Efavirenz, nelfinavir, and stavudine rescue combination therapy in HIV- 1-positive patients heavily pretreated with nucleoside analogues and protease inhibitors

Elena Seminari, Franco Maggiolo, Paola Villani, Fredy Suter, Angelo Pan, Mario B. Regazzi, Carmine Tinelli, Renato Maserati

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Abstract

Tolerability, activity, and pharmacokinetic parameters of a combination therapy with efavirenz (EFV), nelfinavir (NFV), and stavudine (d4T) were evaluated in this study. Forty-seven HIV-1-infected study subjects, naive to NFV and nonnucleoside reverse transcriptase inhibitors (NNRTIs), who had experienced virologic failure while being treated with combination antiretroviral therapies including protease inhibitors (PIs), were enrolled. At baseline, HIV-1 viral load in plasma was 4.8 log10, CD4+ count was 204 cells/μl (both mean values); patients had received a mean of 3.1 different treatments (range, 2-5 treatments). Study medications were generally well tolerated; 7 of 47 patients (14.8%) were dropped from the study because of related drug toxicity. At week 24, mean plasma viral load (pVL) was reduced by 1.9 log10, with mean CD4+ count increased to 324 cells/μl (±59% from baseline); pVL was below the limit of detection (500 copies/ml) in 46.1% of patients. An extended follow-up study was performed at 12 months. Results showed a reduction of 1.7 log10 in pVL from basal values that was consistent with values observed at months 3 and 6. A history of previous use of PIs represented a negative prognostic marker. Sequencing analysis, performed in a subset of patients, showed the presence of multiple point mutations associated with PI resistance. Pharmacokinetic analysis demonstrated a marked inter-individual variability in NFV plasma concentrations, producing in 4 of 18 patients (22%) trough concentrations lower than minimum effective concentration. In pretreated patients, further studies are needed to characterize the pharmacokinetic factors that affect response to therapy and the association of these results with the 95% inhibitory concentration (IC95) determined by phenotyping.

Original languageEnglish
Pages (from-to)453-460
Number of pages8
JournalJournal of Acquired Immune Deficiency Syndromes and Human Retrovirology
Volume22
Issue number5
Publication statusPublished - Dec 15 1999

Fingerprint

efavirenz
Nelfinavir
Stavudine
Protease Inhibitors
Nucleosides
HIV-1
Viral Load
Pharmacokinetics
CD4 Lymphocyte Count
Therapeutics
Reverse Transcriptase Inhibitors
Drug-Related Side Effects and Adverse Reactions
Point Mutation
Limit of Detection

Keywords

  • Efavirenz
  • HIV-1 infection
  • Nelfinavir
  • Rescue therapy
  • Stavudine

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Virology

Cite this

@article{4e1a97bb5da84bbe9a1882e544b8e2c6,
title = "Efavirenz, nelfinavir, and stavudine rescue combination therapy in HIV- 1-positive patients heavily pretreated with nucleoside analogues and protease inhibitors",
abstract = "Tolerability, activity, and pharmacokinetic parameters of a combination therapy with efavirenz (EFV), nelfinavir (NFV), and stavudine (d4T) were evaluated in this study. Forty-seven HIV-1-infected study subjects, naive to NFV and nonnucleoside reverse transcriptase inhibitors (NNRTIs), who had experienced virologic failure while being treated with combination antiretroviral therapies including protease inhibitors (PIs), were enrolled. At baseline, HIV-1 viral load in plasma was 4.8 log10, CD4+ count was 204 cells/μl (both mean values); patients had received a mean of 3.1 different treatments (range, 2-5 treatments). Study medications were generally well tolerated; 7 of 47 patients (14.8{\%}) were dropped from the study because of related drug toxicity. At week 24, mean plasma viral load (pVL) was reduced by 1.9 log10, with mean CD4+ count increased to 324 cells/μl (±59{\%} from baseline); pVL was below the limit of detection (500 copies/ml) in 46.1{\%} of patients. An extended follow-up study was performed at 12 months. Results showed a reduction of 1.7 log10 in pVL from basal values that was consistent with values observed at months 3 and 6. A history of previous use of PIs represented a negative prognostic marker. Sequencing analysis, performed in a subset of patients, showed the presence of multiple point mutations associated with PI resistance. Pharmacokinetic analysis demonstrated a marked inter-individual variability in NFV plasma concentrations, producing in 4 of 18 patients (22{\%}) trough concentrations lower than minimum effective concentration. In pretreated patients, further studies are needed to characterize the pharmacokinetic factors that affect response to therapy and the association of these results with the 95{\%} inhibitory concentration (IC95) determined by phenotyping.",
keywords = "Efavirenz, HIV-1 infection, Nelfinavir, Rescue therapy, Stavudine",
author = "Elena Seminari and Franco Maggiolo and Paola Villani and Fredy Suter and Angelo Pan and Regazzi, {Mario B.} and Carmine Tinelli and Renato Maserati",
year = "1999",
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journal = "Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology",
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T1 - Efavirenz, nelfinavir, and stavudine rescue combination therapy in HIV- 1-positive patients heavily pretreated with nucleoside analogues and protease inhibitors

