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Prognostic Value of HIV-1 Syncytium-Inducing Phenotype for Rate of CD4+ Cell Depletion and Progression to AIDS

Maarten Koot, MSc; Ireneus P. M. Keet, MD; Aster H. V. Vos; Ruud E. Y. de Goede, BSc; Marijke Th. L. Roos, BSc; Roel A. Coutinho, MD, PhD; Frank Miedema, PhD; Peter Th. A. Schellekens, MD, PhD; and Matthijs Tersmette, MD, PhD
[+] Article and Author Information

From the Netherlands Red Cross Blood Transfusion Service, the University of Amsterdam, Amsterdam, The Netherlands; the Municipal Health Service, Amsterdam, The Netherlands. Requests for Reprints: M. Tersmette, MD, PhD, Department of Clinical Viro-Immunology, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, P.O. Box 9406, 1006 AK Amsterdam, The Netherlands. Acknowledgments: The authors thank M. Bakker and N. Albrecht van Lent for technical assistance, Drs. W. Schaasberg and C. Kuiken for statistical analysis, and Drs. G.J.A. Offerhaus and H. Schuitemaker for critically reading the manuscript; as well as thank MRC AIDS Research Project, Hertfordshire, United Kingdom, for providing the MT-2 cells. Grant Support: By RGO/WVC (Ministry of Public Health, no. 90016) and the Netherlands Foundation of Preventive Medicine (28-1079). Dr. Frank Miedema is a senior fellow of the Royal Netherlands Academy of Art and Sciences.


Copyright 2004 by the American College of Physicians


Ann Intern Med. 1993;118(9):681-688. doi:10.7326/0003-4819-118-9-199305010-00004
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Objective: To investigate the relation between detection of syncytium-inducing (SI), human immunodeficiency virus type 1 (HIV-1) variants, rate of CD4+ cell decline, and clinical progression.

Design: Prospective study during a 2.5-year follow-up period; cohort study with pairwise matched controls.

Setting: The Amsterdam cohort study on the course of HIV-1 infection in homosexual men.

Participants: Asymptomatic HIV-1-infected men (n = 225) were tested for the presence of SI variants and were studied prospectively for CD4+ cell decline and clinical progression. In addition, 45 men with a defined moment of appearance of SI variants and45 matched controls without SI variants were compared for CD4+ cell decline.

Measurements: Syncytium-inducing variants were detected by cocultivation of peripheral blood mononuclear cells with the MT-2 T-cell line.

Results: During a 30-month period, 70.8% of the men with SI variants progressed to AIDS, compared with 15.8% of men without SI variants at entry (P<0.0001). Multivariable Cox proportional-hazard analysis, controlling for CD4+ cell count and HIV-p24 antigenemia, showed a relative hazard for SI variants of 6.7 (95% CI, 3.5 to 12.7). In the matched control study, before the appearance of SI variants, CD4+ cell counts of 45 men with SI variants and their controls were compared. Syncytium-inducing variants emerged at a mean CD4+ cell count of 0.48 109/L (CI, 0.42 to 0.54), coinciding with the onset of a threefold increased rate of CD4+ cell decline. Men developing AIDS with SI variants had decreased CD4+ cell counts (0.08 109/L; 95% CI, 0.05 to 0.12) at the time of diagnosis compared with persons progressing to AIDS without SI variants (0.25 109/L; 95% CI, 0.15 to 0.41) (P = 0.0035).

Conclusions: The HIV-1 biological phenotype is a practical, binary marker for progression to AIDS, which is independent of decreased CD4+ cell counts and antigenemia. Appearance of SI variants, occurring 2 years before progression to AIDS on the average, is predictive for a significantly increased rate of CD4+ cell decline.

Figures

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Figure 1.
Kaplan-Meier plot of the cumulative progression to AIDS of 188 nonzidovudine-treated men.

Patients were stratified according to their HIV-1 phenotype at the start of the study. The numbers of men at risk for each time point is indicated. NSI = nonsyncytium-inducing isolates; SI = syncytium-inducing isolates.

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Figure 2.
Cumulative progression to AIDS after phenotype conversion.

Nonzidovudine-treated, asymptomatic cohort men were aligned for the moment of viral phenotype conversion (time zero). The number of men at risk for each time point is indicated.

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Figure 3.
CD4+ cell counts (mean SE) of the 188 men in the prospective study.nnn

The men were stratified into three groups according to the evolution of their viral phenotype during the study as follows: SI variants absent (NSI) until the end of follow-up ( = 144); conversion from NSI to SI variants in the course of the study ( = 22); SI variants already present at entry into the study ( = 22). NSI = nonsyncytium-inducing isolates; SI = syncytium-inducing isolates.

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Figure 4.
CD4+ cell counts (mean SE) related to HIV-1 phenotype conversion.

Forty-five control men without SI isolates (A) were aligned for the match moment with the 45 patients (time zero). Men with SI isolates (B) were aligned for the moment of phenotype conversion (time zero). The bold arrow indicates the mean CD4+ cell count at the time of NSI to SI phenotype conversion. The number of men analyzed at each time point is indicated. NSI = nonsyncytium-inducing isolates; SI = syncytium-inducing isolates.

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Figure 5.
CD4+ cell counts (mean SE) before AIDS related to HIV-1 phenotype.

Patients were stratified according to HIV-1 phenotype at the moment of AIDS diagnosis and were aligned for the moment of AIDS diagnosis (time zero). The number of patients analyzed at each time point in both groups is indicated. NSI = nonsyncytium-inducing isolates; SI = syncytium-inducing isolates.

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