Emergence of resistance is one of the drawbacks associated with treatment interruptions (TI), especially when regimens include nonnucleoside reverse transcriptase inhibitors (NNRTIs), because of ...their long half-life. ISS-PART was a randomized trial comparing a continuous treatment arm with a TI arm in which 136 patients underwent five treatment interruptions, each followed by 3 months of therapy, over 2 years. To minimize the potential risk of developing resistance, patients on NNRTIs were requested, at each TI, to interrupt nevirapine (NVP) or efavirenz (EFV) 3 or 6 days before the other drugs, respectively. To determine if a difference in drug levels existed during TIs between patients with and without resistance we compared NNRTI concentrations in the 12 patients (6 on NVP and 6 on EFV) who developed NNRTI mutations during TIs with those of 20 patients (10 on NVP and 10 on EFV) who retained a wild-type virus. Genotypic resistance and drug concentrations were analyzed on plasma samples collected 15 days after each drug interruption. Overall, EFV was quantifiable in 28% (16/57) and NVP in 22.9% (14/61) of evaluable samples collected during TIs, with no difference between patients with and without mutations. Median EFV or NVP concentrations at each TI were not significantly different between patients with and without mutations. Although the staggered stop strategy was not completely effective in preventing exposure to suboptimal levels, no evident correlation was found between NNRTI concentrations and the emergence of resistance, suggesting that other factors (such as the presence of drug-resistant minority variants) could also play an important role in these patients.
In this study we noninvasively followed for a mean period of 46 months 21 patients with different grades of myotonic dystrophy to evaluate the course of the involvement of the cardiac conducting ...system. Six patients (28.6%), 1 affected by a mild and 5 by a severe form of the neuromuscular disorder, showed appearance or deterioration of conduction disturbances suggesting a serious derangement of the specialized tissue; in 3 of them a permanent demand pacemaker was implanted. Conduction defects are the most frequent cardiac manifestations in myotonic dystrophy and become worse with time, mainly in patients with higher degrees of the disease. Furthermore, first-degree atrioventricular block may represent an early sign of developing of more advanced conduction defects.
Factors influencing the outcome of structured treatment interruptions (STIs) in HIV chronic infection are not fully elucidated.
In ISS-PART, 273 subjects were randomly assigned to arm A (137 assigned ...to continuous highly active antiretroviral therapy HAART) and arm B (136 assigned to 5 STIs of 1, 1, 2, 2, and 3 months' duration, each followed by 3 months of therapy). Main outcome measures were the proportion of subjects with a CD4 count >500 cells/mm3, the rate of virologic failure, and the emergence of resistance at 24 months.
The proportion of subjects with a CD4 count >500 cells/mm3 was higher in arm A than in arm B (86.5% vs. 69.1%; P = 0.0075). Pre-HAART CD4 cell count and male gender were independent predictors of a CD4 count >500 cells/mm3 in arm B. The overall risk of virologic failure was not increased in arm B; however, it was higher in the 38 subjects who had resistance mutations in the rebounding virus. Archived mutations at baseline and the use of a regimen that included an unboosted protease inhibitor (PI), compared with nonnucleoside reverse transcriptase inhibitor-based HAART, independently predicted the emergence of plasma mutations during STI (P = 0.002 for DNA mutations and P = 0.048 for PI-based HAART).
Our results suggest that patients with preexisting mutations and treated with unboosted PI-based HAART should not be enrolled in studies of time-fixed treatment interruptions, being at higher risk of developing plasma mutations during STI and virologic failure at therapy reinstitution.
In this multicenter study (ISS 902), 554 previously untreated patients with <500 CD4 cells/mm3 and mildly symptomatic human immunodeficiency virus disease were randomized to receive zidovudine or ...didanosine (ddI). After a mean follow-up of 20 months, 80 patients (40 zidovudine, 40 ddI) had died and 146 had at least one AIDS-defining event (73 zidovudine, 73 ddI). Overall, no difference was found between treatments with respect to progression to AIDS or death. The analysis of relative risk (RR) of progression over time, however, showed an initially minor risk for zidovudine patients and an inversion in the zidovudine-ddI RR in the second and third years of follow-up. Didanosine showed a greater effect on CD4 cell count response. The two drugs confirmed the toxicity patterns already reported in other trials, with a low occurrence of pancreatitis (ddI 1.3%, zidovudine 0.4%). The overall results suggest that, in this population, zidovudine and ddI monotherapies have comparable long-term clinical efficacy and that more powerful regimens should be preferred.
