Indinavir
Tóm tắt
Indinavir is a protease inhibitor used in the treatment of patients with HIV infection. Combination antiretroviral therapy with indinavir plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) is associated with greater reductions in viral load, greater increases in CD4+ cell counts, and reduced morbidity and mortality when compared with 2 NRTIs alone. In the landmark clinical trial ACTG 320, the rate of progression to AIDS or death (primary end-point) among zidovudine-experienced patients treated with indinavir, zidovudine and lamivudine was approximately half that of patients who received only zidovudine plus lamivudine (6 vs 11%; p < 0.001). The durability of an indinavir-containing regimen was demonstrated in Merck protocol 035, an ongoing trial in which a significant proportion of patients had sustained viral suppression for up to 3 years. Merck protocol 039, also an ongoing trial, showed a greater effect on surrogate markers of HIV disease progression with indinavir-based triple therapy than with zidovudine plus lamivudine or indinavir monotherapy in patients with advanced disease (median baseline CD4+ count 15 cells/µL). Numerous additional clinical trials have established the beneficial antiviral and immunological effects of indinavir in both antiretroviral-naive and -experienced patients with HIV infection. Indinavir is associated with various drug class-related adverse events, including gastrointestinal disturbances (e.g. nausea, diarrhoea), headache and asthenia/fatigue. A lipodystrophy syndrome has been commonly reported with indinavir and other protease inhibitors combined with NRTIs, but it has also been reported in many protease inhibitor-naive patients, and a definitive causal link has not been established between the syndrome and protease inhibitors. Nephrolithiasis may develop in about 9% of patients receiving indinavir but does not appear to be associated with other protease inhibitors; <0.5% of patients receiving indinavir discontinue the drug because of nephrolithiasis, which may be the extreme end of a continuum of crystal-related renal syndromes. Additional renal problems (e.g. nephropathy) have been reported in small numbers of patients receiving indinavir.
In summary, indinavir is a protease inhibitor with well documented efficacy when used as part of combined therapy in patients with HIV infection. Both US and UK treatment guidelines continue to recommend protease inhibitor-based regimens including indinavir as a first-line option. Indinavir is being studied as a twice daily and once daily regimen with a low dosage of ritonavir as a way to alleviate tolerability, drug interaction and patient compliance/adherence issues. Indinavir-containing triple therapy has demonstrated positive effects not only on surrogate markers of disease progression, but also on clinical end-points of mortality and morbidity in patients with HIV disease. Protease inhibitors are a significant advance in the care of patients with HIV infection, and, in an era of vidence-based medicine, indinavir represents an important component of anti-retroviral treatment strategies. Indinavir is an HIV protease inhibitor. It acts by binding to the HIV protease active site and inhibiting post-translational processing, thereby resulting in the formation of immature noninfectious viral particles and interruption of viral spread. Indinavir inhibited HIV replication by 95% at concentrations ranging from approximately 25 to 100 nmol/L in vitro, and an additive or synergistic antiviral effect was demonstrated in most studies combining indinavir with other antiretroviral agents in cell culture. Amino acid substitutions of HIV protease are the primary determinants of resistance to protease inhibitors, and there are at least 11 substitutions which may contribute to resistance to indinavir. However, ≥3 amino acid substitutions are required and only certain combinations of substitutions confer resistance to indinavir. Cross resistance can develop among the entire protease inhibitor class. Indeed, a high degree of cross resistance with other protease inhibitors has been demonstrated in indinavir-resistant clinical isolates of HIV selected during indinavir therapy. After oral administration, indinavir is rapidly absorbed in the fasting state. Time to achieve maximum plasma drug concentration is approximately 0.8 hours. Steady-state peak plasma drug concentration (Cmax), minimum plasma drug concentration (Cmin) and area under the plasma drug concentration-time curve (AUC) values are 12.6 µmol/L, 0.25 µmol/L and 30.7 µmol/L · h with indinavir 800mg every 8 hours. The rate but not the extent of absorption is reduced when indinavir is taken with a low-fat meal. Administration of indinavir with a high-fat meal markedly reduces the rate and extent (by approximately 35 to 75%) of drug absorption; however, food has little effect on indinavir pharmacokinetics when the drug is administered with a low dose of ritonavir. Indeed, concurrent administration of ritonavir appears to improve the overall pharmacokinetic profile of indinavir, by increasing plasma trough concentrations of indinavir and providing more consistent indinavir exposure throughout the dosage interval (such that twice daily, rather than every 8 hour, administration of indinavir is possible). Plasma protein binding of indinavir is approximately 60% and the elimination half-life is approximately 1.8 hours. Indinavir undergoes extensive metabolism by cytochrome P-450 (CYP) 3A4 isoenzymes to several metabolites (the activity of which is unknown). Approximately 11% of an administered dose is eliminated unchanged in the urine, the remainder is eliminated in the faeces as indinavir metabolites and unabsorbed indinavir. Indinavir is associated with a number of pharmacokinetic drug interactions, some of which are clinically significant and necessitate dosage modifications or avoidance of concomitant administration. Drug interactions appear to be more common with ritonavir and less common with saquinavir than with indinavir on the basis of inhibitory effects of the drugs on cytochrome P-450 (CYP) 3A4 isoenzymes. In the landmark ACTG 320 trial, progression to AIDS or death (primary end-point) occurred in 6% of patients randomised to receive indinavir, zidovudine and lamivudine compared with 11% of those who received zidovudine plus lamivudine (p < 0.001), i.e. a relative reduction of ≈50%. The intention-to-treat analysis included 1156 zidovudine-experienced patients who received study treatment for a median duration of 38 weeks. Overall mortality, a secondary outcome measure, was 1.4 and 3.1%, respectively (p = 0.04). Numerous clinical trials have evaluated the effects of indinavir-containing regimens on surrogate markers of HIV disease progression, i.e. serum or plasma (hereafter simplified to ‘plasma’) HIV RNA levels (viral load) and CD4+ cell counts. In studies in antiretroviral therapy-experienced