Comparison of two once-daily regimens with a regimen consisting of nelfinavir, didanosine, and stavudine in antiretroviral therapy-naïve adults: 48-week results from the Antiretroviral Regimen Evaluation Study (ARES).

BACKGROUND: To improve the dosing frequency and pill burden of antiretroviral therapy, we compared two once-daily dosed regimens to a twice-daily dosed regimen. METHOD: HIV-1-infected, antiretroviral drug-naïve adults were randomized to either twice-daily nelfinavir and stavudine and once-daily didanosine (regimen A) or simplified once-daily dosed antiretroviral regimens consisting of nevirapine, didanosine, and lamivudine (regimen B) or saquinavir, ritonavir, didanosine, and lamivudine (regimen C). RESULTS: At 48 weeks of therapy, the proportion of patients with a blood plasma HIV-1 RNA concentration (pVL) <50 copies/mL by intention-to treat analysis was 42.3%, 50.0%, and 56.5% for regimens A (n = 26), B (n = 22), and C (n = 23), respectively. The time to a pVL <50 copies/mL for the first time was significantly shorter in regimen C, and there was significantly more progression to CDC events in regimen B. These differences are possibly due to differences in baseline characteristics. Adverse events were lowest for regimen C; more signs associated with mitochondrial toxicity occurred in regimen A. Increase in CD4 count was comparable between arms. CONCLUSION: No statistically significant difference in efficacy was found between the two investigated once-daily dosed treatment regimens (B and C) and the reference (A). Regimen C possibly had a better virological response and less toxicity than regimens A and B.

The steady-state plasma pharmacokinetics of indinavir alone and in combination with a low dose of ritonavir in twice daily dosing regimens in HIV-1-infected individuals.

OBJECTIVE: To explore the steady-state plasma pharmacokinetics of indinavir in twice daily dosing regimens with and without the co-administration of 100 mg ritonavir. DESIGN: Observational pharmacokinetic study. PATIENTS: HIV-1-infected individuals who use indinavir alone (1200 mg twice daily, n = 6), or the combination of 100 mg ritonavir twice daily plus either 800 mg (n = 6), or 1200 mg indinavir twice daily (n = 2). METHODS: Steady-state pharmacokinetics of indinavir and ritonavir were assessed by drawing 12 blood samples during an 8-h period after ingestion of the medication. RESULTS: Significant differences were observed for indinavir pharmacokinetics between the dosing regimens indinavir 1200 mg twice daily alone and indinavir/ ritonavir 800/100 mg twice daily with respect to the mean trough concentration (0.21 and 0.99 microg/ml, respectively, P = 0.002), the mean maximum concentration (13.79 and 8.74 microg/ml, respectively, P = 0.028), and for the mean plasma elimination half-life (1.6 and 3.2 h, respectively, P = 0.001). The combination indinavir/ritonavir 1200/100 mg twice daily led to very high exposure to indinavir and was not well tolerated. However, the combination indinavir/ritonavir 800/100 mg twice daily was well tolerated and resulted in therapeutic concentrations of indinavir with improved trough concentrations and similar maximum concentrations as observed with the licensed dosage of 800 mg three times daily. CONCLUSION: Combination of indinavir and 100 mg ritonavir in twice daily dosing regimens significantly affects the pharmacokinetic profile of indinavir. The results of this observational study provide a pharmacologic basis for the combination of indinavir (800 mg) and ritonavir (100 mg) in twice daily dosing regimens.

Renal extraction of atrial natriuretic peptide in hypertensive patients with or without renal artery stenosis.

