Dose reduction effective in alleviating symptoms of saquinavir toxicity.

Gastrointestinal intolerance is a limitation of boosted saquinavir antiretroviral treatment. We present three HIV-infected individuals whose severe toxicity symptoms started directly after initiation of a standard dose saquinavir hard-gel capsule-containing regimen (saquinavir/ritonavir 1000/100 mg). All patients underwent immediate 12 h pharmacokinetic (PK) assessment and showed extraordinarily high saquinavir plasma exposure. All three patients did not recover until the saquinavir exposure was decreased. This pilot case study anticipates a new concept of 'direct PK'-guided individual dose interventions under close viral load monitoring. Two major reasons for symptomatic saquinavir overexposure were defined: impaired liver function in a chronic hepatitis C virus co-infected individual at normal liver performance parameters and a delayed cytochrome p450 enzyme autoinduction. Overexposure seems to be an independent intolerance factor. Although delayed autoinduction is not well established as a reason for adverse events in saquinavir therapy, this observation may be confirmed in the near future by increased use.

Pharmacokinetics and tolerability of a combination of indinavir, lopinavir and ritonavir in multiply pretreated HIV-1 infected adults.

OBJECTIVES: The authors evaluated the pharmacokinetics and tolerability of indinavir/lopinavir/ritonavir in a protease inhibitor only combination. METHODS: Plasma drug levels of patients taking indinavir/lopinavir/ritonavir 800/400/100mg twice daily (n = 24, group 1) were compared to patients taking either lopinavir/ritonavir 400/100mg (n = 35, group2) or indinavir/ritonavir 800/100mg (n = 33, group3) twice daily plus nucleos(t)ide reverse transcriptase inhibitors (NRTI). Steady-state drug concentrations were measured by LC/MS/MS. Minimum and maximum concentrations (C subsetmin, C subsetmax), area under the concentration-time curve (AUC subset0-12h), total clearance (CL subsettot) and half-life (t1/2) were calculated. HIV viral load, CD4 cell count and adverse events causing early termination of therapy were correlated over a period of 48 weeks. RESULTS: Plasma levels of lopinavir/ritonavir were significantly enhanced when combined with indinavir compared to a regimen of lopinavir/ritonavir+NRTI: Mean lopinavir AUC subset(0-12h) 80,912 ng*h/mL vs. 60,548 ng*h/mL; C subsetmin 4,633 ng/mL vs. 3,258 ng/mL; C subsetmax 8,023 ng/mL vs. 6,710 ng/mL. Mean ritonavir AUC(0-12h) 6,907 ng*h/mL vs. 3,467 ng*h/mL; Cmin 220 ng/mL vs. 125 ng/mL; C subsetmax 1,059 ng/mL vs. 522 ng/mL. Indinavir levels were comparable for both indinavir containing regimen. A significantly smaller number of patients stopped indinavir/lopinavir/ritonavir therapy (group1: 16.7%) than indinavir/ritonavir + NRTI treatment (group3: 45.5%) due to adverse events. Virological failure was the main reason for early termination of treatment with indinavir/lopinavir/ ritonavir before week 48 (group1: 50%). CONCLUSIONS: indinavir/lopinavir/ritonavir 800/400/ 100mg twice daily represents a therapy option with an adequate safety but only short term efficacy for extensively pretreated patients.

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.

OBJECTIVES: 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 naive to treatment with nonnucleoside reverse transcriptase inhibitors (NNRTIs) and ABC, but multiple pretreatment and treatment failure were allowed. DESIGN: An open-label, single-centre pilot study of duration 48 weeks was conducted. ABC was added to the original treatment with two NRTIs and one PI at baseline, and at week 6 the PI was replaced by EFV. At each study visit, CD4 cell count, viral load [measured by polymerase chain reaction (PCR)] and clinical chemistry were measured. Fasting blood samples were taken at baseline and at weeks 12, 24, 36 and 48 to measure levels of cholesterol [high-density lipoprotein (HDL)/low-density lipoprotein (LDL)], triglycerides, insulin and C-peptide. Additionally, an oral glucose tolerance test (OGTT) was performed. A bioelectric impedance analysis (BIA) and a single slice abdominal and mid-thigh computed tomography (CT) scan were carried out to assess changes in body composition. RESULTS: Thirty patients were included in the study. Three patients experienced ABC-hypersensitivity and one patient demonstrated virological failure caused by nonadherence. At week 48, all remaining patients had viral loads < 50 copies/mL with stable CD4 counts. The fasting metabolic parameters and abdominal fat distribution remained unchanged. CONCLUSIONS: In heavily pretreated patients, ABC and EFV in combination provide an effective, simplified and well-tolerated alternative to PI treatment.

[Clinical presentation and management of the severe acute respiratory syndrome (SARS)]. / Klinik und Behandlung des schweren akuten respiratorischen Syndroms.

