The effect of treatment intensification in HIV-infection: a study comparing treatment with ritonavir/saquinavir and ritonavir/saquinavir/stavudine

Gisolf, Elizabeth H.; Jurriaans, Suzanne; Pelgrom, Jolanda; Wanzeele, Filip Van; Ende, Marchina E. van der; Brinkman, Kees; Borst, M J; Wolf, Frank de; Japour, Anthony J.; Danner, Sven A.

doi:10.1097/00002030-200003100-00014

Cited by 42 publications

(34 citation statements)

References 13 publications

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“…However, the difference between the 2 treatment arms in this study cannot be explained by a difference in immune restoration. The treatment groups did not differ in their CD4 ϩ and CD8 ϩ lymphocyte response to therapy [21]; moreover, the change in CD4 ϩ or CD8 ϩ lymphocyte counts was not associated with the occurrence of LEE.…”

Section: Discussionmentioning

confidence: 85%

Risk Factors for Hepatotoxicity in HIV-1--Infected Patients Receiving Ritonavir and Saquinavir with or without Stavudine

Gisolf¹,

Dreezen²,

Danner³

et al. 2000

Clinical Infectious Diseases

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Liver enzyme elevation (LEE) is commonly observed after combination antiretroviral therapy (ARVT) for HIV infection is begun. Potential risk factors for LEE after treatment with ritonavir and saquinavir with or without stavudine were investigated in 208 HIV-infected patients, by use of the Cox proportional hazard model. Eighteen patients (9%) developed LEE during the 48-week follow-up. Multivariate analysis, adjusted for baseline levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), showed that hepatitis B surface antigen (HBsAg) positivity (relative risk [RR], 8.8; 95% confidence interval [CI], 3.3-23.1) and the use of stavudine (RR, 4.9; 95% CI, 1.5-16.0) were the only significant risk factors for developing LEE. After LEE occurred, ALT and AST concentrations decreased by >50% in 13 of 14 patients who continued ARVT during LEE. In this study, it appeared safe to continue ARVT during LEE; however, more data from larger studies are required to confirm this finding.

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Section: Discussionmentioning

confidence: 85%

Risk Factors for Hepatotoxicity in HIV-1--Infected Patients Receiving Ritonavir and Saquinavir with or without Stavudine

Gisolf¹,

Dreezen²,

Danner³

et al. 2000

Clinical Infectious Diseases

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“…On the basis of published literature, we estimated the likely virologic suppression rate of the first through fifth sequential line of therapy in patients with and patients without virus with genotypic resistance who were starting an efavirenz-based or a lopinavir/ritonavir-based initial regimen (table 2) [31][32][33][34][35][36][37][38]. Because limited data exist regarding efficacy of therapy with primary resistance, we estimated outcomes using studies of treatment-experienced patients and then varied the outcomes in sensitivity analyses.…”

Section: Analytic Overviewmentioning

confidence: 99%

Should Resistance Testing Be Performed for Treatment-Naive HIV-Infected Patients? A Cost-Effectiveness Analysis

Sax

Islam

Walensky

et al. 2005

Clinical Infectious Diseases

176

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“…Combination therapy using two protease inhibitors (PIs), either with or without accompanying therapy with nucleoside reverse transcriptase inhibitors (NRTIs), has been utilized in both therapy-naïve (2,7,17) and therapy-experienced patients. The rationale for dual PI therapy includes both the nonoverlapping resistance profiles of some PIs and, in particular, the pharmacokinetic enhancement of most PIs by coadministration with ritonavir (RTV) (10).…”

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confidence: 99%

In Vitro Antiviral Interaction of Lopinavir with Other Protease Inhibitors

Molla

Vasavanonda

et al. 2002

Antimicrob Agents Chemother

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The in vitro inhibition of wild-type human immunodeficiency virus (HIV) by combinations of lopinavir and six other protease inhibitors over a range of two-drug combination ratios was evaluated. Combinations of lopinavir with indinavir, nelfinavir, amprenavir, tipranavir, and BMS-232632 generally displayed an additive relationship. In contrast, a consistent, statistically significant synergistic inhibition of HIV type 1 replication with combinations of lopinavir and saquinavir was observed. Analysis of the combination indices indicated that lopinavir with saquinavir was synergistic over the entire range of drug combination ratios tested and at all levels of inhibition in excess of 40%. Cellular toxicity was not observed at the highest drug concentrations tested. These results suggest that administration of combinations of the appropriate dose of lopinavir with other protease inhibitors in vivo may result in enhanced antiviral activity with no associated increase in cellular cytotoxicity. More importantly, the observed in vitro synergy between lopinavir and saquinavir provides a theoretical basis for the clinical exploration of a novel regimen of lopinavir-ritonavir and saquinavir.Combination therapy using two protease inhibitors (PIs), either with or without accompanying therapy with nucleoside reverse transcriptase inhibitors (NRTIs), has been utilized in both therapy-naïve (2, 7, 17) and therapy-experienced patients. The rationale for dual PI therapy includes both the nonoverlapping resistance profiles of some PIs and, in particular, the pharmacokinetic enhancement of most PIs by coadministration with ritonavir (RTV) (10). Unlike combination regimens containing agents that act by inhibition of different viral enzymes, mechanism-based synergy of PI combinations is unlikely, based on the competitive nature of inhibition of human immunodeficiency virus (HIV) protease. Thus, the in vitro antiviral interactions of PIs have generally been found to be additive (3,6,14). However, pharmacologic mechanisms possibly leading to either synergy or antagonism between PIs theoretically exist (e.g., competitive absorption and/or egress from cells, competitive binding to serum proteins). For example, in one study, the in vitro interactions between indinavir (IDV) and saquinavir (SQV) and between IDV and nelfinavir (NFV) were found to be antagonistic (14, 16; D. J. Manion, D. P. Merrill, T. C. Chou, and M. S. Hirsch, Abstr. 36th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 11, p. 186, 1996). In contrast, antiviral synergy was observed between RTV and SQV and between RTV and tipranavir (TPV) in the presence or absence of human serum (3; A. Molla, S. Vasavanonda, T. Chernyavskiy, J. Praestgaard, A. Hsu, T. Lin, E. Sun, W. Kohlbrenner, and D. Kempf, Program Abstr. 2nd Int. Workshop HIV Drug Resist. Treat. Strategies, abstr. 39, p. 27, 1998).Lopinavir (LPV; ABT-378) is a novel peptidomimetic HIV protease inhibitor with approximately 10-fold greater in vitro potency than RTV in the presence of human serum (15). Pharmacokineti...

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The effect of treatment intensification in HIV-infection: a study comparing treatment with ritonavir/saquinavir and ritonavir/saquinavir/stavudine

Cited by 42 publications

References 13 publications

Risk Factors for Hepatotoxicity in HIV-1--Infected Patients Receiving Ritonavir and Saquinavir with or without Stavudine

Risk Factors for Hepatotoxicity in HIV-1--Infected Patients Receiving Ritonavir and Saquinavir with or without Stavudine

Should Resistance Testing Be Performed for Treatment-Naive HIV-Infected Patients? A Cost-Effectiveness Analysis

In Vitro Antiviral Interaction of Lopinavir with Other Protease Inhibitors

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