Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A.

BACKGROUND: Valoctocogene roxaparvovec delivers a B-domain-deleted factor VIII coding sequence with an adeno-associated virus vector to prevent bleeding in persons with severe hemophilia A. The findings of a phase 3 study of the efficacy and safety of valoctocogene roxaparvovec therapy evaluated after 52 weeks in men with severe hemophilia A have been published previously. METHODS: We conducted an open-label, single-group, multicenter, phase 3 trial in which 134 men with severe hemophilia A who were receiving factor VIII prophylaxis received a single infusion of 6×1013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in the annualized rate of treated bleeding events at week 104 after receipt of the infusion. The pharmacokinetics of valoctocogene roxaparvovec were modeled to estimate the bleeding risk relative to the activity of transgene-derived factor VIII. RESULTS: At week 104, a total of 132 participants, including 112 with data that were prospectively collected at baseline, remained in the study. The mean annualized treated bleeding rate decreased by 84.5% from baseline (P<0.001) among the participants. From week 76 onward, the trajectory of the transgene-derived factor VIII activity showed first-order elimination kinetics; the model-estimated typical half-life of the transgene-derived factor VIII production system was 123 weeks (95% confidence interval, 84 to 232). The risk of joint bleeding was estimated among the trial participants; at a transgene-derived factor VIII level of 5 IU per deciliter measured with chromogenic assay, we expected that participants would have 1.0 episode of joint bleeding per year. At 2 years postinfusion, no new safety signals had emerged and no new serious adverse events related to treatment had occurred. CONCLUSIONS: The study data show the durability of factor VIII activity and bleeding reduction and the safety profile of valoctocogene roxaparvovec at least 2 years after the gene transfer. Models of the risk of joint bleeding suggest that the relationship between transgene-derived factor VIII activity and bleeding episodes is similar to that reported with the use of epidemiologic data for persons with mild-to-moderate hemophilia A. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.).

Mortality among persons in care with hepatitis C virus infection: the Chronic Hepatitis Cohort Study (CHeCS), 2006-2010.

BACKGROUND: The number of deaths in hepatitis C virus (HCV)-infected persons recorded on US death certificates has been increasing, but actual rates and causes of death in these individuals have not been well elucidated. METHODS: Disease-specific, liver-related, and non-liver-related mortality data for HCV-infected patients in an observational cohort study, the Chronic Hepatitis Cohort Study (CHeCS) at 4 US healthcare systems, were compared with multiple cause of death (MCOD) data in 12 million death certificates in 2006-2010. Premortem diagnoses, liver biopsies, and FIB-4 scores (a noninvasive measure of liver damage) were examined. RESULTS: Of 2 143 369 adult patients seen at CHeCS sites in 2006-2010, 11 703 (0.5%) had diagnosed chronic HCV infection, and 1590 (14%) died. The majority of CHeCS decedents were born from 1945 to 1965 (75%), white (50%), and male (68%); mean age of death was 59 years, 15 years younger than MCOD deaths. The age-adjusted mortality rate for liver disease in CHeCS was 12 times higher than the MCOD rate. Before death, 63% of decedents had medical record evidence of chronic liver disease, 76% had elevated FIB-4 scores, and, among those biopsied, 70% had moderate or worse liver fibrosis. However, only 19% of all CHeCS decedents and only 30% of those with recorded liver disease had HCV listed on their death certificates. CONCLUSIONS: HCV infection is greatly underdocumented on death certificates. The 16 622 persons with HCV listed in 2010 may represent only one-fifth of about 80 000 HCV-infected persons dying that year, at least two-thirds of whom (53 000 patients) would have had premortem indications of chronic liver disease.

How can we improve tracking of transplanted tissue in the United States?

Currently an estimated two million tissues are distributed for transplantation annually. With increasing use of recovered tissue, clusters of transplant-transmitted infection have shown the difficulty of tracking tissues from an infected donor to the recipient. The challenge of tissue tracking to multiple transplant recipients was illustrated in a recent investigation of transmission of hepatitis C virus infection from a donor of organs and tissues. When a tissue bank issued a recall of the donated tissue, the Centers for Disease Control and Prevention was notified to assist public health authorities; the mean time to locate and notify the physicians who had transplanted the tissue was 13 days, while the mean time to notify, inform, and test the patients was 29 days. Lack of common coding and nomenclature was one of the key challenges in tracking tissue to the recipient. Some changes that could improve timeliness in the event of a recall includes: (1) standardized tissue nomenclature and coding through unique donor identifiers; (2) tissue traceability requirements using systems similar to that used for blood products; (3) a surveillance system for adverse events that provides feedback at the provider level.