or both-experienced and -naive patients (mean or median baseline plasma HIV RNA4.39 to 5.12 log10copies/ml), ≥24 weeks of indinavir-containing double or triple therapy was associated with reductions from baseline plasma HIV RNA levels ranging from 1.6 to 2.7 log10copies/ml. The percentage of patients with plasma HIV RNA levels below the limit of detection (LOD; typically 400 or 500 copies/ml) ranged from 45 to 90%. CD4+ counts ranged from 15 to 344 cells/µL at baseline and increased by 86 to 243 cells/µL after ≽24 weeks of therapy. These results were broadly similar to those in studies which included only antiretroviral treatment-naive patients. Intention-to-treat analysis in 2 pivotal, randomised, double-blind, multicentre trials (Merck protocols 035 and 039; both are ongoing) showed that triple therapy with indinavir, zidovudine and lamivudine was significantly more effective at improving surrogate markers of disease progression than a combined regimen of zidovudine plus lamivudine or indinavir monotherapy in zidovudine-experienced patients with HIV infection. In the Merck protocol 035 trial, the antiviral/immunological effect was sustained for up to 3 years in approximately two-thirds of patients, thus demonstrating good durability. Median baseline CD4+ cell count in the Merck protocol 039 trial was just 15 cells/µL; thus, efficacy with indinavir-containing triple therapy has been demonstrated even in patients with very advanced disease. In general, the proportion of patients with plasma HIV RNA level below the LOD after 12 to 36 weeks of therapy ranged from 61 to 83% in studies involving small numbers of patients with HIV infection (antiretroviral therapy-experienced or naive) who received indinavir in conjunction with another protease inhibitor [(with or without nucleoside reverse transcriptase inhibitors (NRTIs)]. One trial showed a much lower proportion of patients achieved HIV RNA levels below the LOD, but these patients had previously received extensive antiretroviral therapy. Concurrent protease inhibitor treatment included nelfinavir, saquinavir (soft-gelatin capsule or formulation not stated), ritonavir or amprenavir. Mean changes from baseline in CD4+ cell counts and plasma HIV RNA levels were broadly similar to those observed in studies in which indinavir was combined with 2 NRTIs. Several nonrandomised trials of 8 to 78 weeks’ duration have evaluated indinavir (usually in combination with zidovudine and lamivudine) in children infected with HIV, but most have included small numbers of patients. In general, indinavir-containing regimens have demonstrated similar effects on surrogate markers of HIV disease progression in paediatric patients to those in adult patients. All prospective studies in ≥15 children showed at least a modest improvement from baseline in CD4+ cell count and/or viral load. Indinavir, like other protease inhibitors, is associated with a number of adverse events, including gastrointestinal symptoms (nausea, abdominal pain, vomiting), headache and asthenia/fatigue. In comparative clinical studies, there was at least a trend towards a lower incidence of serious adverse events with indinavir-containing regimens than with ritonavir-containing regimens. Saquinavir-containing regimens tended to be associated with fewer adverse events than both of these protease inhibitor-containing regimens. When indinavir was used in combination with other protease inhibitors (e.g. ritonavir), adverse events were usually mild and transient in nature and most frequently included diarrhoea, nausea, rash, headache, fatigue and perioral tingling/numbness (the latter related specifically to ritonavir). Nephrolithiasis has been seen to occur in approximately 9% of patients receiving indinavir (193 of 2071 patients according to pooled clinical trial data; duration of therapy not stated) and does not appear to be associated with other protease inhibitors. Most patients who develop nephrolithiasis are able to continue indinavir therapy after adequate hydration and temporary interruption of indinavir (e.g. 1 to 3 days); less than 0.5% of patients treated with indinavir discontinue therapy because of nephrolithiasis (7 of 2071 patients). Thus, approximately 4% of those who develop indinavir-induced nephrolithiasis (7 of 193 patients) need to discontinue the drug. Indinavir-associated crystalluria appears to be more common than nephrolithiasis and is sometimes accompanied by urological symptoms. It is possible that indinavir may be associated with a continuum of crystal-related renal syndromes ranging from frank nephrolithiasis (e.g. renal stones and flank pain with or without haematuria) to asymptomatic crystalluria. Other renal problems, such as renal insufficiency or nephropathy, have been reported with indinavir in small numbers of patients. Indirect hyperbilirubinaemia occurs in about 10% of patients treated with indinavir, although there are no known clinical consequences or sequelae. Less than 1% of patients receiving the drug have hyperbilirubinaemia accompanied by elevations in serum ALT or AST levels. Lipodystrophy or a lipodystrophy syndrome involving body fat redistribution and metabolic effects appears to be another common adverse event among patients with HIV infection treated with antiretroviral therapy including protease inhibitor-containing combination therapy, although a direct causal link between protease inhibitors and the syndrome has not been established. There is currently no consensus case-definition for the syndrome and, consequently, the reported incidence has varied significantly and is also seen with antiretroviral regimensnot containing a protease inhibitor. The recommended dosage of indinavir is 800mg orally every 8 hours. Trials show that, for optimal absorption, indinavir should be administered with water 1 hour before or 2 hours after a meal. Indinavir may be administered with a light meal such as dry toast with jelly/jam or corn flakes with skim milk and sugar. Patients taking indinavir must drink at least 1.5L of liquids each day (24-hour period) to ensure adequate hydration and reduce the risk of nephrolithiasis. In patients with mild to moderate hepatic insufficiency due to cirrhosis, the dosage of indinavir should be reduced to 600mg every 8 hours. Pharmacokinetic and clinical data suggest that, for patients who would otherwise creceive the standard recommended dosage of indinavir 800mg every 8 hours, the dosage interval may be extended to twice daily when indinavir is used with a low dose of ritonavir (total daily dosage of indinavir has varied in trials). In addition, there are no food restrictions with regimens of indinavir plus a low dose of ritonavir.
Tài liệu tham khảo
Molla A, Japour A. HIV protease inhibitors. Curr Opin Infect Dis 1997 Dec; 10:491–5
Flexner C. HIV-protease inhibitors. N Engl J Med 1998; 338: 1281–92
Physicians’ Desk Reference. 53rd ed. Montvale, (NJ), USA: Medical Economics Company, Inc, 1999
