Daclatasvir/peginterferon lambda-1a/ribavirin in patients with chronic HCV infection and haemophilia who are treatment naïve or prior relapsers to peginterferon alfa-2a/ribavirin.

AIM: This study explores the potential role of a novel interferon-containing regimen for treatment of patients with chronic hepatitis C (CHC) and underlying haemophilia. METHODS: This trial (NCT01741545) was an open-label, non-randomized phase 3 study, which included adult haemophiliacs with hepatitis C virus (HCV). Patients with HCV genotypes (GT)-2 or -3 were treated with Lambda-IFN/ribavirin (RBV)/daclatasvir (DCV) for 12 weeks (cohort A). Patients with HCV GT-1b or -4 were treated with Lambda-IFN/RBV/DCV for 12 weeks, followed by Lambda-IFN/RBV for an additional 12 weeks (cohort B). The primary endpoint was the proportion of patients with a sustained virologic response at post-treatment follow-up week 12 (SVR12). Clinical development of Lambda-IFN was discontinued during this trial leading to study termination before a 24-week post-treatment follow-up was obtained for all participants. RESULTS: Overall, 51 patients were treated (cohort A, n = 12; cohort B, n = 39). The proportion of patients achieving SVR12 was 92% in cohort A and 90% in cohort B. Therapy was generally well tolerated. The most common adverse events (AEs) were related to elevations in serum transaminases and/or bilirubin. Five serious AEs, four discontinuations due to AEs, and no deaths were reported. The rate of grade 3-4 bilirubin elevations was 17-18% across cohorts. CONCLUSION: Lambda-IFN/RBV/DCV treatment demonstrated a high SVR rate and was generally well tolerated with a safety profile consistent with expectations for this special patient population. This study supports use of DCV as part of a combination treatment regimen for haemophiliacs with CHC.

A randomized, placebo-controlled study of the NS5B inhibitor beclabuvir with peginterferon/ribavirin for HCV genotype 1.

Beclabuvir is a potent, non-nucleoside inhibitor of the HCV NS5B RNA polymerase, with nanomolar activity against HCV genotypes 1, 3, 4, 5 and 6 in vitro. This study evaluated the efficacy and safety of beclabuvir, in combination with peginterferon alfa-2a (pegIFN) and ribavirin (RBV), in HCV genotype 1. In this randomized (1:1:1), double-blinded, placebo-controlled, dose-ranging phase 2a study, 39 treatment-naive patients chronically infected with HCV genotype 1 were treated for 48 weeks with beclabuvir (75 mg or 150 mg) plus pegIFN (180 µg) and RBV (1000 mg/day [<75 kg] or 1200 mg/day [≥ 75 kg]) vs pegIFN/RBV alone. The primary efficacy endpoint of extended rapid virologic response (undetectable HCV RNA at treatment weeks 4 and 12) was achieved by 76.9% (10/13) of patients receiving beclabuvir 75 mg and 38.5% (5/13) receiving beclabuvir 150 mg vs 0% receiving pegIFN/RBV alone. Higher response rates were observed among patients receiving beclabuvir 75 mg for all secondary efficacy endpoints, including sustained virologic response at follow-up weeks 12 or 24. Three patients experienced virologic breakthrough on treatment, all in the beclabuvir 150-mg treatment group. Beclabuvir was well tolerated at both doses, with the most commonly observed adverse events (headache, fatigue, nausea, decreased appetite, irritability, depression and insomnia) consistent with those observed with pegIFN/RBV. In conclusion, beclabuvir was both effective and well tolerated when administered in combination with pegIFN/RBV for the treatment of chronic HCV GT 1, supporting the study of beclabuvir as part of an all-oral regimen for HCV GT1.

Nevirapine induced opiate withdrawal among injection drug users with HIV infection receiving methadone.

