Brenda Dauer

Saquinavir drug exposure is not impaired by the boosted double protease inhibitor combination of lopinavir/ ritonavir

Objective: To assess the pharmacokinetic interaction of saquinavir and lopinavir/ritonavir. Design: Patients from the Frankfurt HIV cohort with limited reverse transcriptase inhibitor (RTI) options received the protease inhibitor (PI) combination of saquinavir (soft-gel capsules, 1000 mg twice a day) plus lopinavir/ritonavir (400/100 mg twice a day), without RTI (LOPSAQ group). A control group received the same doses of saquinavir and ritonavir plus two to three RTI (RITSAQ group). A steady-state 12 h pharmacokinetic assessment was performed. Methods: Plasma levels of saquinavir, ritonavir and lopinavir were determined by liquid chromatography–tandem mass spectrophotometry. Minimum and maximum plasma concentrations (Cmin and Cmax), the clearance (Cltot) and the area under the concentration time curve (AUC) were calculated. Results: Data were collected from 45 patients (LOPSAQ) and 32 patients (RITSAQ). There was no significant difference between the groups for median saquinavir Cmin, Cmax, Cltot and AUC (LOPSAQ: 543 ng/ml, 2300 ng/ml, 1020 ml/min and 16 977 ng*h/ml; RITSAQ: 427 ng/ml, 2410 ng/ml, 1105 ml/min and 15 130 ng*h/ml). Median ritonavir Cmin, Cmax and AUC were lower, the Cltot was higher in the LOPSAQ group (78 ng/ml, 428 ng/ml and 2972 ng*h/ml, 551 ml/min) compared with RITSAQ (194 ng/ml, 683 ng/ml and 6506 ng*h/ml, 266 ml/min; P < 0.001). Lopinavir levels were similar to historical data. Conclusion: Effective plasma levels of both saquinavir and lopinavir can be achieved by the co-administration of saquinavir soft-gel capsules and lopinavir/ritonavir. This boosted double PI combination could be an effective option for patients with limited RTI options.

Use of viral load measured after 4 weeks of highly active antiretroviral therapy to predict virologic outcome at 24 weeks for HIV-1-positive individuals.

SummaryEarly prediction of suboptimal viral response to highly active antiretroviral therapy (HAART) is vital to prevent early development of drug resistance. We used logistic regression to predict the odds of achieving virologic suppression (<50 copies/mL) after 24 weeks of HAART in 656 antiretroviral-naive patients starting HAART at the J.W. Goethe University, Chelsea and Westminster, and Royal Free Hospitals according to their week 4 viral load. Therapy changes involving the switch of a single antiretroviral were assumed to have occurred for toxicity reasons and ignored. Because complete regimen changes or additions of new antiretrovirals could be due to virologic failure, patients were counted as virological failures at week 24. Three hundred sixty (84%) of 430 patients with viral loads of <1000 copies/mL, 106 (61%) of 175 with viral loads between 1001 and 10,000 copies/mL, 11 (37%) of 30 with viral loads between 10,001 and 100,000 copies/mL, and 5 (24%) of 21 with viral loads of >100,000 copies/mL at week 4 subsequently attained virologic suppression at 24 weeks. The odds of attaining virologic suppression at 24 weeks was 65% lower for every 1-log higher viral load at week 4 (odds ratio, 0.35; 95% confidence interval, 0.27–0.45). The proportion of patients with an undetectable viral load at 24 weeks among those who have not attained a viral load of <1000 copies/mL by 4 weeks is quite low. We suggest that this group of patients should be particularly closely monitored.

Pharmacokinetics of Saquinavir, Atazanavir, and Ritonavir in a Twice-Daily Boosted Double-Protease Inhibitor Regimen

ABSTRACT The objective of this study was to evaluate the pharmacokinetics of atazanavir (ATV), saquinavir (SQV), and ritonavir (RTV) in a boosted double-protease inhibitor (PI) therapy regimen without reverse transcriptase inhibitors (RTIs). The study design was as follows. Patients with limited RTI options received a PI combination of 300/100 mg ATV/RTV once daily and 1,000 mg SQV twice daily (group 1; n = 49) without RTI comedication. The results were compared to the plasma concentrations of PIs of patients taking either 300 mg ATV/100 mg RTV once daily plus RTIs (group 2; n = 72) or patients taking 1,000 mg SQV/100 mg RTV plus RTIs (group 3; n = 90). The study methods were as follows. Patients were given a 12/24-h pharmacokinetic assessment at steady state. Drug concentrations were measured by liquid chromatography-tandem mass spectrometry. The minimum and maximum concentrations (Cmin and Cmax), area under the concentration-time curve under steady-state conditions (AUCss), elimination half-life, time of maximum concentration and lag time were subject to statistical analysis. The results show that patients treated with ATV/SQV/RTV exhibited significantly high SQV concentrations and moderate enhancement of the AUCss of ATV in comparison to those of patients of the control groups: for SQV in groups 1 and 3, the geometric mean (GM) of the AUCss was 22,794 versus 15,759 ng·h/ml (GM ratio [GMR] = 1.45; P < 0.05), the GM of the Cmax was 3,257 versus 2,331 ng/ml (GMR = 1.40; P < 0.05), and the GM of the Cmin was 438 versus 437 ng/ml (GMR = 1.00); for ATV in groups 1 and 2, the GM of the AUCss was 39,154 versus 33,626 ng·h/ml (GMR = 1.16), the GM of the Cmax was 3,488 versus 2,924 ng/ml (GMR = 1.20), and the GM of the Cmin was 515 versus 428 ng/ml (GMR = 1.21). RTV levels were comparable for all groups. A subgroup analysis detected only marginal differences in ATV plasma exposure if combined with tenofovir-disoproxilfumarate and without it. We conclude that our pharmacokinetic results support the use of a boosted double-PI regimen of ATV/SQV/RTV as a treatment option for patients who need antiretroviral therapy without RTIs.

