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January 8, 1997, Vol 277, No. 2 >
ARTICLE | January 8, 1997

HIV-1 Protease Inhibitors: Title and subTitle BreakA Review for Clinicians FREE

Steven G. Deeks, MD; Mark Smith, MD, MBA; Mark Holodniy, MD; James O. Kahn, MD
[+] Author Affiliations

Dr Deeks has received honoraria from Merck, Hoffmann-La Roche, Glaxo Wellcome, Bristol-Myers Squibb, and Agouron. Dr Kahn has received honoraria from Merck, Glaxo Wellcome, Bristol-Myers Squibb, and Agouron. Clinical trials supported by Merck, Glaxo Wellcome, Bristol-Myers Squibb, Hoffmann-LaRoche, Gilead Sciences, and Agouron provide the University of California support for studies directed by Drs Kahn and Deeks.

Reprints: James Kahn, MD, University of California, San Francisco, 995 Potrero Ave, San Francisco General Hospital, San Francisco, CA 94110 (e-mail: jkahn@sfaids.ucsf.edu).


JAMA. 1997;277(2):145-153. doi:10.1001/jama.1997.03540260059037
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Article
References

Objective.  —The clinical care of people infected with human immunodeficiency virus (HIV) has been substantially affected by the introduction of HIV-specific protease inhibitors (Pis). The 4 Pls available are saquinavir mesylate, ritonavir, indinavir sulfate, and nelfinavir mesylate. Comparison studies have not been reported; therefore, an assessment of the available data to aid clinicians and patients in choosing appropriate treatment will be presented.

Data Sources.  —A systematic review of peer-reviewed publications, abstracts from national and international conferences, and product registration information through September 1996.

Study Selection and Data Extraction.  —Criteria used to select studies include their relevance to Pls, having been published in the English language, and pertinence for clinicians. Data quality and validity included the venue of the publication and relevance to clinical care.

Data Synthesis.  —Oral adminstration of ritonavir, indinavir, or nelfinavir generates sustainable drug serum levels to effectively inhibit the protease enzyme; however, saquinavir may not generate sustained levels necessary to inhibit the protease enzyme. Patients treated with ritonavir, indinavir, or nelfinavir experience similar reductions in viral load and increases in CD4+ lymphocytes; smaller effects occur among those treated with saquinavir. Two randomized placebo-controlled studies conducted among patients with severe immune system suppression and substantial zidovudine treatment experience demonstrated reduced HIV disease progression and reduced mortality with PI treatment. Genotypic resistance to Pls occurs; the clinical relevance of resistance is unclear. The costs of these agents including required monitoring impose new and substantial costs.

Conclusions.  —The Pls have emerged as critical drugs for people with HIV infection. Optimal use involves combination with reverse transcriptase inhibitors. Resistance develops to each agent, and cross-resistance is likely. These agents must be used at full doses with attention to ensuring patient compliance. The expense of these agents may be offset by forestalling disease progression and death and returning people to productive life. Selecting the initial PI must be individualized, and factors to consider include proven activity, possible toxicities, dosing regimens, drug interactions, and costs.