BACKGROUND: Pharmacokinetic interactions complicate and potentially compromise the use of antiretroviral and other HIV therapeutic agents in patients with HIV disease. This may be particularly so among those receiving treatment for substance abuse. OBJECTIVE: We describe seven cases of opiate withdrawal among patients receiving chronic methadone maintenance therapy following initiation of therapy with the non-nucleoside reverse transcriptase inhibitor, nevirapine. DESIGN: Retrospective chart review. RESULTS: In all seven patients, due to the lack of prior information regarding a significant pharmacokinetic interaction between these agents, the possibility of opiate withdrawal was not anticipated. Three patients, for whom methadone levels were available at the time of development of opiate withdrawal symptoms, had subtherapeutic methadone levels. In each case, a marked escalation in methadone dose was required to counteract the development of withdrawal symptoms and allow continuation of antiretroviral therapy. Three patients continued nevirapine with methadone administered at an increased dose; however, four chose to discontinue nevirapine. CONCLUSION: To maximize HIV therapeutic benefit among opiate users, information is needed about pharmacokinetic interactions between antiretrovirals and therapies for substance abuse.

Cellular restoration in HIV infected persons treated with abacavir and a protease inhibitor: age inversely predicts naive CD4 cell count increase.

OBJECTIVE: To characterize early and later indices of cellular restoration among HIV-1 infected persons treated with abacavir and one protease inhibitor and to identify predictors of CD4 cell increases. METHODS: Flow-cytometric analyses of lymphocyte phenotypes among 71 antiretroviral treatment naive adults in a 48 week treatment trial. RESULTS: During the first 4 weeks of therapy, increases in naive and memory CD4 cells and in B cells were seen; naive CD8 cells increased while CD8 cells remained stable as memory CD8 cells decreased. During the second phase total CD4 and naive CD4 and CD8 cells increased while total CD8 and memory CD8 cells decreased. The numbers of CD4 cells that expressed CD28 increased from a median of 308 x 10(6)/l at baseline to 477 x 10(6)/l at week 48. Higher baseline plasma HIV-1 RNA levels predicted the magnitude of early CD4 (r = 0.35; P = 0.01), memory CD4 (r = 0.38; P = 0.001) and CD28 CD4 cell (r = 0.29; P = 0.01) restoration but was not related to second phase changes. Younger age predicted a greater second phase (but not first phase) increase in naive CD4 cells (r = -0.31; P = 0.03). CONCLUSIONS: Higher baseline levels of HIV-1 replication determine the magnitude of first phase CD4 cell increases after suppression of HIV-1 replication. Second phase (primarily naive) CD4 cell increases are not related to HIV-1 replication but are inversely relate to age suggesting that thymic potential is a major determinant of long term cellular restoration in HIV-1 infected persons receiving antiretroviral therapy.

Antiretroviral activity and safety of abacavir in combination with selected HIV-1 protease inhibitors in therapy-naive HIV-1-infected adults.

OBJECTIVE: To assess antiretroviral efficacy and safety of abacavir in combination with selected HIV-1 protease inhibitors. DESIGN: A 48-week, open-label study. MATERIALS AND METHODS: Eighty-two antiretroviral naive HIV-1-infected adults (CD4 cell count > or = 100 cells/mm3, plasma HIV-1 RNA > or = 5,000 copies/ml) were randomly assigned to receive abacavir (300 mg twice daily) in combination with standard doses of one of five protease inhibitors: indinavir, saquinavir soft-gel, ritonavir, nelfinavir or amprenavir. Adults who met protocol-defined switch criteria at or after week 8 could modify their randomized therapy. Antiretroviral activity was assessed by the proportion of subjects with plasma HIV-1 RNA < or = 400 and < or = 50 copies/ml, and by changes in plasma HIV-1 RNA levels and CD4 cell counts. Safety was assessed by monitoring clinical adverse events and laboratory abnormalities. RESULTS: At week 48, the proportion of subjects in the indinavir, saquinavir, ritonavir, nelfinavir and amprenavir groups with plasma HIV-1 RNA < or = 400 copies/ml was 53, 50, 50, 41 and 56%, respectively, and the proportion with HIV-1 RNA < or = 50 copies/ml was 47, 56, 50, 47, and 44%, respectively (by intent-to-treat analysis). Median reductions from baseline in plasma HIV-1 RNA for each group ranged from 1.7 to 2.4 log10 copies/ml. The median CD4 cell count increase from baseline was 195, 131, 116, 136 and 259 cells/mm3 in the indinavir, saquinavir, ritonavir, nelfinavir, and amprenavir groups, respectively. Overall, the most common adverse events attributed to study drugs were diarrhoea, nausea, malaise/fatigue, headache and perioral paresthesia. The frequency of treatment-limiting adverse events did not differ between groups. CONCLUSIONS: Abacavir is safe and effective when used in combination with a protease inhibitor.

