); Estonia Tartu Ülikool (Irja Lutsar);
France Aquitaine cohort (Geneviève Chêne, Francois Dabis, Rodolphe Thiebaut), French Hospital Database (Dominique Costagliola), 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 (Heiner 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).