The renin-angiotensin-aldosterone system plays a major role in renovascular hypertension, but the relationship between renin release and the renal fractional extraction of atrial natriuretic peptide (ANP) in this condition is not well defined. We measured ANP levels in the renal veins and aortas of 49 untreated hypertensive patients studied under standardized conditions immediately before renal angiography. Twenty-one patients had renal artery stenosis, 13 of which were unilateral and 8 bilateral. Five of the 13 patients with unilateral renal artery stenosis had an elevated renin ratio (> or = 1.5). Patients with renal artery stenosis were older (P < .01) and had higher systolic pressures (P < .05) than patients with essential hypertension. Arterial levels of ANP were significantly higher in patients with unilateral or bilateral renal artery stenosis than in patients with essential hypertension (P < .05). Patients with hypertension and left ventricular hypertrophy had significantly higher arterial ANP levels than those with no hypertrophy (40 versus 26 pmol/L, P < .05), but in patients with renal artery stenosis, arterial ANP levels were similar in those with or without hypertrophy. Renal venous ANP levels were significantly higher in stenotic than in normal kidneys. Moreover, in unilateral renal artery stenosis, stenotic kidneys of patients with an elevated renin ratio (stenotic kidney/contralateral kidney > or = 1.5) had a significantly higher renal venous ANP level than stenotic kidneys of patients with normal renin ratio (30 versus 17 pmol/L, P < .05). However, the median fractional extraction of ANP was similar, around 0.50 (range, 0 to 0,83), in normal kidneys of hypertensive patients and in stenotic and contralateral kidneys of patients with renal artery stenosis. A significant inverse correlation between arterial ANP and renal venous active plasma renin concentration was found for normal kidneys (r= -.62, P < .01) of hypertensive patients without hypertrophy. However, for stenotic kidneys, no such relationship was apparent. A significant correlation between arterial ANP and the arteriovenous difference of ANP (r = +.92, P < .001) was found. This relationship was similar for normal and stenotic kidneys. In conclusion, an inverse relationship between arterial ANP and renal venous active plasma renin concentration exists in normal kidneys of essential hypertensive patients without left ventricular hypertrophy. Furthermore, data of ANP extraction through normal and stenotic kidneys suggest that saturation of ANP extraction does not occur. Increased levels of ANP in renal artery stenosis are likely caused by enhanced cardiac secretion of this peptide.

Interpretation of renal angiography by radiologists.

OBJECTIVE: Different radiologists may show considerable variation in their interpretation of renal angiograms. We therefore wished to establish the reliability of their interpretation. DESIGN: Assessment of the intra- and inter-observer agreement of the interpretation of renal angiograms. SETTING: Tertiary referral university hospital. PATIENTS: Hypertensive patients suspected of renovascular hypertension on clinical grounds or on the basis of renography. INTERVENTIONS: Patients were prospectively selected to undergo a renal angiography via the femoral approach. MAIN OUTCOME MEASURES: Intra- and inter-observer agreement of the degree and site of stenosis. RESULTS: The difference between two estimates of the degree of stenosis ranged from 0 to 65% for the individual readers and from 0 to 75% between two readers. When the site of greatest stenosis was in the origin of the renal artery, the intra-observer agreement kappa ranged from 0.54-0.71, the inter-observer agreement across multiple readers being 0.43. In a post hoc analysis using two different cut-off points of stenosis (50 or 70%), the intra- and inter-observer agreement was better at the 70% cut-off-point. In a subset of patients with stenosis and a renin ratio greater than 1.5, both the intra- and inter-observer agreement were much better than when all angiograms were considered. CONCLUSIONS: Assessment of the diagnostic performance of three experienced radiologists in their interpretation of renal artery angiograms indicates that the intra- and inter-observer agreement with respect to their estimates of the degree of stenosis and the site of greatest stenosis are rather poor but their diagnostic performance improves in patients with stenosis and a renin ratio greater than 1.5. There is a need for more objective assessment of renal artery lesions.

Stenosis and renographic characteristics in renovascular disease.

UNLABELLED: This study was designed to determine the degree of renal artery stenosis (RAS) which produces changes in renographic parameters. METHODS: The angiographic severity of luminal narrowing in RAS was compared to 131I-hippuran renographic characteristics in 72 patients who have been selected for renal angiography because of suspected renovascular hypertension. RESULTS: Significant differences in Tmax, T1/2 and counts under the curve to Tmax were apparent at 30% of arterial luminal narrowing when stenotic and nonstenotic kidneys were compared. In patients with unilateral RAS, the difference in counts under the Tmax curve between pairs of kidneys was also significantly different at 30% of stenosis. Patients with bilateral stenosis, on the other hand, could not be differentiated well from patients with essential hypertension because the Tmax value on either side or the difference of Tmax between the two kidneys and the values of the other parameters were similar, except for the difference in counts to Tmax. Based on these findings it seems that bilateral RAS does not "mimic" unilateral stenosis in renographic terms, but rather, resembles a normal situation. CONCLUSION: Significant renographic changes can occur at 30% of arterial luminal narrowing in renal artery disease.

