Randomized Trial to Evaluate Indinavir/Ritonavir versus Saquinavir/Ritonavir in Human Immunodeficiency Virus Type 1–Infected Patients: The MaxCmin1 Trial

Dragsted, Ulrik Bak; Gerstoft, Jan; Pedersen, Court; Peters, Barry; Durán, Adriana; Obel, Niels; Castagna, Antonella; Cahn, Pedro; Clumeck, Nathan; Bruun, Johan N.; Benetucci, Jorge; Hill, Andrew; Cassetti, Isabel; Vernazza, Pietro; Youle, Michael; Fox, Zoë; Lundgren, Jens D.

doi:10.1086/377288

Cited by 120 publications

(107 citation statements)

References 22 publications

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“…No significant differences could be found between plasma SQV levels and gender, weight, or the presence of hepatitis and/or cirrhosis, except for a slight trend toward higher SQV C min levels in cirrhotic patients. The efficacy in the ITT analysis in our series (69.5%) is lower than that reported with the 1,600/100-mg once-daily regimen and similar to that observed in the MaxCmin2 trial with a 1,000/100 twice-daily dose (2,12,13,16,26). However, only five patients (3.3%) had virological failure despite adequate C min levels but with a confirmed poor adherence.…”

Section: Discussionsupporting

confidence: 73%

“…The efficacy of this dosage has been proved as part of highly active antiretroviral therapy (HAART), although the required pill burden and dosing frequency are disadvantageous factors for adherence (15,33). Since nonresistant viruses require lower PI concentrations in plasma to be inhibited (33) and a relationship among dose, exposure, and response to SQV has been demonstrated (18), we decided to evaluate the clinical efficacy of the lowest pharmacokinetically assayed SQVr dosage (1,200/100 mg once daily) in treatment-naive or limited PI-experienced HIV-infected patients on the basis of plasma pharmacokinetic data but also assessing intracellular concentrations (the true effect compartment of SQV).…”

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confidence: 99%

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Clinical and Pharmacokinetic Data Support Once-Daily Low-Dose Boosted Saquinavir (1,200 Milligrams Saquinavir with 100 Milligrams Ritonavir) in Treatment-Naive or Limited Protease Inhibitor-Experienced Human Immunodeficiency Virus-Infected Patients

Marín‐Niebla¹,

López‐Cortés

Ruiz-Valderas

et al. 2007

Antimicrob Agents Chemother

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We evaluated the plasma and intracellular pharmacokinetics, clinical efficacy, and safety of once-daily low-dose boosted saquinavir (SQVr; 1,200 of saquinavir [SQV] with 100 mg of ritonavir) plus two nucleotide reverse transcriptase inhibitors in treatment-naive or limited protease inhibitor (PI)-experienced human immunodeficiency virus (HIV)-infected patients. A prospective study without entry restrictions on the plasma HIV-RNA (VL) or CD4 cell count was carried out. Plasma and intracellular SQV levels were measured by high-performance liquid chromatography. Efficacy was evaluated by an intention-to-treat analysis; treatment failure was defined as virological failure (a VL of >50 copies/ml after 24 weeks or a confirmed rebound to >50 copies/ml) or interruption for any reason. A total of 151 patients were included in the study (106 of them either had never received PI or had no previous virological failure on PIs) and could be characterized as follows: previous C3 stage, 28.9%; injection-drug users, 69.1%; subjects with chronic viral hepatitis, 53%; and subjects with cirrhosis, 10%. The median baseline CD4 level was 184/l, and the median VL was 4.8 log 10 copies/ml. Median C max , area under the concentration-time curve from 0 to 24 h, and C min plasma and intracellular SQV levels were 3,672 and 10,105 ng/ml, 34,283 and 99,535 ng ⅐ h/ml, and 359 and 1,062 ng/ml, respectively. The efficacy as determined by intention to treat at 52 weeks was 69.7% (96% in the on-treatment analysis), with similar results regardless of the baseline VL and CD4 counts. Only five patients had virological failure despite adequate C min levels, but with a poor adherence (the only variable related to virological failure). Adverse events caused the withdrawal of the treatment in four patients (2.6%). In conclusion, given the pharmacokinetic profile, efficacy, and tolerability of this regimen, once-daily low-dose SQVr may be considered a treatment option in treatment-naive or limited PI-experienced HIV-infected patients, with the additional benefit of being currently the least-expensive PI-based regimen available.

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Section: Discussionsupporting

confidence: 73%

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confidence: 99%

Clinical and Pharmacokinetic Data Support Once-Daily Low-Dose Boosted Saquinavir (1,200 Milligrams Saquinavir with 100 Milligrams Ritonavir) in Treatment-Naive or Limited Protease Inhibitor-Experienced Human Immunodeficiency Virus-Infected Patients

Marín‐Niebla¹,

López‐Cortés

Ruiz-Valderas

et al. 2007

Antimicrob Agents Chemother

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“…For example, hyperlipidaemia was observed when RTV was used at a dosage of 100 mg twice daily to boost both indinavir 800 mg twice daily and saquinavir 1000 mg twice daily in the MaxCMin1 study [17]. Ritonavir, given at a dosage 200 mg once daily plus fosamprenavir 1400 mg once daily, was associated with higher rates of hypertriglyceridaemia than was NFV 1250 mg twice daily in the SOLO Study [18].…”

Section: Discussionmentioning

confidence: 99%

The effect of low‐dose ritonavir monotherapy on fasting serum lipid concentrations