REFERENCES

1 +
Carpenter CCJ, Fischl MA, Hammer SM, et al, for the International AIDS Society—USA.  Antiretroviral therapy for HIV infection in 1996: recommendations of an international panel . JAMA . 1996;;276:146-154.
2 +
Kohl NE, Emini EA, Scheif WA, et al.  Active human immunodeficiency virus protease is required for viral infectivity . Proc Natl Acad Sci U S A . 1988;;85:4686-4690.
3 +
Roberts NA, Martin JA, Kinchington D, et al.  Rational design of peptide-based HIV proteinase inhibitors . Science . 1990;;248:358-361.
4 +
Navia MA, Fitzgerald PMD, McKeever BM, et al.  Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1 . Nature . 1989;;337:615-620.
5 +
Wlodawer A, Miller M, Jaskolski M, et al.  Conserved folding in retroviral proteinases: crystal structure of a synthetic HIV-1 protease . Science . 1989;;245:616-621.
6 +
Invirase (saquinavir mesylate) package insert. Nutley, NJ: Roche Laboratories; Hoffman-LaRoche Inc.
7 +
Norbeck D, Kumar G, Marsh K, et al. Ritonavir and saquinavir: potential for two-dimensional synergy between HIV protease inhibitors. In: Programs and abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society for Microbiology; September 17-20, 1995; San Francisco, Calif. Abstract LB7.
8 +
Cohen C, Sun E, Cameron W, et al. Ritonavirsaquinavir combination treatment in HIV-infected patients. In: Program and abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society for Microbiology; September 15-18,1996; New Orleans, La. Abstract LB7b.
9 +
Norvir (ritonavir) package insert. Abbott Park, Ill: Abbott Pharmaceuticals.
10 +
Crixivan (indinavir sulfate) package insert. West Point, Pa: Merck and Company Inc.
11 +
Viracept (nelfinavir mesylate, AG1343). Expanded Access Program protocol AG1343-515. Agouron Pharmaceuticals: San Diego, Calif.
12 +
Collier AC, Coombs RW, Schoenfeld DA, et al, for the AIDS Clinical Trials Group.  Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine . N Engl J Med . 1996;;334:1011-1017.
13 +
Cameron W, Heath-Chiozzi M, Kravcik S, et al. Prolongation of life and prevention of AIDS in advanced HIV immunodeficiency with ritonavir. In: Program and abstracts of the Third Conference on Retroviruses and Opportunistic Infections; January 28-February 1,1996; Washington, DC. Abstract LB6a.
14 +
Norvir (ritonavir) package insert, revised November 1996. Abbott Park, Ill: Abbott Pharmaceuticals.
15 +
Gathe J, Burkhardt B, Hawley P, Conant M, Peterkin J, Chapman S. A randomized phase II study of Viracept, a novel HIV protease inhibitor, used in combination with stavudine vs stavudine alone. In: Program and abstracts of the XI International Conference on AIDS; July 7-12,1996; Vancouver, British Columbia. Abstract MoB413.
16 +
McQuade TJ, Tomasselli AG, Liu L, et al.  A synthetic HIV-1 protease inhibitor with antiviral activity arrests HIV-like particle maturation . Science . 1990;;247:454-456.
17 +
Meek TD, Labert DM, Dreyer BB, et al.  Inhibition of HIV-1 protease in infected T-lymphocytes by synthetic peptide analogues . Nature . 1990;;343:90-92.
18 +
Craig JC, Duncan IB, Hockley D, Grief C, Roberts NA, Mills JS.  Antiviral properties of Ro 31-8959, an inhibitor of human immunodeficiency virus (HIV) proteinase . Antiviral Res . 1991;;16:295-305.
19 +
Vaca JP, Dorsey BD, Schleif WA, et al.  L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor . Proc Natl Acad Sci U S A . 1994;;91:4096-4100.
20 +
Kempf DJ, Marsh KC, Paul D, et al.  Antiviral and pharmacokinetic properties of C2 symmetric inhibitors of the human immunodeficiency virus type 1 protease . Antimicrob Agents Chemother . 1991;;35:2209-2214.
21 +
Kempf DJ, Marsh KC, Denissen JF, et al.  ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has a high oral bioavailability in humans . Proc Natl Acad Sci U S A . 1995;;92:2484-2488.
22 +
Danner SA, Carr A, Leonard JM, et al, for the European-Australian Collaborative Ritonavir Study Group.  A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease . N Engl J Med . 1995;;333:1528-1533.
