December 02, 2013 The Cost of an Unfortunate Mistake
November 17, 2013 HCV is for Hope, Courage, Victory.
Updated December 07, 2013 11:20 pm EST
December 2, 2013
The other day, I read how the newly released sofosbuvir treatment for hepatitis C will carry a price tag of USA$80,000 = $AUD87,727. That is certainly a small fortune, comparable to a deposit for a nice house in Sydney, Australia; or an above average salary. Whilst I could never save up that amount of money myself, I am therefore very grateful that the cost of treatment will be fully subsidised by the Australian Government's Medicare system. Whilst I was already aware that the drugs for hepatitis C are very expensive, I just still can not come to terms with the fact that sofosbuvir will be nearly three times as expensive as interferon!!
Thinking of the USA$80,000 price tag also got me wondering about whether it might lead to a new wave of discrimination against the most highly affected group infected with the hepatitis C virus: injecting drug users. Considering that recent reports in the UK reveal that the sharing of needles is still occurring in countries where needle and syringe programs exist, will it unnecessarily follow that the high price of new hepatitis C drugs may lead to a greater expectation for injecting drug users somehow to prove that they are not going to be at future risk of reinfection? But aren't we all automatically entitled to receive health care, irrespective of race, gender or sexual orientation?
Sometimes, I empathise with the fact that doctor's do not want to prescribe such expensive drugs for the treatment of hepatitis C to a user group that may still be actively engaged in an activity that represents 60% of hepatitis C virus infections world-wide. I can understand their frustration, as after all, to see a person come back reinfected due to unsafe injecting practises (and yes, this does occur despite the fact there are needle and syringe programs in place across Australia, New Zealand and the UK that offer injecting drug users access to sterile equipment) is, arguably, a considerable waste of money. And time, and effort (especially if treatment is repeated). However, there is concrete evidence to suggest that the treatment of hepatitis C among injecting drug users can effectively reduce transmission. Is this not the hope for all of those affected by the virus to effectively reduce transmission?
Then I got thinking about how alcohol and tobacco cause so many health related problems that also require expensive health care treatment. However, the difference remains that these products are taxed. Is this a reasonable argument for the legalisation of illicit drugs, or not? After all, the money the Government miss out on in the way of tax for the sale illicit drugs is in the millions! More importantly, is this also the reason for why those that consume heavily taxed substances, such as cigarettes and alcohol, effortlessly receive expensive health care? As opposed to those that do not? As someone that is living with an infectious disease as a result of illicit drug use, I feel strongly that there is an obvious gap that can only be described as grossly unfair. To determine if a person should be entitled to health care based on their individual preferences is simply a form of discrimination. Sadly, this is a reality that a lot of injecting drug users (past and present) still face today. In my humble opinion, it merely indicates that the Government desperately needs to review the harmful laws regarding drug policy.
If anything, I am still feeling so overwhelmed that I will receive such an expensive course of treatment for a very unfortunate mistake I once made. Whereas last time, I never planned to stop injecting drugs, this time, I know I have. If anything, I am looking forward to the peace and mind that if, in the future, I receive another blood test that indicates the virus is still detected after treatment, then nobody will be able to accuse me wrongfully of sharing needles ever again. Because even though I am by no mean anti-drugs, or anti-drug users, I am certainly not in favour of being treated discriminately anymore for any reason.
Personally, this will be a peace of mind that I consider priceless, forever.
December 02, 2013
Hey there, my name is Rita.I am 53 (be 54 in 2 weeks) I was an LPN for 29 years. I got Hep c while working in an E.R. and a patient came into the E.R. and was bleeding badly.I had a open "booboo" on my lower arm and despite the fact I had a bandage on my arm and was wearing protective gloves, this patients’ Hep C blood mixed in with my open wound and the rest is sadly history.
I went on with my life for several years and was the picture of health. I began to notice as did others around me that I was getting very tired often. I had always been a ball of energy, a real go getter so to speak. My GP noticed I was low on energy (I worked in the office with my GP). So he said something had to be wrong with me because I was staying so tired and began to have n/v and losing weight. He did LFT's on me that came back elevated and then followed that with a Hepatitis panel. Sure enough I was diagnosed with Hep C April of 2011. I had a biopsy and am genotype 1A with (at that time a stage & grade of 2/3) VL at that time was 33 million. I began triple therapy in August of that year. Well I lasted for 3 months on treatment and they had to take me off. My load had began to go up despite the fact I was on treatment. The doc said that my body was immune to the meds and that I couldn't take any of those 3 meds again. But I sure had most of the side effects. I tell ya. I was diagnosed the end of last year with cirrhosis.That is where I stand now. I'm waiting and praying that a new treatment comes out for which I am a candidate to take. We all MUST hold each others hands and walk this path and journey together. Who knows what a Hepper goes thru better than another Hepper ....... Hugs and love brothers and sisters.
Journal of Infectious Diseases
Advance Access published November 23, 2013
Elijah Paintsil1, Mawuena Binka2, Amisha Patel2, Brett D. Lindenbach3, and Robert Heimer2
1 Departments of Pediatrics & Pharmacology, Yale School of Medicine, New Haven, CT
2 Department of the Epidemiology of Microbial Diseases, Yale School of Public Health,
New Haven, CT
3 Microbial Pathogenesis, Yale School of Medicine, New Haven, CT
Correspondence to: Elijah Paintsil, MD., Departments of Pediatrics and Pharmacology,
Yale School of Medicine, 464 Congress Avenue, New Haven, Connecticut 06520, USA.
Phone: 203-785-6101 Fax: 203-785-6961; email: email@example.com
Background: Healthcare workers may come into contact with fomites containing infectious HCV during preparation of plasma, or following placement or removal of venous lines. Similarly, injection drugs users may come into contact with fomites. Hypothesizing that prolonged viability of HCV in fomites may contribute significantly to incidence; we determined the longevity of virus infectivity and the effectiveness of antiseptics.
Methods: We determined the volume of drops misplaced during transfer of serum or plasma. Aliquots equivalent to the maximum drop volume of plasma spiked with 2a HCV reporter virus were loaded into 24-well plates. Plates were stored uncovered at three temperatures: 4°, 22°, and 37°C for up to 6 weeks before viral infectivity was determined in a microculture assay.
Results: The mean volume of an accidental drop was 29 µl (min - max of 20 - 33 µl). At storage temperatures 4° and 22°C, we recovered viable HCV from the low titer spots for up to 6 weeks of storage. The rank order of HCV virucidal activity of commonly used antiseptics was bleach (1:10) > cavicide (1:10) > ethanol (70%).
Conclusions: The hypothesis of potential transmission from fomites was supported by the experimental results. The anti-HCV activity of commercial antiseptics varied.
