Impact of age on viral kinetics of peginterferon alfa-2a/ribavirin in chronic hepatitis C: final analysis from the PROPHESYS cohort.

The population of patients with chronic hepatitis C viral infection is ageing; however, elderly, hepatitis C-infected patients are understudied and less frequently treated. This subanalysis of data from the multinational PROPHESYS study examined associations between age (≤65 vs >65 years), on-treatment virological response and sustained virological response (SVR) in patients treated with peginterferon alfa-2a (40KD)/ribavirin in accordance with local licences. PROPHESYS comprised three cohorts studied in 19 countries according to country-specific legal and regulatory requirements. This subanalysis includes treatment-naive HCV mono-infected patients assigned to receive peginterferon alfa-2a (40KD)/ribavirin, with 6276 individuals aged ≤65 years and 349 aged >65 years. Rapid virological response (RVR) rates by Week 4 were consistently lower in older genotype (G) 1 (21.6% vs 27.2% in younger patients), G2 (80.7% vs 85.1%) and G3 (60.0% vs 74.2%) patients. SVR rates were significantly lower (29.8% vs 43.0%) and relapse rates significantly higher (43.1% vs 26.7%) in older G1 patients (P = 0.0002 vs ≤65 years). In contrast, SVR and relapse rates were similar in G2 and G3 patients regardless of age. The positive predictive value of RVR for SVR was comparable in older and younger G1 patients (66.7% vs 68.6%, respectively) and higher in older G2 (80.7% vs 75.6%) and G3 (77.8% vs 66.8%) patients. Virological response rates are generally lower in elderly CHC patients, and RVR is a reliable positive predictor of SVR in patients >65 years.

Therapy for human gastrointestinal microsporidiosis.

Gastrointestinal microsporidiosis is a major cause of diarrhea and wasting in persons with acquired immune deficiency syndrome (AIDS). Microsporidia demonstrate properties of both true eukaryotes and prokaryotes. The biology of microsporidia makes its elimination from the gastrointestinal tract therapeutically challenging. This organism depends greatly on the host for its energy needs and reproduction; microsporidial spores are impervious to the elements. Microsporidial infection of the gastrointestinal tract, principally with Enterocytozoon bieneusi and Encephalitozoon intestinalis in patients with AIDS has been treated with different medical regimens with variable success. The less common pathogen, E. intestinalis, responds well to albendazole, making it excellent first-line therapy, but such is not the case for E. bieneusi. None of the benzimidazoles has been demonstrated to be efficacious for E. bieneusi. On the other hand, E. bieneusi has shown excellent clinical therapeutic response to either direct action with fumagillin or its analogue, TNP-470, or indirectly by immune enhancement by suppression of the HIV virus with more aggressive, highly effective antiretroviral therapy. Further work is necessary to fully establish proper therapeutic protocols and manage side effects of the treatments. Other promising forms of therapy such as polyamine inhibitors and thalidomide demonstrate certain effectiveness in treatment of microsporidian in vitro (polyamine inhibitors) and in selected cases in vivo (thalidomide). Lack of either sufficiently suggestive or definitive human studies prevents the endorsement of these modes of therapy for treatment of gastrointestinal microsporidiosis at this time.

Steroid metabolism by monkey and human spermatozoa.

Freshly ejaculated spermatozoa from monkey and human were washed and incubated with tritium labelled androgens or estradiol to study the pattern of spermatozoa steroid metabolism. When equal concentrations of steroid substrates were used for incubation, monkey and human spermatozoa showed very similar pattern of steroid conversion. Spermatozoa from both species converted testosterone mainly to androstenedione, but reverse conversion of androstenedione to testosterone was negligible. Estradiol-17 beta was converted mainly to estrone. The close similarity between the spermatozoa of monkey and men in their steroid metabolic pattern indicates that the rhesus monkey could be an useful animal model to study the effect of drugs on the metabolic pattern of human spermatozoa.

Suppression of testicular and epididymal functions in a non-human primate (bonnet monkey) by combined administration of a gonadotropin-releasing hormone antagonist and testosterone buciclate.

