Correspondence
Improvement in CD4+ Cell Counts despite Persistently Detectable HIV Load
N Engl J Med 1998; 338:1074-1075April 9, 1998
- Article
To the Editor:
A major goal of antiretroviral therapy for human immunodeficiency virus (HIV) infection should be to keep the viral load undetectable or at least suppressed as fully as possible.1,2 For patients with detectable viral loads, changes in medication have been advocated on the basis of studies demonstrating that viral load is a surrogate marker for the clinical progression of HIV infection. However, patients who have persistently elevated viral loads despite treatment with highly active antiretroviral agents (generally a protease inhibitor and two reverse-transcriptase inhibitors) have few therapeutic options. There are a limited number of drugs available, and medication cross-resistance, antagonism, and side effects are matters of concern.3
I describe two patients with AIDS treated with salvage regimens of antiretroviral therapy who had dramatic increases in CD4+ T-cell counts and improvement in clinical status despite the presence of persistently elevated HIV viral loads. Patient 1 was a 35-year-old woman who presented in 1992 with eosinophilic folliculitis and a CD4+ T-cell count of 40 per microliter. Patient 2 was a 38-year-old man who presented in 1993 with cryptococcal meningitis and a CD4+ T-cell count of 30 per microliter. The course of both patients was complicated by Pneumocystis carinii pneumonia, recurrent herpes, and severely depressed CD4+ T-cell counts despite treatment with zidovudine, didanosine, stavudine, and lamivudine, alone or in combination. Both patients began a regimen of zidovudine, lamivudine, and indinavir but had elevated viral loads and persistently low CD4+ T-cell counts (Figure 1Figure 1
Changes in Peripheral-Blood CD4+ T-Cell Counts and HIV Viral Load in Patients 1 and 2.). Patient 1 was switched to a regimen of nelfinavir, didanosine, lamivudine, and stavudine in October 1996. Patient 2 was switched to a regimen of ritonavir, saquinavir, didanosine, and stavudine in March 1997. Compliance with medication, as indicated by pharmacy records and patient reporting, was excellent. At the most recent assessment, CD4+ T-cell counts in Patients 1 and 2 had risen to 528 and 375 cells per microliter, respectively, despite only modest falls in the viral load of less than 1 log to 46,110 and 92,850 copies per milliliter, respectively. Neither patient has had further opportunistic infections, and both have returned to work or school.It remains to be seen how long the patients' responses will be maintained. Moreover, the extent to which the elevations in CD4+ T-cell counts reflect other variables pertaining to immunologic reconstitution is unknown.4 Although controlled trials are needed to determine the optimal salvage regimens in patients with elevated viral loads despite treatment with highly active antiretroviral agents, dramatic increases in the CD4+ T-cell count may occur despite the presence of relatively large viral loads. It may be premature for one to change antiretroviral therapy solely on the finding of a detectable viral load, especially in patients for whom therapeutic options are limited.
4 ReferencesStuart M. Levitz, M.D.
Boston Medical Center, Boston, MA 021181
Carpenter CC ,Fischl MA ,Hammer SM , et al. Antiretroviral therapy for HIV infection in 1997: updated recommendations of the International AIDS Society-USA panel. JAMA 1997;277:1962-1969
CrossRef | Web of Science | Medline2
Saag MS . Use of HIV viral load in clinical practice: back to the future. Ann Intern Med 1997;126:983-985
Web of Science | Medline3
McDonald CK ,Kuritzkes DR . Human immunodeficiency virus type 1 protease inhibitors. Arch Intern Med 1997;157:951-959
CrossRef | Web of Science | Medline4
Autran B ,Carcelain G ,Li TS , et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997;277:112-116
CrossRef | Web of Science | Medline
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CrossRef7