Baseline and postcaptopril renal blood flow measurements in hypertensives suspected of renal artery stenosis.

UNLABELLED: Renal blood flow (RBF) measurements using first-pass radionuclide angiography with DTPA, a glomerularly filtered agent, failed to show significant differences between normal and stenotic kidneys. Since MAG3 is an ideal agent for the study of RBF, this agent might be an attractive alternative tracer to detect differences in RBF. METHODS: An angiographically controlled prospective study was performed in 48 hypertensive patients, in whom a diagnosis of renovascular hypertension was suspected on clinical grounds. The study was done to determine whether RBF measurements using first-pass radionuclide angiography with 99mTc-MAG3 could be helpful in the diagnostic work-up of the patients. Additionally, the study was done before and after ACE-inhibition. RESULTS: On renal angiography, 29 patients showed to have normal renal arteries (50 patients had normal kidneys and 8 patients had small kidneys). Nineteen patients had renal artery stenosis (13 uni- and 6 bilateral disease). In the patients with normal kidneys, the mean value of RBF measurements ranged from 10.5% to 10.9% of cardiac output. Only small stenotic and small kidneys with normal renal arteries showed a significant reduced baseline RBF as compared with normal kidneys (both p < 0.05); this difference disappeared after ACE-inhibition only for the small kidneys with normal renal arteries. In patients with stenosed kidneys, RBF tended to be reduced both at baseline and after captopril, but the differences with normal kidneys were not statistically significant. After ACE-inhibition RBF increased in the majority of kidneys, but postcaptopril RBF data did not differ significantly from those at baseline. CONCLUSION: RBF measurements using first-pass radionuclide angiography with 99mTc-MAG3, either before or after ACE-inhibition, cannot reliably discriminate between patients with essential hypertension and patients with renal artery stenosis.

Interpretation of captopril renography by nuclear medicine physicians.

UNLABELLED: This study was designed to assess intra- and interobserver variability and diagnostic accuracy of nuclear medicine physicians in their evaluation of baseline and captopril renograms. METHODS: The diagnostic performance of three experienced nuclear medicine physicians according to their interpretation of baseline, captopril and paired renograms was assessed. To this end, the readers evaluated the renograms of 28 hypertensive patients in whom a diagnosis of renovascular hypertension was suspected on the basis of clinical clues. All patients also underwent angiography. The readers were unaware of the angiographic diagnosis. RESULTS: Thirteen of 28 patients proved to have renal artery stenosis (8 unilateral, 5 bilateral) on renal angiography. The concordance in the renographic diagnoses between the three readers was reasonably good, with an intraobserver agreement and kappa (observed agreement corrected for chance) ranging from 64% to 89% and from 0.52 to 0.75, respectively, and an interobserver agreement and kappa ranging from 68% to 86% and from 0.61 to 0.82. The sensitivity of their interpretation of paired baseline plus captopril renograms in relation to the angiographic diagnosis is poor and below 50%. The post-test probability of RAS in case of a negative renographic study was found to be rather similar to the pre-test probability (prevalence) of 46%. Blinding readers to which renogram was obtained after captopril imaging increased their accuracy. CONCLUSION: The intra- and interobserver agreement between experienced nuclear medicine physicians who evaluate renograms was found to be reasonably good. Blinding readers as to which renogram is the pre- and post-captopril image seems to enhance their diagnostic accuracy in instances of positive scans.

'Captopril test', with blood pressure and peripheral renin as response variables in hypertensive patients with suspected renal artery stenosis.