Debouck C. The HIV-1 protease as a therapeutic target for AIDS. AIDS Res Hum Retroviruses 1992; 8: 153–64
Vacca 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 Apr 26; 91: 4096–100
Emini EA, Schleif WA, Deutsch P, et al. In vivo selection of HIV-1 variants with reduced susceptibility to the protease inhibitor L-735,524 and related compounds. Adv Exp Med Biol 1996; 394: 327–31
Deminie C, Bechtold C, Stock D, et al. Evaluation of d4T, ddI and BMS-186,318 in two-drug combinations against HIV replication [abstract no. 294]. 3rd Conference on Retroviruses and Opportunistic Infections; 1996 Jan 28–Feb 2: 107
Mulato AS, Cherrington JM. Anti-HIV activity of adefovir (PMEA) and PMPA in combination with antiretroviral compounds: in vitro analyses. Antiviral Res 1997 Nov; 36: 91–7
St. Clair MH, Pennington KN, Rooney J, et al. In vitro comparison of selected triple-drug combinations for suppression of HIV-1 replication: the inter-company collaboration protocol. J Acquir Immune Defic Syndrom Hum Retrovirol 1995; 10 Suppl. 2:S83–91
Patick AK, Boritzki TJ, Bloom LA. Activities of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor nelfmavir mesylate in combination with reverse transcriptase and protease inhibitors against acute HIV-1 infection in vitro. Antimicrob Agents Chemother 1997 Oct; 41: 2159–64
Merrill DP, Manion DJ, Chou T-C, et al. Antagonism between human immunodeficiency virus type 1 protease inhibitors indinavir and saquinavir in vitro. J Infect Dis 1997 Jul; 176: 265–8
Condra JH. Resistance to HIV protease inhibitors. Haemophilia 1998 Jul; 4: 610–5
Hirsch MS, Conway B, D’Aquila RT, et al. Antiretroviral drug resistance testing in adults with HIV infection: implications for clinical management. JAMA 1998 Jun 24; 279: 1984–91
Lorenzi P, Opravil M, Hirschel B, et al. Impact of drug resistance mutations on virologic response to salvage therapy. AIDS 1999; 13:F17–21
Tisdale M, Myers RE, Maschera B, et al. Cross-resistance analysis of human immunodeficiency virus type 1 variants individually selected for resistance to five different protease inhibitors. Antimicrob Agents Chemother 1995 Aug; 39: 1704–10
PDR Generics. 4th ed. Montvale, (NJ): Medical Economics, 1998
Condra JH, Schleif WA, Blahy OM, et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature 1995 Apr 6; 374: 569–71
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 Dec; 70: 8270–6
Havlir D, Hellmann N, Petropoulos C, et al. Viral rebound in the presence of indinavir without protease inhibitor resistance [abstract no. LB12]. 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4, Chicago
Patick AK, Duran M, Cao Y, et al. Genotypic and phenotypic characterization of human immunodeficiency virus type 1 variants isolated from patients treated with the protease inhibitor nelfinavir. Antimicrob Agents Chemother 1998; 42: 2637–44
Larder B, Kemp S, Bloor S, et al. A complete survey in over 1,500 clinical HIV-1 isolates, of phenotypic and genotypic protease inhibitor resistance profiles (including gag cleavage site sequences) and their relation to therapy history [abstract]. AIDS 1998 Nov; 12 Suppl. 4: S11
Giannakopoulos G, Johnson E, Eng RHK. Impact of protease inhibitor switch on HIV viral load in HIV1 infections [abstract no. 83.030]. 8th International Congress for Infectious Diseases; 1998 May 15–18; Boston, 243
Rachlis AR, Palmer RH, Bast M, et al. Predictors of decreases in plasma HIV-1 RNA in patients treated with indinavir [abstract no. A-17]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28; Toronto, 4
Deeks SG, Hecht FM, 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(6): F35–43
Sampson MS, Barr MR, Torres RA, et al. Viral load changes in nelfinavir treated patients switched to a second protease inhibitor after loss of viral suppression [abstract no. LB-5]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28; Toronto, 9
Birch C. On the issue of cross-resistance between protease inhibitors [letter]. AIDS 1998 Apr 16; 12: 680–1
Balani SK, Woolf EJ, Hoagland VL, et al. Disposition of indinavir, a potent HIV-1 protease inhibitor, after an oral dose in humans. Drug Metab Dispos 1996 Dec; 24: 1389–94
Yeh KC, Deutsch PJ, Haddix H, et al. Single-dose pharmacokinetics of indinavir and the effect of food. Antimicrob Agents Chemother 1998 Feb; 42: 332–8
Yajima T, Yajima Y, Inaba K, et al. Phase I study on indinavir (MK-639), a HIV protease inhibitor — single dose study in healthy male volunteers [in Japanese]. Rinsholyaku 1997; 13(4): 875–89
Chiba M, Hensleigh M, Nishime JA, et al. Role of cytochrome P450 3A4 in human metabolism of MK-639, a potent human immunodeficiency virus protease inhibitor. Drug Metab Dispos 1996 Mar; 24: 307–14
Acosta EP, Henry K, Baken L, et al. Indinavir concentrations and antiviral effect. Pharmacotherapy 1999; 19(6): 708–12
Harris M, Durakovic C, Rae S, et al. A pilot study of nevirapine, indinavir, and lamivudine among patients with advanced human immunodeficiency virus disease who have had failure of combination nucleoside therapy. J Infect Dis 1998 Jun; 177: 1514–20
Squires KE, Saag MS, Teppler H, et al. Phase I studies of L-735,524, an HIV protease inhibitor: pharmacokinetics, tolerability and short-term antiviral activity [abstract]. Clin Res 1994 Apr; 42: 280A
Murphy RL, Sommadossim J-P, Lamson M, et al. Antiviral effect and pharmacokinetic interaction between nevirapine and indinavir in persons infected with human immunodeficiency virus type 1. J Infect Dis 1999; 179: 1116–23
Stein DS, Fish DG, Bilello JA, et al. A 24-week open-label phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir). AIDS 1996 May; 10:485–92
Carver PL, Fleisher D, Zhou SY, et al. Meal composition effects on the oral bioavailability of indinavir in HIV-infected patients. Pharm Res 1999; 16(5): 718–24
Hsu A, Heath-Chiozzi M, Ashbrenner E, et al. Evaluation of ritonavir/indinavir BID regimens — 400mg of indinavir in combination with 200, 300, or 400mg of ritonavir in healthy volunteers [abstract]. AIDS 1998 Nov; 12 Suppl. 4: S28
Saah AJ, Winchell G, Seniuk M, et al. Multiple-dose pharmacokinetics (PK) and tolerability of indinavir (IDV) ritonavir (RTV) combinations in healthy volunteers [abstract no. 362]. 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; Chicago
Burger DM, Hugen PWH, Prins JM, et al. Pharmacokinetics of an indinavir/ritonavir 800/100mg bid regimen [abstract no. 363]. 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; Chicago
Barry M, Gibbons S, Back D, et al. Protease inhibitors in patients with HIV disease: clinically important pharmacokinetic considerations. Clin Pharmacokinet 1997 Mar; 32: 194–209
Martin C, Sönnerborg A, Olof Svensson J, et al. Indinavir-based treatment of HIV-1 infected patients: efficacy in the central nervous system. AIDS 1999; 13: 1227–32
Brinkman K, Kroon F, Hugen PWH, et al. Therapeutic concentrations of indinavir in cerebrospinal fluid of HIV-1-infected patients [letter; comment]. AIDS 1998 Mar 26; 12: 537