We studied 122 relatives (18 parents, 33 siblings, 57 offspring, 10 nephews and 4 nieces; mean age 34 +/- 19 years) of 33 patients with hypertrophic cardiomyopathy (HC) to analyze the incidence and ...clinical significance of electrocardiographic and echocardiographic abnormalities. On the basis of conventional echocardiographic criteria 12 first-degree relatives were considered to be affected by HC. Thirteen first-degree relatives and 1 niece were judged as having probable but not definite HC, i.e. left ventricular (LV) wall thicknesses over the 95% upper limit of confidence interval for age and body surface area or borderline ventricular septal thickness but a septal-to-free wall thickness ratio > or = 1.3 in the absence of an identifiable origin. Ninety relatives had normal echocardiographic findings. The remaining 6 subjects were found to have essential hypertension and were therefore excluded from consideration. Electrocardiogram (ECG) showed major or minor abnormalities in all relatives with HC, in 7 of the 14 probably affected by HC and in 20 of the 90 with normal echocardiogram. Of the 122 relatives 44 (38 with normal echocardiogram and 6 probably affected by HC) were reexamined over a mean period of 4.3 years (range 2-7). In the course of the follow-up 3 subjects modified their cardiac status. Two offspring who had at entry LV hypertrophy at ECG as isolated cardiac abnormality developed HC over a period of 5 years. A sibling who had only minor electrocardiographic abnormalities in the first study became probably affected by HC 3 years later.
We performed signal-averaged electrocardiography and 24-h ambulatory electrocardiographic monitoring in 53 patients with myotonic dystrophy to determine the incidence and clinical significance of ...ventricular late potentials. Patients were followed up for a mean period of 31 ± 17 months (range 11–68 months). At entry, none of the patients had bundle branch block on 12-lead electrocardiogram and none had wall motion abnormalities on routine echocardiogram. Also, no patient had history of syncope or clinical evidence of ischemic heart disease or a documented sustained ventricular tachycardia. A group of 47 healthy subjects matched for age and sex also underwent signal-averaged electrocardiography for comparison with the patient group. Late potentials were diagnosed in the presence of at least two of the following measures: duration of the filtered QRS > 114 ms, root-mean-square voltage of the terminal 40 ms of the filtered QRS < 20 μV, and duration of the low-amplitude (< 40 μV) signals of terminal filtered QRS > 38 ms. Late potentials were more frequent in patients than in controls: 18 of the 53 patients (34%) showed late potentials compared with four of the 47 controls (8.5%) (
P < 0.01). In 45 patients (85%) no ventricular ectopy (40 cases) or infrequent premature ventricular complexes (five cases) were detected on Holter monitoring. Complex ventricular arrhythmias were traced in the remaining eight patients. These were six of the 18 patients with, and two of the 45 patients without late potentials (33% vs. 6%, respectively;
P < 0.01). Only two of the eight patients with complex ventricular arrhythmias were documented to have repeated three-beat runs of ventricular tachycardia; both patients also had late potentials. During the period of observation there were no sudden deaths. Two patients required permanent pacemakers for appearance of serious conduction defects and recurrent syncope. Therefore, ventricular late potentials are a frequent finding in patients with myotonic dystrophy. In our series they were sensitive in predicting complex ventricular arrhythmias being present in 75% of cases and correctly identifying the patients with ventricular tachycardia. However, specificity and positive predictive value were unacceptable due to the high false-positive rate. Also, the absence of cardiac catastrophic events during follow-up calls in question the prognostic value of ventricular late potentials in myotonic dystrophy.