The global burden of morbidity and mortality from hepatitis C virus (HCV) infection is truly pandemic with more than 170 million people currently infected 1 _ENREF_1. Since there is currently no vaccine for HCV and available treatment regimens are limited by efficacy, cost, and side effects, prevention of HCV transmission remains the primary strategy for curbing the HCV epidemic. HCV is transmitted primarily through parenteral exposure to blood or body fluids contaminated with HCV. Injecting drug use (IDU), mother-to-child transmission, multiple heterosexual partners, accidental needle injuries, and transfusion of blood or blood products are among the most relevant risk factors for HCV acquisition2-4
The epidemiology of HCV has changed in the last decade. Transmission from blood transfusions and surgical procedures have all but disappeared in developed countries 5 . There have been modest but insufficient declines in incidence among IDUs in locations with broad implementation of syringe exchange programs6-12. Nosocomial transmissions of HCV increasingly account for a large proportion of new HCV infections (i.e., 20% to 50%) in developed countries13-17. Thus, the relative impact and burden of nosocomial HCV transmission might be greater now than a decade ago. In an Italian study of 214 patients with acute HCV infections18, the most relevant associated risk factors were: history of medical procedures (32%) (e.g., hospitalization, surgery, endoscopy, dialysis, blood transfusion, dental treatment, or other invasive procedures) and intravenous drug use (30%). Interestingly, among the patients classified under medical procedures almost half of them did not have surgery or any invasive procedures while on admission. This has been corroborated by a study from Spain where the investigators found that the only documented risk factor among patients with acute HCV infection was hospital admission19. One can speculate that these patients might have been exposed to HCV-contaminated surfaces during hospitalization. We hypothesized that occupational and iatrogenic HCV infections may be due in part to the ability of the virus to remain viable on fomites and other hospital equipment for prolonged periods.
We recently established a microculture assay for propagation of cell culture derived HCV (HCVcc) in small volumes by using a genetically engineered reporter virus derived from the HCVcc clone20,21. Using our microculture assay system, we performed a set of experiments to replicate the circumstances in which healthcare workers or patients may come into contact with HCV dried upon surfaces that include preparation of plasma, handling of hemodialysis equipment, and following placement or removal of venous lines. To our knowledge this constitutes the first study to closely simulate conditions leading to nosocomial transmission of HCV
MATERIALS AND METHODS
Plasmids and Viruses
The construction of the Jc1/GLuc2A reporter virus, a derivative of the chimeric genotype 2a FL-J6/JFH with a luciferase gene from Gaussia princeps inserted between the p7 and NS2 genes, has been reported previously 21,22. Viral stocks of Jc1/GLuc2A reporter virus were prepared by RNA transfection of Huh-7.5 cells. The titer of HCVcc was quantified by infecting cells with serial dilutions of the stock virus and determining the dilution that will infect 50% (TCID50) of the wells by using the method of Reed and Muench 23
Human hepatoma cells highly permissive for HCVcc (Huh-7.5 subline)24 were maintained as subconfluent, adherent monolayers in Dulbecco’s Modified Eagle’s Medium (DMEM) supplemented with 10% heat-inactivated fetal calf serum and 1 mM non-essential amino acids (Invitrogen, Carlsbad, CA) at 37°C and 5% CO2
Determination of the volume of accidentally misplaced HCVcc-contaminated plasma on surfaces
The most likely circumstances in which healthcare workers or patients may come into contact with HCV dried upon surfaces are following spillage of HCV-contaminated blood, serum, or plasma during the course of preparing a blood sample for analysis or removing a venous line. To simulate such accidents, we obtained ethylenediaminetetraacetic acid (EDTA)-anticoagulated blood from HIV and HCV seronegative donors. The tube was centrifuged at 2000 rpm for 15 minutes and a rubber dropper was used to aspirate and transfer the plasma into several vials for storage as per practice and recommendation of the clinical microbiology laboratory at Yale-New Haven Hospital. The procedure was done in a biosafety cabinet with a foil mat to collect accidental drops of plasma. The experiment was done on two occasions and at each occasion 10 accidental drops were weighed. The volume of the drop was calculated based on the formula that 1 ml weighs 1 gram. The mean, with standard deviation of the mean, and maximum volumes were calculated.
Desiccation of displaced HCVcc-contaminated plasma drops on work surfaces
To determine how quickly the plasma dried on the surface we seeded the wells in uncovered 24-well tissue culture plates with the maximum accidentally dropped volume (33 µl). The 24-well plates were stored in a refrigerator at 4°C, on a benchtop at 22°C, or in an incubator at 37°C, and observed every 60 minutes until all replicates (20 drops) had dried. The time to dryness in these storage conditions was recorded. To determine the effect of humidity on time to dryness, we, in a separate experiment, recorded the temperature and humidity using an analog thermo-hygrometer instrument (General Tools, New York, NY, USA) three times a day (7 - 9 am; 12 noon - 1 pm; and 3 -5 pm) for a week. The mean humidity, with standard deviation of the mean was calculated.
Viability of dried HCVcc on surfaces
We spotted 33 µl of plasma spiked with HCVcc on the 24-well plates. They were either immediately tested for viable virus or stored at 4°C, 22°C, and 37°C for up to 6 weeks before testing. Twenty replicates were tested per condition and the experiment was repeated on two separate occasions. Negative controls comprised of plasma without virus. The day before each time point, 96-well plates were seeded with 6.4 x 103 Huh-7.5 cells/well in 100 µl of medium and incubated at 37°C in 5% CO2. To test for infectivity, the dried spots were rehydrated and reconstituted with 100 µl of culture medium. The medium from the wells was gently aspirated from the cells and replaced with 100 μl of the reconstituted virus mixture. After 5 h of incubation, the cells were washed with sterile PBS to remove the input virus; fresh medium was added and incubated for 3 days. After 3 days, culture supernatant was harvested and mixed with 20 μl of lysis buffer before luciferase activity was measured by using luciferase assay reagent kit (Promega, Madison, WI) and a luminometer (Synergy HT, BioTek, Winooski, VT). The relative luciferase activity (RLA) was determined to be linearly related to HCV infectivity16.