Hepatitis E virus among persons who inject drugs, San Diego, California, USA, 2009-2010.

Data about prevalence of hepatitis E virus infection in persons who inject drugs are limited. Among 18-40-year-old persons who inject drugs in California, USA, prevalence of antibodies against hepatitis E virus was 2.7%. This prevalence was associated with age but not with homelessness, incarceration, or high-risk sexual behavior.

Sexually transmitted infections among US women and men: prevalence and incidence estimates, 2008.

BACKGROUND: Most sexually active people will be infected with a sexually transmitted infection (STI) at some point in their lives. The number of STIs in the United States was previously estimated in 2000. We updated previous estimates to reflect the number of STIs for calendar year 2008. METHODS: We reviewed available data and literature and conservatively estimated incident and prevalent infections nationally for 8 common STIs: chlamydia, gonorrhea, syphilis, herpes, human papillomavirus, hepatitis B, HIV, and trichomoniasis. Where available, data from nationally representative surveys such as the National Health and Nutrition Examination Survey were used to provide national estimates of STI prevalence or incidence. The strength of each estimate was rated good, fair, or poor, according to the quality of the evidence. RESULTS: In 2008, there were an estimated 110 million prevalent STIs among women and men in the United States. Of these, more than 20% of infections (22.1 million) were among women and men aged 15 to 24 years. Approximately 19.7 million incident infections occurred in the United States in 2008; nearly 50% (9.8 million) were acquired by young women and men aged 15 to 24 years. Human papillomavirus infections, many of which are asymptomatic and do not cause disease, accounted for most of both prevalent and incident infections. CONCLUSIONS: Sexually transmitted infections are common in the United States, with a disproportionate burden among young adolescents and adults. Public health efforts to address STIs should focus on prevention among at-risk populations to reduce the number and impact of STIs.

The estimated direct medical cost of selected sexually transmitted infections in the United States, 2008.

BACKGROUND: Millions of cases of sexually transmitted infections (STIs) occur in the United States each year, resulting in substantial medical costs to the nation. Previous estimates of the total direct cost of STIs are quite dated. We present updated direct medical cost estimates of STIs in the United States. METHODS: We assembled recent (i.e., 2002-2011) cost estimates to determine the lifetime cost per case of 8 major STIs (chlamydia, gonorrhea, hepatitis B virus, human immunodeficiency virus (HIV), human papillomavirus, genital herpes simplex virus type 2, trichomoniasis and syphilis). The total direct cost for each STI was computed as the product of the number of new or newly diagnosed cases in 2008 and the estimated discounted lifetime cost per case. All costs were adjusted to 2010 US dollars. RESULTS: Results indicated that the total lifetime direct medical cost of the 19.7 million cases of STIs that occurred among persons of all ages in 2008 in the United States was $15.6 (range, $11.0-$20.6) billion. Total costs were as follows: chlamydia ($516.7 [$258.3-$775.0] million), gonorrhea ($162.1 [$81.1-$243.2] million), hepatitis B virus ($50.7 [$41.3-$55.6] million), HIV ($12.6 [$9.5-$15.7] billion), human papillomavirus ($1.7 [$0.8-$2.9] billion), herpes simplex virus type 2 ($540.7 [$270.3-$811.0] million), syphilis ($39.3 [$19.6-$58.9] million), and trichomoniasis ($24.0 [$12.0-$36.0] million). Costs associated with HIV infection accounted for more than 81% of the total cost. Among the nonviral STIs, chlamydia was the most costly infection. CONCLUSIONS: Sexually transmitted infections continue to impose a substantial cost burden on the payers of medical care in the United States. The burden of STIs would be even greater in the absence of STI prevention and control efforts.

Indications for testing among reported cases of HCV infection from enhanced hepatitis surveillance sites in the United States, 2004-2010.