In forty six hypertensive patients in whom a high level of clinical suspicion for renovascular hypertension was present on the basis of clinical clues, a captopril test was performed with either 25 mg of captopril or placebo on 2 separate days to determine prospectively the value of the captopril test. Blood pressure (BP) and peripheral renin were used as response variables. All patients had discontinued their anti-hypertensive medication and were not salt depleted. In all patients selective renal angiography was performed irrespective of the results of the captopril test. Twenty patients proved to have uni- or bilateral renal artery stenosis (RAS) giving a prevalence of 43%. After the placebo and after captopril there were no significant changes (absolute or proportional) in BP values between patients with essential hypertension or RAS, either for all measurements or if only the fall in BP was taken into account. The receiver operator characteristic curves of both baseline and post-captopril peripheral renin levels indicate that the captopril test does not discriminate appropriately between patients with essential hypertension and RAS. Therefore, we would not advise the use of the captopril test as a screening test for RAS in hypertensive patients in whom a high level of clinical suspicion for RAS is already present.

Patterns of morbidity and mortality in AIDS patients on Pneumocystis carinii prophylaxis who died during hospital admission: a report of 50 diseased patients.

BACKGROUND: Since the introduction of prophylaxis against Pneumocystis carinii pneumonia (PCP) the pattern of illnesses related to AIDS has changed. PCP prophylaxis may delay the first AIDS-defining illness (ADI) and shifts the clinical manifestations of AIDS to illnesses other than PCP. METHODS: Morbidity and mortality patterns were studied of the first 50 diseased HIV-infected patients who died during hospital admission since the introduction of PCP prophylaxis. RESULTS: The survival of patients after the diagnosis of AIDS in all patients was 13 months, with no difference in survival between patients who were on zidovudine for more than 6 months before the diagnosis of AIDS and those who were not on zidovudine. PCP was seen in 10 patients as the first ADI who were unaware of being HIV-infected and two during the course of their disease due to inappropriate use of prophylaxis. None of the 50 patients died from PCP. Twenty-five patients suffered from complications of the central nervous system (CNS) and these were the major immediate cause of death. CONCLUSIONS: Our findings show that due to the use of PCP prophylaxis the incidence of PCP is low, but that PCP is still a common disease in patients unaware of their HIV infection. On the other hand, our findings suggest that CNS disease is the major immediate cause of death in patients on PCP prophylaxis.

Concealed lung abscess in critically ill, mechanically ventilated patients.

We describe 3 critically ill patients with pneumonia complicated by lung abscesses and contralateral pneumonia due to spill of purulent secretions into the healthy lung. Although the clinical picture of lung abscess often runs an indolent course, this was not observed in these critically ill patients, who all died from this complication. Diagnosis was delayed as chest X-ray underestimated lung pathology compared to computed tomography (CT) scan. Therefore percutaneous chest tube drainage and placement of a double-lumen endobronchial tube to protect the healthy lung were delayed and spill of purulent secretions into the contralateral lung occurred. These cases show the importance of rapid evaluation by CT scan of the chest in mechanically ventilated patients with slowly resolving infiltrates on chest X-ray.

Treatment of acute hepatitis C virus infection in HIV+ patients: Dutch recommendations for management.

With a rising incidence of acute hepatitis C virus (HCV) infection in patients coinfected with the human immunodeficiency virus (HIV), there is a need for evidence-based treatment recommendations. There are no randomised trials available and published studies differ with respect to design, patient characteristics and number of patients included, making a comparison between studies difficult. However, it is critical to standardise treatment for this group of patients in order to optimise the outcome of therapy. The Dutch Society for HIV Physicians proposed to write recommendations for the treatment of acute HCV in HIV -coinfected patients. Combination therapy with pegylated interferon-alpha and ribavirin is the preferred regimen initiated preferably within 12 weeks after the diagnosis of acute HCV. A treatment duration of 24 weeks is recommended in case of a favourable virological response (either achievement of a rapid virological response or a > 2 log10 decrease plus undetectable HCV-RNA at week 12). In all other patients prolonging the duration of therapy to 48 weeks should be considered.

High-output cardiac failure due to excessive shunting in a hemodialysis access fistula: an easily overlooked diagnosis.

