Advertisement
Review article| Volume 22, ISSUE 3, P741-757, September 2002

Antivirals against HIV-1

      Clinical illness caused by HIV infection results from the progressive decline of CD4+ T lymphocytes and immune dysregulation associated with viral replication. In untreated individuals, CD4+ T lymphocytes decline by approximately 50 to 100 cells/mm3 annually. As counts decline, typically asymptomatic patients are at increased risk for a variety of opportunistic infections or malignancies associated with impaired cellular immune function or the inability to make appropriate immune responses following exposure to neoantigens. When an individual's CD4+ T lymphocyte count falls below 200 cells/mm3, or s/he develops one of a specified number of opportunistic infections or malignancies, that individual is considered to have AIDS. Morbidity and mortality associated with HIV infection increased rapidly following the recognition of this syndrome in 1981, and by 1994, AIDS was the leading cause of death in the United States among men and women ages 15–45. The antiretroviral therapy era began in 1987 following the Food and Drug Administration (FDA)-approval of zidovudine, a nucleoside analog reverse transcriptase inhibitor; however, it was not until 1996, when HIV viral load assays were developed that could quantify the copy number of HIV RNA present in plasma, that investigators and clinicians could appropriately evaluate the antiviral efficacy of therapy. This important technical breakthrough and the availability of HIV protease inhibitors led to a dramatic decline in the morbidity and mortality associated with the disease [
      • Palella Jr., F.J
      • Delaney K.M
      • Moorman A.C
      • et al.
      Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV outpatient study investigators.
      ], as demonstrated in Fig. 1.
      Figure thumbnail gr1
      Fig. 1Decline in deaths attributable to HIV infection. (From Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV outpatient study investigators. New Eng J Med 1998;338:853–60; with permission.)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribers receive full online access to your subscription and archive of back issues up to and including 2002.

      Content published before 2002 is available via pay-per-view purchase only.

      Subscribe:

      Subscribe to Clinics in Laboratory Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Palella Jr., F.J
        • Delaney K.M
        • Moorman A.C
        • et al.
        Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV outpatient study investigators.
        N Engl J Med. 1998; 338: 853-860
        • Haase A.T
        Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissue.
        Annu Rev Immunol. 1999; 17: 625-656
        • Haase A.T
        • Henry K
        • Zupancic M
        • et al.
        Quantitative image analysis of HIV-1 infection in lymphoid tissue.
        Science. 1996; 274: 985-989
        • Ho D.D
        • Neumann A.U
        • Perelson A.S
        • et al.
        Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.
        Nature. 1995; 373: 123-126
        • Wei X
        • Ghosh S.K
        • Taylor M.E
        • et al.
        Viral dynamics in human immunodeficiency virus type 1 infection.
        Nature. 1995; 373: 117-122
        • Gulick R.M
        • Mellors J.W
        • Havlir D
        • et al.
        Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy.
        N Engl J Med. 1997; 337: 734-743
        • Haggerty S
        • Stevenson M
        Predominance of distinct viral genotypes in brain and lymph node compartments in HIV-1-infected individuals.
        Viral Immunol. 1991; 4: 121-131
        • Overbaugh J
        • Anderson R.J
        • Ndinya-Achola J.O
        • et al.
        Distinct but related human immunodeficiency virus type 1 variant populations in genital secretions and blood.
        AIDS Res Hum Retroviruses. 1996; 12: 107-115
        • Zhu T
        • Wang N
        • Carr A
        • et al.
        Genetic characterization of human immunodeficiency virus type 1 in blood and genital secretions: evidence for viral compartmentalization and selection during sexual transmission.
        J Virol. 1996; 70: 3098-3107
        • Mansky L.M
        • Temin H.M
        Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase.
        J Virol. 1995; 69: 5087-5094
        • Chun T.W
        • Stuyver L
        • Mizell S.B
        • et al.
        Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy.
        Proc Natl Acad Sci USA. 1997; 94: 12193-12197
        • Finzi D
        • Hermankova M
        • Pierson T
        • et al.
        Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy.
        Science. 1997; 278: 1295-1300
        • Wong J.K
        • Hezareh W
        • Gunthard H.F
        • et al.
        Recovery of replication-competent HIV despite prolonged suppression of plasma viremia.
        Science. 1997; 278: 1291-1295
      1. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolecents. Available at: http://www.hivatis.org. Accessed February 15, 2002.

        • Cameron D.W
        • Japour A.J
        • Xu Y
        Ritonavir and saquinavir combination therapy for the treatment of HIV infection.
        AIDS. 1999; 13: 213-224
        • Staszewski S
        • Morales-Ramirez J
        • Tashima K.T
        • et al.
        Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults.
        New Eng J Med. 1999; 341: 1865-1873
        • Gulick R.M
        • Mellors J.W
        • Havlir D
        • et al.
        3-year suppression of HIV viremia with indinavir, zidovudine, and lamivudine.
        Ann Intern Med. 2000; 131: 35-39
        • Dornadula G
        • Zhang H
        • van Uitert B
        • et al.
        Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy.
        JAMA. 1999; 282: 1627-1632
        • Furtado M.R
        • Callaway D.S
        • Phair J.P
        • et al.
        Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy.
        N Engl J Med. 1999; 340: 1614-1622
        • Pakker N.G
        • Notermans D.W
        • de Boer R.J
        • et al.
        Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation.
        Nat Med. 1998; 4: 208-214
        • Lederman M.M
        • Connick E
        • Landay A
        • et al.
        Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: results of AIDS Clinical Trials Group Protocol 315.
        J Infect Dis. 1998; 178: 70-79
        • Douek D.C
        • McFarland R.D
        • Keiser P.H
        • et al.
        Changes in thymic function with age and during the treatment of HIV infection.
        Nature. 1998; 396: 690-695
        • McCune J.M
        • Loftus R
        • Schmidt D.K
        • et al.
        High prevalence of thymic tissue in adults with human immunodeficiency virus-1 infection.
        J Clin Invest. 1998; 101: 2301-2308
        • Autran B
        • Carcelain G
        • Li T.S
        • et al.
        Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease.
        Science. 1997; 277: 112-116
        • Rosenberg E.S
        • Billlingsley J.M
        • Caliendo A.M
        • et al.
        Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia.
        Science. 1997; 278: 1447-1450
      2. Carmona A, Knobel H, Guelar A, et al. Factors influencing survival in HIV infected patients treated with HAART [abstract TuOrB417]. Presented at the 13th International AIDS Conference. Durban, South Africa, 2000.

