Low trough levels of tipranavir in a combination antiretroviral therapy of tipranavir/ritonavir and tenofovir require therapeutic drug monitoring.

The new non-peptidic protease inhibitor tipranavir is used boosted with ritonavir in a 500/200 mg bid scheme. Multiple drug interactions are described for both drugs because of their different action in CYP450 3A4 and p-glycoprotein. In this retrospective analysis of 22 patients during therapy with tipranavir/ritonavir (TPV) 500 mg/200 mg bid, we found significantly decreased TPV-trough levels in combination with tenofovir (15.32+/-5.22 microg/ml) in comparison to TPV trough levels without tenofovir (20.21+/-14.87 microg/ml). Therapeutic drug monitoring of TPV is recommended.

Efavirenz-therapy in HIV-patients with underlying liver disease: importance of continuous TDM of EFV.

OBJECTIVE: Many HIV-patients have a chronic liver disease due to HBV-/HCV-coinfections and/or consume of alcohol. In these patients therapy with EFV is often problematic because of NNRTI associated liver toxicity. Measurement of EFV plasmalevels and dose adjustment using TDM should be evaluated in this study. METHODS: EFV-plasmasamples were standardized drawn 12h after ingestion. Measurement of 576 EFV plasmalevels was performed by HPLC. EFV plasmalevels as well as ALT-, AST- and GGT-values of 64 patients treated with EFV (5206 weeks) were measured regularly. 16 patients had a HCV-coinfection, 3 had a HBV-coinfection and 5 had an concomitant alcoholic liver disease. Maximal changes of ALT-, AST- and GGT-values (DeltaALT, DeltaAST, DeltaGGT), CD4-/CD8 cells and HIV-RNA were registered during therapy. Dose adjustment was performed for EFV plasmalevels out of target range 1000-4000 ng/ml. RESULTS: EFV plasmalevels of 40 HIV-patients (2288 +/- 1199 ng/ml) showed no significant differences compared to plasmalevels of HIV/HCV-patients (2391 +/- 976 ng/ml) or to plasmalevels of HIV/HBV-patients (1913 +/- 288 ng/ml) or to those of HIV-patients with alcoholic liver disease (1702 +/- 506 ng/ml). In 24 HIV-patients with underlying liver disease median DeltaGGT was +25 IU/l, median DALT was +13 IU/l and median DeltaAST was +8 IU/l. Dose adjustment was performed in 1 patient during study period. Increasing rates of ALT-, AST- and GGT-values showed no significant differences between liver healthy HIV-patients and those with a liver disease. 44 patients with continuous EFV plasmalevels in target range reached a viral suppression <100 c/ml during therapy. CONCLUSIONS: EFV-plasmalevels of HIV-infected patients showed no significant differences compared to EFV-plasmalevels of coinfected patients with concomitant liver disease. In those patients DeltaALT, DeltaAST and DeltaGGT were not significantly different than in liver-healthy HIV-patients with normal EFV-plasmaconcentrations. EFV plasmalevels in target range of 1000-4000 ng/ml correlate to a good viral response. One patient after dose adjustment was able to continue therapy. Using TDM EFV therapy in patients with underlying liver disease is save.

Lipid lowering therapy with fluvastatin and pravastatin in patients with HIV infection and antiretroviral therapy: comparison of efficacy and interaction with indinavir.