Factors associated with viral rebound among highly treatment-experienced HIV-positive patients who have achieved viral suppression

More and more highly treatment‐experienced patients are achieving viral suppression. However, the durability of suppression remains unclear.

Quadruple Nucleos(t)ide Reverse Transcriptase Inhibitors-Only Regimen of Tenofovir Plus Zidovudine/Lamivudine/Abacavir in Heavily Pre-Treated HIV-1 Infected Patients: Salvage Therapy or Backbone Only?

BACKGROUND We investigated the virologic and immunologic responses to a mono-class, nucleoside/nucleotide reverse transcriptase inhibitor - combination therapy consisting of tenofovir and zidovudine/lamivudine/abacavir in therapy experienced patients. METHODS Retrospective study of 122 patients. Primary analysis was performed at 48 weeks. Virologic response was defined as viral load levels less than 400 copies/ml. RESULTS About half of the patients had switched to tenofovir+ zidovudine/lamivudine/abacavir for simplification purposes or toxicity while the other half had experienced virologic failure. 80/122 (66%) responded. Median viral load decreased to 78 copies/ml at week 48; median CD4 count increased to 321 cells/mm(3). Of the 42 virologic failures, only 3 patients failed after week 24. 24/35 patients who had been on a non-suppressive zidovudine/lamivudine/abacavir-only regimen at baseline and added tenofovir to intensify, responded. 41/53 patients who switched from any nucleoside reverse transcriptase inhibitor-only regimen improved or maintained suppression. Genotypes were available for 85/122 patients. The only predictor of virologic failure was the combination 41L+210W+215Y/F mutational pattern. 16 of the patients who failed on tenofovir+ zidovudine/lamivudine/abacavir therapy selected new primary nucleoside reverse transcriptase inhibitor resistance mutations that they previously did not have. 48/85 (56%) patients with genotype tests had at least 3 (3-10; median 4) nucleoside reverse transcriptase inhibitor resistance-associated mutations in the past. CONCLUSIONS Patients heavily pre-treated with nucleoside analogues may show response to mono-class tenofovir+ zidovudine/lamivudine/abacavir therapy despite having a history of failure with nucleoside reverse transcriptase inhibitors. Lower baseline viral load, higher baseline CD4 count were significant predictors for response. Archived 41L+210W+215Y/F mutational pattern was significantly associated with non-response.

The Protease Inhibitor Transfer Study (PROTRA 1): abacavir and efavirenz in combination as a substitute for a protease inhibitor in heavily pretreated HIV-1-infected patients with undetectable plasma viral load.

The aim of the study was to evaluate the safety and efficacy of abacavir (ABC) and efavirenz (EFV) instead of a protease inhibitor (PI) in HIV‐1‐infected subjects treated with two nucleoside reverse transcriptase inhibitors (NRTIs) and one PI with undetectable viral loads (<50 HIV‐1 RNA copies/mL). To be eligible for inclusion, patients had to have a history of viral load <400 copies/mL for at least 3 months and had to be naïve to treatment with nonnucleoside reverse transcriptase inhibitors (NNRTIs) and ABC, but multiple pretreatment and treatment failure were allowed.

The LOPSAQ study: a pharmacokinetic analysis of a boosted double protease inhibitor (PI)‐ salvage therapy with saquinavir (SQV) plus lopinavir/ritonavir (LPV/RTV) without reverse transcriptase inhibitors (RTI) in HIV‐1 positive adults

To evaluate the difference in pharmacokinetics (PK) of responders vs. non‐responders to a boosted double PI‐therapy of SQV+LPV/RTV in an open label cohort study.

The CRIXILOP cohort study: indinavir plasma exposure is not affected by lopinavir/ritonavir co‐administration in a boosted double protease inhibitor (PI)‐only therapy regimen

For HIV patients who have lost treatment options with reverse transcriptase inhibitors(RTI), a PI‐only regimen is a therapy alternative. Objective: To investigate the potential pharmacokinetic interaction of a boosted double PI‐only regimen of Lopinavir and Ritonavir(LPV/RTV) plus Indinavir(IDV). Methods: We determined plasma drug levels of LPV, RTV and IDV in 19 HIV 1‐infected adult patients, taking IDV800mg and LPV400/RTV100mg BID only and compared the results to control groups of patients with IDV800mg/RTV100mg BID(+2 or 3RTI) or LPV400/RTV100mg BID(+2 or 3RTI). PK analysis based on a non‐compartmental model. Results (see table ):