Dynamic tailoring of treatment durations improves efficiency of hepatitis C treatment with pegylated interferon and ribavirin.

The treatment durations for hepatitis C are guided by the analysis of hepatitis C virus (HCV) RNA in blood at certain time points. This multicentre, randomized open label trial evaluated the utility and performance of individualized treatment durations guided by viral decline rates in 103 patients with HCV genotype 1 infection. Pegylated interferon 2a and ribavirin were given as standard of care (SOC) for 24, 48 or 72 weeks or as dynamic treatment (DT) for 24-72 weeks. The DT duration was based on the time point when log HCV RNA would reach 0 log copies/mL, as estimated by the second-phase decline. The rate of sustained virologic response was 63% for SOC and 54% for DT, but this difference was not significant in multiple regression analysis taking predictive factors such as interleukin-28B genotypes, age and baseline viremia into account (P = 0.45). The mean required treatment time per cured patient was 51 weeks for DT as compared with 58 weeks for SOC (P = 0.22) when given per protocol (n = 95) and was significantly shorter (42 vs 51 weeks) among patients who achieved undetectable HCV RNA (P = 0.01). We conclude that DT was feasible and increased efficiency. The estimated time point for 0 log viral copies/mL is a new and quantitative response variable, which may be used as a complement to the qualitative variable rapid virologic response. The outcome parameter treatment weeks per cured patient could become a useful tool for comparing treatment efficiency also in the era of directly acting antivirals.

Hepatitis C virus RNA kinetics during the initial 12 weeks treatment with pegylated interferon-alpha 2a and ribavirin according to virological response.

SUMMARY: To optimize treatment of chronic hepatitis C early identification of patients who will not achieve a sustained virological response (SVR) is desirable. We investigated hepatitis C virus (HCV) RNA kinetics at day 1 (in 15 patients; genotypes 1 and non-1, 9 and 6 respectively) at weeks 1, 4 and 12 (in 53 patients; genotypes 1 and non-1, 19 and 34, respectively) during treatment with pegylated interferon alpha-2a and ribavirin. Patients with SVR had a significantly more pronounced mean log10 decline from baseline in HCV RNA levels at weeks 1 and 4 compared with patients who failed to achieve SVR (1.99 vs 0.85 at week 1, P = 0.0003 and 2.89 vs 1.72 at week 4, P = 0.0159), whereas no difference was noted after day 1. For patients with a 2-log10 decrease in HCV RNA levels at day 7, the positive predictive value (PPV) for a SVR was 92%, whereas week 12 was the best time point for predicting a later nonresponse [negative predictive value (NPV) 92%] in patients failing to achieve a 2-log10 drop. For patients with genotype non-1 and a 2-log10 decrease in HCV RNA levels the PPV for a SVR was 89% week 1, and 79% weeks 4 and 12. The corresponding NPV for patients with genotype non-1 were 43, 40 and 100% respectively. During treatment with pegylated interferon alpha-2a plus ribavirin the HCV RNA decline at week 1 was an accurate predictor of SVR in patients who had achieved a 2-log10 drop in HCV RNA levels, whereas the lack of such decline week 12 was an accurate marker of a nonresponse.

Virological, biochemical and histological effects of human lymphoblastoid interferon in Swedish patients with chronic hepatitis C.

Thirty-eight Swedish patients with chronic hepatitis C were randomly assigned to receive either 3 million units (MU) or 5 MU of human lymphoblastoid interferon-alpha-n1 (Wellferon) three times per week for either 6 or 12 months. The patients were monitored biochemically, histologically and by quantitative polymerase chain reaction for circulating HCV RNA, during therapy and for the following year. Overall, 22 (58%) of the patients lost detectable hepatitis C virus (HCV) viraemia during therapy but eight of these patients relapsed during follow-up, leaving 14 (37%) sustained responders. Patients infected with HCV non-type 1 genotypes were significantly more likely to achieve a sustained response than were those infected with HCV type 1 (63% vs 10.5%, P = 0.001). Sustained virological responses were also associated with lower pretreatment viraemia level, younger age, absence of cirrhosis and the higher interferon dosage regimens but these associations failed to reach statistical significance. In 97% of patients there was concordance between virological and biochemical responses, and a statistically significant (P = 0.005) improvement in the Knodell histological activity index was observed in the virological sustained responders.

Transient high titers of HIV-1 in plasma and progression of disease.

Periodic quantitative HIV-1 plasma cultures were performed on 28 seropositive individuals who had CD4 cells < or = 300/mm3 and who were enrolled in three clinical trials testing the efficacy of didanosine versus zidovudine monotherapy. Most plasma cultures were negative or of low titer (1-100 tissue culture infective dose/ml of plasma), but there were 14 instances of high-titered plasma viremia (> or = 1,000 tissue culture infective dose/ml of plasma) seen in 11 individuals. These peaks in plasma culture titers were significantly associated either with rapidly decreasing CD4 cell numbers or with CD4 cells already < 50/mm3. In addition, patients who experienced these episodes of high-titered plasma viremia were more apt to have clinical complaints of fever, rash, flu-like illness, and/or opportunistic infection and also the syncytium-inducing HIV-1 phenotype and progression of disease.

Reactivation of hepatitis B virus infection with an unusual pattern of serological markers.

A 73-year-old man presented with acute hepatitis, judged to be a reactivation of hepatitis B virus infection. His serum samples during a follow-up time of 16 months showed an unusual pattern of serological markers. He was consistently HBeAg positive, HBsAg fluctuated just under the cut-off value and he had a low level of circulating anti-HBs. By electron microscopy numerous aggregates of surface antigen particles, but not complete virions were seen. He was HBV DNA positive by hybridization. The complete precore and core genes and a region of the surface gene were amplified from his serum by PCR. These findings emphasize the need for expanded serological testing in some patients with acute clinical hepatitis.