23 +
Gulick R, Mellors J, Havlir D, et al. Potent and sustained antiretroviral activity of indinavir in combination with zidovudine and lamivudine. In: Program and abstracts of the Third Conference on Retroviruses and Opportunistic Infections; January 28-February 1, 1996; Washington, DC. Abstract LB7.
24 +
Schapiro JM, Winters MA, Stewart F, et al.  The effect of high dose saquinavir on viral load and CD4+ T cell counts in HIV-infected patients . Ann Intern Med . 1996;;124:1039-1050.
25 +
Lalezari J, Haubrich R, Burger HU, et al. Improved survival and decreased progression of HIV in patients treated with saquinavir (Invirase, SQV) plus HIVID (zalcitabine, ddC). In: Program and abstracts of the XI International Conference on AIDS; July 7-12,1996; Vancouver, British Columbia. Abstract LB.B.6033.
26 +
Markowitz M, Saag M, Powderly WG, et al.  A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection . N Engl J Med . 1995;;333:1534-1539.
27 +
Cameron DW, Heath-Chiozzi M, Kravick S, Mills R, Potthoff A, Henry D, for the Advanced HIV Ritonavir Study Group. Prolongation of life and prevention of AIDS complications in advanced HIV immunodeficiency with ritonavir update. In: Program and abstracts of the XI International Conference on AIDS; July 7-12,1996; Vancouver, British Columbia. Abstract MoB411.
28 +
Nabulsi A, Revicki D, Conway D, Maurath C, Mill R, Leonard J. Quality of life consequences of adding ritonavir to current antiviral therapy for advanced HIV patients. In: Program and abstracts of the XI International Conference on AIDS; July 7-12,1996; Vancouver, British Columbia. Abstract LB.B.6046.
29 +
Heath-Chiozzi M, Leonard J, Henry D, et al. Anti-HIV activity and lymphocyte surrogate marker response dynamics to ritonavir therapy in advanced HIV immunodeficiency. In: Program and abstracts of the Third Conference on Retroviruses and Opportunistic Infections; January 28-February 1,1996; Washington, DC. Abstract LB6b.
30 +
Berry P, Kahn J, Cooper R, et al. Antiretroviral activity and safety of indinavir (IDV) alone and in combination with zidovudine (ZDV) in ZDV-naive patients with CD4 cell counts of 50-500 cells/mm3. In: Program and abstracts of the XI International Conference on AIDS; July 7-12, 1996; Vancouver, British Columbia. Abstract Th.B.6019.
31 +
Gulick R, Mellors J, Havlir D, et al. Potent and sustained antiretroviral activity of indinavir (IDV), zidovudine (ZDV) and lamivudine (3TC). In: Program and abstracts of the XI International Conference on AIDS; July 7-12,1996; Vancouver, British Columbia. Abstract Th.B.931.
32 +
Coffin JM.  HIV Population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy . Science . 1995;;267:483-489.
33 +
Saag MS, Holodniy M, Kuritzkes DR, et al.  HIV viral load markers in clinical practice: recommendations of an International AIDS Society—USA Expert Panel . Nat Med . 1996;;2:625-629.
34 +
Boucher C, Nijhuis M, Schipper P, et al. Detection of drug sensitive infectious HIV-1 after one year of ritonavir treatment in a patient with persistent undetectable plasma HIV-1 RNA. In: Abstracts of the Fifth International Workshop on HIV Drug Resistance; July 3-6, 1996; Whistler, British Columbia. Abstract 70.
35 +
Markowitz M, Cao Y, Hurley A, et al. Triple therapy with AZT and 3TC in combination with nelfinavir mesylate in 12 antiretroviral-naive subjects chronically infected with HIV-1. In: Program and abstracts of the XI International Conference on AIDS; July 7-12, 1996; Vancouver, British Columbia. Abstract LB.B.6031.
36 +
Markowitz M, Mo H, Kempf D, et al.  Selection and analysis of human immunodeficiency virus type 1 variants with increased resistance to ABT-538, a novel protease inhibitor . J Virol . 1995;;69:701-706.
37 +
Jacobsen H, Hanggi M, Ott M, et al.  In vivo resistance to a human immunodeficiency virus type 1 proteinase inhibitor: mutations, kinetics, and frequencies . J Infect Dis . 1996;;173:1379-1387.
