The Relation of Virologic and Immunologic Markers to Clinical Outcomes after Nucleoside Therapy in HIV-Infected Adults with 200 to 500 CD4 Cells per Cubic Millimeter
David A. Katzenstein, M.D., Scott M. Hammer, M.D., Michael D. Hughes, Ph.D., Holly Gundacker, M.S., J. Brooks Jackson, M.D., Susan Fiscus, Ph.D., Suraiya Rasheed, M.D., Tarek Elbeik, Ph.D., Richard Reichman, M.D., Anthony Japour, M.D., Thomas C. Merigan, M.D., Martin S. Hirsch, M.D., for The AIDS Clinical Trials Group Study 175 Virology Study Team
Background We studied measures of human immunodeficiency virus(HIV) replication, the viral phenotype, and immune function(CD4 cell counts) and the relation of changes in these indicatorsto clinical outcomes in a subgroup of patients in a controlledtrial of early antiretroviral treatment for HIV, the AIDS ClinicalTrials Group Study 175.
Methods The 391 subjects, each of whom entered the study witha single screening CD4 cell count of 200 to 500 per cubic millimeter,were randomly assigned to receive zidovudine alone, didanosinealone, zidovudine plus didanosine, or zidovudine plus zalcitabine.Plasma concentrations of HIV RNA were assessed in 366 subjects,and viral isolates from 332 subjects were assayed for the presenceof the syncytium-inducing phenotype.
Results After eight weeks, the mean (±SE) decrease frombase line in the concentration of HIV RNA, expressed as thechange in the base 10 log of the number of copies per milliliter,was 0.26±0.06 for patients treated with zidovudine alone,0.65±0.07 for didanosine alone, 0.93±0.10 forzidovudine plus didanosine, and 0.89±0.06 for zidovudineplus zalcitabine (P<0.001 for each of the pairwise comparisonswith zidovudine alone). Multivariate proportional-hazards modelsshowed that higher base-line concentrations of plasma HIV RNA,less suppression of plasma HIV RNA by treatment, and the presenceof the syncytium-inducing phenotype were significantly associatedwith an increased risk of progression to the acquired immunodeficiencysyndrome and death. After adjustment for these measures of viralreplication and for the viral phenotype, CD4 cell counts werenot significant predictors of clinical outcome.
Conclusions Both the risk of the progression of HIV diseaseand the efficacy of antiretroviral therapy are strongly associatedwith the plasma level of HIV RNA and with the viral phenotype.The changes in the plasma concentration of HIV RNA predict thechanges in CD4 cell counts and survival after treatment withreverse-transcriptase inhibitors.
Source Information
From the Stanford University Medical Center, Stanford, Calif. (D.A.K., T.C.M.); Harvard Medical School (S.M.H., A.J., M.S.H.) and Harvard School of Public Health (M.D.H., H.G.), Boston; Case Western Reserve University, Cleveland (J.B.J.); the University of North Carolina, Chapel Hill (S.F.); the University of Southern California, Los Angeles (S.R.); the University of California at San Francisco, San Francisco (T.E.); and the University of Rochester, Rochester, N.Y. (R.R.).
Address reprint requests to Dr. Katzenstein at the Division of Infectious Diseases, S-156, Stanford University Medical Center, Stanford, CA 94305.
Sanders, G. D., Bayoumi, A. M., Holodniy, M., Owens, D. K.
(2008). Cost-Effectiveness of HIV Screening in Patients Older than 55 Years of Age. ANN INTERN MED
148: 889-903
[Abstract][Full Text]
Chen, P., Hubner, W., Spinelli, M. A., Chen, B. K.
(2007). Predominant Mode of Human Immunodeficiency Virus Transfer between T Cells Is Mediated by Sustained Env-Dependent Neutralization-Resistant Virological Synapses. J. Virol.
81: 12582-12595
[Abstract][Full Text]
Perrin, L., Pawlotsky, J. M., Bouvier-Alias, M., Sarrazin, C., Zeuzem, S., Colucci, G.