Virucidal effect of antiseptics on viability of contaminated HCVcc on surfaces
We used three antiseptics – bleach (Clorox), ethanol, and cavicide (Metrex) - to determine the effect of antiseptics on infectivity of HCVcc contaminated spots by using a culture media without virus as negative control. Positive controls consisted of cell culture media with virus. These antiseptics are readily available in hospitals and research laboratories. Bleach is available as 6% sodium hypochlorite and is diluted 1:10 in tap water before use, while ethanol is available for use as 70% ethanol 25-27. Cavicide is ready-to-use without dilution as per product insert. Prior to testing virucidal activity, it was necessary to determine the cytotoxic effects of the antiseptics on the Huh-7.5 cells. Briefly, 33 μl of test antiseptic was pipetted onto a 24-well plate. The antiseptic was combined with 297 μl of culture media (i.e., 1:10 dilution) and the mixture was passed through MicroSpin S-400 HR columns (GE Healthcare, Freiburg, Germany) according to the manufacturer’s instructions. 300 μl of column eluate or mixture not passed through the columns was added to Huh-7.5 cells seeded the previous day in a 48-well plate at 3.0 x104 cells/well in 300 μl of medium, to make a final volume of 600 μl and then incubated overnight at 37°C. After a day of further incubation, cell growth was determined with the alamarBlue® assay (Invitrogen) as manufacturer’s instructions. Cell growth was determined as a function of relative fluorescence measured at 530 nm excitation and 590 nm emission (Synergy HT Plate Reader, BioTek, Winooski, VT). Five replicates were tested per condition and the experiment was repeated twice.
We modified a previously described protocol to test for the infectivity of HCVcc after exposure to test antiseptic28. In brief, an equal volume of test antiseptic was pipetted onto 33 µl HCVcc contaminated spots for an exposure period of one minute, whereafter, 264 μl of culture media was added to the virus-antiseptic mixture (i.e., 1:10 dilution) and reconstituted. To reduce the cytotoxicity of antiseptics, each mixture was passed through a MicroSpin S-400 HR column according to the manufacturer’s instructions. Then 300 μl of eluate passed through the column or mixture without column purification was added to Huh-7.5 cells in a 48-well plate at 3 x 104 cells/well in 300 μl of medium to make a final volume of 600 μl. The cells were washed with sterile PBS after 4 h to remove input virus and incubated in 200 µl fresh media for 3 days. The infectivity of HCVcc was determined by luciferase assay as described above. Ten replicates were tested per condition and the experiment conducted on three occasions.
Volume of accidentally misplaced HCVcc contaminated plasma
The experiment was done on three occasions, and on each occasion 10 drops were weighed. The mean volume of the drops, calculated on the basis that 1 ml weighs 1 gram, was 29 ± 5 μl and the range was 18 to 33 μl. Since the maximum drop volume of 33 μl presents the most risk of transmission, we used 33 μl throughout our study.
Time to drying of HCVcc contaminated drops at different temperatures
Dried droplets of serum contaminated with HCV may be inconspicuous and, therefore, more likely than a liquid droplet to cause accidental exposures to HCV. We determined how long it took a drop of HCVcc contaminated plasma to dry at 4°, 22° and 37°C. We determined the mean temperature and relative humidity in the refrigerator, the benchtop, and the incubator over a week. The temperature was 4 ± 1°, 22 ± 0°, and 37 ± 0°C in the refrigerator, the benchtop, and the incubator, respectively. The humidity was 53 ± 10%, 44 ± 5%, and 82 ± 1% at 4°, 22° and 37°C, respectively. The order of time to dryness was 4, 24, and 28 hrs at 22° (benchtop), 4° (refrigerator), and 37°C (incubator), respectively. Thus time to dryness correlated positively with the humidity of the storage condition.
Infectivity of dried HCVcc on surfaces at different temperatures
We investigated the infectivity of HCVcc after drying on surfaces at different temperatures. Aliquots of 33 µl of HCVcc contaminated serum were pipetted into 24-well plates and stored for up to six weeks. Twenty spots of dried HCVcc for each combination of storage time and temperature were reconstituted with culture media after storage and introduced into our assay system 20. The proportion of HCVcc positive dried spots and the infectivity per HCVcc dried spot were determined. The results presented here came from at least three independent experiments.
First, we used a low titer stock of HCVcc, (i.e., equivalent to 104 infectious units/mL) to determine the infectivity of HCVcc after drying and storage for up to 6 weeks. We observed a negative correlation between storage temperature and HCVcc infectivity (Figure 1A). With an assay detection limit of 1000 RLA (2-3 times over the background luciferase activity), we recovered viable HCVcc from dried spots stored at 37°C until day 7 of storage. In contrast, at storage temperatures 4° and 22C°, we recovered replicating HCVcc from all the spots for up to 6 weeks of storage. The infectivity, measured by RLA of the reconstituted spots, declined rapidly over time inversely to the storage temperature (Figure 1B). At storage temperatures of 4° and 22°C, we observed a sharp decline in infectivity over the first two weeks followed by persistent but lower infectivity through week six (Figure 1B). This is consistent with our previous report of biphasic decay rate of HCVcc20.
By using a high titer stock of HCVcc (equivalent to106 infectious units/mL), we observed a prolonged infectivity of HCVcc at all storage temperatures. Almost 100% of the contaminated spots stored at 4° and 22°C remained positive for HCVcc through three weeks of storage (Figure 2A). At 37°C, 100% of the spots were positive till 10 days of storage and then declined to 40% and 0% at days 14 and 21, respectively (Figure 2A). The infectivity of the HCVcc recovered from the high titer HCVcc contaminated spots was in general 2 to 3-fold higher than the RLA of the low titer HCVcc at each time point. Infectivity was inversely proportional to the storage temperature. We observed a 50% reduction in infectivity at day 3, 14 and 21 for storage temperatures 37°, 22°, and 4°, respectively (Figure 2B).
Effect of antiseptics on infectivity of HCVcc on surfaces
To investigate the virucidal effect of bleach, ethanol, and cavicide, we first determined the effects of these antiseptics on the growth of Huh-7.5 cells by using the alamarBlue® assay. When we tried undiluted bleach and cavicide, which were diluted 1:10 before addition to the tissue culture system, we found they were uniformly ctytotoxic to Huh-7.5 cells whereas 70% ethanol had no significant effect on cell growth (Figure 3A). Cell growth was almost restored to control levels with a 1:10 dilution of bleach and a 1:20 dilution of cavicide following passage of the solution through MicroSpin S-400 HR columns (Figure 3A). Cavicide at a 1:10 dilution reduced growth by 70% relative to the control.