38 +
Markowitz M, Cao Y, Hurley A, et al. Triple therapy with AZT, 3TC, and ritonavir in 12 subjects newly infected with HIV-1. In: Program and abstracts of the XI International Conference on AIDS; July 7-12,1996; Vancouver, British Columbia. Abstract Th.B.933.
39 +
Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD.  HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time . Science . 1996;;271:1582-1586.
40 +
Perelson AS, Essunger P, Markowitz M, Ho D. How long should treatment be given if we had an antiretroviral regimen that completely blocks HIV replication. In: Program and abstracts of the XI International Conference on AIDS; July 7-12,1996; Vancouver, British Columbia. Abstract Th.B.390.
41 +
Salminen MO, Robertson D, Sharp PM, Han BH, Burker DS, McCutchan RE. Continuous in vivo recombination between HIV-1 strains of genetic subtypes A and C. In: Program and abstracts of the XI International Conference on AIDS; July 7-12,1996; Vancouver, British Columbia. Abstract TuA511.
42 +
Condra JH, Schleif WA, Blahy OM, et al.  In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors . Nature . 1995;;374:569-571.
43 +
Eberle J, Bechowsky B, Rose D, et al.  Resistance of HIV type 1 protease inhibitor Ro 31-8959 . AIDS Res Hum Retroviruses . 1995;;11:671-676.
44 +
Condra JH, Schleif WA, Blahy OM, et al. In vivo evolution of resistance to the HIV-1 protease inhibitor indinavir. In: Program and abstracts of the 3rd Conference on Retroviruses and Opportunistic Infections; January 28-February 1, 1996; Washington, DC. Abstract 145.
45 +
Condra JH, Holder DJ, Schleif WA, et al.  Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor . J Virol . 1996;;70:8270-8276.
46 +
Molla A, Korneyeva M, Gao Q, et al.  Ordered accumulation of mutations in HIV-1 protease confers resistance to ritonvair . Nat Med . 1996;;2:760-766.
47 +
Patick AK, Duran M, Cao Y. Genotypic and phenotypic characterization of HIV-1 variance isolated from in vitro selection studies and from patients treated with the protease inhibitor, nelfinavir. In: Abstracts of the Fifth International Workshop on HIV Drug Resistance; July 3-6,1966; Whistler, British Columbia. Abstract 29.
48 +
Emini E, Condra JH, Schleif WA, et al. Maintenance of long-term virus suppression in patients treated with the HIV-1 protease inhibitor, Crixivan (indinavir). In: Program and abstracts of the XI International Conference on AIDS; July 7-12,1996; Vancouver, British Columbia. Abstract MO.B.170.
49 +
Korneyeva M, Molla A, Kempf D, et al. Clinical and virological responses to ritonavir, an inhibitor of HIV protease. In: Program and abstracts of the XI International Conference on AIDS; July 7-12, 1996; Vancouver, British Columbia. Abstract MO.B.1137.
50 +
Condra JH, Holder DJ, Schleif WA, et al. Bidirectional inhibition of HIV-1 drug resistance selection by combination therapy with indinavir and reverse transcriptase inhibitors. In: Program and abstracts of the XI International Conference on AIDS; July 7-12, 1996; Vancouver, British Columbia. Abstract Th.B.932.
51 +
Winslow R.  Health plans to cover new AIDS drugs, but issues of cost, treatment remain . Wall Street Journal . (July 12) , 1996;:A2.
52 +
Ho DD.  Time to hit HIV: early and hard . N Engl J Med . 1995;;333:450-451.
53 +
Information Marketing System America. National Prescription Audit. Plymouth Meeting, Pa: 1996.
54 +
People With AIDS (PWA) Health Group. Protease Inhibitors At-A-Glance Fact Sheet . New York, NY: People With AIDS Working for Health Inc; 1996;.
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Pollard R, Petersen D, Hardy D, et al. Stavudine (d4T) and didanosine (ddI) combination therapy in HIV-infected subjects: antiviral effect and safety in an ongoing pilot randomized double-blind trial. In: Program and abstracts of the XI International Conference on AIDS; July 7-12, 1996; Vancouver, British Columbia. Abstract ThB293.