OBJECTIVES: Centers for Disease Control and Prevention has recommended a 1-time HCV test for persons born from 1945 through 1965 to supplement current risk-based screening. We examined indications for testing by birth cohort (before 1945, 1945-1965, and after 1965) among persons with past or current HCV. METHODS: Cases had positive HCV laboratory markers reported by 4 surveillance sites (Colorado, Connecticut, Minnesota, and New York) to health departments from 2004 to 2010. Health department staff abstracted demographics and indications for testing from cases' medical records and compiled this information into a surveillance database. RESULTS: Of 110, 223 cases of past or current HCV infection reported during 2004-2010, 74, 578 (68%) were among persons born during 1945-1965. Testing indications were abstracted for 45, 034 (41%) cases; of these, 29 ,544 (66%) identified at least 1 Centers for Disease Control and Prevention-recommended risk factor as a testing indication. Overall, 74% of reported cases were born from 1945 to 1965 or had an injection drug use history. CONCLUSIONS: These data support augmenting the current HCV risk-based screening recommendations by screening adults born from 1945 to 1965.

Comparison of ProSeal laryngeal mask airway size 2 and 2½ in anesthetized and paralyzed pediatric patients with same weight group: A prospective randomized clinical study.

CONTEXT: ProSeal laryngeal mask airway (PLMA) efficacy in pediatric anesthesia. AIMS: The aim of this study was to compare PLMA size 2 and 2½ in anesthetized paralyzed pediatric patients weighing 20-30 kg undergoing elective surgery. SETTINGS AND DESIGN: A prospective randomized study was conducted in a tertiary care teaching hospital. MATERIALS AND METHODS: A total of 60 American Society of Anesthesiologists I pediatric patients of either sex having body weight between 20 and 30 kg undergoing elective surgeries were randomly allocated to PLMA of either size 2 or 2½. Standardized anesthetic technique with propofol, sevoflurane, vecuronium bromide, nitrous oxide was used in all patients. Parameters such as number of attempts, time to achieve an effective airway, hemodynamic parameters, drain tube test, oropharyngeal leak pressure (OPL), gastric tube placement, and postoperative adverse events were noted. Statistical analysis by Kolmogorov-Smirnov analysis, Mann-Whitney U-test, Student's t-test, Wilk's lambda test and power analysis was done. RESULTS: There were no significant differences in demographic variables, ease of insertion and ventilation, number of insertion attempts, hemodynamics, and postoperative complications. OPLs were slightly higher in PLMA size 2½ (27.38 ± 6.36 vs. 22.62 ± 2.85 cm H2O, respectively; P = 0.001) than size 2. CONCLUSIONS: Both PLMA size 2 and 2½ provided adequate seal pressures that would allow positive pressure ventilation in healthy children. Thus PLMA of either size 2 or 2½ can be used as a reliable airway device in children weighing 20-30 kg.

General anesthesia in tetanus patient undergoing emergency surgery: A challenge for anesthesiologist.

Tetanus is an acute often fatal disease produced by gram positive obligate anaerobic bacterium Clostridium tetani. Tetanolysin damages local tissue and provides optimal conditions for bacterial multiplication. It is therefore important to perform a wide debridement of any wound suspected of being a portal of entry for the bacteria. Little evidence exists to recommend specific anesthetic protocols. We encountered a child scheduled for fracture both bone forearm with developing tetanus. Initial management done with intravenous (i.v) diazepam, phenobarbitone, and metronidazole. After premedication with midazolam and fentanyl, induction was done by propofol 60 mg, vecuronium 2.5 mg, ventilated with O2+ N2O 50:50 with sevoflurane 2% and tracheal intubation was done with 5.5 ID cuffed PVC endotracheal tube. Anesthesia was maintained with sevoflurane 2% and vecuronium intermittently when required. Intraop vitals were stable. On completion of surgery, reversal given and patient was extubated uneventfully and shifted to recovery room. Little evidence exists to recommend specific anesthetic technique for tetanus patient posted for surgery. When present, obvious wounds should be surgically debrided. Ideally patients considered for surgery should undergo anesthesia and surgery before severe autonomic dysfunction develops. Most anesthetic managements are based on limited evidence. However, we used sevoflurane and vecuronium successfully, further study is needed to establish their efficacy and safety. Major challenges lie in the control of muscle rigidity and spasm, autonomic disturbances and prevention of complications.

Markers of resistance to anti-EGFR therapy in colorectal cancer.