2005

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ObjectivesRitonavir (RTV) at doses of 400 mg twice a day (bid) or higher adversely affects serum lipids. However, the effect of RTV 100 mg bid on serum lipids is unknown. We conducted a study to evaluate the effect of RTV 100 mg bid on fasting serum lipid profiles in HIV-negative healthy volunteers. MethodsRitonavir 100 mg bid was administered for 14 days to 20 healthy HIV-seronegative adults with normal serum lipids. After a 7-day washout, lopinavir/ritonavir (LPV/RTV) 400/100 mg bid was administered for 14 days. Fasting serum lipid parameters were measured twice at baseline, after 14 days of RTV, and after 14 days of LPV/RTV, and comparisons were made at each time-point for levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, the total/HDL cholesterol ratio and triglycerides.Results After 14 days of RTV 100 mg bid, total cholesterol level increased by 10.2% (Po0.001), LDL cholesterol level increased by 16.2% (Po0.001), triglyceride levels increased by 26.5% (Po0.001), HDL cholesterol level decreased by 5.4% (Po0.01) and the total/HDL cholesterol ratio increased by 17.3% (Po0.001). The addition of LPV 400 mg bid to RTV 100 mg bid resulted in no significant further changes in LDL cholesterol or triglyceride level or total/HDL cholesterol ratio, but there were significant increases in both total cholesterol (8.0% increase; P 5 0.007) and HDL cholesterol levels (6.7% increase; P 5 0.008). ConclusionsRitonavir dosed at 100 mg bid significantly increased the concentration of total cholesterol, LDL cholesterol, total/HDL cholesterol ratio and triglycerides and reduced HDL cholesterol concentration. The addition of LPV 400 mg bid to RTV 100 mg bid further increased both total and HDL cholesterol levels without affecting the total/HDL ratio. IntroductionTreatment of HIV/AIDS changed dramatically in the mid1990s with the introduction of highly active antiretroviral therapy (HAART), which initially consisted of one or more HIV protease inhibitors (PIs) together with two nucleoside reverse transcriptase inhibitors (NRTIs). PI-based HAART resulted in dramatic reductions in mortality [1], hospitalization [2], and the incidence of most opportunistic infections [1,3]. However, PI therapy has been associated with a number of adverse effects, including hyperlipidaemia [4]. Preliminary data suggest that PI-induced hyperlipidaemia is associated with an increased risk of atherosclerotic heart and cerebrovascular disease [5], as with genetic/dietary hyperlipidaemia. When the PI ritonavir (RTV) was introduced, it was used as the sole PI therapy at a dosage of 600 mg twice daily. The initial studies of RTV monotherapy demonstrated that RTV caused significant increases in serum cholesterol, and marked increases in serum triglycerides [6,7]. In a study of 11 HIV-negative volunteers who received 2 weeks of RTV 500 mg twice daily, fasting cholesterol level increased by In recent years, the use of RTV at 'full' doses of 600 mg twice daily has nearly disappeared from clinical ...

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“…Clinical efficacy has been observed with this dosage in trials as part of highly active antiretroviral therapy (HAART) (9). Pharmacoenhancement of protease inhibitors (PIs) with lowdose ritonavir due to the potent inhibition of CYP3A4 (18) has been extensively reported (1,8).…”

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confidence: 99%

Intracellular and Plasma Pharmacokinetics of Saquinavir-Ritonavir, Administered at 1,600/100 Milligrams Once Daily in Human Immunodeficiency Virus-Infected Patients

Ford

Boffito

Wildfire

et al. 2004

Antimicrob Agents Chemother

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Ritonavir-boosted saquinavir (SQV/r) is currently licensed as a twice-daily regimen. Reducing the pill burden with once-daily dosing may improve adherence. Intracellular concentrations of drugs must be related to the clinical efficacy of protease inhibitors. The aims of the study were to determine the cellular and plasma saquinavir and ritonavir concentrations, to determine the half-lives (t 1/2 s) of the drugs in each compartment, and to examine relationships between drug accumulation and lymphocyte subset P glycoprotein (P-gp) expression. Venous blood samples from 12 human immunodeficiency virus-infected patients receiving a hard-gel formulation of SQV/r (1,600/100 mg once daily) were collected at 2, 6, 12, and 24 h after dosing. Peripheral blood mononuclear cells were separated by density gradient centrifugation, and P-

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Randomized Trial to Evaluate Indinavir/Ritonavir versus Saquinavir/Ritonavir in Human Immunodeficiency Virus Type 1–Infected Patients: The MaxCmin1 Trial

Cited by 120 publications

References 22 publications

Clinical and Pharmacokinetic Data Support Once-Daily Low-Dose Boosted Saquinavir (1,200 Milligrams Saquinavir with 100 Milligrams Ritonavir) in Treatment-Naive or Limited Protease Inhibitor-Experienced Human Immunodeficiency Virus-Infected Patients

Clinical and Pharmacokinetic Data Support Once-Daily Low-Dose Boosted Saquinavir (1,200 Milligrams Saquinavir with 100 Milligrams Ritonavir) in Treatment-Naive or Limited Protease Inhibitor-Experienced Human Immunodeficiency Virus-Infected Patients

The effect of low‐dose ritonavir monotherapy on fasting serum lipid concentrations

Intracellular and Plasma Pharmacokinetics of Saquinavir-Ritonavir, Administered at 1,600/100 Milligrams Once Daily in Human Immunodeficiency Virus-Infected Patients

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