Kravcik S, Gallicano K, Roth V, et al. Cerebrospinal fluid HIV RNA and drug levels with combination ritonavir and saquinavir. J Acquir Immune Defic Syndr 1999; 21(5): 371–5
Foudraine NA, Jurriaans S, Weverling GJ, et al. Plasma and cerebrospinal fluid HIV-RNA and drug levels after 48 weeks of follow up of patients treated with AZT/3TC or d4T/3TC with sequential addition of indinavir [abstract]. AIDS 1998 Nov; 12 Suppl. 4: S33
Gisslén M, Hagberg L, Svennerholm B, et al. HIV-1 RNA is not detectable in the cerebrospinal fluid during antiretroviral combination therapy. AIDS 1997 Jul 15; 11: 1194
Gisslén M, Hagberg L, Norkrans G, et al. Combination therapy with zidovudine, lamivudine and indinavir reduces cerebrospinal fluid HIV-1 RNA levels to below detection limit [abstract]. J Neurovirol 1998 Jun; 4: 351
Gisslén M, Svennerholm B, Fuchs D, et al. Neurological efficacy of stavudine, zidovudine, and lamivudine [letter]. Lancet 1998 Aug 1; 352: 402–3
Collier AC, Marra C, Coombs RW, et al. Cerebrospinal fluid (CSF) indinavir (IDV) and HIV RNA levels in patients on chronic indinavir therapy [abstract]. Clin Infect Dis 1997 Aug; 25: 359
Enting RH, Hoetelmans RMW, Lange JMA, et al. Antiretroviral drugs and the central nervous system. AIDS 1998 Oct 22; 12: 1941–55
Koudriakova T, Iatsimirskaia E, Utkin I, et al. Metabolism of the human immunodeficiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome P4503A4/3A5: mechanism-based inactivation of cytochrome P4503A by ritonavir. Drag Metab Dispos 1998 Jun; 26: 552–61
Moyle GJ, Gazzard BG. A risk-benefit assessment of HIV protease inhibitors. Drag Saf 1999 Apr; 20: 299–321
Balani SK, Arison BH, Mathai L, et al. Metabolites of L-735,524, a potent HIV-1 protease inhibitor, in human urine. Drug Metab Dispos 1995 Feb; 23: 266–70
Kakuda TN, Struble KA, Piscitelli SC. Protease inhibitors for the treatment of human immunodeficiency viras infection. Am J Health System Pharm 1998 Feb 1; 55: 233–54
Vigano A, Sala N, Miletich F, et al. Indinavir pharmacokinetics in children with HIV infection [abstract no. A-56]. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1998 Sep 24; San Diego, 18
Burger DM, Hugen PWH, de Groot R. Pharmacokinetics of indinavir in HIV-infected children [abstract]. AIDS 1998 Nov; 12 Suppl. 4: S93
Brundage RC, Kline MW, Harris AT, et al. Population pharmacoinetics of indinavir, didanosine and stavudine in children [abstract no. 423]. 6th Conference on Retrovirases and Opportunistic Infections; 1999 Jan 31–Feb 4; Chicago
Squires K, Riddler S, Havlir D, et al. Co-administration of indinavir (IDV) 1200mg with nelfinavir (NFV) 1250 mg in a twice daily regimen: preliminary safety, PK activity [abstract no. 364]. 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; Chicago
Burger DM, Hugen PWH, Prins J, et al. Pharmacokinetics of indinavir in a bid regimen with or without low-dose ritonavir [abstract]. AIDS 1998 Nov; 12 Suppl. 4: 10
van Heeswijk RPG, Veldkamp AI, Hoetelmans RMW, et al. The steady-state plasma pharmacokinetics of indinavir alone or in combination with ritonavir in twice daily dosing regimens in HIV-1 infected patients. International Congress on Drug Therapy in HIV Infection; 1998 Nov 8–12; Glasgow
Hsu A, Granneman GR, Cao G, et al. Pharmacokinetic interaction between ritonavir and indinavir in healthy volunteers. Antimicrob Agents Chemother 1998 Nov; 42: 2784–91
Burger DM, Hugen PWH, Ter Hofstede HJM, et al. Dose-finding study of a once daily indinavir/ritonavir regimen in healthy volunteers [abstract no. 321]. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999 Sep 26–29; San Francisco
Saah A, Winchell G, Seniuk M, et al. Multiple-dose pharmacokinetics (PK) and tolerability of indinavir (IDV) and ritonavir (RTV) combinations in a once-daily regimen in healthy volunteers (Merck 089) [abstract no. 329]. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999 Sep 26–29; San Francisco
Ferry JJ, Herman BD, Carel BJ, et al. Pharmacokinetic drug-drag interaction study of delavirdine and indinavir in healthy volunteers. J Acquir Immune Defic Syndr Hum Retrovirol 1998 Jul 1; 18:252–9
Fiske WD, Mayers D, Wagner K, et al. Pharmacokinetics of DMP 266 and indinavir multiple oral doses in HIV-1 infected individuals [abstract no. 535]. 4th Conference on Retroviruses and Opportunistic Infections; 1996 Jan 28–Feb 1; Washington (DC)
De Wit S, Debier M, De Smet M, et al. Effect of fluconazole on indinavir pharmacokinetics in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 1998; 42: 223–7
Rana KZ, Okereke CS, Melbourne KM, et al. Effect of GMCSF on the pharmacokinetics of indinavir in HIV-infected patients [abstract no. A-72]. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy 1998 24 Sep: San Diego, California, 22
Piscitelli SC, Vogel S, Figg WD, et al. Alteration in indinavir clearance during interleukin-2 infusions in patients infected with the human immunodeficiency virus. Pharmacotherapy 1998 Nov–Dec; 18: 1212–6
Cantilena L, McCrea J, Blazes D, et al. Lack of a pharmacokinetic interaction between indinavir and methadone [abstract]. Clin Pharmacol Ther 1999 Feb; 65: 135
Hugen PWH, Burger DM, ter Hofstede HJM, et al. Concomitant use of indinavir and omeprazole: risk of antiretroviral subtherapy [abstract]. AIDS 1998 Nov; 12 Suppl. 4: S29
Burger DM, Hugen PW, Kroon FP, et al. Pharmacokinetic interaction between the proton pump inhibitor omeprazole and the HIV protease inhibitor indinavir [letter]. AIDS 1998 Oct 22; 12: 2080–2
Malaty LI, Kuper JJ. Drug interactions of HIV protease inhibitors. Drug Saf 1999 Feb; 20: 147–69
von Moltke LL, Greenblatt DJ, Grassi JM, et al. Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir. J Clin Pharmacol 1998; 38: 106–11
Eagling VA, Back DJ, Barry MG. Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. Br J Clin Pharmacol 1997 Aug; 44: 190–4
Rosenthal E, Sala F, Chichmanian R-M. Ergotism related to concurrent administration of ergotamine tartrate and indinavir [letter]. JAMA 1999 Mar 17; 281: 987
Hammer SM, Squires KE, Hughes MD, et al. 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. N Engl J Med 1997 Sep 11; 337: 725–33
Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy [see comments]. N Engl J Med 1997 Sep 11; 337: 734–9
Gulick RM, Mellors JW, Havlir D, et al. Simultaneous vs sequential initiation of therapy with indinavir, zidovudine, and lamivudine for HIV-1 infection: 100-week follow-up. JAMA 1998 Jul 1; 280: 35–41
Mellors JW, Rinaldo Jr CR, Gupta P, et al. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 1996; 272: 1167–70
Mellors JW, Muñoz A, Giorgi JV, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997; 126: 946–54
Miller V, Staszewski S, Nisius G, et al. Risk of new AIDS diseases in people on triple therapy. Lancet 1999 Feb 6; 353: 463
O’Brien WA, Hartigan PM, Daar ES, et al. Changes in plasma HIV RNA levels and CD4+ lymphocyte counts predict both response to antiretroviral therapy and treatment failure. Ann Intern Med 1997; 126(12): 939–45