Epidermal growth factor receptor (EGFR) is a therapeutic target in colorectal cancer (CRC). The benefit from EGFR inhibitors appears to be limited to a subset of patients with CRC. Mechanisms of resistance to EGFR inhibitors are being identified. KRAS codon 12 activating mutation is a predominate mechanism of resistance to EGFR inhibitors in around 40% of patients with advanced CRC. Other potential mechanisms of resistance include ligand expression, increased EGFR number, mutations of BRAF and activation of alternate signaling pathways.

Comparison of recovery profile for propofol and sevoflurane anesthesia in cases of open cholecystectomy.

OBJECTIVE: Sevoflurane and propofol are considered to be the agents of choice in surgeries of short duration due to their better recovery profile and few post-operative complications. This study was designed to compare the early recovery profile of sevoflurane and propofol anesthesia in patients undergoing open cholecystectomy. MATERIALS AND METHODS: A total of 60 patients of either sex with American Society of Anesthesiologists grade 1 and 2 scheduled for elective cholecystectomy were prospectively randomized into two groups. Group S (30 patients) were maintained with sevoflurane anesthesia (1-2%), while in Group P (30 patients) were maintained with propofol infusion (75-125 µg/kg/min) in both the groups the anesthetic concentration/dose was so adjusted to keep hemodynamic parameter (mean arterial pressure and heart rate) within 15% of their respective baselines values. RESULTS: It was observed that there was no significant difference (P > 0.05) between there early recovery profile that includes spontaneous eye opening (7.5 ± 1.6 min for sevoflurane group and 6.9 ± 1.7 min for propofol group), following simple verbal command (9.2 ± 2.2 min for sevoflurane group and 8.9 ± 1.9 min for propofol group) and extubation time (10.7 ± 2.3 min for sevoflurane group and 10.3 ± 2.0 min for propofol group) but there was a significant difference (P < 0.05) in incidence of post-operative nausea and vomiting (PONV) in both groups. CONCLUSION: Propofol is as good as sevoflurane for maintenance of anesthesia in surgeries like open cholecystectomy with an added advantage of lower incidence of PONV owing to its intrinsic antiemetic properties.

Use of the International Classification of Diseases, 9th revision, coding in identifying chronic hepatitis B virus infection in health system data: implications for national surveillance.

OBJECTIVE: With increasing use electronic health records (EHR) in the USA, we looked at the predictive values of the International Classification of Diseases, 9th revision (ICD-9) coding system for surveillance of chronic hepatitis B virus (HBV) infection. MATERIALS AND METHODS: The chronic HBV cohort from the Chronic Hepatitis Cohort Study was created based on electronic health records (EHR) of adult patients who accessed services from 2006 to 2008 from four healthcare systems in the USA. Using the gold standard of abstractor review to confirm HBV cases, we calculated the sensitivity, specificity, positive and negative predictive values using one qualifying ICD-9 code versus using two qualifying ICD-9 codes separated by 6 months or greater. RESULTS: Of 1 652 055 adult patients, 2202 (0.1%) were confirmed as having chronic HBV. Use of one ICD-9 code had a sensitivity of 83.9%, positive predictive value of 61.0%, and specificity and negative predictive values greater than 99%. Use of two hepatitis B-specific ICD-9 codes resulted in a sensitivity of 58.4% and a positive predictive value of 89.9%. DISCUSSION: Use of one or two hepatitis B ICD-9 codes can identify cases with chronic HBV infection with varying sensitivity and positive predictive values. CONCLUSIONS: As the USA increases the use of EHR, surveillance using ICD-9 codes may be reliable to determine the burden of chronic HBV infection and would be useful to improve reporting by state and local health departments.

Chlamydia and gonorrhea screening using urine-based nucleic acid amplification testing among males entering New York City jails: a pilot study.

This article describes a pilot screening program to detect Chlamydia trachomatis (Ct) and Neisseria gonorrhoeae (Ng) sexually transmitted infections (STIs) in adolescent and adult males newly incarcerated in New York City jails using urine-based nucleic acid amplification technology (NAAT). Between December 8 and 22, 2003, 2,417 males were tested; 162 (6.7%) were found positive for Ct and/or Ng STIs, with 138 (86.8%) exhibiting no STI signs or symptoms and 102 (63%) treated prior to jail release. Younger age, positive urine leukocyte esterase test, and ≥11 recent sex partners were predictors of STI. Urine-based screening and treatment was feasible in this setting and identified STI that would otherwise have been undetected. Jails may thus be important venues for targeted male STI screening.