BACKGROUND: Lipoprotein disorders in HIV-positive patients receiving highly active antiretroviral therapy (HAART) are becoming a major concern in HIV treatment, since there is growing evidence for an association between HAART-induced hyperlipidemia and increased cardiovascular risk. Yet relatively few data are available on the possible interactions of HAART and treatment with statins. PATIENTS AND METHODS: In this prospective study, 25 HIV-positive, treatment-experienced patients (five female, 20 male, all Caucasian) were treated with either fluvastatin or pravastatin. Total cholesterol, low density lipoprotein (LDL) and high density lipoprotein (HDL) levels, and serum triglycerides were determined at regular intervals, as well as therapeutic drug monitoring to assess possible drug interactions. RESULTS: In 13 pravastatin-treated patients, a decrease in total cholesterol levels (from 7.12 mmol/l to 6.29 mmol/l) after 12 weeks of therapy was seen. In 12 patients treated with fluvastatin, a permanent reduction of total cholesterol (from 6.46 mmol/l to 5.31 mmol/l) after 12 weeks was observed. The reduction of LDL levels was 30.2% in the fluvastatin group and 14.4% in the pravastatin group. In eight patients receiving an indinavir-containing HAART, indinavir plasma levels were not significantly influenced. No effect on triglycerides or HDL was observed. CONCLUSION: Fluvastatin and pravastatin are efficient in lowering total and LDL cholesterol levels in HIV-positive patients receiving HAART. Furthermore, no influence on indinavir plasma levels could be observed. Therefore, both compounds seem to be a viable treatment option in HAART-induced hypercholesterolemia.

Liquid chromatographic method for the determination of uridine in human serum.

To evaluate uridine levels in humans we developed a very sensitive and specific high-performance liquid chromatographic method for the determination of uridine in serum. We use techniques which are available in a standard analytical laboratory. Chromatographic analysis was carried out on a Phenomenex Aqua C18 5 micro 125A column protected by a guard cartridge system. Potassium dihydrogen phosphate buffer-acetonitrile was used as an eluent and oxypurinol as the internal standard. All sample preparation steps were done at 4 degrees C and the autosampler was cooled down to 4 degrees C. The calibration curve was linear throughout the calibration range from 0.25 to 100 micromol/l. This method was primarily established to evaluate uridine serum levels in patients with HIV infection since patients on highly active antiretroviral therapy (HAART) might develop metabolic disturbances that could lead to severe and fatal lactic acidosis due to mitochondrial toxicity. It is suggested that a limited or inadequate uridine supply is at least in part responsible for the onset of such deterioration.

Resolution of HCV infection in a HIV-infected patient under HAART after several hepatitis flare-ups.

Highly active antiretroviral therapy (HAART) has been shown to have a beneficial effect on several opportunistic and other coinfections of HIV infected individuals. The effect of HAART on HCV coinfections is controversial. We describe the case of a patient, in whom a close temporal relationship between changes in HIV viremia, HCV viremia and ALT levels was observed. Longterm suppression of HIV replication by HAART was associated with a normalization of ALT levels and finally clearance of the HCV infection. Our data suggest that improved immune functions due to reductions of the HIV load led to a better control and finally resolution of the HCV infection in this patient.

Combined surgical and antifungal treatment of a subcutaneous infection due to Paecilomyces lilacinus.

Paecilomyces lilacinus was the causal agent of a case of subcutaneous infection in a patient with liver cirrhosis. Surgical treatment in combination with systemic amphotericin B therapy led to complete recovery. Retrospectively performed microdilution testing revealed dose dependent in vitro susceptibility of the isolate to voriconazole (MIC = 2 g/ml) and terbinafine (MIC = 1 microg/ml).

No influence of the P-glycoprotein genotype (MDR1 C3435T) on plasma levels of lopinavir and efavirenz during antiretroviral treatment.

BACKGROUND: In a retrospective study of HIV patients under antiretroviral therapy, we investigated the influence of the MDR1 genotype (C3435T) on plasma levels of lopinavir (LPV) and efavirenz (EFV). METHODS: The MDR1 genotype was analysed from 67 patients who were treated with LPV (n = 32; mean treatment period 53 weeks) and/or EFV (n = 43, mean treatment period 105 weeks) between 1999 and 2003. Plasma levels of LPV (trough levels) and EFV (12-h-levels) were determined every three months. Data were analysed by the Kruskal-Wallis test. RESULTS: There were no significant differences in the LPV and EFV plasma levels with respect to the MDR1 3435 genotype. CONCLUSIONS: We did not find evidence for an influence of the MDR1 3435 genotype on plasma levels of LPV and EFV.