A community-based regional ventilator weaning unit: development and outcomes.

STUDY OBJECTIVE: Description of the development of a community-based weaning unit and the outcomes from that unit. DESIGN: Review of admissions, classified by etiology of ventilator dependence, with attention to disposition, length of stay, and time to wean. SETTING: Long-term acute-care facility in Worcester, Mass. PATIENTS: Two hundred seventy-eight ventilator-dependent patients admitted to a ventilator unit from 1988 through May 1995. Admissions criteria did not include prognostic considerations. INTERVENTIONS: Selected patients were entered into a formal weaning program beginning in 1992. MEASUREMENTS: Through the study period, there was a substantial growth in annual admissions, primarily due to increases in patients surviving a catastrophic acute illness. Overall, 107 of 278 (38%) patients were liberated from mechanical ventilation for at least 7 consecutive days and nights. Of the patients admitted 1993 to 1995, 31% died, 20% were discharged to a long-term care facility, 29% returned home, and 18% either remained as residents of the unit or had been transferred to acute-care facilities and were unavailable for follow-up. The highest weaning success was seen in patients with ventilator dependence from postoperative causes (58%) and acute lung injury (57%); the least success was seen in patients with ventilator dependence from COPD and neuromuscular diseases (22% each). The average time from admission to weaning fell within each diagnostic category throughout the study period. CONCLUSIONS: Rehabilitation-based ventilator weaning units play an important role in the spectrum of medical care necessary in population centers. Excellent results can result from community-based units with open admissions policies.

Progressive outer retinal necrosis and acute retinal necrosis in fellow eyes of a patient with acquired immunodeficiency syndrome.

PURPOSE: To describe an unusual concurrence of acute retinal necrosis and progressive outer retinal necrosis in fellow eyes of a patient with acquired immunodeficiency syndrome (AIDS). METHODS: Interventional case report. In a 37-year-old man with AIDS and herpes zoster keratitis in the right eye, progressive outer retinal necrosis developed in the right eye and acute retinal necrosis developed in the left eye. RESULTS: Disparate presentations of retinitis persisted in each eye, and retinal detachment and vision loss ensued in both eyes despite antiviral therapy. CONCLUSION: Distinct features of acute retinal necrosis and progressive outer retinal necrosis do not necessarily reflect systemic factors, and they may be variant manifestations of the same underlying infection.

A medical evaluation of the use of qat in North Yemen.

The data presented in this paper examine the frequent statements that the regular use of the drug qat by the people of North Yemen is harmful to their health. The research strategy employed performance of blind physical examinations as well as extensive interviews with 335 females and 371 males in and around the cities of Sanaa, Taiz and Hodeida who had been selected using a quota sample. The sample was classified into heavy, light and non-chewers of the qat plant, and systematic comparisons were made. In general, few diseases or conditions occurred with enough frequency to permit detailed analysis and fewer yet were associated with qat-use. Where associations occurred, differences by sex were often strong. Conditions most strongly associated with use by both sexes were histories of gastritis and insomnia, and the general body system groupings of gastrointestinal disorders. In males the strongest associations were with the histories of anorexia, constipation, insomnia and headaches, as well as the general history of respiratory difficulties. In females strong associations were seen between qat-use and the diagnosis of acute gastritis, and histories of jaundice, bronchitis and hepatic diseases. When effects of age and residence were corrected for by Mantel-Haenszel odds ratios on these items, some of the associations were diminished even further. In general, remarkably few of the allegations regarding the direct effects of qat-use on health by Western visitors to Yemen were supported by this study.

Indinavir nephropathy in an AIDS patient with renal insufficiency and pyuria.

Indinavir has been described to cause crystalluria and nephrolithiasis in a variable number of treated patients. Acute renal failure, often reversible with discontinuation of the medication, induction of a diuresis and correction of urinary obstruction if present, occurs in a smaller percent of patients. One recent report described renal biopsy findings, indinavir crystals within cellular casts in the collecting tubules, in a patient receiving this antiretroviral agent. We report a second case of a patient with mild renal insufficiency and pyuria following indinavir therapy and describe similar renal biopsy findings.