Based on the cytotoxicity results, experiments using bleach diluted 1:10 and 1:100, cavicide diluted 1:10 and 1:20, and ethanol at 70% and 7% were conducted by using MicroSpin S-400 HR columns29 prior to adding eluate to the microculture system. After 1 min exposure to bleach (1:10 dilution), cavicide (1:10), and ethanol (70%), the percentage of positive contaminated HCVcc spots were 0%, 3 ± 6%, and 13 ± 6%, respectively (Figure 3B). Further dilutions of bleach (1:100), cavicide (1:20), and ethanol (7%) resulted in 17 ± 6%, 43 ± 6%, and 90 ± 17% positive spots, respectively. For certain viruses, passage through a MicroSpin column could reduce viral infectivity30, therefore, we performed a control experiment comprising HCVcc without exposure to any antiseptic and with or without passage through a MicroSpin column prior to infection of Huh 7.5 cells. The infectivity was 80 ± 10% and 100% for HCVcc with and without passage through MicroSpin column, respectively (Figure 3B). We next tested the infectivity of HCVcc without MicroSpin column after exposure to antiseptic at concentrations that are least cytotoxic. After 1 min exposure to bleach (1:100 dilution), cavicide (1:20), 70% ethanol, and 7% ethanol, the percentage of positive contaminated HCVcc spots were 30 ± 10%, 60 ± 36%, 30 ± 35%, and 93 ± 12%, respectively (Figure 3B). The infectivity of residual HCVcc after passage through MicroSpin column (Figure 3C) was correlated with the likelihood of recovery of viable HCVcc. RLA was highest for 7% ethanol (with 27 of 30 spots yielding viable HCVcc) and lowest for 1:10 cavicide (1 of 30 spots yielding viable HCV).
In our simulation of real world risks of HCV transmission in settings conducive to exposure to HCV-contaminated fomites, we observed that HCVcc could maintain infectivity for up to 6 weeks at 4° and 22°C. This finding supports our hypothesis that the increasing incidence of nosocomial HCV infections may be due to accidental contact with HCV-contaminated fomites and other hospital equipment even after prolonged periods following their deposition. Moreover, we found that HCVcc infectivity was influenced by HCVcc viral titer and the temperature and humidity of the storage environment. Furthermore, the commercially available antiseptics reduced the infectivity of HCVcc on surfaces only when used at the recommended concentrations 25,27, but not when further diluted.
Although there have been two previous studies on infectivity and stability of HCV on surfaces28,31, to our knowledge, this is the first study that closely simulates the natural events likely to cause transmission of HCV. First, Kamili et al. reported that 100 µl aliquots of chimpanzee plasma contaminated with HCV was still infectious when dried and stored at room temperature for up to 16 hours 31. Transmission of infection did not occur after 16 hours to up 7 days of storage. More recently, Doerrbecker et al. demonstrated that 50 µl of cell culture-derived HCV dried on steel discs remains infectious for up to 5 days at room temperature28. The limitations of these previous studies include simulation of HCV transmission under artificial drying conditions. Furthermore, Doerrbecker et al. found that the infectivity of the virus recovered from the carrier system was 10-fold lower than that stored in liquid media. Therefore, one can speculate that the duration of infectivity observed in their study could be an underestimation. Moreover, differences in the three assay systems (e.g., in vivo versus in vitro assay; artificial versus passive desiccation) might account for the different durations of survival reported. Our study sought to overcome some of these limitations by determining the exact size of accidentally misplaced HCVcc-contaminated plasma and allowing the drops to dry under natural conditions. The fact that under these conditions we found HCVcc to be infectious for up to 6 weeks, consistent with our previous report that HCVcc survived in tuberculin syringes for up to 63 days 20, is of public health concern. Taken together, these studies show that HCVcc remains potentially infectious for prolonged periods of time, ranging from 16 hours to 6 weeks depending on the assay system. We previously reported on the biphasic decay rate of our genotype 2a HCVcc at room temperature; a rapid decline of infectivity within the first 6 h followed by a second phase of a relatively slow exponential decay 20. This is consistent with recent report on thermostability of 7 genotypes including 2a genotype 32. Such prolonged infectivity could contribute to the increasing incidence of nosocomially acquired HCV infections.
Of infection control relevance is the fact that all the HCVcc-contaminated spots dried at room air within 4 hours, becoming inconspicuous and therefore more likely to cause accidently exposures to HCV. HIV was also reported to dry at room temperature within 3 hours and retain infectivity for up to 7 days 33,34. The infectivity of HCVcc and HIV when stored at room temperature for several days is consistent with that of other envelope viruses 35,36. The prolonged infectivity of these viruses has been attributed, in part, to their lipid envelope, which resists drying and protects the viral capsid from the deleterious effects of dehydration 37. Hepatitis B virus, another lipid-enveloped hepatotropic virus, was reported to survive up to 7 days at room temperature; further time points were not available due to a laboratory mishap 38. The resilience of these viruses at room temperature raises the possibility of their being transmitted through fomites. Our findings support the surveillance data on increasing incidence of nosocomial transmissions of HCV in developed countries 13-17. Interestingly, most of the patients who acquired HCV in the hospital had no surgeries or invasive procedures; their only risk was hospital admission18,19. Fomites could, therefore, be an important vehicle for transmission of HCV in the hospital and household settings.
Finally, given the infection control implications of our findings, we decided to investigate if commonly used antiseptics are effective against HCV. We demonstrated that bleach, cavicide, and ethanol are effective at their recommended concentrations 25-27. It is possible that the efficacy of cavicide at 1:10 is overestimated because the disinfectant itself reduced host cell viability by 70%. Further dilution of each antiseptic proved sub-optimal (Figures 3B and C.The finding for ethanol paralleled that of Ciesek et al., who found that HCV titers decreased at concentrations of 30% and 40% but complete inactivation did not occur at an exposure time of 5 min29. However, undiluted concentrations of several hand antiseptics (based on povidone-iodine, chlorhexidine digluconate, and triclosan) reduced HCV infectivity to undetectable levels 29. Thus, there are several commercially available antiseptics that are effective against HCV.
Our study, which sought to improve upon prior studies, still has some limitations. First, the assay employs a genetically modified HCV laboratory clone derived from a genotype 2a virus that may not reflect survival characteristics of human isolates. However, the thermostability pattern of our virus is similar to that of other genotypes 32. Second, the spiking of HCVcc-seronegative blood might not sufficiently replicate the biological factors present in the blood of HCV-infected individuals that could moderate HCV transmission and infectivity. However, the consistency of our results with previous in vitro studies and epidemiologic studies reporting transmission of HCV in healthcare setting and through sharing of injection paraphernalia39-43 support our findings.
In conclusion, we have demonstrated that HCVcc can remain infectious at room temperature for up to 6 weeks. Our hypothesis of potential transmission from fomites was supported by the experimental results and provides the biological basis for recent observational studies reporting increasing incidence of nosocomial HCV infections and continued high incidence among people who inject drugs.
This study was made possible by grant from NIH/NIDA (R01 DA030420 to RH). EP is a Yale CTSA scholar and was supported by Clinical Translational Science Award (CTSA) Grant Number UL1 RR024139 from the National Center for Research Resources (NCRR). The development of the Jc1/GLuc2A system involved NIH funding (1K01CA107092 and 1R01AI076259, both to B.D.L).