Efavirenz plasma levels for the prediction of treatment failure in heavily pretreated HIV-1 infected patients.

OBJECTIVE: Efavirenz (EFV) plasma levels have been discussed as a predictor of treatment failure in HIV infected patients. The aim of this prospective, open-labeled, case-control study was to evaluate pretreated patients in regards to efavirenz plasma levels and efficacy of therapy. METHODS: Blood samples were obtained monthly from 33 patients receiving efavirenz in combination with other antiretroviral agents for at least 3 months. EFV plasma concentrations and potease inhibitor (PI) plasma levels were measured by high-performance liquid chromatography (HPLC). EFV plasma levels were correlated with efficacy. In patients with virologic failure genotypic resistance testing was performed. RESULTS: Mean efavirenz plasma levels (n = 240) of 33 patients were 3.119 +/- 2.497 ng/ml. There were no significant differences between median efavirenz plasma levels of 24 patients (72%) with a HIV-RNA < 20 copies/ml (2.168 ng/ml), 3 patients with HIV-RNA of 20 500 copies/ml (3.362 ng/ml), and 6 patients with a virologic failure (>500 copies/ml) (2.190 ng/ml) respectively. Efavirenz plasma levels below 1.000 ng/ml were found in 4/27 effective treated patients, and in 4/6 patients with virologic failure. In all patients with virologic failure multiple NRTI, NNRTI and PI mutations were found in genotypic resistance testing. CONCLUSION: An individual EFV plasma level below 1.000 ng/ml in one single measurement seems to be predictive of viral failure and the developement of genotypic resistance. Therapeutic drug monitoring of EFV might be helpful, especially in heavily pretreated patients, to reach long term sufficently effectiveness of therapy.

Triple antiviral re-therapy for chronic hepatitis C with interferon-alpha, ribavirin and amantadine in nonresponders to interferon-alpha and ribavirin.

BACKGROUND: Therapy options for patients with chronic hepatitis C who failed prior treatment are needed. In recent studies triple antiviral therapy with Interferon-alpha, ribavirin, and amantadine seemed to increase sustained virological response rates in this group. METHOD: To evaluate efficacy, side effects and safety of a triple re-therapy in an open labeled prospective study, we compared 23 nonresponders to interferon monotherapy (9 nonresponders, 3 relapsers, 11 with breakthrough) with 23 nonresponders to standard combination therapy (interferon plus ribavirin) (16 nonresponders, 7 breakthroughs). All outpatients enrolled for re-therapy received interferon-alpha 2a (6 mega units [MU] three times in week), ribavirin (1000-1200 mg daily in divided doses) and amantadine (200 mg daily) for six months. In case of virological re-therapy response (negative qualitative HCV RNA) study medication was continued with interferon monotherapy for another six months. RESULTS: Sustained virological response was achieved in 16 (35%) out of 46 prior therapy nonresponders. Response rates were dependent on pretreatment outcome. In the standard combination therapy group only 1 (6%) primary nonresponder achieved sustained response, but none of the 9 monotherapy nonresponders did. After primary breakthrough sustained response was seen in 8 of 11 (73%) patients in the interferon monotherapy and in 5 of 7 (71%) in the combination therapy group. Of 3 monotherapy relapsers 2 (66%) did also clear the virus sustained. Safety profile under triple therapy was similar to the previous therapy. Compliance was higher and side effects lower in those patients already experienced in combination therapy. CONCLUSION: In patients with a breakthrough or relapse after interferon monotherapy or standard combination therapy with interferon and ribavirin a re-therapy with a triple combination of interferon, ribavirin, and amantadine results in a high rate of sustained virological response.

A sebaceous tumor in a patient with acquired immunodeficiency syndrome.