A dialysis arteriovenous fistula caused life-threatening high-output cardiac failure in a 66-year-old patient. Excessive shunting through the dialysis fistula was demonstrated by invasive measurement of cardiac output, systemic arterial blood pressure, systemic vascular resistance, and oxygen consumption before and after temporary occlusion of the dialysis fistula. Noninvasive echocardiographic evaluation of the influence of fistula compression on cardiac output and noninvasive duplex measurement of the fistula flow also confirmed the diagnosis. Following surgical closure of the fistula, the patient's condition improved, and signs of congestive heart failure subsided. High-output cardiac failure is a rare complication of dialysis arteriovenous fistulas. The diagnosis may remain unrecognized for longer periods. Noninvasive methods for estimation of the hemodynamic importance of a fistula may be of help in the establishment of the proper diagnosis.

Renal arterial and venous endothelin in hypertensive patients with or without renal artery stenosis.

Immunoreactive endothelin (ir-ET) levels were measured in the renal veins and aorta of 43 untreated hypertensive patients immediately before renal angiography. None of the patients used antihypertensive medication. Twenty-seven patients had renal artery stenosis, 17 of which were unilateral and 10 bilateral. Seven of the 17 patients with unilateral renal artery stenosis had an elevated renin ratio. Of the 16 patients with essential hypertension 6 had a unilateral small kidney with a normal blood supply. Although there was a trend towards higher levels of ir-ET in patients with renal artery stenosis, no significant differences in endothelin levels (venous or arterial) were found between different groups of patients or groups of kidneys. More than 75% of kidneys extracted endothelin, there being no significant differences between groups of kidneys. In conclusion, our data demonstrate that endothelin levels and renal endothelin extraction are comparable in essential hypertension and in hypertension associated with renal artery stenosis. Whereas renal uptake or endothelin is the rule, some kidneys, however, release this peptide irrespective of the presence or absence of renal artery stenosis.

Quantitative residual cortical activity measurement: appropriate test for diagnosis of renal artery stenosis?

OBJECTIVES: To evaluate the diagnostic validity of quantitative measurement of residual cortical activity (RCA) in renal artery stenosis (RAS). METHODS: In 45 patients with a high clinical likelihood of renovascular hypertension (RVH) and unimpaired renal function, dynamic imaging was performed after an intravenous bolus injection of 148 MBq (99m)Tc MAG3 for both baseline renoscintigraphy and captopril renography following oral application of 50 mg captopril. RCA was measured according to the Sfakianakis method: RCA = cortical counts at 20 min/counts at peak x100%. An increase in RCA of >/=5% from baseline was considered indicative of RAS. After renography, all patients underwent selective transfemoral angiography with the digital subtraction technique. A luminal reduction of >/=50% was considered as proof of RAS. RESULTS: The number of kidneys that had a change of >/=5% in RCA values was 12 (27.2%) in normal kidneys, 7 (58.3%) in the patients with bilateral RAS, 14 (82.3%) in the patients with unilateral RAS, and 21 (72.4%) in overall kidneys with RAS. The positive test ratio in pathologic groups was significantly higher than normal (p < 0.05). The sensitivity and specificity of the RCA test were 72.4 and 72.7%, respectively; the positive and negative predictive values were 63.6 and 80%, respectively. CONCLUSION: Quantitative measurements of RCA can be used as a diagnostic parameter of renal artery stenosis and may contribute of the diagnostic accuracy of visual interpretation and other renographic diagnostic criteria.

Zidovudine and interferon-alpha combination therapy versus zidovudine monotherapy in subjects with symptomatic human immunodeficiency virus type 1 infection.