(1) The authors do not have a commercial or other association that might pose a conflict of interest.
(2) This study was made possible by grant from NIH/NIDA (R01 DA030420 to RH). EP is a Yale CTSA scholar and was supported by Clinical Translational Science Award (CTSA) Grant Number UL1 RR024139 from the National Center for Research Resources (NCRR). The development of the Jc1/GLuc2A system involved NIH funding (1K01CA107092 and 1R01AI076259, both to B.D.L). The content of the paper is solely the responsibility of the authors and do not necessarily represent the official view of NIH or NCRR.
(3) Correspondence to: Elijah Paintsil, MD., Departments of Pediatrics and Pharmacology, Yale School of Medicine, 464 Congress Avenue, New Haven, Connecticut 06520, USA. Phone: 203-785-6101 Fax: 203-785-6961; email: firstname.lastname@example.org
December 2, 2013, 5:42 p.m. ET
By John Kell
Conatus Pharmaceuticals Inc.'s (CNAT) shares jumped Monday after the biotechnology firm said its treatment for chronic liver disease has been granted a status that could mean quicker approval.
The company disclosed the U.S. Food and Drug Administration has granted orphan status to its treatment for liver-transplant patients. Orphan drugs, defined as experimental treatments for diseases with fewer than 200,000 patients at any one time, can mean quicker approval, tax benefits for the developer and seven years' protection from competition after approval.
Investors cheered the news, sending shares up 14% to $6.99 in after-hours trading.
The FDA's orphan-drug designation was granted for emricasan, a treatment Conatus has studied in over 500 subjects across 10 clinical trials. The company's initial development strategy targets patients with acute-on-chronic liver failure, chronic liver failure, and patients who have developed liver fibrosis postorthotopic liver transplant due to Hepatitis C virus infection.
The company expects to conduct further trials in 2014.
The National Institutes of Health estimates that 5.5 million Americans have chronic liver disease or cirrhosis. According to the European Association for the Study of the Liver, 29 million Europeans have chronic liver disease.
Write to John Kell at email@example.com
John G. Bartlett, MD
December 02, 2013
The challenge of HIV management seemed impossible up to 1996, but since then, it has been an incredible journey that no one saw coming. We now have 28 antiretroviral drugs, huge databases to assiduously track the incredible progress, an army of specialists to provide state-of-the-art care, and near-normal longevity for most who take standard treatment.
Many opine that the war on HIV/AIDS is largely over. But wait. The field of HIV science, patients, and providers never stops.
This review tabulates 10 key changes in HIV testing, clinical care, and healthcare delivery that will probably have a significant impact on where we go from here.
New Tests for Earlier Detection and Better Control of HIV
Fourth-Generation HIV Test
The new test adds p24 antigen to the HIV antibody test to permit detection of the disease before seroconversion, which is when the Western blot (WB) becomes positive. This test is approved by the US Food and Drug Administration (FDA), and its use is recommended by the Centers for Disease Control and Prevention for screening patients because it can detect HIV during the early acute retroviral syndrome stage at Fiebig stage 2 -- unlike the WB results, which require waiting for 2-3 months after viral transmission at Fiebig stage 5.
Advantages of this early detection include (1) the possibility of functional cure (discussed below); (2) treatment at the time of maximum risk for transmission; and (3) the opportunity for direct entry into HIV care vs the long delay required for obtaining a positive WB result. This delay also promotes the problem that 20%-25% of patients with a positive WB never actually receive these results so their care may be delayed indefinitely.
Point-of-Care HIV Viral Load Testing
Point-of-care (POC) HIV testing has been extremely successful as a screening tool to detect HIV. Now, there is a POC CD4 count test that permits staging HIV at the site of care, and it is anticipated that a POC viral load test will also be available, although the timeline for this development is unclear.
The advent of the POC viral load test permits patients to test their own viral load to facilitate HIV management in an outpatient setting, often without the need for frequent medical evaluation except to test for drug toxicity, comorbidities, and HIV-related complications. The long-term goal would be self-care akin to standard diabetes management.
Preventing, Treating, and Curing Disease
Early HIV Therapy to Achieve "Functional Cure"
There is now good evidence to show that the HIV reservoir with chronic HIV infection is substantial and is probably an important factor in immune activation and our inability to achieve cure, despite viral suppression with traditional monitoring.
Note that "cure" is now described in 2 categories: a "sterilizing cure," in which the virus is eliminated, and a "functional cure," in which the virus continues to be present but does not require antiretroviral therapy (ART) for viremic control.
The "Berlin patient" who underwent stem cell transplantation is regarded as the only person to have achieved sterilizing cure. The "Mississippi baby" is considered a functional cure because she has had virologic control off therapy for longer than 1 year after being treated at birth and briefly after birth, but it is not clear that the virus is eliminated.
Possibly the best example of the impact of early therapy is the VISCONTI cohort. This is a group of patients in France treated early in the course of HIV infection who have remained off ART for months or years, without treatment or detectable virus.
The presumed explanation is that treatment early in the course of acute infection limits substantial infection of the reservoir. Thus, recognition of acute disease with rapid implementation of ART now becomes an important priority in the context of HIV management.
Preventing HIV Infection
The rate of new cases of HIV infection in the United States has held steady at around 50,000-55,000 cases per year since 1996, even though many effective methods for preventing HIV transmission are available. There does not seem to be any strategy that consistently reduces annual rates of new infections despite 17 years of trying.
We have a particularly important development in the HPTN 052 trial, which showed that "treatment is prevention" -- presumably because HIV infection, like virtually all infections, obeys the rule that probability of transmission is directly correlated with inoculum size. This tactic makes biologic sense and has now been proven in a well-controlled clinical trial.
This is a game-changer in the sense that universal ART coverage is now a commonly accepted strategy in the United States and will be recommended by the World Health Organization when resources are available. The dual goal is to improve both individual health and public health based on mathematical modeling showing that treatment is an effective prevention strategy. Preexposure prophylaxis (PrEP) is a newer option and seems to work in clinical trials, but the challenge of adherence may make it more difficult to implement in practice. Interestingly, concerns raised 55 years ago with the introduction of the first birth control pill, Enovid, are now being raised with PrEP, including cost, side effects, and impact on sexual behavior.
Eliminating the Hepatitis C Coinfection Cohort
It is estimated that 30%-35% of persons with HIV infection also have hepatitis C infection. In the United States, hepatitis C infection is the major cause of liver failure, liver transplant, and liver death, with an annual mortality that now exceeds that of HIV.