Vella S, Tomino C, Fragola V, et al. ISS-IP1: a phase III, randomised, comparative multicenter trial of ritonavir versus indinavir in 1251 nucleoside-experienced patients with less than 50 CD4 /mm3 [abstract]. AIDS 1998 Nov; 12 Suppl. 4: 16
Salzberger B, Rockstroh J, Wieland U, et al. Clinical and virological efficacy of antiretroviral combination therapy [abstract]. AIDS 1998 Nov; 12 Suppl. 4: S43
Carbonnel F, Maslo C, Beaugerie L, et al. Effect of indinavir on HIV-related wasting. AIDS 1998; 12: 1777–84
Foudraine NA, Weverling GJ, van Gool T, et al. Improvement of chronic diarrhoea in patients with advanced HIV-1 infection during potent antiretroviral therapy. AIDS 1998; 12: 35–41
Silva M, Skolnik PR, Gorbach SL, et al. The effect of protease inhibitors on weight and body composition in HIV-infected patients. AIDS 1998 Sep 10; 12: 1645–51
Tumbarello M, Tacconelli E, de GDK, et al. HIV-associated bacterial pneumonia in the era of highly active antiretroviral therapy. J Acquir Immune Defic Syndrom Hum Retrovirol 1999 Feb 1; 20: 208–9
Ferrando S, van Gorp W, McElhiney M, et al. Highly active antiretroviral treatment in HIV infection: benefits for neuropsychological function. AIDS 1998 May 28; 12: F65–70
Tozzi V, Balestra P, Galgani S, et al. Protease inhibitors based regimens and neuropsychological performance in HIV-1 patients [abstract]. J Neurovirol 1998 Jun; 4: 368
Binquet C, Saillour F, Bernard N, et al. Survival of HIV-infected patients with cytomegalovirus retinitis under highly active antiretroviral therapy. AIDS 1998 Dec 24; 12: 2502–4
Walsh JC, Jones CD, Barnes EA, et al. Increasing survival in AIDS patients with cytomegalovirus retinitis treated with combination antiretroviral therapy including HIV protease inhibitors. AIDS 1998; 12: 613–8
Casado JL, Perez-Elias MJ, Marti-Belda P, et al. Improved outcome of cytomegalovirus retinitis in AIDS patients after introduction of protease inhibitors. J Acquir Immune Defic Syndrom Hum Retrovirol 1998 Oct 1; 19: 130–4
Merck abandons twice-daily Crixivan. Scrip 1998 Sep 25(2373): 15
Merck discontinues study arms with twice-daily dosing of crixivan (R) in combination with reverse transcriptase inhibitors twice-daily studies with crixivan and other protease inhibitors continue [online]. Available from URL: http://www.prnewswire.com/cgi-bin [Accessed 22 Sep 1998]
Carr A, Hudson J, Hoy J, et al. Ozcombo I: control of HIV replication in treatment naive patients in a randomised trial of HAART [abstract no. 633]. 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4, Chicago
Florence E, Colebunders R, Vandercam B, et al. A randomised clinical trial comparing a ritonavir/saquinavir (RTV-SQV) versus an indinavir (IDV) containing triple therapy regimen (Iris Study) [abstract]. AIDS 1998 Nov; 12 Suppl. 4: S34
Gazzard B, AVANTI Study Group. AVANTI 2. A randomised, double blind, comparative trial to evaluate the efficacy, safety and tolerance of AZT/3TC vs AZT/3TC/indinavir in antiretroviral naive patients: 100week data [abstract]. AIDS 1998 Nov; 12 Suppl. 4: S35
Murphy RL, Katlama C, Johnson V, et al. The Atlantic study: a randomized open-label trial comparing two protease inhibitor (PI)-sparing antiretroviral strategies versus a standard PI-containing regimen, 48 week data [abstract no. LB-22]. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy: Late Breaker Abstracts, 1999 Sep 26–29, San Francisco
Pialoux G, Raffi F, Brun-Vezinet F, et al. 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. N Engl J Med 1998 Oct 29; 339: 1269–76
Staszewski S, Keiser P, Gathe J, et al. Ziagen/combivir is equivalent to indinavir/combivir in antiretroviral therapy (ART) naive adults at 24 weeks (CNA3005) [abstract no. 20]. 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4, Chicago
Thompson M, Roberts A, Wheat LJ, et al. Randomized study of adefovir dipivoxil (ADV) in combination with indinavir (IDV) and reverse transcriptase inhibitors for treatment-naive HIV-infected patients [abstract]. AIDS 1998 Nov; 12 Suppl. 4:S76
Katlama C, Murphy R, Johnson V, et al. The Atlantic Study: a randomised open-label study comparing two protease inhibitors (PI)-sparing antiretroviral strategies versus a standard PI-containing regimen [abstract no. 18]. 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4, Chicago
Cohen Stuart JW, Schuurman R, Burger DM, et al. Randomized trial comparing saquinavir soft gelatin capsules versus indinavir as part of triple therapy (CHEESE study). AIDS 1999; 13(7): F53–8
Cohen Stuart JWT, Schuurmann R, Richter C, et al. Randomized trial comparing saquinavir-sgc versus indinavir as part of triple therapy: 48 weeks data on efficacy and safety [abstract no. 601]. Seventh European Conference on Clinical Aspects and Treatment of HIV-Infection; 1999 Oct 23–27; Lisbon
Gulick R, Mellors J, Havlir D, et al. Treatment with indinavir (IDV), zidovudine (ZDV) and lamivudine (3TC): three-year follow-up [abstract no. 388]. 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; Chicago
Haas DW, Fessel WJ, Delapenha RA, et al. A phase III, double-blind, placebo-controlled, multicenter study to determine the effectiveness and tolerability of the combination of efavirenz (EFV, SUSTIVA DMP 266) and indinavir (IDV) versus IDV in HIV-1-infected patients receiving nucleoside analogue therapy (NRTI) at 24 weeks (study DMP 266-020) [abstract]. Clin Microbiol Infect 1999 Mar; 5 Suppl. 3: 54–5
Havlir DV, Marschner IC, Hirsch MS, et al. Maintenance antiretroviral therapies in HIV-infected subjects with undetectable plasma HIV RNA after triple-drug therapy. N Engl J Med 1998 Oct 29; 339: 1261–8
Hirsch M, Steigbigel R, Staszewski S, et al. A randomized, controlled trial of indinavir, zidovudine, and lamivudine in adults with advanced human immunodeficiency virus type 1 infection and prior antiretroviral therapy. J Infect Dis 1999; 180: 659–65
Kabeya K, de Wit S, Sommereijns B, et al. Picasso: a randomized comparative outcome trial of indinavir (I) and ritonavir (R) in protease inhibitors (PI) naive HIV patients (P) with CD4 below 100 cells/micrograms [abstract]. AIDS 1998 Nov; 12 Suppl. 4:S35
Kirk O, Katzenstein TL, Gerstoft J, et al. Combination therapy containing ritonavir plus saquinavir has superior short-term antiretroviral efficacy: a randomized trial. AIDS 1999; 13(1): F9–F16
Morales-Ramirez J, Tashima K, Hardy D, et al. A phase II, multi-center randomized, open label study to compare the antiretroviral activity and tolerability of efavirenz (EFV) + indinavir (IDV), versus EFV + zidovudine + lamivudine (3TC), versus IDV + 3TC at greater than 36 weeks [DMP 266-006] [abstract no. 1-103]. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy 1998 Sep 24: San Diego, (CA), 394
Tashima K, Staszewski S, Stryker R, et al. A phase III, multi-center, randomized, open-label study to compare the anti-retroviral activity and tolerability of efavirenz (EFV) + indinavir (IDV), versus EFV + zidovudine (ZDV) + lamivudine (3TC), versus IDV + ZDV + 3TC at 48 weeks (study DMP 266-006) [abstract no. LB-16]. 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; Chicago