(2006). Multicenter Performance Evaluation of a New TaqMan PCR Assay for Monitoring Human Immunodeficiency Virus RNA Load. J. Clin. Microbiol.
44: 4371-4375
[Abstract][Full Text]
Foca, M., Moye, J., Chu, C., Matthews, Y., Rich, K., Handelsman, E., Luzuriaga, K., Paul, M., Diaz, C., Women and Infants Transmission Study,
(2006). Gender Differences in Lymphocyte Populations, Plasma HIV RNA Levels, and Disease Progression in a Cohort of Children Born to Women Infected With HIV. Pediatrics
118: 146-155
[Abstract][Full Text]
Sanders, G. D., Bayoumi, A. M., Sundaram, V., Bilir, S. P., Neukermans, C. P., Rydzak, C. E., Douglass, L. R., Lazzeroni, L. C., Holodniy, M., Owens, D. K.
(2005). Cost-Effectiveness of Screening for HIV in the Era of Highly Active Antiretroviral Therapy. NEJM
352: 570-585
[Abstract][Full Text]
Piliero, P. J.
(2003). Early Factors in Successful Anti-HIV Treatment. J Int Assoc Physicians AIDS Care (Chic Ill)
2: 10-20
[Abstract]
DeVange Panteleeff, D., Emery, S., Richardson, B. A., Rousseau, C., Benki, S., Bodrug, S., Kreiss, J. K., Overbaugh, J.
(2002). Validation of Performance of the Gen-Probe Human Immunodeficiency Virus Type 1 Viral Load Assay with Genital Swabs and Breast Milk Samples. J. Clin. Microbiol.
40: 3929-3937
[Abstract][Full Text]
Chernoff, D. N.
(2002). The Significance of HIV Viral Load Assay Precision: A Review of the Package Insert Specifications of Two Commercial Kits. J Int Assoc Physicians AIDS Care (Chic Ill)
1: 134-140
[Abstract]
Kostrikis, L. G., Touloumi, G., Karanicolas, R., Pantazis, N., Anastassopoulou, C., Karafoulidou, A., Goedert, J. J., Hatzakis, A.
(2002). Quantitation of Human Immunodeficiency Virus Type 1 DNA Forms with the Second Template Switch in Peripheral Blood Cells Predicts Disease Progression Independently of Plasma RNA Load. J. Virol.
76: 10099-10108
[Abstract][Full Text]
Dybul, M., Fauci, A. S., Bartlett, J. G., Kaplan, J. E., Pau, A. K.
(2002). Guidelines for Using Antiretroviral Agents among HIV-Infected Adults and Adolescents: The Panel on Clinical Practices for Treatment of HIV. ANN INTERN MED
137: 381-433
[Abstract][Full Text]
Jennings, C., Brambilla, D. J., Bremer, J. W.
(2002). Ratio of Two Successive Optical Densities from the Roche HIV-1 Monitor Test as a Measure of Accuracy of Estimates of Human Immunodeficiency Virus RNA Concentration. J. Clin. Microbiol.
40: 1067-1068
[Abstract][Full Text]
Demeter, L. M., Hughes, M. D., Coombs, R. W., Jackson, J. B., Grimes, J. M., Bosch, R. J., Fiscus, S. A., Spector, S. A., Squires, K. E., Fischl, M. A., Hammer, S. M.
(2001). Predictors of Virologic and Clinical Outcomes in HIV-1-Infected Patients Receiving Concurrent Treatment with Indinavir, Zidovudine, and Lamivudine: AIDS Clinical Trials Group Protocol 320. ANN INTERN MED
135: 954-964
[Abstract][Full Text]
Kahn, J. G., Haile, B., Kates, J., Chang, S.
(2001). Health and Federal Budgetary Effects of Increasing Access to Antiretroviral Medications for HIV by Expanding Medicaid. Am. J. Public Health
91: 1464-1473
[Abstract][Full Text]
Gilbert, P. B., DeGruttola, V., Hammer, S. M., Kuritzkes, D. R.