The sudden and dramatic change in hepatitis C management is now virtually guaranteed, with an extraordinary array of new drugs expected to cure the majority of hepatitis C-infected patients.
P4P4P to Address the Gardner HIV Cascade Challenge
The Gardner cascade is well known to the HIV care community, but it represents a humbling pox on our HIV care system because it shows the very disappointing reality of HIV outcome. Despite the availability of powerful drugs for virtually all patients, only about 28% of the estimated 1.1 million Americans with HIV infection have achieved the goal of no detectable virus. The major issues accounting for this disappointing outcome are lapses in care at each step of the cascade -- testing, enrollment in care, retention in care, and adherence to ART. Many articles have been written about this cascade and have described possible methods to address each step, but none have clearly achieved a major advance.
The potential breakthrough in this stalemate is P4P4P, or "pay for performance for patients," which provides financial or other reward for patients to get tested, engage care, stay in care, and achieve viral suppression. It is now being studied in a controlled trial in Washington, DC, and Bronx, New York.
The reason for optimism is that P4P4P seems to have worked well in virtually all areas of chronic care that are dependent on patient adherence, including hypertension, diabetes, smoking, obesity, and measurement of INR. This approach to medical management of chronic disease is controversial, so it is not included in HIV guidelines or polite discussions, even though it is low-cost and virtually always works. Instead, we spend long hours and great resources to achieve this goal by other methods.
It is anticipated that the well-controlled National Institutes of Health-sponsored trial of P4P4P will impart validity and acceptability to this rarely discussed topic.
New Approaches in HIV Therapeutics on the Horizon
There will always be a need for new antiretroviral agents owing to resistance and toxicity, but the small number of new drugs in the pipeline possibly reflects the adequacy of the current supply of 28 FDA-approved agents as well as the anticipated rush to generics (discussed below).
However, there is increasing enthusiasm about the use of nanotechnology to achieve novel antiretroviral drug formulations to facilitate viral control, such as long-acting rilpivirine (rilpivirine LA) and the new integrase inhibitor GSK744.[14,15] These drugs are given parenterally and maintain therapeutic levels for 1-3 months. Both are currently in clinical trials to treat persons at risk for HIV infection (ie, as PrEP) and patients with established HIV infection.
It is anticipated that this will bring a new method of HIV management that is completely different from what we are currently doing, and it is especially appealing for populations in whom daily pill taking is a great challenge.
The other anticipated departure from contemporary practice is the abandonment of "2 nukes and a third drug" -- the 3-drug combination containing 2 nucleoside reverse transcriptase inhibitors and a "third drug" -- the basic combination that has been standard since 1996.
A New Paradigm for HIV Care Delivery
Redefining the HIV Provider
It seems clear that healthcare reform will have a major impact on medical care in general, and certainly on HIV care as well.[16,17] One of the key issues is defining who will be the HIV care provider. Will it be done primarily by an HIV specialist, will HIV be enveloped within primary care, or will there be some sort of mix, as with diabetes?
Arguments for the shift to primary care include the fact that HIV care is now much easier with the current menu of drugs and more than 50% of the patients with HIV are now older than 50 years, so diseases of aging must also be addressed. However, the HIV Medicine Association and the Infectious Diseases Society of America defines an HIV care provider as a provider with a panel size of at least 25 HIV-infected patients, even though there are no data to support superior outcomes by this definition in studies conducted over the past 20 years.
The impression of payers is that most patients will be able to keep their current provider, but we should expect great variations by state and payer in the coming years.
Evolving Ethical Issues in HIV Care
The ethics of HIV care under healthcare reform is a good example of an evolving controversy that is likely to have an important impact on HIV drug selection in the future. It is very reminiscent of the highly quoted 1993 editorial by Marcia Angell, former editor of the New England Journal of Medicine, which stated that the doctor had become a "double agent," considering our sometimes conflicted obligation to both the patient and the payer.
This will be an individual provider/patient issue with unpredictable outcomes, but it is likely to introduce a new and very uncomfortable decision process. Although we are reminded that our oath is to be the advocate of the individual patient, we also recognize that we work in a society that is screaming for lower healthcare costs.
Generic Drugs for HIV
HIV care is expensive, with annual costs averaging $25,000-$30,000, of which 67%-70% is spent on antiretroviral drugs. In the United States, healthcare reform is coming just as first-line HIV drugs are starting to go off patent. The anticipated result is great pressure for the use of generic drugs for HIV treatment, as for all medical conditions.
A cost analysis using generic efavirenz plus generic lamivudine with trade-branded tenofovir shows a potential savings compared with Atripla® of $6000 per patient per year, or about $940 million per year on the basis of current US sales. The switch would require the patient to take 3 pills once daily instead of 1 pill once daily. This would be a difficult transition for some patients, but the convenience factor may be a hard sell to payers given relative costs.
It seems likely that some payers will require the change and that the issue will become increasingly important as more drugs become generic, guidelines change, and payers become more savvy. Additional factors that could affect its acceptance are the future of the AIDS Drug Assistance Plan (ADAP) and an interesting recent proposal that patient expense for drugs should be routinely included in the description of side effects, as well as the recommendation from the American College of Physicians that we be "parsimonious" in our delivery of care. These possible changes in ADAP, the introduction of generics, and the attention to cost in HIV care delivery could have a marked impact on HIV patient management.
1. Nasrullah M, Wesolowski LG, Meyer WA 3rd, et al. Performance of a fourth-generation HIV screening assay and an alternative HIV diagnostic testing algorithm. AIDS. 2013;27:731-737. Abstract
2. Reid SD, Fidler SJ, Cooke GS. Tracking the progress of HIV: the impact of point-of-care tests on antiretroviral therapy. Clin Epidemiol. 2013;5:387-396.
3. Lisziewicz J, Rosenberg E, Lieberman J, et al. Control of HIV despite the discontinuation of antiretroviral therapy. N Engl J Med. 1999;340:1683-1684. Abstract
4. Persaud D, Gay H, Ziemniak C, et al. Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med. 2013 Oct 23. [Epub ahead of print]
5. Sáez-Cirión A, Bacchus C, Hocqueloux L, et al; ANRS VISCONTI Study Group. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog. 2013;9:e1003211.
6. Cohen MS, Smith MK, Muessig KE, Hallett TB, Powers KA, Kashuba AD. Antiretroviral treatment of HIV-1 prevents transmission of HIV-1: where do we go from here? Lancet. 2013;382:1515-1524.
7. Doherty M, Ford N, Vitoria M, Weiler G, Hirnschall G. The 2013 WHO guidelines for antiretroviral therapy: evidence-based recommendations to face new epidemic realities. Curr Opin HIV AIDS. 2013;8:528-534.