The ability of a long-acting androgen, testosterone buciclate (TB), to induce suppression of testicular and epididymal sperm functions when given in combination with a potent GnRH antagonist (Antide) either on day 1 or 45 of Antide administration (days 1-90) as well as the ability of TB to maintain Antide-induced suppression of spermatogenesis were evaluated in adult bonnet monkeys. A group of untreated animals (group I) acted as controls. All animals given Antide and androgen simultaneously (group II) became azoospermic but at different times. When androgen administration was delayed 45 days after start of Antide treatment (group III), the mean sperm concentration remained in the normospermic range and only three animals became azoospermic. Antide given alone (group IV) induced azoospermia in three animals and oligospermia in the remaining animals; spermatogenesis recovered when Antide was withdrawn and TB was injected. In all Antide-treated animals (groups II-IV), non-motile spermatozoa or sperm with non-progressive motility and poor gel penetrability were seen in the ejaculate.

Evaluation of the ability of a new long-acting androgen ester to maintain accessory gland function in castrated rhesus monkey.

The ability of 40 mg of milled suspension of a new long-acting androgen ester (20 Aet-1) to restore and maintain accessory gland function was compared with that of testosterone enanthate (TE) in castrated adult rhesus monkeys. Castration did not abolish the ejaculatory response since only two animals did not void semen in the postcastration period. A single intramuscular injection of 40 mg of these compounds stimulated accessory gland function at levels lower than in the pretreatment period. 20 Aet-1-induced stimulation of prostatic acid phosphatase activity never exceeded control levels unlike that induced by testosterone enanthate which caused hyperstimulation on day 21 of drug treatment. In terms of support of accessory gland function, 20 Aet-1 would appear to offer hope of being a successful androgen for supplementation therapy in male animals.

Evaluation of efficacy, safety, and reversibility of combination regimen of cyproterone acetate and testosterone buciclate in bonnet monkey.

A combination regimen of cyproterone acetate (CPA) and testosterone buciclate (TB) was evaluated for its contraceptive efficacy, safety, and reversibility in bonnet monkeys. Cyproterone acetate (5 mg in 0.2 mL of olive oil) injected daily for 180 days, in combination with 40 mg testosterone buciclate given i.m. on days 0, 60, and 120 in the monkeys of group II (n = 6) induced azoospermia in all animals by 120 days, which was maintained until day 210. By day 240 sperm concentration increased gradually and reached baseline values by day 330. When 5mg of cyproterone acetate was injected daily for a similar duration in combination with a higher dose (80 mg) of testosterone buciclate in the monkeys of group III (n = 6) on days 0, 60, and 120, uniform and consistent azoospermia could not be achieved and two animals remained oligozoospermic even after 180 days of treatment. Mean sperm concentration did not return to baseline values until the day that the study ended, i.e. day 330. In groups II and III serum testosterone levels were elevated (p <0.05) from days 9-120 except on day 150 and returned to near baseline values by day 330. Serum testosterone levels were higher in group III compared to group II. The sperm concentration and testosterone levels in control animals (group I; n = 6) showed fluctuations. Lipid profile and liver function parameters did not show significant changes in any group. The present data clearly indicate that administration of CPA and TB in proper dosage combination can provide an effective, safe, and reversible method of male contraception.

Analysis of causes of death in liver transplant recipients who survived more than 3 years.

Few studies have examined causes of death in long-term survivors of orthotopic liver transplantation (OLT). We reviewed causes of death among 299 adult liver transplant recipients who survived more than 3 years after OLT at 2 centers. Thirty-eight of the 299 patients subsequently died. Nonhepatic causes accounted for 22 of 38 late deaths (58%). Death caused by malignancies occurred in 9 patients between 3.3 and 8.0 years after OLT. Eight patients died of cardiovascular complications. The 6 patients who died of myocardial infarction had risk factors for coronary artery disease. Hepatic failure caused by recurrent liver disease or chronic rejection accounted for 16 of 38 late deaths (42%). These 16 patients were younger than patients who died of nonhepatic complications (mean ages, 50.7 v 62.1 years; P =.001). However, the mean interval between OLT and death was similar among patients who died of nonhepatic versus hepatic causes. Nine patients had recurrent liver disease leading to death, and 8 of 9 patients had recurrent chronic hepatitis C virus (HCV) infection. Chronic rejection resulting in graft failure and death occurred in 7 patients. In summary, de novo malignancies and cardiovascular complications accounted for more than half the late deaths. Patients who died of nonhepatic causes were significantly older than patients who died of hepatic causes. Chronic rejection and recurrent HCV infection accounted for the majority of hepatic causes of death. With longer follow-up, graft failure resulting from recurrent HCV infection will become the major cause of death in late survivors.