Residual viraemia is detectable in the majority of human immunodeficiency virus (HIV)-infected subjects with plasma HIV-1 RNA <50 copies ml(-1). In the present study, the impact of repeated treatment ...interruptions on residual HIV-1 viraemia was investigated in 58 subjects enrolled in the ISS-PART, a multicentre, randomized clinical trial comparing 24 months of continuous (arm A) and intermittent (arm B) highly active antiretroviral therapy (HAART). Residual viraemia was measured by a modified Roche Amplicor HIV-1 RNA assay (limit of detection 2.5 copies ml(-1)). At baseline, the median value of residual viraemia was 2.5 copies ml(-1) in both arms; after 24 months, the median value was 2.5 in arm A and 8.3 in arm B. The median change from baseline to month 24 was significantly different between patients under continuous or intermittent HAART: 0 copies ml(-1) (range -125.2 to +82.7) of HIV-1 RNA in arm A versus 2.1 copies ml(-1) (range -80 to +46.8) in arm B (P=0.024). These results suggest that intermittent HAART tends to modify HIV-1 viraemia set point even if a virological response is achieved after HAART reinstitution.
We analysed the diagnostic performance of the signal-averaged QRS duration for the detection of left ventricular hypertrophy in 100 consecutive outpatients (62 men and 38 women; mean age, 49.8 +/- ...11.8 years) with essential hypertension and compared the results with some of the currently employed electrocardiographic criteria. Forty-eight healthy subjects (24 men and 24 women; mean age, 46.4 +/- 12.1) with normal physical, electrocardiographic and echocardiographic findings served as a control group to derive normal reference values for signal-averaged QRS duration. Twenty-six (26%) hypertensives (22 men and 4 women) had left ventricular hypertrophy echocardiographically defined as a left ventricular mass > or = 261 g in men and > or = 172 g in women or left ventricular mass index > or = 125 g/m2 in men and > or = 112 g/m2 in women. The signal-averaged QRS duration was different in patients with than in those without left ventricular hypertrophy (102.1 +/- 10.8 vs. 95.8 +/- 8.4 ms; P < 0.01). Also, in the group with left ventricular hypertrophy QRS duration was longer, although not significantly different, in men than in women (103.5 +/- 10.7 vs. 94.2 +/- 8.8 ms; P n.s.). The correlation between the signal-averaged QRS duration and left ventricular mass was weak but statistically significant in men (r = 0.34; P < 0.05) in women (r = 0.30; P < 0.05) and in men and women together (r = 0.42; P < 0.01). Partition values of filtered QRS duration > or = 114 ms in men and > or = 107 ms in women were used to diagnose left ventricular hypertrophy as these values were above the upper limits in our control men and women when 95% confidence intervals were calculated. These criteria were insensitive (12%) but highly specific (99%) for left ventricular hypertrophy. The use of a single threshold value of filtered QRS duration > or = 111 ms in both sexes combined improved sensitivity modestly (15%) while maintaining a good specificity (95%). Also, we tested the following standard electrocardiographic criteria: the Sokolow-Lyon index, the Romhilt-Estes point score > or = 4 points and > or = 5 points, the Cornell voltage criteria, the sum of QRS voltages in all 12 leads > 175 mm, and the QRS duration > 90 ms. Sensitivities ranged from 4% to 58% and specificities from 74% to 99%.
We analysed the performance of the electrocardiogram in diagnosing left ventricular hypertrophy in 70 patients with isolated left anterior hemiblock and in 75 patients with right bundle branch block, ...either isolated (44 cases) or associated (31 cases) with left anterior hemiblock. Left ventricular hypertrophy defined as an echocardiographically determined left ventricular mass greater than 261 g in men and 172 g in women or left ventricular mass index greater than 125 g/m2 in men and 112 g/m2 in women was present in 48 subjects (57%) with isolated left anterior hemiblock and 33 subjects (44%) with right bundle branch block. In patients with isolated left anterior hemiblock the best results were obtained using the SV1 or SV2 + (RV6 + SV6) greater than 25 mm with 74% in sensitivity and 67% in specificity; the criterion SIII + (R + S) maximal in a precordial lead greater than or equal to 30 mm showed a sensitivity of 74% but a specificity of 47%. In the whole group of patients with right bundle branch block none of the criteria nor combination of criteria achieved an acceptable performance (sensitivities ranged from 17% to 41% and specificities ranged from 54% to 85%). When these patients were divided according to the presence or absence of concomitant left anterior hemiblock the electrocardiographic indexes mostly showed, in comparison to whole group, higher values in sensitivity and lower values in specificity in right bundle branch block plus left anterior hemiblock and an opposite behaviour in isolated right bundle branch block.
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