8. Myers JE, Sepkowitz KA. A pill for HIV prevention: déjà vu all over again? Clin Infect Dis. 2013;56:1604-1612.
9. Afdhal NH, Zeuzem S, Schooley RT, et al; New Paradigm of HCV Therapy Meeting Participants. The new paradigm of hepatitis C therapy: integration of oral therapies into best practices. J Viral Hepat. 2013;20:745-760. Abstract
10. Gardner EM, McLees MP, Steiner JF, Del Rio C, Burman WJ. The spectrum of engagement in HIV care and its relevance to test-and-treat strategies for prevention of HIV infection. Clin Infect Dis. 2011;52:793-800. Abstract
11. Kullgren JT, Troxel AB, Loewenstein G, et al. Individual- versus group-based financial incentivesfor weight loss: a randomized, controlled trial. Ann Intern Med. 2013;158:505-514. Abstract
12. Thompson MA, Mugavero MJ, Amico KR, et al. Guidelines for improving entry into and retention in care and antiretroviral adherence for persons with HIV: evidence-based recommendations from an International Association of Physicians in AIDS Care panel. Ann Intern Med. 2012;156:817-833. Abstract
13. Greenberg AE, Hader SL, Masur H, Young AT, Skillicorn J, Dieffenbach CW. Fighting HIV/AIDS in Washington, D.C. Health Aff (Millwood). 2009;28:1677-1687. Abstract
14. Flexner C, Saag M. The antiretroviral drug pipeline: prospects and implications for future treatment research. Curr Opin HIV AIDS. 2013;8:572-578.
15. Spreen WR, Margolis DA, Pottage JC Jr. Long-acting injectable antiretrovirals for HIV treatment and prevention. Curr Opin HIV AIDS. 2013;8:565-571.
16. Martin EG, Schackman BR. What does U.S. health reform mean for HIV clinical care? J Acquir Immune Defic Syndr. 2012;60:72-76.
17. Martin EG, Meehan T, Schackman BR. AIDS Drug Assistance Programs: managers confront uncertainty and need to adapt as the Affordable Care Act kicks in. Health Aff (Millwood). 2013;32:1063-1071. Abstract
18. Angell M. The doctor as double agent. Kennedy Inst Ethics J. 1993;3:279-286. Abstract
19. Gebo KA, Fleishman JA, Conviser R, et al; HIV Research Network. Contemporary costs of HIV healthcare in the HAART era. AIDS. 2010;24:2705-2715. Abstract
20. Walensky RP, Sax PE, Nakamura YM, et al. Economic savings versus health losses: the cost-effectiveness of generic antiretroviral therapy in the United States. Ann Intern Med. 2013;158:84-92. Abstract
21. Ubel PA, Abernethy AP, Zafar SY. Full disclosure -- out-of-pocket costs as side effects. N Engl J Med. 2013;369:1484-1486. Abstract
22. Neumann PJ. What we talk about when we talk about health care costs. N Engl J Med. 2012;366:585-586. Abstract
11:07 pm | Monday, December 2nd, 2013
The Hepatology Society of the Philippines, along with its partners in the National Viral Hepatitis Task Force (NVHTF), a multisectoral coalition of stakeholders who have a shared interest in viral hepatitis control and prevention, recently launched a National Viral Hepatitis Task Force, which aims to work for greater viral hepatitis prevention and control in the country.
The HPS’ partners include the Department of Health, World Health Organization, Philippine Society for Microbiology and Infectious Diseases, Philippine College of Physicians, Philhealth, Philippine Pediatric Society, Philippine Society of Gastroenterology, Yellow Warriors Society of the Philippines and the Department of Labor and Employment.
In the Philippines, hepatitis B and hepatitis C are major public health problems that remain largely ignored. It is estimated that 16.7 percent, or some 7.3 million, adult Filipinos are chronically infected with the hepatitis B virus.
That means 1 out of 7 Filipinos are living with hepatitis B. This rate is double the average prevalence rate in the Western Pacific region. In addition, although data is limited, as much as 1 percent of Filipinos may be infected with the hepatitis C virus.
Many Filipinos die of liver cancer and liver cirrhosis, both of which are known consequences of chronic hepatitis B and hepatitis C infection.
“Hepatitis B and hepatitis C are among the most common causes of liver cancer,” said Dr. Diana Payawal, current president of HSP and executive council member of Asian Pacific Association for the Study of the Liver. “In the Philippines, hepatitis B is the leading cause of liver cancer.”
Liver cancer is the third leading cause of cancer, and is the second leading cause of cancer death in the country. In addition to the toll on their health, persons with hepatitis B or hepatitis C suffer stigma and discrimination, said Dr. Payawal.
At the moment, the Philippines does not have a comprehensive program on the prevention and control of hepatitis B and hepatitis C. In 2010, the World Health Assembly passed resolution WHA 63.18, which urges all member states to adopt a comprehensive approach to the prevention and control of viral hepatitis.
The HSP has convened the National Viral Hepatitis Task Force which will develop and maintain a national strategy to eliminate or significantly decrease the prevalence of hepatitis B and hepatitis C in the Philippines.
The NVHTF has created a strategic plan, called “Prevention and Control of Hepatitis B and Hepatitis C in the Philippines: A Call to Action,” to serve as a roadmap for its efforts. The roadmap adopts the framework of the WHO Global Hepatitis Program, which uses four axes to address viral hepatitis: Axis 1 is about raising awareness, promoting partnerships, mobilizing resources; Axis 2 is about evidence-based policy and data for action; Axis 3 touches on prevention of transmission; and Axis 4 involves screening, care and treatment.
PRESS RELEASE December 2, 2013, 7:05 a.m. ET
Idenix Pharmaceuticals Files Patent Infringement and Interference Lawsuits Against Gilead Sciences
CAMBRIDGE, Mass., Dec. 2, 2013 (GLOBE NEWSWIRE) -- Idenix Pharmaceuticals, Inc. (Nasdaq:IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today announced that it has filed two lawsuits against Gilead Sciences, Inc. (Nasdaq:GILD): a patent infringement lawsuit in the United States District Court in Boston, Massachusetts and a separate patent infringement and interference lawsuit in the United States District Court in Wilmington, Delaware.
The Massachusetts infringement lawsuit alleges that Gilead infringes two U.S. patents co-owned by Idenix (6,914,054 and 7,608,597) that cover methods of treating the hepatitis C virus using 2'-methyl nucleosides. In this lawsuit, Idenix is seeking a declaration that Gilead's imminent distribution, importation, use, sale or offer to sell drugs containing sofosbuvir, a 2'-methyl nucleoside compound, infringes Idenix's patents.