Ruiz N, Manion D, Riddler S, et al. Durable clinical anti-HIV-1 activity at 84 weeks and tolerability for efavirenz (EFV) in combination with indinavir (IDV) [study DMP 266-003, cohortIV] [abstract]. AIDS 1998 Nov; 12 Suppl. 4: S36
Wit F, van Leeuwen R, Weverling GJ, et al. Outcome and predictors of failure of highly active antiretroviral therapy: one-year follow-up of a cohort of human immunodeficiency virus type 1-infected persons. J Infect Dis 1999 Apr; 179: 790–8
Hirsch M for the protocol 039 ISG, Meibohm A, Rawlins S, et al. Indinavir (IDV) in combination with ZDV and 3TC in ZDV-experienced patients with CD4 cell count ≤ 50 cells/mm3 — 60 week followup. Available from: URL: http://www.retroconference.org/abstracts [Accessed 14 Sep 1999]
Twice-daily crixivan + nelfinavir — Merck study 061 [online]. Available from: URL: http://www.newspage.com/cgi-bin/NA [Accessed 3 July 1998]
Macias J, Pineda JA, Sänchez B, et al. Antiviral efficacy and tolerance of a quadruple antiretroviral therapy including indinavir plus saquinavir in asymptomatic HIV-infected patients with CD4+ counts ≥500 cells/µL [abstract]. AIDS 1998 Nov; 12 Suppl. 4: S43
O’Brien WA, Atkinson TA, Han X, et al. Combination therapy with indinavir and ritonavir in antiretroviral-experienced patients [abstract no. 2209]. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999 Sep 26–29; San Francisco
Rockstroh JK, Bergmann F, Wiesel W, et al. Efficacy and safety of BID first line ritonavir/indinavir plus double nucleoside combination therapy [abstract]. AIDS 1998 Nov; 12 Suppl. 4: S42
Eron J, Haubrich R, Richman D, et al. Safety and efficacy of amprenavir in combination with other protease inhibitors [abstract]. AIDS 1998 Nov; 12 Suppl. 4: S38
Bermudez MAC, Perez-Tamarit D, Otero MC, et al. Effectiveness of combination with protease inhibitors in the treatment of HIV-infected children [abstract no. 12320]. 12th World AIDS Conference; 1998 Jun 28; Geneva, 77
Chougnet C, Fowke KR, Mueller BU, et al. Protease inhibitor and triple-drug therapy: cellular immune parameters are not restored in pediatric AIDS patients after 6 months of treatment. AIDS 1998 Dec 24; 12: 2397–406
Cohen Stuart JWT, Slieker WAT, Rijkers GT, et al. Early recovery of CD4+ T lymphocytes in children on highly active antiretroviral therapy. AIDS 1998 Nov 12; 12: 2155–9
Kline MW, Fletcher CV, Harris AT, et al. A pilot study of combination therapy with indinavir, stavudine (d4T), and didanosine (ddI) in children infected with the human immunodeficiency virus. J Pediatr 1998 Mar; 132: 543–6
Manfredi R, Monari P, Donzelli C, et al. Protease inhibitors in antiviral therapy of paediatric HIV disease. Acta Paediatr 1998 Jul; 87: 814–6
Melvin AJ, Mohan KM, Manns ALA, et al. Clinical, virologic and immunologic responses of children with advanced human immunodeficiency virus type 1 disease treated with protease inhibitors. Pediatr Infect Dis J 1997 Oct; 16: 968–74
Monpoux F, Sirvent N, Cottalorda J, et al. Stavudine, lamivudine and indinavir in children with advanced HIV-1 infection: preliminary experience. AIDS 1997 Oct; 11: 1523–5
Mueller BU, Sleasman J, Nelson Jr RP, et al. A phase I/II study of the protease inhibitor indinavir in children with HIV infection. Pediatrics 1998 Jul; 102 (Pt 1): 101–9
Nelson R, Sleasman J, Cervia J, et al. Indinavir (IDV) in combination with stavudine (d4T) and lamivudine (3TC) in HIV-infected children [abstract no. 425]. 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; Chicago
Rutstein RM, Feingold A, Meislich D, et al. Protease inhibitor therapy in children with perinatally acquired HIV infection. AIDS 1997 Oct; 11: F107–11
van Rossum AMC, Suur MH, Niesters HGM, et al. Dutch multicenter trial on the treatment of HIV infected children with zidovudine, indinavir and lamivudine [abstract no. P300]. AIDS 1998; 12 Suppl. 4: S92
Vigana A, Pirollo M, Sala N, et al. Long term outcome of potent antiretroviral therapy in HIV-infected children [abstract no. 426]. 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; Chicago
Wintergerst U, Hoffman F, Solder B, et al. Comparison of two antiretroviral triple combinations including the protease inhibitor indinavir in children infected with human immunodeficiency virus. Pediatr Infect Dis J 1998 Jun; 17: 495–9
Crixivan (indinavir sulfate): summary of clinical studies. Merck & Co. Inc., Whitehouse Station, NJ, USA. Data on file
Kirk O, Pedersen C, Gerstoft J, et al. Type of protease inhibitor and low body mass index predict severe and treatment limiting adverse drug reactions in HIV-patients starting protease inhibitor treatment [abstract]. AIDS 1998 Nov; 12 Suppl. 4: S55
Rich JD, Ramratnam B, Chiang M, et al. Management of indinavir associated nephrolithiasis. J Urol 1997 Dec; 158:2228
Bach MC, Godofsky EW. Indinavir nephrolithiasis in warm climates [letter]. J Acquir Immune Defic Syndrom Hum Retrovirol 1997 Mar; 14: 296–7
Kovach DA, Smead J. Increased incidence of indinavir-associated nephrolithiasis in a warm climate [abstract no. 1-59]. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1998 Sep 24; San Diego, 380
Brodie SB, Keller MJ, Ewenstein BM, et al. Variation in incidence of indinavir-associated nephrolithiasis among HIV-positive patients. AIDS 1998 Dec 24; 12: 2433–7
Boubaker K, Sudre P, Bally F, et al. Changes in renal function associated with indinavir. AIDS 1998 Dec 24; 12: F249–54
Martinez F, Mommeja-Marin H, Estepa-Maurice L, et al. Indinavir crystal deposits associated with tubulointerstitial nephropathy. Nephrol Dial Transplant 1998 Mar; 13: 750–3
Grabe DW, Eisele G, Miller C, et al. Indinavir-induced nephropathy. Clin Nephrol 1999 Mar; 51:181–3
Viganó A, Rombolá G, Barbiano di Belgioioso G, et al. Subtle occurrence of indinavir-induced acute renal insufficiency. AIDS 1998 May 28; 12: 954–5
Hermieu JF, Prévot MH, Ravery V, et al. Indinavir-induced acute nephretic flank pain [in French]. Presse Med 1998 Mar 14; 27: 465–7
Hanabusa H, Tagami H, Hataya H. Renal atrophy associated with long-term treatment with indinavir. N Engl J Med 1999 Feb 4; 340: 392–3
Perazella MA, Kashgarian M, Cooney E. Indinavir nephropathy in an AIDS patient with renal insufficiency and pyuria. Clin Nephrol 1998 Sep; 50: 194–6
Ascher DP, Lucy MD. Indinavir sulfate renal toxicity in a pediatric hemophiliac with HIV infection. Ann Pharmacother 1997 Oct; 31: 1146–9
Marroni M, Gaburri M, Mecozzi F, et al. Acute interstitial nephritis secondary to the administration of indinavir [letter]. Ann Pharmacother 1998 Jul–Aug; 32: 843–4
Sarcletti M, Petter A, Zangerle R. Indinavir and interstitial nephritis. Ann Intern Med 1998 Feb 15; 128: 320
Sarcletti M, Petter A, Lhotta K, et al. Sterile pyuria in patients taking indinavir: association with renal dysfunction and an early sign of interstitial nephritis [abstract no. 485]. Clin Infect Dis 1998; 27(4): 1013
