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Background: Daptomycin is a cyclic lipopeptide antibiotic used to treat serious infectious endocarditis caused by Staphylococcus aureus . The pharmacodynamic parameter correlating best with efficacy is the ratio of the estimated area under the concentration (AUC 0-24 )-time curve to the minimum inhibitory concentration. The aim of the study is to develop a limited sampling strategy to estimate AUC 0-24 using a reduced number of samples., Methods: Sixty-eight daptomycin AUC 0-24 values were calculated for 50 White patients who underwent treatment for at least 5 consecutive days. Plasma concentrations were detected using a validated high-performance liquid chromatography-tandem mass spectrometry analytical method, with daptomycin-d5 as an internal standard. Multiple regression was used to evaluate the ability of 2 concentration-time points to predict the AUC 0-24 calculated from the entire pharmacokinetic profile. Prediction bias was calculated as the mean prediction error, whereas prediction precision was estimated as the mean absolute prediction error. The development and validation datasets comprised 40 and 10 randomly selected patients, respectively., Results: The AUC 0-24 (mg*h/L) was best estimated using the daptomycin trough concentration and plasma concentrations detected 2 hours after dosing. We calculated a mean prediction error of 1.6 (95% confidence interval, -10.7 to 10.9) and a mean absolute prediction error of 11.8 (95% confidence interval, 5.3-18.3), with 73% of prediction errors within ±15%., Conclusions: An equation was developed to estimate daptomycin exposure (AUC 0-24 ), offering clinical applicability and utility in generating personalized dosing regimens, especially for individuals at high risk of treatment failure or delayed response., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Data from 20 highly drug-experienced HIV-infected patients receiving tenofovir plus didanosine as part of a salvage regimen were analysed. At baseline, all but one patient harboured a virus bearing at least one nucleoside excision mutation (NEM); in 13 cases (65%) three or more NEM were detectable. After a median of 26 weeks of treatment, two patients (10%) selected the 65R mutation. These results support the hypothesis that NEM hinder the selection of this mutation.

Background: HIV-specific cytotoxic T-cell (CTL) responses are defective in HIV-infected patients undergoing antiretroviral therapy (ART). This defect has been attributed to the decreased antigenic burden secondary to ART-associated suppression of HIV-replication, and is responsible for the rebounds of viraemia that occur when patients interrupt therapy. CTL are stimulated by type 1 cytokines and can kill targets via granule-dependent (perforin and granzymes) and -independent (tumour necrosis factor-alpha, CD95) mechanisms., Methods: Granule-dependent and granule-independent mechanisms of CTL killing, as well as type 1 cytokine production by CD4 T cells, were analysed in 57 chronically HIV-infected ART-treated or ART-untreated individuals., Results: The results can be summarized as follows: the frequency of gp160 (env)-specific interferon-gamma-secreting CD8 T lymphocytes correlates positively with HIV viraemia in ART-treated and -untreated patients; Env-specific perforin- and granzymes-expressing CD8 T lymphocytes, and Env-stimulated perforin and granzymes mRNA, are reduced in ART-treated patients independently of HIV viral load and of type 1 cytokine production; tumour necrosis factor-alpha production is increased in ART-treated individuals; and Env-specific immature CD8+28+27+ cells are only marginally augmented in ART-treated patients, Similar results are observed in cytomegalovirus-specific CD8 T cells and peripheral blood mononuclear cells., Conclusions: A defect of CTL function that selectively affects the granule-dependent mechanisms of lysis is observed in ART-treated individuals. Because interferon-gamma production is higher in these patients, this could be a defect primarily involving CTL. These data suggest an independence of CD8 T-cell numbers and their lytic ability in HIV-infected, ART-receiving patients. Immunomodulants are needed to successfully treat HIV infection.

Genotypes in nine highly protease inhibitor (PI)-experienced patients were studied before and after lopinavir/ritonavir (LPV/r) treatment. Resistance to amprenavir was the rule both before and after LPV/r treatment. Treatment with LPV/r can select for the 50 V mutation. In this setting, significant differences in the inference of the amprenavir phenotype from genotype were observed when using different algorithms.

We studied the pharmacokinetics of amprenavir at doses of 600 mg twice a day or 1200 mg once a day, when co-administered to HIV-positive patients with 400 mg a day of atazanavir without a ritonavir booster. Our preliminary results suggest that amprenavir and atazanavir could be coadministered and that amprenavir could be boosted by atazanavir without the need for ritonavir pharmaco-enhancement.