      3. Walsh JC, Hertogs K, Gazzard B. Viral drug resistance, adherence and pharmacokinetic indices in HIV-1 infected patients on successful and failing protease inhibitor based HAART. Presented at the 40th Interscience Conference of Antimicrobial Agents and Chemotherapy. Toronto, Ontario, Canada, 2000.

        • Paterson D.L
        • Swindells S
        • Mohr J
        • et al.
        Adherence to protease inhibitor therapy and outcomes in patients with HIV infection.
        Ann Intern Med. 2000; 133: 21-30
        • Carr A
        • Samaras K
        • Burton S
        • et al.
        A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors.
        AIDS. 1998; 12: F51-F58
      4. Gharakhanian S, Salhi Y, Nguyen TH, et al. Frequency of lipodystrophy and factors associated with glucose/lipid abnormalities in a cohort of 650 patients treated by protease inhibitors. Presented at the 6th Conference on Retroviruses and Opportunistic Infections. Chicago, IL, 1999.

      5. Thiebaut R, Daucourt V, Malvy D, et al. Lipodystrophy, glucose and lipid metabolism dysfunctions. Presented at the 1st International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. San Diego, CA, 1999.

      6. Bozzette SA, Ake C, Carpenter A, et al. Cardio- and cerebrovascular outcomes with changing process of anti-HIV therapy in 36,766 US verterns. Presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle, WA, 2002.

        • Schuurman R
        • Nijhuis M
        • van Leeuwen R
        • et al.
        Rapid changes in human immunodeficiency virus type 1 RNA load and appearance of drug-resistant virus populations in persons treated with lamivudine (3TC).
        J Infect Dis. 1995; 171: 1411-1419
        • Murphy R.L
        • Gulick R.M
        • DeGruttola V
        • et al.
        Treatment with amprenavir alone or amprenavir with zidovudine and lamivudine in adults with human immunodeficiency virus infection.
        J Infect Dis. 1999; 179: 808-816
        • St. Clair M.H
        • Martin J.L
        • Tudor W.G
        • et al.
        Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase.
        Science. 1991; 253: 1557-1559
      7. Coakley EP, Doweiko JP, Bellosillo NA, et al. HIV drug resistance profiles and clinical and virologic outcomes among HIV-infected subjects with stable detectable plasma viral loads <1,000 copies/mL for at least 12 months. Presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle, WA, 2002.

      8. Whitcomb JM, Paximos EE, Huang W, et al. The presence of nucleoside analogue mutations (NAMs) is highly correlated with reduced susceptibility to all NRTIs. Presented at the 9th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, 2002.

        • Finzi D
        • Blankson J
        • Siliciano J.D
        • et al.
        Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy.
        Nat Med. 1999; 5: 512-517
      9. Charpentier C, Dwyer DE, Lecossier D, et al. Coexistence and coevolution of viral populations with distinct genotypes in patients failing treatment with protease inhibitors. Presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle, WA, 2002.

      10. Whitcomb J, Deeks SG, Huang W, et al. Reduced susceptibility to NRTI is associated with NNRTI hypersensitivity to virus from HIV+ infected patients. Presented at the 7th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA, 2000.

        • Little S.J
        • Daar E.S
        • D'Aquila R.T
        • et al.
        Reduced antiretroviral drug susceptibility among patients with primary HIV infection.
        JAMA. 1999; 282: 1142-1149
      11. Little SJ, Daar ES, Holte S, et al. Persistence of transmitted drug resistance among subjects with primary HIV infection not receiving antiretroviral therapy. Presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle, WA, 2002.

        • Fischl M.A
        • Richman D.D
        • Grieco M.H
        • et al.
        The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial.
        N Engl J Med. 1987; 322: 185-191
        • Volberding P.A
        • Lagakos S.W
        • Koch M.A
        • et al.
        Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter.
        N Engl J Med. 1990; 322: 941-949
        • Deeks S.G
        • Hecht F.M
        • Swanson M
        • et al.
        HIV RNA and CD4 cell count response to protease inhibitor therapy in an urban AIDS clinic: response to both initial and salvage therapy.
        AIDS. 1999; 13: F35-F43
      12. Egger M. Progression of HIV-1 infected drug-naive patients starting potent antiretroviral therapy: multicohort analysis of 12,040 patients [abstract LB-18]. Presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, 2001.

        • Baxter J.D
        • Mayers D.L
        • Wentworth D.N
        • et al.
        A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy.
        AIDS. 2000; 14: F83-F93
      13. Cohen C, Hunt S, Sension M, et al. Phenotypic resistance testing significantly improves response to therapy: a randomized trial (VIRA3001). Presented at the 7th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA, 2002.

      14. Parkin NT, Chappey C, Masoldo L, et al. Incidence and nature of phenotype-genotype discordance: maximizing the utility of resistance testing. Presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle, WA, 2002.