Productivity and quality improvements in health care through airboss mobile messaging services.

The US health care industry is in the midst of revolutionary changes. Under tremendous pressures from third-party payers and managed care programs to control costs while providing high quality medical services, health care entities are now looking at information technologies to help them achieve their goals. These goals typically include improved productivity, efficiency and decision-making capabilities among staff members. Moreover, hospitals and other health care facilities that provide a broad and integrated range of inpatient and outpatient care, wellness and home care services are in the best position to offer comprehensive packages to managed care and private insurers. Many health care providers and administrators are considered mobile employees. This mobility can range from intra-building and intra-campus to multi-site and metropolitan areas. This group often relies on a variety of information technologies such as personal computers, communicating laptops, pagers, cellular phones, wireline phones, cordless phones and fax machines to stay in touch and handle information needs. These health care professionals require mobile information access and messaging tools to improve communications, control accessibility and enhance decision-making capabilities. AirBoss mobile messaging services could address the health care industry's need for improved messaging capabilities for its mobile employees. The AirBoss family of services supports integrated voice services, data messaging, mobile facsimile and customized information delivery. This paper describes overview of the current mobile data networking capability, the AirBoss architecture, the health care-related applications it addresses and long-term benefits. In addition, a prototype application for mobile home health care workers is illustrated. This prototype application provides integrated e-mail, information services, web access, real-time access and update of patient records from wireline or wireless networks, and cross media delivery and notification. It provides seamless wide area access to patient data in a secure environment, thus providing a continuity of care from the hospital to home.

HMOs: where are the savings?

HMOs may yet become an important means for effecting health care savings. But to attain that goal, they must confront the challenges facing them--such as regulatory restrictions and intense competition.

Esophageal actinomycosis in a patient with AIDS.

Actinomycosis has been rarely reported in patients with HIV/AIDS in contrast to other opportunistic and common pathogens. We report a case of esophageal ulcer disease, secondary to actinomycosis occurring in a patient with recurrent odynophagia. The diagnosis was made histologically only after repeated upper endoscopy with biopsies.

Interleukin-12 enhancement of antigen-specific lymphocyte proliferation correlates with stage of human immunodeficiency virus infection.

The effect of interleukin (IL)-12 on T lymphocyte function was assessed in 47 human immunodeficiency virus (HIV)-infected persons of different disease stages and 16 seronegative controls. Lymphoproliferative responses (LPR) were measured to various HIV and non-HIV antigens and mitogens using peripheral blood mononuclear cells cultured with or without IL-12. Without exogenous IL-12, 96% of HIV-seropositive persons responded to mitogens, 77% to >=1 non-HIV antigen, and 11% to >=1 HIV antigen. Supplementation with IL-12 augmented LPR of HIV-seropositive persons to non-HIV antigens; however, the effect was greatest for those with higher CD4 cells (40% vs. 9% for those with >200 vs. <=200 CD4 cells/mm3). Addition of IL-12 also enhanced LPR to HIV antigens in 30% of subjects. This effect was most pronounced for those with>500 CD4 cells/mm3 (56% [P<. 05]). These findings suggest that impaired T lymphocyte recognition of foreign antigen, including HIV, can be reconstituted in part for selected HIV-seropositive persons.

Oral infections due to cytomegalovirus in immunocompromised patients.

Herpes group virus infections in the immunocompromised host are associated with significant morbidity and mortality. Herpes simplex virus (HSV) and to a lesser extent varicella zoster virus (VZV) have long been recognized as causes of oral and peri-oral lesions in subjects undergoing bone marrow transplantation and in individuals infected with the Human Immunodeficiency Virus (HIV). A role for Cytomegalovirus (CMV) in such lesions is less clear and not well documented. This report describes two bone marrow transplant recipients and one individual infected with HIV in whom CMV was implicated as the cause of oral lesions. Diagnostic and management issues as well as clinical implications are discussed.

Review of pneumococcal endocarditis in adults in the penicillin era.

