Bridging the Gap: Conference Record [Abstract book, International Conference on AIDS (12th: 1998: Geneva, Switzerland)]

156 Abstracts 13348-13351

12th World AIDS Conference

Methods: LTNP were initially defined as HIV infected >10 years with CD4
counts persistently >500 cells/mm3 in the absence of antiretroviral therapy. Kaplan Meier methods were used to estimate time to 1993 AIDS diagnosis, death,
and time to loss of LTNP status after 10 years. Participants initiating antiretroviral
therapy prior to a decline in CD4 < 500 cells/mm3 were censored at initiation of
therapy. Cox proportional hazards models were used to evaluate predictors of
loss of LTNP status.
Results: Among 622 MSM with well-characterized dates of seroconversion,
median time to AIDS was 9.8 years. At 18 years after seroconversion, the estimated probability of developing AIDS was 86% (95% CI 80-89%). Median time
to death was 11.8 years; 18 years after seroconversion, estimated mortality was
75% (95% CI 72-79%). Of 596 men infected >10 years, 67 (11%) were initially
LTNP and an additional 15% were alive, AIDS-free, but not followed. In KaplanMeier analysis of those 67 men, only 14% (95% CI 3-26%) were estimated to
remain LTNP after 18 years of infection. There was considerable heterogeneity
of plasma viral levels among LTNP (range <500-129,000 copies/ml by bDNA
assay), and plasma viral level was the strongest independent predictor of LTNP
status (relative hazard 2.8 per log bDNA, 95% CI 1.42-5.54). We were able to
isolate virus from PBMC culture without CD8+ depletion on at least one occasion
in 14/15 LTNP tested. Of 19 LTNP with genetic testing of chemokine alleles, 32%
were heterozygous for the CCR5A32 allele, 8% for the CCR2641 allele, and 37%
for either.
Conclusion: Long-term nonprogression was a relatively rare phenomenon in
our cohort of long-term HIV infected MSM, accounting for only 2% of all HIVinfected MSM 18 years after seroconversion. Plasma viral level predicts loss of
LTNP status, suggesting that LTNP who have maintained high CD4 counts in
the presence of moderate plasma viral loads should initiate antiretroviral therapy. Current described variants in chemokine receptors account for a minority of
LTNPs.
13348 The molecular epidemiology of long-term asymptomatic
HIV infection in Australia
Lesley Ashton1, D. Rhode2, A. Solomon2, N. Deacon2, A. Carr2, D.A. Cooper3,
J. Kaldor'. 'NCHECR, 376 Victoria St. Darlinghurst, NSW2010; 2MacFarlane
Burnet Centre for Medical Research, Melbourne; 3Centre for Immunology, St.
Vincent's Hospital, Sydney, Australia
Objectives: To determine virological, immunological and genetic characteristics
of a cohort of long-term nonprogressors (LTNP) with a particular focus on the
degree of viral diversity in the nef/LTR region.
Methods: Individuals were eligible for the study if they had documented HIV
seropositivity for >8 years and were asymptomatic with a CD4 count >500
cells/ill. Blood specimens were examined for HIV isolation and quantification,
T-cell subsets, p24-ICD, f2 -microglobulin, CCR5 and CCR2b genotype and
deletions in the nef/LTR region of the HIV-1 genome. Viral diversity in the nef/LTR
region was initially examined by PCR analysis of genomic DNA isolated from
uncultured PBMCs from 69 study participants enrolled in the Australian LTNP cohort. Genetic variation in the nef/LTR region was further determined by nucleotide
sequencing for 30 of these individuals.
Results: Gross deletions in nef/LTR were observed in 3 individuals and mixed
populations of viral species (HIV-1 quasispecies) with deletions and insertions
were seen in several others. Increased genetic diversity in the nef/LTR region,
as measured by the mean nucleotide distance in pairwise comparisons, was
associated with decreased levels of CD4+ T-cells, increased levels of serum
f2-microglobulin and an increased frequency of CCR2b heterozygosity (p <
0.001). Viral diversity did not appear to be a function of duration of infection or
age at infection and did not correlate with plasma levels of HIV-1 RNA, CD8+
T-cells or p24-ICD at the time of sequence determination.
Conclusions: Preliminary results showed that sequence diversity in the
nef/LTR region is variable in LTNPs and suggest that increased viral diversity in the nef/LTR region may be associated with decreased levels of circulating
CD4+ T-cells. However, further investigations are necessary to determine the
exact functional role of these viral species in delaying disease progression.
|187*/13349 Long term survivors under observed effectiveness
of highly active antiretroviral therapy
Alvaro Muioz1, G. McFarlane1, L.K. Schrager2, J.W. Mellors3, J.B. Margolick1,
J.P. Phair4, R. Detels5. 1 Johns Hopkins School of Public Health, Room E7008,
615 N Wolfe Street, Baltimore, MD; 2National Institutes of Health, Bethesda, MD;
3University of Pittsburgh, Pittsburgh, PA; 4Northwestern University Medical
School, Chicago, IL; SUCLA School of Public Health, Los Angeles, CA, USA
Objectives: To estimate, in a large cohort of seroconverters, the percentages of
individuals predicted to be AIDS-free for 20 years or more from HIV seroconversion (SC) under the conditions of treatment usage observed from July 1995 to
June 1997 when highly active antiretroviral therapy (HAART) became available.
Methods: Study population consisted of 475 participants in the Multicenter
AIDS Cohort Study whose SC was observed in 1984 to 1997, and who con
tributed time at risk for AIDS between 1/90 and 6/97. During the period from
1/90 to 6/95, single or combination nucleoside reverse transcriptase inhibitors
(NRTI) were used; while in 7/95 to 6/97, increasing use of HAART (2 NRTIs
+ protease inhibitor) occurred. Using the person-time contributions to the two
calendar periods with years since seroconversion as the time scale, we identified
a parametric model that described and predicted the times to AIDS under the
conditions of the two calendar periods and by age at SC.