Detection of infectious immune complexes in human immunodeficiency virus type 1 (HIV-1) infections: correlation with plasma viremia and CD4 cell counts.

The detection of infectious immune complexes in plasma after human immunodeficiency virus (HIV) infection may be useful as a surrogate marker of progression of disease and may help in understanding the pathogenesis of AIDS. Polyethylene glycol (PEG) precipitates of plasma were tested for the presence of HIV p24 antigen and infectious virus. Results were compared with data from cell and plasma cultures, plasma p24 antigen, CD4 cell counts, and stage of disease. PEG precipitation increased the detection rate of the p24 antigen assay from 38.3% to 58.7%. There was a significant correlation between precipitable p24 antigen and plasma viremia, changes in CD4 cell counts, and progression of disease. The sensitivity of the PEG-precipitable p24 antigen assay versus traditional p24 antigen testing was 59.0% and the specificity 91.7%. The assay was reproducible and may be a useful determinant of viral load, clinical progression, and antiretroviral efficacy.

Frequency of thromboembolic complications in patients with acute pneumonia and pyelonephritis.

Infectious complications increase the risk of postoperative thromboembolism. In order to assess the risk of deep vein thrombosis (DVT) in acute infections not associated with surgery, 36 patients with acute pneumonia or pyelonephritis were evaluated regarding development of DVT with the 125I-fibrinogen uptake test with confirmative phlebography. 1/15 patients with pyelonephritis and 1/21 patients with pneumonia developed DVT. No fatal pulmonary embolism was seen. The frequency of DVT was thus 6%. This low figure may be due to early mobilization of the patients and does not motivate routine anticoagulant prophylaxis against thromboembolic complications in patients with acute infections.

Low specificity of the 125I-fibrinogen uptake test for the diagnosis of deep vein thrombosis in patients with erysipelas of the leg.

The 125I-fibrinogen test was evaluated as a diagnostic tool for deep vein thrombosis in patients with erysipelas. In the investigated group of 43 patients, several showed an increased uptake that could not be verified by subsequent phlebography. The false positive test may have been caused by the local inflammatory process. The 125I-fibrinogen test seems to be too unspecific to be used for diagnosing deep vein thrombosis in this patient group.

Effect on platelet aggregation of oral administration of 10 non-steroidal analgesics to humans.

Platelet aggregation was investigated in platelet-rich plasma from normal volunteers before and at various times after intake of 10 analgesic drugs. The drugs used were aspirin, piroxicam, naproxen, indomethacin, diclofenac, ibuprofen, diflunisal, paracetamol and oxyphenbutazone. Aggregation of the platelets was induced by adrenaline or ADP and the first and second waves of aggregation were evaluated. It was found that no drug exerted any effect on the first wave of aggregation. The second wave of aggregation was abolished by aspirin that produced a long-lasting effect for 5-8 d. Piroxicam also abolished the second wave of aggregation and this effect persisted on the 2 following d. Naproxen was normalized in half of the volunteers on the 2nd d. The inhibition caused by indomethacin and diclofenac was corrected on the 2nd d. Ibuprofen and diflunisal produced a definite but short-term effect. The effect of salicylic acid was weak. Paracematol and oxyphenbutazone did not affect platelet aggregation.

Investigations on the effect of antimicrobial drugs on platelet aggregation in vitro and ex vivo.

The influence of ten betalactam antibiotics and ten other antibiotics on platelet aggregation induced by ADP or adrenaline was investigated in vitro. In concentrations of 900 mg/l most antimicrobial drugs exerted a moderate inhibition that was not seen in concentrations of 90 mg/l that better corresponded to therapeutic levels. The influence on the platelets of a single large intravenous dose was also tested using eight antimicrobial drugs, viz. benzylpenicillin, ampicillin, carbenicillin, piperacillin, cloxacillin, cefuroxime, cefotaxime and erythromycin. Each drug was given to five healthy volunteers but none caused any significant inhibition of platelet aggregation. The second wave of aggregation persisted after administration of the drugs and it was even seen after the administration of such a high dose as 10 g of carbenicillin.

Netilmicin: clinical evaluation of efficacy and toxicity of a new aminoglycoside.

The efficacy and toxicity of netilmicin, a new semisynthetic aminoglycoside, was clinically evaluated in fifty-two patients with moderate to severe infections with Gram-negative rods or Staph. aureus. Average duration of treatment was 14 days and mean total dose 2,960 mg. One-hour mean value of netilmicin serum concentration was 6.4 microgram/ml and mean trough value 1.2 microgram/ml. Forty-four patients were cured or improved. In twenty-one of them the effect could be attributed to netilmicin alone; the other twenty-three had a combined therapy. No improvement took place in five, but four of them could not be regarded as netilmicin failure. One patient with Pseudomonas aeruginosa infection was possible failure. The sensitivity of the causative bacteria to netilmicin was studied and compared with amikacin, gentamicin, sisomicin and tobramycin. Vestibular function and hearing acuity was thoroughly examined by electronystagmography and audiography. Drug-related VIIIth nerve damage could not be confirmed in any of our patients. Five patients showed a rise of serum creatinine of 30 mumol/l. This shows that netilmicin, similar to other aminoglycosides, is a potential nephrotoxic drug. Netilmicin appears to be an efficacious aminoglycoside and the oto- and nephrotoxicity is low, if careful attention is paid to the renal function and the serum concentrations of the drug.