Figures

Tables

Interactive Graphics

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Carpenter CCJ, Fischl MA, Hammer SM, et al, for the International AIDS Society—USA.  Antiretroviral therapy for HIV infection in 1996: recommendations of an international panel . JAMA . 1996;;276:146-154.
2 +
Kohl NE, Emini EA, Scheif WA, et al.  Active human immunodeficiency virus protease is required for viral infectivity . Proc Natl Acad Sci U S A . 1988;;85:4686-4690.
3 +
Roberts NA, Martin JA, Kinchington D, et al.  Rational design of peptide-based HIV proteinase inhibitors . Science . 1990;;248:358-361.
4 +
Navia MA, Fitzgerald PMD, McKeever BM, et al.  Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1 . Nature . 1989;;337:615-620.
5 +
Wlodawer A, Miller M, Jaskolski M, et al.  Conserved folding in retroviral proteinases: crystal structure of a synthetic HIV-1 protease . Science . 1989;;245:616-621.
6 +
Invirase (saquinavir mesylate) package insert. Nutley, NJ: Roche Laboratories; Hoffman-LaRoche Inc.
7 +
Norbeck D, Kumar G, Marsh K, et al. Ritonavir and saquinavir: potential for two-dimensional synergy between HIV protease inhibitors. In: Programs and abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society for Microbiology; September 17-20, 1995; San Francisco, Calif. Abstract LB7.
8 +
Cohen C, Sun E, Cameron W, et al. Ritonavirsaquinavir combination treatment in HIV-infected patients. In: Program and abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society for Microbiology; September 15-18,1996; New Orleans, La. Abstract LB7b.
9 +
Norvir (ritonavir) package insert. Abbott Park, Ill: Abbott Pharmaceuticals.
10 +
Crixivan (indinavir sulfate) package insert. West Point, Pa: Merck and Company Inc.
11 +
Viracept (nelfinavir mesylate, AG1343). Expanded Access Program protocol AG1343-515. Agouron Pharmaceuticals: San Diego, Calif.
12 +
Collier AC, Coombs RW, Schoenfeld DA, et al, for the AIDS Clinical Trials Group.  Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine . N Engl J Med . 1996;;334:1011-1017.
13 +
Cameron W, Heath-Chiozzi M, Kravcik S, et al. Prolongation of life and prevention of AIDS in advanced HIV immunodeficiency with ritonavir. In: Program and abstracts of the Third Conference on Retroviruses and Opportunistic Infections; January 28-February 1,1996; Washington, DC. Abstract LB6a.
14 +
Norvir (ritonavir) package insert, revised November 1996. Abbott Park, Ill: Abbott Pharmaceuticals.
15 +
Gathe J, Burkhardt B, Hawley P, Conant M, Peterkin J, Chapman S. A randomized phase II study of Viracept, a novel HIV protease inhibitor, used in combination with stavudine vs stavudine alone. In: Program and abstracts of the XI International Conference on AIDS; July 7-12,1996; Vancouver, British Columbia. Abstract MoB413.
16 +
McQuade TJ, Tomasselli AG, Liu L, et al.  A synthetic HIV-1 protease inhibitor with antiviral activity arrests HIV-like particle maturation . Science . 1990;;247:454-456.
17 +
Meek TD, Labert DM, Dreyer BB, et al.  Inhibition of HIV-1 protease in infected T-lymphocytes by synthetic peptide analogues . Nature . 1990;;343:90-92.
18 +
Craig JC, Duncan IB, Hockley D, Grief C, Roberts NA, Mills JS.  Antiviral properties of Ro 31-8959, an inhibitor of human immunodeficiency virus (HIV) proteinase . Antiviral Res . 1991;;16:295-305.
19 +
Vaca JP, Dorsey BD, Schleif WA, et al.  L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor . Proc Natl Acad Sci U S A . 1994;;91:4096-4100.
20 +
Kempf DJ, Marsh KC, Paul D, et al.  Antiviral and pharmacokinetic properties of C2 symmetric inhibitors of the human immunodeficiency virus type 1 protease . Antimicrob Agents Chemother . 1991;;35:2209-2214.
21 +
Kempf DJ, Marsh KC, Denissen JF, et al.  ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has a high oral bioavailability in humans . Proc Natl Acad Sci U S A . 1995;;92:2484-2488.
22 +
Danner SA, Carr A, Leonard JM, et al, for the European-Australian Collaborative Ritonavir Study Group.  A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease . N Engl J Med . 1995;;333:1528-1533.