The prevalence of cutaneous malignancies is higher in immunosuppressed patients. Here, we describe a case with a rapid growing and unusually large sebaceous tumor in a patient with acquired immunodeficiency syndrome. Sebaceous adenomas are commonly rare, benign tumors of sebaceous glands. An association of AIDS and a solitary, large sebaceous adenoma has not been described yet. This emphasizes the role of an intact immune system in the suppression of benign and malignant tumors. tubular adenoma; tumor; AIDS

Therapeutic drug monitoring of indinavir in HIV-infected patients undergoing HAART.

BACKGROUND: Therapeutic drug monitoring (TDM) of protease inhibitors (PI) is gaining increasing importance for the management of HIV-infected patients undergoing highly active antiretroviral therapy (HAART). The PI indinavir (IDV) is widely used in HAART regimens. Combinations of IDV with ritonavir (RTV) have been used to increase the plasma concentration of IDV. However, the desirable IDV concentration range in clinical practice remains to be elucidated. PATIENTS AND METHODS: To study the value of TDM for IDV in clinical practice, a retrospective analysis of 501 plasma samples of patients treated with IDV in various dosages was performed. IDV levels were determined during routine outpatient visits. Analysis was performed by high pressure liquid chromatography (HPlC) with UV detection. RESULTS: A widespread range of IDV plasma concentrations was seen both within and between patients. The mean IDV level during therapy with IDV 2.4 g/d was 3,260 ng/ml (95% CI: 2,903 ng/ml; 3,618 ng/ml). IDV levels at a dose of IDV 1.6 g/d in combination with RTV resulted in a mean IDV plasma concentration of 4,191 ng/ml (95% CI: 3,356 ng/ml; 5,026 ng/ml). There was no significant difference between plasma levels at the doses of 2.4 g/d and 1.6 g/d. 35 of all 130 patients treated with IDV reached only suboptimal IDV plasma concentrations below the limit of 150 ng/ml. There was no statistically significant difference between the number of patients below an IDV plasma concentration of 150 ng/ml in the various dosage regimens. CONCLUSION: During therapy with IDV in a b.i.d. scheme, similar IDV plasma concentrations and a comparable number of patients with subinhibitory plasma concentrations were observed when compared to a therapeutic regimen with t.i.d. dosing. In this study, even at various times of plasma sampling after oral ingestion, TCM facilitated the surveillance of patients compliance.

Efficacy and safety of an initial daily dosing regimen of interferon-alpha-2a in treatment-naive patients with chronic hepatitis C and HCV genotype 1.

Between January 1996 and February 1999 we treated two groups of patients with chronic hepatitis C and HCV genotype 1 according to different treatment regimens. 29 patients in group were treated in a prospective, open trial and received an initial dose of 6 MU Interferon-alpha-2a daily. In case of virologic response within the first 12 weeks of treatment a dosage reduction to 6 MU three times weekly was performed until the end of week 12 and 3 MU three times weekly thereafter until the completion of month 12. 35 patients in group 2 received 5 MU (Interferon-alpha-2b) or 6 MU (Interferon-alpha-2a) three times a week. If serum HCV RNA was negative after three months of treatment patients received 3 MU thrice weekly until completion of month 12. This regimen was considered standard therapy at the time of treatment. In both groups therapy was stopped in patients in whom HCV RNA remained detectable after 12 weeks of treatment or in patients who underwent virological breakthrough. The end point was a sustained virologic response defined as the absence of serum HCV RNA 6 months after treatment was completed. Primary response rates as defined by negative serum HCV RNA within the first 12 weeks of treatment were 59% in group 1 and 17% in group 2. Sustained response rates were 10% in group 1 and 3% in group 2. Initial daily dosing as in group 1 was therefore not associated with a higher sustained response rate compared to standard therapy. The safety profile was in accordance with the known side effects of interferon-alpha and was comparable in both treatment groups.

High-performance liquid chromatographic method for the determination of HIV-1 non-nucleoside reverse transcriptase inhibitor efavirenz in plasma of patients during highly active antiretroviral therapy.