BACKGROUND AND OBJECTIVE: In February 2003, a newly emerged infectious disease was described, the etiology of which was initially unknown. It is referred to under the term SARS. In the beginning, it spread in some regions South-East Asia. Import infections appeared in many other parts of the world. Based on the first cases in Germany, this report illustrates the clinical appearance, the diagnostic results and the management of this new disease. PATIENTS AND METHODS: We analysed the data of two patients with SARS and one suspected patient. The results of radiological, laboratory, microbiological and physical examinations were abstracted and compared with the data obtained in other regions. RESULTS: Two of the three patients under our care developed SARS disease. This is characterised by fever of sudden onset lasting for more than 5 days, rapidly changing consolidations in chest x-ray not affected by antimicrobial therapy, leuko-, lympho- as well as thrombopenia with a compromised pulmonary function later in the course. Close contacts with SARS patients does not regularly result in full development of the disease. Secretion of a coronavirus could be detected in respiratory samples during the febrile phase and in feces for a longer time. It is still an open question whether bedrest and antibiotic prophylaxis by themselves or an additional administration of ribavirin and corticosteroids can improve the outcome. CONCLUSION: SARS is a new and highly contagious lung disease. It is crucial to be able to recognize the clinical appearance and the diagnostic features of this disease at an early stage, in order to prevent a further dissemination of the disease.

The impact of protease inhibitor-containing highly active antiretroviral therapy on progression of HIV disease and its relationship to CD4 and viral load.

OBJECTIVE: To compare the rate of disease progression according to viral load and CD4 cell count in patients receiving or not receiving highly active antiretroviral therapy (HAART), defined as protease inhibitor-containing regimens. DESIGN: An observational study, with prospectively collected data. METHODS: All patients attending the HIV Outpatient clinic as of 1 January 1995 (n = 2083) were included. Follow-up was until the first AIDS-defining event or death. Associations between viral load or CD4 cell count and disease progression were assessed using a person-years approach. Event rates were compared using Poisson regression analysis; a multivariate model was used to assess the independent effects of CD4, viral load and treatment group on event rates and to consider interactions between these variables. RESULTS: The event rates increased with lower CD4 cell count and higher viral load for both treatment groups and were generally lower in the HAART group. In a multivariate analysis, lower CD4 cell counts and higher viral loads remained significantly associated with disease progression, irrespective of treatment group. However, the event rate was significantly lower for the HAART group compared with the control group (relative rate 0.53, P < 0.001). CONCLUSIONS: HAART-treated patients with high viral loads and CD4 cell counts experienced reduced disease progression compared with individuals with the same CD4 cell count and viral load not receiving HAART. Consequently, the short-term prognosis associated with viral load levels and CD4 cell counts may differ in patients on HAART. Whether this effect will be observed with non-protease-inhibitor-containing HAART is not known at this time.

CD4 lymphocyte count as a predictor of the duration of highly active antiretroviral therapy-induced suppression of human immunodeficiency virus load.

The association between CD4 cell count and duration of virus load suppression was investigated in 558 patients in the Frankfurt HIV Clinic Cohort who had begun highly active antiretroviral therapy and who had virus load declines to 500 copies/mL; P=.0001). Baseline virus load was not associated with virus load rebound. Lower baseline CD4 cell counts were associated with increased risk of viral rebound; however, this risk was significantly reduced in persons with low baseline CD4 cell counts who experienced substantial increases in CD4 cell counts during follow-up.

Mega-HAART: preliminary results and correlation with baseline resistance.

This is a brief report of preliminary results of the assessment of the correlation between baseline viral drug susceptibility and virological response in patients receiving mega-HAART. A total of 37 patients received > or = 6 drugs with a median follow-up of 8 months. There was evidence of extensive loss of viral drug susceptibility at baseline among the 24 patients analysed. Results showed that the magnitude and duration of virological response was associated with phenotypic viral drug resistance, although resistance did not lead to virological failure in all cases, and susceptibility did not lead to response in all cases.

Dual resistance to zidovudine and lamivudine in patients treated with zidovudine-lamivudine combination therapy: association with therapy failure.

Human immunodeficiency virus type 1 (HIV-1) strains dually resistant to zidovudine and lamivudine (3TC) may arise during zidovudine-3TC combination therapy. The objective of this cross-sectional study (n = 43 patients) was to test the association between therapy response (clinical and immunologic) to zidovudine-3TC and the level of phenotypic zidovudine resistance and zidovudine resistance-associated genotype of 3TC-resistant isolates. Other variables included were baseline CD4+ cell count, baseline Centers for Disease Control and Prevention (CDC) classification, virus load, and time receiving zidovudine. Phenotypic resistance was assessed using a recombinant virus assay. Genotypic analysis was based on population sequencing of plasma HIV-1. In a univariate analysis using a logistic regression model, it was found that therapy response was significantly associated with phenotypic and genotypic zidovudine resistance, baseline CD4+ cell count, and virus load. After adjustment for all variables, phenotypic resistance to zidovudine remained the only significantly associated factor, independent of baseline CD4+ cell count, baseline CDC classification, and virus load.