(2001). Virologic and Regimen Termination Surrogate End Points in AIDS Clinical Trials. JAMA
285: 777-784
[Abstract][Full Text]
Ikuta, K., Suzuki, S., Horikoshi, H., Mukai, T., Luftig, R. B.
(2000). Positive and Negative Aspects of the Human Immunodeficiency Virus Protease: Development of Inhibitors versus Its Role in AIDS Pathogenesis. Microbiol. Mol. Biol. Rev.
64: 725-745
[Abstract][Full Text]
Samri, A., Haas, G., Duntze, J., Bouley, J.-M., Calvez, V., Katlama, C., Autran, B.
(2000). Immunogenicity of Mutations Induced by Nucleoside Reverse Transcriptase Inhibitors for Human Immunodeficiency Virus Type 1-Specific Cytotoxic T Cells. J. Virol.
74: 9306-9312
[Abstract][Full Text]
Gulick, R. M.
(2000). Assessing the Benefits of Antiretroviral Therapy. ANN INTERN MED
133: 471-473
[Full Text]
Emery, S., Bodrug, S., Richardson, B. A., Giachetti, C., Bott, M. A., Panteleeff, D., Jagodzinski, L. L., Michael, N. L., Nduati, R., Bwayo, J., Kreiss, J. K., Overbaugh, J.
(2000). Evaluation of Performance of the Gen-Probe Human Immunodeficiency Virus Type 1 Viral Load Assay Using Primary Subtype A, C, and D Isolates from Kenya. J. Clin. Microbiol.
38: 2688-2695
[Abstract][Full Text]
Paredes, R., Mocroft, A., Kirk, O., Lazzarin, A., Barton, S. E., van Lunzen, J., Katzenstein, T. L., Antunes, F., Lundgren, J. D., Clotet, B., for the EuroSIDA Study Group,
(2000). Predictors of Virological Success and Ensuing Failure in HIV-Positive Patients Starting Highly Active Antiretroviral Therapy in Europe: Results From the EuroSIDA Study. Arch Intern Med
160: 1123-1132
[Abstract][Full Text]
Christopherson, C., Kidane, Y., Conway, B., Krowka, J., Sheppard, H., Kwok, S.
(2000). PCR-Based Assay To Quantify Human Immunodeficiency Virus Type 1 DNA in Peripheral Blood Mononuclear Cells. J. Clin. Microbiol.
38: 630-634
[Abstract][Full Text]
Juste, R. A., Ott, T. L., Kwang, J., Bazer, F. W., de la Concha-Bermejillo, A.
(2000). Effects of recombinant ovine interferon-{tau} on ovine lentivirus replication and progression of disease. J. Gen. Virol.
81: 525-532
[Abstract][Full Text]
Holodniy, M., Rainen, L., Herman, S., Yen-Lieberman, B.
(2000). Stability of Plasma Human Immunodeficiency Virus Load in VACUTAINER PPT Plasma Preparation Tubes during Overnight Shipment. J. Clin. Microbiol.
38: 323-326
[Abstract][Full Text]
Campbell, T. B., Sevin, A., Coombs, R. W., Peterson, G. C., Rosandich, M., Kuritzkes, D. R., Mladenovic, J., Landay, A., Wong, R., Ambruso, D., Miles, S., Pomerantz, R. J., Schooley, R. T., the Adult AIDS Clinical Trials Group 285 Study Tea,
(2000). Changes in human immunodeficiency virus type 1 virus load during mobilization and harvesting of hemopoietic progenitor cells. Blood
95: 48-55
[Abstract][Full Text]
Severson, J. L., Tyring, S. K.