Tashima KT, Horowitz JD, Rosen S. Indinavir nephropathy. N Engl J Med 1997 Jan 9; 336: 138–9
Chen SC, Nankivell BJ, Dwyer DE. Indinavir-induced renal failure [letter]. AIDS 1998 Mar 5; 12: 440–1
Witte M, Tobon A, Gruenenfelder J, et al. Anuria and acute renal failure resulting from indinavir sulfate induced nephrolithiasis. J Urol 1998 Feb; 159: 498–9
Benveniste O, Longuet P, Duval X, et al. Two episodes of acute renal failure, rhabdomyolysis, and severe hepatitis in an AIDS patient successively treated with ritonavir and indinavir. Clin Infect Dis 1999; 28: 1180–1
Kopp JB, Miller KD, Falloon J. Indinavir and interstitial nephritis [letter (reply)]. Ann Intern Med 1998 Feb 15; 128: 320–1
Tsao JW, Kogan SC. Indinavir crystalluria. N Engl J Med 1999; 340: 1329
Clayman RV. Crystalluria and urinary tract abnormalities associated with indinavir. J Urol 1998 Aug; 160: 633
Gagnon RF, Tsoukas CM, Watters AK. Light microscopy of indinavir urinary crystals [letter]. Ann Intern Med 1998 Feb 15; 128: 321
Kopp JB, Miller KD, Mican JA, et al. Crystalluria and urinary tract abnormalities associated with indinavir [see comments]. Ann Intern Med 1997 Jul 15; 127: 119–25
Tecimer SN, Tsoukas CM, Watters AK, et al. Prospective long-term evaluation of urine abnormalities in HIV+ patients treated with indinavir [abstract]. AIDS 1998 Nov; 12 Suppl. 4:S42
Deeks SG, Smith M, Holodniy M, et al. HIV-1 protease inhibitors: a review for clinicians. JAMA 1997 Jan 8; 277: 145–53
Carr A, Samaras K, Thorisdottir A, et al. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999; 353: 1–16
Kotler DP. Summary Report: First International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. San Diego, CA, USA, June 26–28, 1999. Available from: URL: http://hiv.medscape.com/Medscape/HIV/journal/1999/v05.n04/mha0712.kotl/mha0712.kotl-01.html
Brinkman K, Smeitink JA, Romijn JA, et al. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of anti-retroviral-therapy-related lipodystrophy. Lancet 1999; 354: 1112–5
Gervasoni C, Ridolfo AL, Trifirò G, et al. Redistribution of body fat in HIV-infected women undergoing combined anti-retroviral therapy. AIDS 1999; 13: 465–71
Madge S, Kinloch de Loes S, Mercey D, et al. Lipodystrophy in patients naive to protease inhibitors. AIDS 1999; 13:735–7
Saint-Marc T, Touraine J-L. “Buffalo hump” in HIV-1 infection [letter]. Lancet 1998; 352: 319–20
Lo JC, Mulligan K, Tai VW, et al. “Buffalo hump” in men with HIV-1 infection. Lancet 1998; 351: 867–70
Bernasconi E, Carota A, Magenta L, et al. Lipodystrophy and hyperlipidemia associated with protease inhibitors [abstract no. P143]. AIDS 1998; 12 Suppl. 4: S52
Carr A, Samaras K, Chisholm DJ, et al. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet 1998; 351: 1881–3
Carr A, Cooper DA. Lipodystrophy associated with an HIV-protease inhibitor. N Engl J Med 1998 Oct 29; 339: 1296
Aboulafia DM, Bundow D. Buffalo hump in a patient with the acquired immunodeficiency syndrome. N Engl J Med 1998 Oct 29; 339: 1297
Spenatto N, Viraben R. Early lipodystrophy occurring during post-exposure prophylaxis. Sex Transmit Infect 1998 Dec; 74: 455
Fischer T, Schwörer H, Ramadori G. Benign symmetrical lipomatosis (peripheral lipodystrophy) during antiretroviral treatment of HIV infection [in German]. Dtsch Med Wochenschr 1998 Dec 11; 123: 1512–6
Hengel RL, Watts NB, Lennox JL. Benign symmetric lipomatosis associated with protease inhibitors. Lancet 1997 Nov 29; 350: 1596
Bonnet E, Cuzin L, Sailler L, et al. Associated lipodystrophy metabolic disorders due to protease inhibitor containing regimens [abstract no. 12299]. 12th World AIDS Conference; 1998 Jun 28; Geneva, 72
Miller KD, Jones E, Yanovski JA, et al. Visceral abdominal-fat accumulation associated with use of indinavir. Lancet 1998 Mar 21; 351: 871–5
Roth VR, Kravcik S, Angel JB. Development of cervical fat pads following therapy with human immunodeficiency virus type 1 protease inhibitors. Clin Infect Dis 1998 Jul; 27: 65–7
Schindler JT, Spooner KM, Decker CF. ‘Buffalo humps’ associated with protease inhibitors [letter]. Ann Intern Med 1998 Jul 15; 129: 164
Babl FE, Regan AM, Pelton SI. Abnormal body-fat distribution in HIV-1-infected children on antiretrovirals. Lancet 1999 Apr 10; 353: 1243–4
Protease inhibitors. Aust Adv Drug ReactBull 1998 May; 17: 6
De Luca A, Murri R, Damiano F, et al. Correspondence [letter]. Lancet 1998; 352: 320
Veny A, Bonjoch A, Romeu J, et al. Cumulative risk for developing protease inhibitor associated lipodystrophy (PI-AL) in HIV-infected patients [abstract no. 1-92]. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1998 Sep 24; San Diego, 390–1
Henry K, Melroe H, Huebesch J, et al. Experience with the national cholesterol education program (NCEP) guidelines for the identification and treatment of protease inhibitor related lipid abnormalities: results of a prospective study [abstract no. 671]. 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; Chicago
Hsia J, Simon GL, Parenti DM, et al. Lipid and lipoprotein abnormalities with indinavir in human immunodeficiency virus infection [abstract]. J Am Coll Cardiol 1999 Feb; 33 Suppl. A: 293A
Vancouwenberghe C, King JH, Gordon J, et al. Clinical investigation of the incidence and severity of elevated cholesterol and triglycerides in AIDS patients receiving protease inhibitor therapy [abstract no. I-69]. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1998 Sep 24; San Diego, 384
Nelson MR, Moyle G, Newell A. The incidence of hyperlipidaemia with protease inhibitors (PI) [abstract]. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1998 Sep 24: 389
Segerer S, Bogner JR, Walli R, et al. Hyperlipidemia under treatment with proteinase inhibitors. Infection 1999; 27(2): 77–81
Robertson M, Nessly M, Aversa D, et al. Changes in serum cholesterol and triglyceride levels in patients treated with indinavir or NRTIs [abstract no. 648]. 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; Chicago
Martínez E, Casamitjana R, Conget I, et al. Protease inhibitor-associated hyperinsulinaemia. AIDS 1998 Oct 22; 12: 2077–9
Dube MP, Johnson DL, Currier JS, et al. Protease inhibitor-associated hyperglycaemia. Lancet 1997 Sep 6; 350: 713–4
Bouchard O, Gavazzi G, Leclercq P, et al. Onset diabetes mellitus associated with protease inhibitor therapy [abstract no. 12308]. 12th World AIDS Conference; 1998 Jun 28; Geneva, 74–75
Canadian Adverse Drug Reaction Newsletter: communiqué. Can Adverse Drug React Newslett 1997 Oct; 7: 953–4
Besson C, Jubault V, Viard JP, et al. Ketoacidosis associated with protease inhibitor therapy. AIDS 1998 Jul 30; 12: 1399–400
Rodriguez-Rosado R, Soriano V, Jiménez-Nácher I, et al. Diabetes mellitus associated with the use of protease inhibitors [abstract]. AIDS 1998 Nov; 12 Suppl. 4: S54
Eastone JA, Decker CF. New-onset diabetes mellitus associated with use of protease inhibitor. Ann Intern Med 1997 Nov 15; 127:948