Background: Control of HIV replication can be observed in highly active antiretroviral therapy (HAART)-treated and, occasionally, in HAART-naive patients. The immunological correlates of these situations were examined in a longitudinal study., Design: A prospective study. Immunovirological analyses in 16 chronically HIV-infected, HAART-naive patients (time 0) who started HAART. Fifteen patients (short-term HAART) were re-evaluated after 24 months (time 1). Results were compared with those of 30 patients who received HAART for more than 12 months before the study period (long-term HAART) and were analysed at the same timepoints. Fifteen patients who were antiviral therapy naive (naive) at both timepoints were also studied., Results: Over a 24-month period CD4 and CD8 cell counts and viraemia remained unchanged in naive and long-term HAART patients; CD4 cell counts increased and viraemia diminished in short-term HAART individuals. Antigen-stimulated proliferation was unmodified in naive and short-term HAART patients, but improved in long-term HAART individuals. Gp160-stimulated IL-2 and IFN-gamma production was augmented in long-term HAART patients and marginally modified in other patients. IL-7 production was unmodified in naive individuals, augmented in short-term HAART patients, and diminished in long-term HAART patients. Chemokine production was similar in all patients. Naive patients showed the highest CD8 cell counts at both timepoints., Conclusion: HAART has a major impact on the outcome of HIV infection, even if functional immune modulation in HAART-treated patients is evident only after long periods of therapy. Low but detectable HIV replication in HAART-naive patients with preserved immune functions might not be associated with CD4 cell reduction, functional immune defects, or changes in viraemia., (Copyright 2002 Lippincott Williams & Wilkins)

Background: Suppression of human immunodeficiency virus (HIV) replication can be obtained in chronically infected individuals by highly active antiretroviral therapy (HAART) and can also be observed in antiretroviral-naïve patients. The immunological correlates of these two situations were examined., Design and Methods: Cross-sectional study involving 32 HIV-infected patients with undetectable HIV plasma viraemia (< 500 copies/ml) and either antiretroviral-naive (n = 14) or undergoing HAART therapy with two nucleoside reverse transcriptase inhibitors (NRTI) plus one (n = 13) or two (n = 5) protease inhibitors (PI). CD4 counts, disease duration, and CDC clinical stage were comparable between the two groups of individuals. Immune parameters (antigen- and mitogen-stimulated proliferation and cytokine production; cytokine mRNA; beta chemokine production; HIV coreceptors mRNA) were analysed in all patients., Results: Results showed immune profiles to be profoundly different in antiretroviral-naive in comparison with HAART-treated patients. Thus: (1) T-cell proliferation to HIV-specific and HIV-unrelated antigens is potent in antiretroviral-naive but suppressed in HAART-treated individuals; (2) interleukin-(IL)2, IL-12 and interferon gamma (IFNgamma) production is robust in naive patients; and (3) a high CCR5/low CXCR4 pattern of HIV coreceptors-specific mRNA is observed in naive but not in HAART-treated patients. In contrast with these observations, no clear differences were detected when beta chemokine production by either peripheral blood mononuclear cells or purified CD8+ T-cells was analysed. Results from HAART-treated patients undergoing therapy with one PI and two NRTI or two PI and two NRTI were in very close agreement., Conclusions: These data suggest that control over HIV replication can be independently achieved by pharmacological or immunologic means. HAART is associated with weaker HIV-specific and -non-specific immune responses.

Efavirenz (EFV, DMP-266) is a new antiretroviral agent belonging to the class of nonnucleoside reverse transcriptase inhibitors. It has recently been approved by the Food and Drug Administration in management of human immunodeficiency virus (HIV). Preliminary pharmacokinetic studies on EFV in healthy volunteers show that the drug may influence the metabolism of protease inhibitors. For the determination of EFV in human plasma, a validated and specific reverse-phase high-performance liquid chromatography (HPLC) method, with UV detection, was developed. We used 100 microL plasma sample for a liquid-liquid extraction with diethyl ether after basification. The mobile phase was a mixture of acetonitrile and water, pumped at a flow rate of 1.2 mL/min. Ultraviolet detection was carried out at a wavelength of 247 nm. Retention times for EFV and internal standard (IS) were 5.3 and 4.5 minutes, respectively, and there was no chromatographic interference from other commonly administered drugs. The limit of detection was 100 ng/mL. The described assay is a rapid and accurate method for measurement of EFV in plasma: the easy preparation and small sample size makes this assay highly suitable for pharmacokinetic studies and routine clinical analysis in patients with HIV. In addition, the reproducibility of the method is only moderately increased by including IS, so analyzing without IS may be an alternative.