(1999). Relation Between Herpes Simplex Viruses and Human Immunodeficiency Virus Infections. Arch Dermatol
135: 1393-1397
[Abstract][Full Text]
Bucher, H. C., Guyatt, G. H., Cook, D. J., Holbrook, A., McAlister, F. A., for the Evidence-Based Medicine Working Group,
(1999). Users' Guides to the Medical Literature: XIX. Applying Clinical Trial Results; A. How to Use an Article Measuring the Effect of an Intervention on Surrogate End Points. JAMA
282: 771-778
[Full Text]
Valdez, H., Lederman, M. M., Woolley, I., Walker, C. J., Vernon, L. T., Hise, A., Gripshover, B. M.
(1999). Human Immunodeficiency Virus 1 Protease Inhibitors in Clinical Practice: Predictors of Virological Outcome. Arch Intern Med
159: 1771-1776
[Abstract][Full Text]
Michael, N. L., Herman, S. A., Kwok, S., Dreyer, K., Wang, J., Christopherson, C., Spadoro, J. P., Young, K. K. Y., Polonis, V., McCutchan, F. E., Carr, J., Mascola, J. R., Jagodzinski, L. L., Robb, M. L.
(1999). Development of Calibrated Viral Load Standards for Group M Subtypes of Human Immunodeficiency Virus Type 1 and Performance of an Improved AMPLICOR HIV-1 MONITOR Test with Isolates of Diverse Subtypes. J. Clin. Microbiol.
37: 2557-2563
[Abstract][Full Text]
Easterbrook, P. J., Goodall, R. L., Babiker, A. G., Yu, L. M., Smith, D., Cooper, D. A., Gazzard, B. G.
(1999). Are HIV-infected patients with rapid CD4 cell decline a subgroup who benefit from early antiretroviral therapy?. J Antimicrob Chemother
43: 379-388
[Abstract][Full Text]
Zazzi, M., Romano, L., Catucci, M., Venturi, G., De Milito, A., Valensin, P. E.
(1999). Clinical Evaluation of an In-House Reverse Transcription-Competitive PCR for Quantitation of Human Immunodeficiency Virus Type 1 RNA in Plasma. J. Clin. Microbiol.
37: 333-338
[Abstract][Full Text]
Lyles, C. M., Vlahov, D., Farzadegan, H., Astemborski, J., Margolick, J. B., Masters, B. A., Schroeder, J., Quinn, T. C.
(1998). Comparison of Two Measures of Human Immunodeficiency Virus (HIV) Type 1 Load in HIV Risk Groups. J. Clin. Microbiol.
36: 3647-3652
[Abstract][Full Text]
Segondy, M., Ly, T.-D., Lapeyre, M., Montes, B.
(1998). Evaluation of the Nuclisens HIV-1 QT Assay for Quantitation of Human Immunodeficiency Virus Type 1 RNA Levels in Plasma. J. Clin. Microbiol.
36: 3372-3374
[Abstract][Full Text]
Segondy, M., Izopet, J., Pellegrin, I., Montes, B., Dumon, B., Pasquier, C., Peeters, M., Fleury, H. J. A., Puel, J., Reynes, J.
(1998). Comparison of the QUANTIPLEX HIV-1 RNA 2.0 Assay with the AMPLICOR HIV-1 MONITOR 1.0 Assay for Quantitation of Levels of Human Immunodeficiency Virus Type 1 RNA in Plasma of Patients Receiving Stavudine-Didanosine Combination Therapy. J. Clin. Microbiol.
36: 3392-3395
[Abstract][Full Text]
Grovit-Ferbas, K., Ferbas, J., Gudeman, V., Sadeghi, S., Goetz, M. B., Giorgi, J. V., Chen, I. S. Y., O'Brien, W. A.
(1998). Potential Contributions of Viral Envelope and Host Genetic Factors in a Human Immunodeficiency Virus Type 1-Infected Long-Term Survivor. J. Virol.