Forty-five subjects with symptomatic human immunodeficiency virus type 1 (HIV-1) infection, CD4+ lymphocyte counts of > or = 150 x 10(6)/L, and Karnofsky scores > or = 60 were enrolled in a multicenter, randomized, controlled trial that compared zidovudine monotherapy and combination therapy for 48 weeks with zidovudine and interferon-alpha (IFN-alpha). Zidovudine with IFN-alpha (n = 25) had a favorable effect on CD4+ cell counts compared with zidovudine alone (n = 20). At all time points analyzed, the mean change from baseline was higher, reaching significance at week 24 (+10% versus -21%; P = .029). At week 48 the difference was -12% versus -45% (P = .07). Anti-CD3 monoclonal antibody-induced T cell reactivity improved temporarily in both groups. Serum HIV p24 antigen levels decreased maximally during the first 12 weeks of treatment. At weeks 0 and 48, polymerase chain reaction analysis for mutations at codons 67 and 215 of the HIV-1 reverse transcriptase gene conferring zidovudine resistance was conducted in 10 subjects receiving zidovudine and in 8 subjects receiving combination therapy. At week 48, 1 of 8 and 4 of 6 samples from the groups receiving zidovudine only or combination therapy, respectively, contained wild type virus at codon 215. Grade 3 or 4 toxicity was uncommon. Drug-related malaise and anorexia were observed more frequently in patients receiving both zidovudine and IFN-alpha.

Steady-state pharmacokinetics of twice-daily dosing of saquinavir plus ritonavir in HIV-1-infected individuals.

OBJECTIVE: To compare the steady state plasma pharmacokinetics of 1000 mg of saquinavir (SQV) in a soft-gel capsule (SGC) formulation in combination with 100 mg of ritonavir (RTV) (capsules) in a twice-daily dosing regimen in HIV-1-infected individuals with historical controls who used 400 mg of SQV in a hard-gel capsule (HGC) formulation in combination with 400 mg of RTV and to investigate the plasma pharmacokinetics of the 1000 mg/100 mg regimen after normal and high-fat breakfasts. DESIGN: Open-label, crossover, steady-state pharmacokinetic study. METHODS: Six HIV-1-infected individuals who used either 1200 mg of SQV (SGC or HGC) three times daily or 400 mg twice daily in combination with 400 mg of RTV twice daily were included. Each patient was switched to 1000 mg of SQV SGC twice daily in combination with 100 mg of RTV twice daily. After 14 days, the patients came to the hospital for assessment of a pharmacokinetic profile during 12 hours. Patients were randomized to receive a high-fat (+/-45 g of fat) or normal (+/-20 g of fat) breakfast. After 7 days, a second pharmacokinetic profile was assessed after ingestion of the drugs with the alternate breakfast. A noncompartmental pharmacokinetic method was used to calculate the area under the plasma concentration versus time curve (AUC0-12h), the maximum plasma concentration (Cmax), the plasma trough concentration (C12h), and the elimination half-life in plasma (t1/2). The obtained pharmacokinetic parameters were compared with those of 12 patients using SQV HGC (400 mg twice daily) in combination with RTV (400 mg twice daily). RESULTS: The median values of the pharmacokinetic parameters for SQV SGC (1000 mg twice daily, normal breakfast) were: AUC0-12h, 18.84 h*mg/L; Cmax, 3.66 mg/L; C12h, 0.40 mg/L; and t1/2, 3.0 hours. The median values of the pharmacokinetic parameters for SQV HGC (400 mg twice daily, normal breakfast) were: AUC0-12h, 6.99 h*mg/L; Cmax, 1.28 mg/L; C12h, 0.23 mg/L; and t1/2, 3.9 hours. The exposure to SQV in the dosing regimen of 1000 mg twice daily in combination with 100 mg of RTV twice daily was significantly higher than the exposure to SQV in a dosing regimen of 400 mg twice daily in combination with 400 mg of RTV twice daily. The pharmacokinetic parameters of SQV SGC in the dosing regimen of 1000 mg twice daily in combination with 100 mg of RTV twice daily were not significantly different after ingestion of a high-fat or normal breakfast (p >.35). CONCLUSIONS: The combination of 1000 mg of SQV SGC twice daily and 100 mg of RTV twice daily resulted in a higher exposure to SQV compared with the exposure to SQV obtained when SQV is used in the 400 mg/400 mg twice-daily combination with RTV. In this small number of patients, no significant differences in exposure were seen after ingestion of either a normal or high-fat breakfast. From a pharmacokinetic perspective, the combination of 1000 mg of SQV SGC twice daily and 100 mg of RTV twice daily seems to be a good option for further clinical evaluation.