A new high-performance liquid chromatographic method for the determination of efavirenz in human plasma is described. Quantitative recovery following liquid-liquid extraction with diethylether from 200 microl of human plasma was achieved. Subsequently, the assay was performed with 67 mM potassium dihydrogen phosphate-acetonitrile as a mobile phase, a XTerraRP 18 column protected with a Phenomenex C18 column and UV detection at 246 nm. Linear standard curves were obtained for concentrations ranging from 25 to 15,000 ng/ml. The calculated intra- and inter-day coefficients of variation were below 10%.

Characterization of HIV-specific proliferative T cell responses in HIV-infected persons.

Virus-specific helper T cell responses are thought to be an important host defense in HIV infection. The proliferative responses to HIV p24, p55, and gp120 were tested in a cohort of 27 HIV-infected subjects. Vigorous proliferative responses directed at the Gag protein with stimulation indices in excess of 6 were detected in 10 of the individuals tested but an Env-specific response was present in only 1 subject. Viral load and proliferative activity to Gag were inversely correlated in untreated individuals. Proliferation was also observed in some individuals treated in the chronic phase of infection, and responses were maintained over time in the absence of detectable viremia. Positive proliferative responses could also occasionally be detected in treated persons with CD4(+) cell counts below 200/microl. Thus, vigorous Gag-specific proliferative responses are present in a minority of HIV-infected individuals and can be detected in individuals receiving highly active antiretroviral therapy at advanced disease stages. Proliferative responses are maintained for an extended time period in the presence of antiviral therapy.

Influence of smoking on cotinine and caffeine plasma levels in patients with alcoholic liver cirrhosis.

BACKGROUND: Retention of caffeine was observed in patients with alcoholic liver cirrhosis and impaired liver function. Cotinine, the major metabolite of nicotine, is transformed by microsomal N-oxidation to secondary metabolites. The aim of this study was to investigate if impaired liver function leads to a retention of cotinine in a similar way to caffeine retention. Furthermure the influence of smoking on cotinine and caffeine plasma levels was studied. METHODS: 91 smokers and 12 nonsmokers with alcoholic liver cirrhosis were subdivided according to their smoking habits. Cotinine plasma levels and fasting caffeine concentrations were measured by a gaschromatographic method. Concentrations of conjugated bile acids were measured by RIA. 10 healthy smokers and 11 nonsmokers were used as a control group. RESULTS: Mean plasma cotinine concentrations found in slight smokers (200 +/- 155 ng/ml), intermediate smokers (384 +/- 223 ng/ml) and heavy smokers (430 +/- 266 ng/ml) with alcoholic liver cirrhosis were significantly higher than in healthy, smoking volunteers with slight, intermediate, and heavy smoking (101 +/- 14; 274 +/- 112; 345 +/- 85 ng/ml) (p <0.01) respectively. In nonsmokers with alcoholic liver cirrhosis plasma cotinine (44 +/- 25 ng/ml) was significantly elevated compared to healthy nonsmokers (27 +/- 19 ng/ml) (p <0.01). - Fasting caffeine plasma levels in patients with alcoholic liver cirrhosis (4.00 +/- 5. 20 microg/ml) were significantly higher than in healthy volunteers (0.91 +/- 0.42 microg/ml) (p <0.01). A decrease of plasma levels was observed in correlation to the amount of smoking in patients with alcoholic cirrhosis (slight smokers: 7.67 +/- 8.54 microg/ml, intermediate smokers: 3.35 +/- 2.91 microg/ml and heavy smokers: 2. 48 +/- 2.68 microg/ml). Conjugated bile acids were elevated in patients with alcoholic liver cirrhosis to 32,56 +/- 38,24 mmol/l. CONCLUSIONS: Increased cotinine plasma levels in smokers and nonsmokers with alcoholic liver cirrhosis demonstrate a cotinine retention in patients with impaired liver function. The inducing effect of smoking is shown by a decrease of fasting caffeine plasma concentrations.