Walli R, Herfort O, Michl GM, et al. Treatment with protease inhibitors associated with peripheral insulin resistance and impaired glucose tolerance in HIV-1-infected patients. AIDS 1998; 12: F167–73
Yarasheski KE, Tebas P, Sigmund C, et al. Insulin resistance in HIV protease inhibitor-associated diabetes. J Acquir Immune Defic Syndr 1999; 21: 209–16
Fleming CA, Cilento JJ, Steger KA, et al. New onset diabetes mellitus (DM) related to protease inhibitors (PI): clinical features, demographics and insulin levels [abstract no. 481]. Clin Infect Dis 1998; 27(4): 1012
Karmochkine M, Raguin G. Severe coronary artery disease in a young HIV-infected man with no cardiovascular risk factor who was treated with indinavir. AIDS 1998 Dec 24; 12: 2499
Sullivan AK, Nelson MR, Moyle GJ, et al. Coronary artery disease occurring with protease inhibitor therapy. AIDS 1998 Nov; 12 Suppl. 4: S54
Vittecoq D, Escaut L, Monsuez JJ. Vascular complications associated with use of HIV protease inhibitors [letter]. Lancet 1998 Jun 27; 351: 1959
Henry K, Melroe H, Huebsch J, et al. Severe premature coronary artery disease with protease inhibitors. Lancet 1998 May 2; 351: 1328
Gallet B, Pulik M, Genet P, et al. Vascular complications associated with use of HIV protease inhibitors [letter]. Lancet 1998 Jun 27; 351: 1958–9
Behrens G, Schmidt H, Meyer D. Vascular complications associated with use of HIV protease inhibitors [letter]. Lancet 1998; 351: 1958
George S, Swindells S, Knudson R, et al. Thromboembolic disease associated with initiation of protease inhibitor therapy [abstract no. 60160]. 12th World AIDS Conference; 1998 Jun 28; Geneva, 1028
Carr A, Brown D, Cooper DA. Portal vein thrombosis in patients receiving indinavir, an HIV protease inhibitor. AIDS 1997 Nov; 11: 1657–8
Ruiz I, Altisent C, Ocaña I, et al. Bleeding in hemophilic pa tients on protease inhibitors [abstract]. AIDS 1998 Nov; 12 Suppl. 4: S55
HIV protease inhibitors and increased bleeding in hemophilia? Can Adverse Drug React Newslet 1997 Jan
Bleeding warnings for protease inhibitors. Scrip 1996 Jul 26(2149): 17
Pollmann H, Richter H, Jürgens H. Platelet dysfunction as the cause of spontaneous bleeding in two haemophilic patients taking HIV protease inhibitors. Thromb Haemost 1998 Jun; 79: 1213–4
Prazuck T, Semaille C, Roques S. Fatal acute haemolysis in an AIDS patient treated with indinavir. AIDS 1998 Mar 26; 12: 531–3
Fonquernie L, Girard PM, Cardon B, et al. Hemolytic jaundice related to ingestion of indinavir (letter) [in French]. Presse Med 1997 Nov 1; 26: 1578
Morrison-Griffiths S, Newman M, O’Mahony C, et al. Haemolytic anaemia associated with indinavir. Postgrad Med J 1999; 75: 313–5
Durand JM. Indinavir and thrombocytopenia [abstract]. AIDS 1999; 13(1): 148–9
Gajewski LD, Melbourne K, Grimone A, et al. Characterization of rash with indinavir [abstract]. J Manage Care Pharm 1997 May–Jun; 3: 296–7
Calista D, Boschini A, Stagno A. Cutaneous side effects induced by indinavir [abstract]. J Eur Acad Dermatol Venerol 1998; 11 Suppl. 2: S196
Aquilina C, Viraben R, Roueire A. Acute generalized exanthematous pustulosis: a cutaneous adverse effect due to prophylactic antiviral therapy with protease inhibitor [abstract]. Arch Intern Med 1998 Oct 26; 158: 2160–1
Teira R, Zubero Z, Muñoz J. Stevens-Johnson syndrome caused by indinavir. Scand J Infect Dis 1998; 30(6): 634–5
John M, Flexman J, French MAH. Hepatitis C virus-associated hepatitis following treatment of HIV-infected patients with HIV protease inhibitors: an immune restoration disease? AIDS 1998 Dec 3; 12 Suppl. 1: 2289–93
Bräu N, Leaf HL, Wieczorek RL, et al. Severe hepatitis in three AIDS patients treated with indinavir [letter; comment]. Lancet 1997 Mar 29; 349: 924–5
Zylberberg H, Pialoux G, Carnot F, et al. Rapidly evolving hepatitis C virus — related cirrhosis in a human immunodeficiency virus-infected patient receiving triple antiretroviral therapy. Clin Infect Dis 1998 Nov; 27: 1255–8
Jeurissen FJF, Schneider MME, Borleffs JCC. Is the combination of hepatitis and indinavir potentially dangerous? [letter]. AIDS 1998 Mar 5; 12:441–2
Matsuda J, Gohchi K, Yamanaka M. Severe hepatitis in patients with AIDS and haemophilia B treated with indinavir [letter]. Lancet 1997 Aug 2; 350: 364
Rodríguez-Rosado R, García-Samaniego J, Soriano V Hepatotoxicity after introduction of highly active antiretroviral therapy. AIDS 1998; 12: 1256
Ault A. FDA warns of potential protease-inhibitor link to hyperglycaemia. Lancet 1997 Jun 21; 349: 1819
1stinternational workshop on adverse drug reactions and lipodystrophy in HIV — rapid report. Available from: URL: http://www.intmedpress.com/lipodystrophy [Accessed 14 Sep 1999]
Polhemus ME, Aronson NE. Persistent nephrolithiasis after discontinuation of indinavir therapy. Clin Infect Dis 1998 Dec; 27: 1536–7
Bruce RG, Munch LC, Hoven AD, et al. Urolithiasis associated with the protease inhibitor indinavir. Urology 1997 Oct; 50: 513–8
Fauci AS. The AIDS epidemic: considerations for the 21st century. N Engl J Med 1999; 341: 1046–50
Kempf DJ, Rode RA, Xu Y, et al. The duration of viral suppression during protease inhibitor therapy for HIV-1 infection is predicted by plasma HIV-1 RNA at the nadir. AIDS 1998; 12: F9–F14
Raboud JM, Montaner JS, Conway B, et al. Suppression of plasma viral load below 20 copies/ml is required to achieve a long-term response to therapy. AIDS 1998; 12: 1619–24
Furtado MR, Callaway DS, Phair JP, et al. Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. N Engl J Med 1999; 340: 1614–22
Zhang L, Ramratnam B, Tenner-Racz K, et al. Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. N Engl J Med 1999; 340: 1605–13
Montaner JSG, Hogg R, Raboud J, et al. Antiretroviral treatment in 1998. Lancet 1998 Dec 12; 352: 1919–22
Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. MMWR 1998 Apr 24; 47 Suppl. RR-5: 43–83
Gazzard B, Moyle G, BHIVA Guidelines Writing Committee. 1998 revision to the British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. Lancet 1998 Jul 25; 352: 314–6
Rachlis AR, Zarowny DP, Canadian HIV Trials Network Antiretroviral Working Group. Guidelines for antiretroviral therapy for HIV infection. Can Med Assoc J 1998 Feb 24; 158: 496–505
Carpenter CCJ, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1998: updated recommendations of the International AIDS Society-USA Panel. JAMA 1998 Jul 1; 280: 78–86
British HIV Association. New BHIVA guidelines for antiretroviral treatment of HIV. Available from: URL: http://www.aidsmap.com/nam/bhiva/index.htm [Accessed 25 Aug 1999]
Palella Jr FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338: 853–60
Egger M, Hirschel B, Francioli P, et al. Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: prospective multicentre study. Swiss HIV Cohort Study. BMJ 1997; 315: 1194–9
Mocroft A, Vella S, Benfield TL, et al. Changing patterns of mortality across Europe in patients infected with HIV-1. Lancet 1998; 352: 1725–30