J. Spritzler, D. Mildvan, A. Russo, D. Asthana, D. Livnat, B. Schock, J. Kagan, A. Landay, D. W. Haas, . (2003) Can Immune Markers Predict Subsequent Discordance between Immunologic and Virologic Responses to Antiretroviral Therapy? Adult AIDS Clinical Trials Group. Clinical Infectious Diseases 37:4, 551-558
CrossRef8
S. Sirois, E. I. Proynov, J.-F. Truchon, C. M. Tsoukas, D. R. Salahub. (2003) A density functional study of the hydrogen-bond network within the HIV-1 protease catalytic site cleft. Journal of Computational Chemistry 24:9, 1110-1119
CrossRef9
José M. Benito, Mariola López, Juan C. Martín, Sara Lozano, Pilar Martínez, Juan González-Lahoz, Vincent Soriano. (2002) Differences in Cellular Activation and Apoptosis in HIV-Infected Patients Receiving Protease Inhibitors or Nonnucleoside Reverse Transcriptase Inhibitors. AIDS Research and Human Retroviruses 18:18, 1379-1388
CrossRef10
Jacques Izopet, Corinne Souyris, Karine Sandres-Saun
, B
CrossRef11
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CrossRef12
Frank J. Palella, Joan S. Chmiel, Anne C. Moorman, Scott D. Holmberg. (2002) Durability and predictors of success of highly active antiretroviral therapy for ambulatory HIV-infected patients. AIDS 16:12, 1617-1626
CrossRef13
Evan Wood, Robert S. Hogg, Benita Yip, Mark W. Tyndall, Christopher H. Sherlock, Richard P. Harrigan, Michael V. O'Shaughnessy, Julio S.G. Montaner. (2002) “Discordant” Increases in CD4 Cell Count Relative to Plasma Viral Load in a Closely Followed Cohort of Patients Initiating Antiretroviral Therapy. JAIDS Journal of Acquired Immune Deficiency Syndromes 30:2, 159-166
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Fausto Baldanti, Stefania Paolucci, Aldo Parisi, Luca Meroni, Giuseppe Gerna. (2002) Emergence of Multiple Drug‐Resistant Human Cytomegalovirus Variants in 2 Patients with Human Immunodeficiency Virus Infection Unresponsive to Highly Active Antiretroviral Therapy. Clinical Infectious Diseases 34:8, 1146-1149
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Lucia Ometto, Davide De Forni, Fiorulla Patiri, Virginie Trouplin, Fabrizio Mammano, Vania Giacomet, Carlo Giaquinto, Daniel Douek, Richard Koup, Anita De Rossi. (2002) Immune reconstitution in HIV-1-infected children on antiretroviral therapy: role of thymic output and viral fitness. AIDS 16:6, 839-849
CrossRef16
Patrick M. Tarwater, Joseph B. Margolick, Jianhua Jin, John P. Phair, Roger Detels, Charles Rinaldo, Janis Giorgi, Alvaro Muñoz. (2001) Increase and Plateau of CD4 T-Cell Counts in the 3½ Years After Initiation of Potent Antiretroviral Therapy. Journal of Acquired Immune Deficiency Syndromes 27:2, 168-175
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Fausto Baldanti, Stefania Paolucci, Roberto Gulminetti, Renato Maserati, Guglielmo Migliorino, Angelo Pan, Franco Maggiolo, Giuditta Comolli, Antonella Chiesa, Giuseppe Gerna. (2001) Higher levels of HIV DNA in memory and naive CD4+ T cell subsets of viremic compared to non-viremic patients after 18 and 24 months of HAART. Antiviral Research 50:3, 197-206
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Patrick M. Tarwater, Joseph B. Margolick, Jianhua Jin, John P. Phair, Roger Detels, Charles Rinaldo, Janis Giorgi, Alvaro Muñoz. (2001) Increase and Plateau of CD4 T-Cell Counts in the 3½ Years After Initiation of Potent Antiretroviral Therapy. JAIDS Journal of Acquired Immune Deficiency Syndromes 27:2, 168-175
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Gastón R. Picchio, Hernan Valdez, Rebecca Sabbe, Alan L. Landay, Daniel R. Kuritzkes, Michael M. Lederman, Donald E. Mosier. (2000) Altered Viral Fitness of HIV-1 Following Failure of Protease Inhibitor-Based Therapy. JAIDS Journal of Acquired Immune Deficiency Syndromes 25:4, 289-295
CrossRef20
Gast??n R. Picchio, Hernan Valdez, Rebecca Sabbe, Alan L. Landay, Daniel R. Kuritzkes, Michael M. Lederman, Donald E. Mosier. (2000) Altered Viral Fitness of HIV-1 Following Failure of Protease Inhibitor-Based Therapy. Journal of Acquired Immune Deficiency Syndromes289-295
CrossRef21