Streptococcus pneumoniae is an infrequent cause of infectious endocarditis in adults. In the past 2 years, however, we have encountered several cases at our institution, and additional cases have been reported in the literature. This infection typically follows pneumonia in the setting of chronic alcoholism and may additionally be complicated by meningitis. Less commonly, pneumococcal endocarditis occurs in other hosts or follows primary infection at other extrapulmonary sites. In such cases, the diagnosis may be initially missed, with a resultant delay in institution of appropriate therapy. Moreover, there are controversies regarding the optimal therapy for infections of this nature in the era of penicillin resistance. Since a comprehensive review of this topic has not been published since 1990, we reviewed cases of pneumococcal endocarditis in the penicillin era, with particular attention to disease recognition, the role of echocardiography, and the dilemmas surrounding medical and surgical therapeutic interventions.

Papular-purpuric gloves and socks syndrome associated with acute parvovirus B19 infection: case report and review.

The papular-purpuric gloves and socks syndrome (PPGSS) was first described in 1990. This syndrome is characterized by fever, acral pruritus, edema, petechiae, and oral erosions. Subsequently, parvovirus B19 has been implicated, in most cases, as the causative agent of this syndrome. To date, with two exceptions, all published cases of PPGSS have been from Europe and the Middle East and have been mainly reported in the dermatology literature. Herein, we report what we believe to be only the second case of documented parvovirus B19-associated PPGSS occurring in the United States. The patient presented with the typical clinical syndrome, and the diagnosis of acute parvovirus B19 infection was documented by serial serologies that demonstrated development of IgM antibody to virus during the acute phase of infection and seroconversion to IgG antibody in the convalescent period. We then review the existing literature on this unusual syndrome and its association with parvovirus B19.

Varicella zoster virus retrobulbar optic neuritis preceding retinitis in patients with acquired immune deficiency syndrome.

OBJECTIVE: This study aimed to describe a recently recognized and rare presentation of varicella zoster virus (VZV) retrobulbar optic neuritis preceding retinitis in patients with acquired immune deficiency syndrome and to identify factors that may relate to improved visual outcome. METHODS: Diagnosis, treatment, and clinical course are described for three eyes of two patients with this viral infection. RESULTS: Patients had decreased vision, headache, and recent zoster dermatitis. Varicella zoster virus retrobulbar optic neuritis was diagnosed on the bases of clinical, laboratory, and electrophysiologic examination results. Profound vision loss and peripheral retinitis ensued despite intravenous antiviral treatment. Combination intravenous and intravitreous antiviral injections were administered with dramatic visual recovery. CONCLUSIONS: Varicella zoster virus retrobulbar optic neuritis should be considered in immunocompromised patients with visual loss. Early diagnosis and aggressive combination therapy via systemic and intravitreous routes may enable return of useful vision.

Haloenol lactones. Potent enzyme-activated irreversible inhibitors for alpha-chymotrypsin.

Haloenol lactones can act as enzyme-activated irreversible inhibitors for alpha-chymotrypsin: acyl transfer to the active site serine releases a halomethyl ketone that remains tethered in the active site during the lifetime of the acyl enzyme, poised to alkylate an accessible nucleophilic residue. To investigate the structural determinants for chymotrypsin suicide inactivation with haloenol lactones, we prepared a series of nine lactones, differing in ring size (6-membered valerolactones and 5-membered butyrolactones) and in the nature of the aromatic substituent (phenyl and alpha-naphthyl), and the halogen (bromine and iodine). The inactivating behavior of these lactones is characterized by a binding constant (Ki) and three rate constants, for inactivation (k2), catalytic hydrolysis (kc), and spontaneous hydrolysis (kh). The six-membered valerolactones were much more potent inactivators than the butyrolactones, having both higher affinity and more rapid inactivation; the alpha-naphthyl-substituted lactones were also more effective, but the nature of the halogen had relatively little effect. The spontaneous rate of hydrolysis of all of these lactones is low. The turnovers per inactivation of these lactones vary from 91-1.7, with some of the alpha-naphthyl-substituted lactones approaching ideal behavior (stoichiometric inactivation). These studies indicate that several haloenol lactones are effective enzyme-activated irreversible inhibitors of chymotrypsin, and that their potency and efficiency depends markedly upon certain structural features of the lactone system.