23 +
Gulick R, Mellors J, Havlir D, et al. Potent and sustained antiretroviral activity of indinavir in combination with zidovudine and lamivudine. In: Program and abstracts of the Third Conference on Retroviruses and Opportunistic Infections; January 28-February 1, 1996; Washington, DC. Abstract LB7.
24 +
Schapiro JM, Winters MA, Stewart F, et al.  The effect of high dose saquinavir on viral load and CD4+ T cell counts in HIV-infected patients . Ann Intern Med . 1996;;124:1039-1050.
25 +
Lalezari J, Haubrich R, Burger HU, et al. Improved survival and decreased progression of HIV in patients treated with saquinavir (Invirase, SQV) plus HIVID (zalcitabine, ddC). In: Program and abstracts of the XI International Conference on AIDS; July 7-12,1996; Vancouver, British Columbia. Abstract LB.B.6033.
26 +
Markowitz M, Saag M, Powderly WG, et al.  A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection . N Engl J Med . 1995;;333:1534-1539.
27 +
Cameron DW, Heath-Chiozzi M, Kravick S, Mills R, Potthoff A, Henry D, for the Advanced HIV Ritonavir Study Group. Prolongation of life and prevention of AIDS complications in advanced HIV immunodeficiency with ritonavir update. In: Program and abstracts of the XI International Conference on AIDS; July 7-12,1996; Vancouver, British Columbia. Abstract MoB411.
28 +
Nabulsi A, Revicki D, Conway D, Maurath C, Mill R, Leonard J. Quality of life consequences of adding ritonavir to current antiviral therapy for advanced HIV patients. In: Program and abstracts of the XI International Conference on AIDS; July 7-12,1996; Vancouver, British Columbia. Abstract LB.B.6046.
29 +
Heath-Chiozzi M, Leonard J, Henry D, et al. Anti-HIV activity and lymphocyte surrogate marker response dynamics to ritonavir therapy in advanced HIV immunodeficiency. In: Program and abstracts of the Third Conference on Retroviruses and Opportunistic Infections; January 28-February 1,1996; Washington, DC. Abstract LB6b.
30 +
Berry P, Kahn J, Cooper R, et al. Antiretroviral activity and safety of indinavir (IDV) alone and in combination with zidovudine (ZDV) in ZDV-naive patients with CD4 cell counts of 50-500 cells/mm3. In: Program and abstracts of the XI International Conference on AIDS; July 7-12, 1996; Vancouver, British Columbia. Abstract Th.B.6019.
31 +
Gulick R, Mellors J, Havlir D, et al. Potent and sustained antiretroviral activity of indinavir (IDV), zidovudine (ZDV) and lamivudine (3TC). In: Program and abstracts of the XI International Conference on AIDS; July 7-12,1996; Vancouver, British Columbia. Abstract Th.B.931.
32 +
Coffin JM.  HIV Population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy . Science . 1995;;267:483-489.
33 +
Saag MS, Holodniy M, Kuritzkes DR, et al.  HIV viral load markers in clinical practice: recommendations of an International AIDS Society—USA Expert Panel . Nat Med . 1996;;2:625-629.
34 +
Boucher C, Nijhuis M, Schipper P, et al. Detection of drug sensitive infectious HIV-1 after one year of ritonavir treatment in a patient with persistent undetectable plasma HIV-1 RNA. In: Abstracts of the Fifth International Workshop on HIV Drug Resistance; July 3-6, 1996; Whistler, British Columbia. Abstract 70.
35 +
Markowitz M, Cao Y, Hurley A, et al. Triple therapy with AZT and 3TC in combination with nelfinavir mesylate in 12 antiretroviral-naive subjects chronically infected with HIV-1. In: Program and abstracts of the XI International Conference on AIDS; July 7-12, 1996; Vancouver, British Columbia. Abstract LB.B.6031.
36 +
Markowitz M, Mo H, Kempf D, et al.  Selection and analysis of human immunodeficiency virus type 1 variants with increased resistance to ABT-538, a novel protease inhibitor . J Virol . 1995;;69:701-706.
37 +
Jacobsen H, Hanggi M, Ott M, et al.  In vivo resistance to a human immunodeficiency virus type 1 proteinase inhibitor: mutations, kinetics, and frequencies . J Infect Dis . 1996;;173:1379-1387.
38 +