Therapeutic drug monitoring of saquinavir in patients during protease inhibitor therapy with saquinavir alone or in combination with ritonavir or nelfinavir.

Therapeutic drug monitoring is essential in HIV-patients undergoing highly active antiretroviral therapy (HAART). Saquinavir (SQV) is used alone or in combination with ritonavir (RTV) or nelfinavir (NLF), respectively, in the context of the HAART drug regimen. The achievable SQV concentration range in clinical practice remains to be elucidated. A non-randomized prospecitve clinical trial 19 patients (group I) receiving SQV (1x600 mg/d Invirase or Fortovase), 29 patients (group II) receiving SQV (2x600 mg/d Fortovase) plus RTV (2x400 mg/d Norvir), and 21 patients (group III) receiving SQV (2x600 mg/d Fortovase) plus NLF (2x750 mg/d Viracept) was conducted to determine SQV plasma concentrations. SQV levels were determined as trough levels during routine outpatient visits. Analysis was performed by HPLC with UV detection. The lowest SQV plasma levels were found in group I (95% CI 89-177 ng/ml). Significantly higher SQV levels were found in group III (combination with NLF) ranging from 242 to 398 ng/ml (95% CI) and in group II (combination with RTV) ranging from 1354 to 1747 ng/ml (95% CI). The IC 50% of 54 ng/ml was not reached in at least one sample during the study (mean duration of study 16+/-10 months) in 14/19 patients of group I, 9/29 patients in group II and 13/21 patients in group III, respectively. A positive correlation between patient compliance, defined by SQV levels in the 95% CI of the used combination, and the HIV RNA plasma level was found. The presented data confirm that therapy with SQV alone may not be effective, since trough levels are near the lower limit of antiretroviral efficacy. Although the combination of SQV with NLF results in higher SQV plasma concentrations in a bid regimen, in more than 60% of the patients SQV concentrations below IC 50 level were detected during the twelve-months study period. The combination of SQV with RTV yields the highest SQV-trough levels. SQV concentrations below the IC 50 were seen in only 31% of patients with the SQV/RTV combination. In conclusion, therapeutic drug monitoring allows an efficient surveillance of patients compliance. In addition, therapeutic drug monitoring represents a valuable tool for management of HAART in patients receiving a complex comedication or suffering from advanced liver disease.

[Acute liver failure after therapeutic hyperthermia]. / Akutes Leberversagen nach Hyperthermiebehandlung.

HISTORY AND ADMISSION FINDINGS: A 49-year-old women with malignant neoplasia had undergone whole body hyperthermia under sedation to a rectal temperature of 42.5 to 42.7 degrees C for about one hour. She failed to awaken afterwards and was admitted in a coma and transferred to the intensive care unit (ICU). There was slight improvement in consciousness in the following 30 hours. INVESTIGATIONS: Clinical and laboratory findings gave a constellation indicating acute liver and renal failure (transaminases ca. 1400 U/l, bilirubin 7.27 mg/dl, serum creatinine 3.15 mg/dl, Quick thromboplastin time under 3.5%, antithrombin III 57%, partial thromboplastin time 70.7 s, platelets 23,000/microliter). Other causes of acute liver failure, especially drug effects, and septicaemia were excluded. TREATMENT AND COURSE: Treatment consisted of infusion of fresh plasma, neomycin and lactulose by mouth, medication to prevent stress ulcer, and total parenteral nutrition which included branched-chain amino acids. The patient regained full consciousness on the regimen and on the 6th day after admission was transferred to an ordinary ward. She was discharged after a further 3 weeks, by which time results of laboratory tests were practically normal. CONCLUSION: The course of the illness as well as the exclusion of any other cause of the acute liver failure in a patients who, 7 days before whole-body hyperthermia had been induced, had shown no signs of liver disease, makes a causal relationship between the hyperthermia and the described abnormalities highly probable. These serious, not previously reported, side effects of whole-body hyperthermia treatment underline the importance of undertaking this form of treatment only if strictest specific criteria are met.