AU - Seminari, Elena

AU - Maggiolo, Franco

AU - Villani, Paola

AU - Suter, Fredy

AU - Pan, Angelo

AU - Regazzi, Mario B.

AU - Tinelli, Carmine

AU - Maserati, Renato

PY - 1999/12/15

Y1 - 1999/12/15

N2 - Tolerability, activity, and pharmacokinetic parameters of a combination therapy with efavirenz (EFV), nelfinavir (NFV), and stavudine (d4T) were evaluated in this study. Forty-seven HIV-1-infected study subjects, naive to NFV and nonnucleoside reverse transcriptase inhibitors (NNRTIs), who had experienced virologic failure while being treated with combination antiretroviral therapies including protease inhibitors (PIs), were enrolled. At baseline, HIV-1 viral load in plasma was 4.8 log10, CD4+ count was 204 cells/μl (both mean values); patients had received a mean of 3.1 different treatments (range, 2-5 treatments). Study medications were generally well tolerated; 7 of 47 patients (14.8%) were dropped from the study because of related drug toxicity. At week 24, mean plasma viral load (pVL) was reduced by 1.9 log10, with mean CD4+ count increased to 324 cells/μl (±59% from baseline); pVL was below the limit of detection (500 copies/ml) in 46.1% of patients. An extended follow-up study was performed at 12 months. Results showed a reduction of 1.7 log10 in pVL from basal values that was consistent with values observed at months 3 and 6. A history of previous use of PIs represented a negative prognostic marker. Sequencing analysis, performed in a subset of patients, showed the presence of multiple point mutations associated with PI resistance. Pharmacokinetic analysis demonstrated a marked inter-individual variability in NFV plasma concentrations, producing in 4 of 18 patients (22%) trough concentrations lower than minimum effective concentration. In pretreated patients, further studies are needed to characterize the pharmacokinetic factors that affect response to therapy and the association of these results with the 95% inhibitory concentration (IC95) determined by phenotyping.

AB - Tolerability, activity, and pharmacokinetic parameters of a combination therapy with efavirenz (EFV), nelfinavir (NFV), and stavudine (d4T) were evaluated in this study. Forty-seven HIV-1-infected study subjects, naive to NFV and nonnucleoside reverse transcriptase inhibitors (NNRTIs), who had experienced virologic failure while being treated with combination antiretroviral therapies including protease inhibitors (PIs), were enrolled. At baseline, HIV-1 viral load in plasma was 4.8 log10, CD4+ count was 204 cells/μl (both mean values); patients had received a mean of 3.1 different treatments (range, 2-5 treatments). Study medications were generally well tolerated; 7 of 47 patients (14.8%) were dropped from the study because of related drug toxicity. At week 24, mean plasma viral load (pVL) was reduced by 1.9 log10, with mean CD4+ count increased to 324 cells/μl (±59% from baseline); pVL was below the limit of detection (500 copies/ml) in 46.1% of patients. An extended follow-up study was performed at 12 months. Results showed a reduction of 1.7 log10 in pVL from basal values that was consistent with values observed at months 3 and 6. A history of previous use of PIs represented a negative prognostic marker. Sequencing analysis, performed in a subset of patients, showed the presence of multiple point mutations associated with PI resistance. Pharmacokinetic analysis demonstrated a marked inter-individual variability in NFV plasma concentrations, producing in 4 of 18 patients (22%) trough concentrations lower than minimum effective concentration. In pretreated patients, further studies are needed to characterize the pharmacokinetic factors that affect response to therapy and the association of these results with the 95% inhibitory concentration (IC95) determined by phenotyping.

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