Markowitz M, Cao Y, Hurley A, et al. Triple therapy with AZT, 3TC, and ritonavir in 12 subjects newly infected with HIV-1. In: Program and abstracts of the XI International Conference on AIDS; July 7-12,1996; Vancouver, British Columbia. Abstract Th.B.933.
39 +
Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD.  HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time . Science . 1996;;271:1582-1586.
40 +
Perelson AS, Essunger P, Markowitz M, Ho D. How long should treatment be given if we had an antiretroviral regimen that completely blocks HIV replication. In: Program and abstracts of the XI International Conference on AIDS; July 7-12,1996; Vancouver, British Columbia. Abstract Th.B.390.
41 +
Salminen MO, Robertson D, Sharp PM, Han BH, Burker DS, McCutchan RE. Continuous in vivo recombination between HIV-1 strains of genetic subtypes A and C. In: Program and abstracts of the XI International Conference on AIDS; July 7-12,1996; Vancouver, British Columbia. Abstract TuA511.
42 +
Condra JH, Schleif WA, Blahy OM, et al.  In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors . Nature . 1995;;374:569-571.
43 +
Eberle J, Bechowsky B, Rose D, et al.  Resistance of HIV type 1 protease inhibitor Ro 31-8959 . AIDS Res Hum Retroviruses . 1995;;11:671-676.
44 +
Condra JH, Schleif WA, Blahy OM, et al. In vivo evolution of resistance to the HIV-1 protease inhibitor indinavir. In: Program and abstracts of the 3rd Conference on Retroviruses and Opportunistic Infections; January 28-February 1, 1996; Washington, DC. Abstract 145.
45 +
Condra JH, Holder DJ, Schleif WA, et al.  Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor . J Virol . 1996;;70:8270-8276.
46 +
Molla A, Korneyeva M, Gao Q, et al.  Ordered accumulation of mutations in HIV-1 protease confers resistance to ritonvair . Nat Med . 1996;;2:760-766.
47 +
Patick AK, Duran M, Cao Y. Genotypic and phenotypic characterization of HIV-1 variance isolated from in vitro selection studies and from patients treated with the protease inhibitor, nelfinavir. In: Abstracts of the Fifth International Workshop on HIV Drug Resistance; July 3-6,1966; Whistler, British Columbia. Abstract 29.
48 +
Emini E, Condra JH, Schleif WA, et al. Maintenance of long-term virus suppression in patients treated with the HIV-1 protease inhibitor, Crixivan (indinavir). In: Program and abstracts of the XI International Conference on AIDS; July 7-12,1996; Vancouver, British Columbia. Abstract MO.B.170.
49 +
Korneyeva M, Molla A, Kempf D, et al. Clinical and virological responses to ritonavir, an inhibitor of HIV protease. In: Program and abstracts of the XI International Conference on AIDS; July 7-12, 1996; Vancouver, British Columbia. Abstract MO.B.1137.
50 +
Condra JH, Holder DJ, Schleif WA, et al. Bidirectional inhibition of HIV-1 drug resistance selection by combination therapy with indinavir and reverse transcriptase inhibitors. In: Program and abstracts of the XI International Conference on AIDS; July 7-12, 1996; Vancouver, British Columbia. Abstract Th.B.932.
51 +
Winslow R.  Health plans to cover new AIDS drugs, but issues of cost, treatment remain . Wall Street Journal . (July 12) , 1996;:A2.
52 +
Ho DD.  Time to hit HIV: early and hard . N Engl J Med . 1995;;333:450-451.
53 +
Information Marketing System America. National Prescription Audit. Plymouth Meeting, Pa: 1996.
54 +
People With AIDS (PWA) Health Group. Protease Inhibitors At-A-Glance Fact Sheet . New York, NY: People With AIDS Working for Health Inc; 1996;.
55 +
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To understand the clinical management of acute heart failure syndromes.
Accreditation Information The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
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Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s “Cited By” API will populate this tab (http://www.crossref.org/citedby.html).
Compression-Only CPR: Pushing the Science Forward
Cone
AAM 2010;304:1493-1495.
All you need to read in the other general journals
BMJ 2010;341:c5893-c1494.
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