72: 8650-8658
[Abstract][Full Text]
Pialoux, G., Raffi, F., Brun-Vezinet, F., Meiffredy, V., Flandre, P., Gastaut, J.-A., Dellamonica, P., Yeni, P., Delfraissy, J.-F., Aboulker, J.-P., The Trilege (Agence Nationale de Recherches sur le,
(1998). A Randomized Trial of Three Maintenance Regimens Given after Three Months of Induction Therapy with Zidovudine, Lamivudine, and Indinavir in Previously Untreated HIV-1-Infected Patients. NEJM
339: 1269-1276
[Abstract][Full Text]
(1998). Antiretroviral Therapy and Medical Management of Pediatric HIV Infection. Pediatrics
102: 1005-1062
[Full Text]
Petersen, L. A
(1998). Recent advances: General medicine. BMJ
317: 792-795
[Full Text]
Deeks, S. G., Barditch-Crovo, P., Lietman, P. S., Hwang, F., Cundy, K. C., Rooney, J. F., Hellmann, N. S., Safrin, S., Kahn, J. O.
(1998). Safety, Pharmacokinetics, and Antiretroviral Activity of Intravenous 9-[2-(R)-(Phosphonomethoxy)propyl]adenine, a Novel Anti-Human Immunodeficiency Virus (HIV) Therapy, in HIV-Infected Adults. Antimicrob. Agents Chemother.
42: 2380-2384
[Abstract][Full Text]
Carpenter, C. C. J., Fischl, M. A., Hammer, S. M., Hirsch, M. S., Jacobsen, D. M., Katzenstein, D. A., Montaner, J. S. G., Richman, D. D., Saag, M. S., Schooley, R. T., Thompson, M. A., Vella, S., Yeni, P. G., Volberding, P. A.
(1998). Antiretroviral Therapy for HIV Infection in 1998: Updated Recommendations of the International AIDS Society-USA Panel. JAMA
280: 78-86
[Abstract][Full Text]
Vener, T., Nygren, M., Andersson, A., Uhlén, M., Albert, J., Lundeberg, J.
(1998). Use of Multiple Competitors for Quantification of Human Immunodeficiency Virus Type 1 RNA in Plasma. J. Clin. Microbiol.
36: 1864-1870
[Abstract][Full Text]
Arts, E. J., Quinones-Mateu, M. E., Albright, J. L., Marois, J.-P., Hough, C., Gu, Z., Wainberg, M. A.
(1998). 3'-Azido-3'-Deoxythymidine (AZT) Mediates Cross-Resistance to Nucleoside Analogs in the Case of AZT-Resistant Human Immunodeficiency Virus Type 1 Variants. J. Virol.
72: 4858-4865
[Abstract][Full Text]
Chan, K. S., Revicki, D. A.
(1998). Changes in Surrogate Laboratory Markers, Clinical Endpoints, and Health-Related Quality of Life in Patients Infected with the Human Immunodeficiency Virus. Eval Health Prof
21: 265-281
[Abstract]
Bartlett, J. A.
(1998). Strategies of Antiretroviral Therapy in Adults. The Oncologist
3: 111-118
[Abstract][Full Text]
Palella, F. J., Delaney, K. M., Moorman, A. C., Loveless, M. O., Fuhrer, J., Satten, G. A., Aschman, D. J., Holmberg, S. D., The HIV Outpatient Study Investigators,
(1998). Declining Morbidity and Mortality among Patients with Advanced Human Immunodeficiency Virus Infection. NEJM
338: 853-860
[Abstract][Full Text]
Montaner, J. S. G., Reiss, P., Cooper, D., Vella, S., Harris, M., Conway, B., Wainberg, M. A., Smith, D., Robinson, P., Hall, D., Myers, M., Lange, J. M. A., for the INCAS Study Group,
(1998). A Randomized, Double-blind Trial Comparing Combinations of Nevirapine, Didanosine, and Zidovudine for HIV-Infected Patients: The INCAS Trial. JAMA
279: 930-937
[Abstract][Full Text]
Palumbo, P. E., Raskino, C., Fiscus, S., Pahwa, S., Fowler, M. G., Spector, S. A., Englund, J. A., Baker, C. J.
(1998). Predictive Value of Quantitative Plasma HIV RNA and CD4+ Lymphocyte Count in HIV-Infected Infants and Children. JAMA
279: 756-761
[Abstract][Full Text]
Nolte, F. S., Boysza, J., Thurmond, C., Clark, W. S., Lennox, J. L.