Evan Wood, Benita Yip, Robert S Hogg, Christopher H Sherlock, Natalie Jahnke, Richard P Harrigan, Michael V O'Shaughnessy, Julio S. G Montaner. (2000) Full suppression of viral load is needed to achieve an optimal CD4 cell count response among patients on triple drug antiretroviral therapy. AIDS 14:13, 1955-1960
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(2000) Highly active antiretroviral therapy including protease inhibitors does not confer a unique CD4 cell benefit. AIDS 14:10, 1383-1388
CrossRef23
W. Jeffrey Fessel, John F. Krowka, Haynes W. Sheppard, Marianne Gesner, Sebastian Tongson, Samuel Weinstein, Michael Ascher, Shirley Kwok, Cindy Christopherson. (2000) Dissociation of Immunologic and Virologic Responses to Highly Active Antiretroviral Therapy. Journal of Acquired Immune Deficiency Syndromes 23:4, 314-320
CrossRef24
Barbara N. Phenix, Jonathan B. Angel, Francis Mandy, Stephen Kravcik, Karl Parato, Kelley A. Chambers, Keith Gallicano, Nanci Hawley-Foss, Sharon Cassol, D. William Cameron, Andrew D. Badley. (2000) Decreased HIV-Associated T Cell Apoptosis by HIV Protease Inhibitors. AIDS Research and Human Retroviruses 16:6, 559-567
CrossRef25
W. Jeffrey Fessel, John F. Krowka, Haynes W. Sheppard, Marianne Gesner, Sebastian Tongson, Samuel Weinstein, Michael Ascher, Shirley Kwok, Cindy Christopherson. (2000) Dissociation of Immunologic and Virologic Responses to Highly Active Antiretroviral Therapy. JAIDS Journal of Acquired Immune Deficiency Syndromes 23:4, 314-320
CrossRef26
Mario Clerici, Elena Seminari, Fredy Suter, Francesco Castelli, Angelo Pan, Mara Biasin, Fulvia Colombo, Daria Trabattoni, Franco Maggiolo, Giampiero Carosi, Renato Maserati. (2000) Different immunologic profiles characterize HIV infection in highly active antiretroviral therapy-treated and antiretroviral-naïve patients with undetectable viraemia. AIDS 14:2, 109-116
CrossRef27
Hernan Valdez, Kimberly Y. Smith, Alan Landay, Elizabeth Connick, Daniel R. Kuritzkes, Harold Kessler, Lawrence Fox, John Spritzler, Joana Roe, Miriam B. Lederman, Howard M. Lederman, Thomas G. Evans, Margo Heath-Chiozzi, Michael M. Lederman. (2000) Response to immunization with recall and neoantigens after prolonged administration of an HIV-1 protease inhibitor-containing regimen. AIDS 14:1, 11-21
CrossRef28
Surendra J. Chavan, Seetha L. Tamma, Mark Kaplan, Merril Gersten, Savita G. Pahwa. (1999) Reduction in T Cell Apoptosis in Patients with HIV Disease Following Antiretroviral Therapy. Clinical Immunology 93:1, 24-33
CrossRef29
Thomas Böhler, Judith Walcher, Gabi Hölzl-Wenig, Magdalena Geiss, Bernd Buchholz, Richard Linde, Klaus-Michael Debatin. (1999) Early effects of antiretroviral combination therapy on activation, apoptosis and regeneration of T cells in HIV-1-infected children and adolescents. AIDS 13:7, 779-789
CrossRef30
Marc Renaud, Christine Katlama, Alain Mallet, Vincent Calvez, Guislaine Carcelain, Roland Tubiana, Marc Jouan, Eric Caumes, Henri Agut, François Bricaire, Patrice Debré, Brigitte Autran. (1999) Determinants of paradoxical CD4 cell reconstitution after protease inhibitor-containing antiretroviral regimen. AIDS 13:6, 669-676
CrossRef31
P.M. Barreiro, M.C. Dona, J. Castilla, V. Soriano. (1999) Patterns of response (CD4 cell count and viral load) at 6 months in HIV-infected patients on highly active antiretroviral therapy. Aids 13:4, 525
CrossRef32
Nadine G. Pakker, Eugene D.M.B. Kroon, Marijke T.L. Roos, Sigrid A. Otto, David Hall, Ferdinand W.N.M. Wit, Dörte Hamann, Marina E. van der Ende, Frans A.P. Claessen, Robert H. Kauffmann, Peter P. Koopmans, Frank P. Kroon, Chris H.H. ten Napel, Herman G. Sprenger, Hugo M. Weigel, Julio S.G. Montaner, Joep M.A. Lange, Peter Reiss, Peter T.A. Schellekens, Frank Miedema. (1999) Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy. AIDS 13:2, 203-212
CrossRef33
C de Mendoza, A Holguín, V Soriano. (1998) False positives for HIV using commercial viral load quantification assays. AIDS 12:15, 2076-2077
CrossRef34
SR Porter, C Scully. (1998) HIV topic update: protease inhibitor therapy and oral health care. Oral Diseases 4:3, 159-163
CrossRef