Results: From 1/90 to 6/95 and from 7/95 to 6/97, 160 and 23 diagnoses
of clinical AIDS were identified among 461 (1722 person-years) and 288 (491
person-years) SCs, respectively. Median age at SC was 33 years. From 1/90 to
6/95 and from 7/95 to 6/97, the percentages receiving NRTI were 57% and 24%,
and those receiving HAART were 0% and 49%, respectively. Using lognormal
regression, predictions of percentages (95% C.I.) of individuals AIDS-free for
more than 20 years after SC according to treatment practices in the two periods
and age at SC were:
Under Treatment Age at SC:
Practices During 25 years 35 years 45 years
1/1990-6/1995 11.5% (8%, 15%) 8.4% (6%, 11%) 6.0% (4%, 9%)
7/1995-6/1997 35.5% (26%, 45%) 29.2% (21%, 37%) 23.4% (16%, 32%)
Conclusions: HAART have not only reduced the incidence of AIDS but, if their
benefit persists, they will have a very significant (p <.001) effect on increasing
the proportions of long term survivors previously reported (Muhoz, JAIDS 1995).
Long term survivorship increases by 3 to 4 times depending on age (from 25
to 45 years) at which SC occurs. By directly modeling AIDS-free times in seroconverters, results provide important insight into the potential long term HIV care
cost-effectiveness of therapies widely used in populations from 7/95 to 6/97.
133501 The Sydney Blood Bank Cohort infected with an
attenuated quasi species of HIV-1: Long-term
non-progression
Jennifer Learmont1, A. Geczy', C. Raynes-Greenow1, W. Dyer1, L. Ashton2,
J. Mills3, J. Sullivan1. 'Australian Red Cross Blood Service, NSW, 153 Clarence
St., Sydney 2000; 2National Centre for HIV Epideniology, Sydney, NSW;
3MacFarlane Burnet Centre, Melbourne, VIC, Australia
Objective: To present an update of the immunological and virological characteristics of the Sydney Blood Bank Cohort of long-term nonprogressors who are
infected with an attenuated quasi species of HIV-1 which is profoundly attenuated
compared with wild-type strains of HIV-1.
Methods: We carried out cross-sectional and longitudinal analysis on lymphocyte subsets, /.microglobin, neopterin concentration and HIV vital load, and we
quantified cutaneous delayed type hypersensitivity (DTH) reactions. We compared
cumulative survival to AIDS for the SBBC and the other transfusion recipients
aged >13 years at the time of infection.
Results: Three of eight recipients in the SBBC are deceased: two since
1994, at age 77 and 83, of causes clearly unrelated to HIV. Surviving members
of the SBBC are asymptomatic 13 to 17 years after HIV infection, and have
never received antiretroviral treatments. Plasma HIV viral load ranges from <2.3
log copies/ml (below detection) to 3.36 log copies/ml. The three living SBBC
members with detectable viral load have declining CD4 lymphocyte numbers,
ranging from -7.3 to -72.5, cells/ml per year. Two of the three members with
BD vital load have stable CD4 lymph counts while one member has increasing
CD4 lymphocyte counts. All but two members of the SBBC have elevated CD8
lymphocyte counts. No member of the SBBC showed a significant increase in
neopterin or /.microglobulin values. The recipients in the SBBC showed normal
scores for testing delayed type hypersensitivity responses and the donor was
anergic. SBBC transfusion recipients have a longer AIDS free survival than all
other non-paediatric HIV-1 infected, transfusion recipients aged >13 years at
infection on the New South Wales Transfusion Acquired HIV registry. (p < 0.001).
Conclusion: The lack of functional Nef protein has resulted in prolonged delay
in HIV progression. After 14-17 years since infection no member of the SBBC
has clinical signs of HIV progression and none has received therapy. Further
work directed at understanding the biological consequences of long term/low
level HIV-1 replication is clearly warranted.
1133511 Probability of progression and predictivity of
immunological and virological parameters in CCR-5
homozygote and A32 heterozygote long-term
non-progressors (LTNPs)
Massimo Galli', C. Balotta2, M. Clerici2, S. Santambrogio2, A. Di Marco2,
M. Clementi3, P. Bagnarelli4. 1Sacco Hospital University of Milan, Via Abarassi
7420157, Milan; 2University of Milan Milan; 3University of Trieste Trieste;
4 University of Ancona Ancona, Italy
Objectives: To evaluate the predictivity of progression of different immunological
and virologic parameters in a cohort of LTNPs.
Methods: The predictivity of progression of immunological, virological and genetic parameters has been evaluated in 52 HIV-1 infected asymptomatic subjects
who maintained CD4 cell counts >500//OL for a median time of 8.2 years (range
7.2-10.6), after seroconversion. In vitro cytokine production was evaluated by
Elisa assays. CCR-5 genotype (wild type/heterozygote condition) was determined
by PCR on genomic DNA.
Plasma viremia and cellular transcripts were performed by competitive PCR,

viral isolation from PBMCs was performed by cocultivation
Results: The time-dependent cumulative probability of maintaining CD4 cell
counts >500//jL was 75% after 1 year and 58% after two years of follow-up. By
stratifying the population for the CD4 count at enrollement (>800 cell/P L, 600-799
cell/jIL and 500-599 cell/p/L), the probability of presenting a CD4 count <500//IL
was significantly different in the three groups (p = 0.0240). We did not observe
predictive values in CD8 counts, citokine in vitro production, HIV-1 viremia and