(1998). Clinical Comparison of an Enhanced-Sensitivity Branched-DNA Assay and Reverse Transcription-PCR for Quantitation of Human Immunodeficiency Virus Type 1 RNA in Plasma. J. Clin. Microbiol.
36: 716-720
[Abstract][Full Text]
(1998). Advances in the Virology of HIV Infection and Implications for Clinical Management. AIDS Clin Care
1998: 1-1
[Full Text]
Yerly, S., Perneger, T. V., Hirschel, B., Dubuis, O., Matter, L., Malinverni, R., Furrer, H., Perrin, L., for the Swiss HIV Cohort Study,
(1998). A Critical Assessment of the Prognostic Value of HIV-1 RNA Levels and CD4+ Cell Counts in HIV-Infected Patients. Arch Intern Med
158: 247-252
[Abstract][Full Text]
Vlahov, D., Graham, N., Hoover, D., Flynn, C., Bartlett, J. G., Margolick, J. B., Lyles, C. M., Nelson, K. E., Smith, D., Holmberg, S., Farzadegan, H.
(1998). Prognostic Indicators for AIDS and Infectious Disease Death in HIV-Infected Injection Drug Users: Plasma Viral Load and CD4+ Cell Count. JAMA
279: 35-40
[Abstract][Full Text]
Hammer, S. M., Squires, K. E., Hughes, M. D., Grimes, J. M., Demeter, L. M., Currier, J. S., Eron, J. J., Feinberg, J. E., Balfour, H. H., Deyton, L. R., Chodakewitz, J. A., Fischl, M. A., Phair, J. P., Pedneault, L., Nguyen, B.-Y., Cook, J. C., The AIDS Clinical Trials Group 320 Study Team,
(1997). A Controlled Trial of Two Nucleoside Analogues plus Indinavir in Persons with Human Immunodeficiency Virus Infection and CD4 Cell Counts of 200 per Cubic Millimeter or Less. NEJM
337: 725-733
[Abstract][Full Text]
Gulick, R. M., Mellors, J. W., Havlir, D., Eron, J. J., Gonzalez, C., McMahon, D., Richman, D. D., Valentine, F. T., Jonas, L., Meibohm, A., Emini, E. A., Chodakewitz, J. A., Deutsch, P., Holder, D., Schleif, W. A., Condra, J. H.
(1997). Treatment with Indinavir, Zidovudine, and Lamivudine in Adults with Human Immunodeficiency Virus Infection and Prior Antiretroviral Therapy. NEJM
337: 734-739
[Abstract][Full Text]
Cavert, W., Notermans, D. W., Staskus, K., Wietgrefe, S. W., Zupancic, M., Gebhard, K., Henry, K., Zhang, Z., Mills, R., McDade, H., Goudsmit, J., Danner, S. A., Haase, A. T.
(1997). Kinetics of Response in Lymphoid Tissues to Antiretroviral Therapy of HIV-1 Infection. Science
276: 960-964
[Abstract][Full Text]
(1997). Major advances in the treatment of HIV-1 infection. DTB
35: 25-29
[Abstract][Full Text]
Phillips, A. N., Smith, G. D., Feder, H. M., Milch, L. R., Srinivasan, V., Beidas, S. O., Corey, L., Holmes, K. K., Katzenstein, D., The AIDS Clinical Trials Group, , Study 175 Investigators,
(1997). Viral Load and Combination Therapy for Human Immunodeficiency Virus. NEJM
336: 958-961
[Full Text]
(1996). Patterns Emerge from ACGT 175, Delta, and CPCRA 007. AIDS Clin Care
1996: 3-3
[Full Text]
Corey, L., Holmes, K. K.
(1996). Therapy for Human Immunodeficiency Virus Infection -- What Have We Learned?. NEJM
335: 1142-1144
[Full Text]
A correction has been published: N Engl J Med 1997;337(15):1097.
Previous