The Delaware infringement and interference lawsuit alleges that Gilead infringes a separate U.S. patent co-owned by Idenix (7,608,600) that covers methods of treating the hepatitis C virus using 2'-methyl-2'-fluoro nucleosides. Idenix is seeking a declaration that Gilead's imminent distribution, importation, use, sale or offer to sell drugs containing sofosbuvir infringes the Idenix '600 patent. Additionally, the Delaware lawsuit asserts a claim for interfering patents between the Idenix '600 patent and a U.S. patent (8,415,322) owned by a Gilead subsidiary, Gilead Pharmasset LLC. Idenix is seeking to have the Gilead '322 patent declared invalid.
"Idenix has invested significant resources in nucleoside drug discovery and in building an intellectual property portfolio that aids in the discovery and development of drugs for the treatment of the hepatitis C virus and other viral diseases," said Maria Stahl, senior vice president and general counsel at Idenix. "While we have attempted to resolve this matter with Gilead without resorting to infringement litigation, we intend to diligently and vigorously protect our patent rights for the benefit of our company and our shareholders and prevent infringing use by others. Idenix remains confident in its patent portfolio and has several patent families that provide the Company coverage for 2'-methyl nucleoside compounds and 2'- methyl, 2'- fluoro nucleoside compounds specifically."
Other Ongoing Patent Disputes
Idenix and Gilead are currently involved in a separate patent interference before the United States Patent and Trademark Office involving a pending Idenix patent application (Application 12/131,868) covering certain 2'- methyl, 2'- fluoro nucleoside compounds and another granted Gilead patent (7,429,572) also related to certain 2'- methyl, 2'- fluoro nucleoside compounds.
Gilead Sciences has also filed suit against Idenix in various jurisdictions outside the United States to invalidate granted Idenix patents covering certain 2'-methyl-2'-fluoro nucleoside compounds and their use in treating HCV or other Flaviviridae viruses.
The patents asserted by Idenix in its Massachusetts infringement lawsuit are not the same patents at issue in the ongoing U.S. patent interference or the ongoing foreign litigations. The patent asserted by Idenix in its Delaware lawsuit is not the same patent application at issue in the ongoing U.S. patent interference, but is in the same patent family.
Idenix Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts, is a biopharmaceutical Company engaged in the discovery and development of drugs for the treatment of human viral diseases. Idenix's current focus is on the treatment of patients with hepatitis C infection. For further information about Idenix, please refer to www.idenix.com.
Idenix Pharmaceuticals Contact:
Teri Dahlman, Dahlman.Teresa@idenix.com
Journal of Hepatology
Article in Press
Received 15 July 2013; received in revised form 22 November 2013; accepted 23 November 2013. published online 02 December 2013.
Due to ethical rules in most countries, long ischemia times are unavoidable prior to organ procurement of donors without a heartbeat, which can cause early graft failure after liver transplantation or late biliary strictures. Hypothermic oxygenated machine perfusion, used prior to graft implantation may rescue these high risk organs.
Eight patients with end stage liver diseases received human livers, obtained after controlled cardiac death (Maastricht category III), with a median donor warm ischemia time of 38 minutes, followed by a standard cold flush and static storage at 4°C. Hypothermic oxygenated perfusion (HOPE) was applied for 1-2 h prior to implantation through the portal vein. The HOPE-perfusate was cooled at 10°C and oxygenated (pO2 60kPa) using an ECOPS device (Organ Assist®). Perfusion pressure was maintained below 3mmHg.
Each machine perfused liver graft disclosed excellent early function after transplantation. The release of liver enzymes and kidney function, as well as ICU and hospital stays were comparable or better than in matched liver grafts from brain death donors. No evidence of intrahepatic biliary complications could be documented within a median follow up of 8.5 months.
This is the first report on cold machine perfusion of human liver grafts obtained after cardiac arrest and subsequent transplantation. Application of HOPE appears well tolerated, easy-to-use, and protective against early and later injuries.
Abbreviations: DCD, donation after cardiac death, DBD, Donation after brain death, HOPE, Hypothermic oxygenated perfusion, ICU,Intensive care unit, HCC, Hepatocellular Carcinoma, IC, Ischemic Cholangiopathy, MELD, Model for end stage liver disease, DAMPs, Danger associated molecular proteins
No full text is available. To read the body of this article, please view the PDF online.
Journal of Hepatology
Article in Press
Received 17 July 2013; received in revised form 9 November 2013; accepted 19 November 2013. published online 02 December 2013.
In light of dramatically changing hepatitis C therapeutic landscape, knowledge of the current burden of HCV infection in the general population of the United States is critical.
Methods and Participants
The National Health and Nutrition Examination survey collects nationally representative data on HCV infection in the civilian population of the United States. Data from 2001 to 2010 were combined for this study. HCV testing was completed in 38,025 participants.
The prevalence of anti-HCV in the United Sates decreased from 1.9% (95% CI1.5%-2.5%) in 2001-2002 to 1.3% (95% CI 0.9%-1.8%) in 2005-2006, and remained stable up to 2010. About 67% of all infected persons were positive for HCV RNA, indicating 2.3 million people with chronic HCV infection, of whom 68% have genotype 1. Seventy percent of infected persons were born between 1945 and 1965, with prevalence of 3.5% (95% CI 2.2%-4.8%). The stable rate since 2006 is mostly related to prevalent cases and foreign born persons migrating into US. Other important risk factors include less education and low economic status. Race, HIV status, number of sexual partners and blood transfusions are no longer associated with HCV infection.
As of 2010, approximately 2.3 million persons were chronically infected with Hepatitis C in the US. Most of those infected are prevalent, rather than incident cases. The prevalence of HCV was on the decline, but has stabilized since 2006. Future studies should explore reasons for no decline in HCV prevalence since 2006.
No full text is available. To read the body of this article, please view the PDF online.
Stockholm, Sweden—Medivir AB (OMX: MVIR), announces that IDENIX has initiated a phase II clinical trial (HELIX-2) evaluating an all-oral, direct-acting antiviral (DAA) HCV combination regimen of simeprevir, samatasvir and TMC647055 with a pharmacokinetic enhancer.
The HELIX-2 trial is a 12-week, randomized, open-label study evaluating the efficacy, safety and tolerability of simeprevir, TMC647055 and samatasvir. The trial will evaluate genotype 1 HCV-infected patients who are either treatment-naïve or who have relapsed after prior treatment with interferon and ribavirin. Patients will receive 75 mg of simeprevir, 50 mg samatasvir and 450 mg of TMC647055 plus a low dose of ritonavir as a pharmacokinetic enhancer, each once daily for 12 weeks, with or without the addition of ribavirin.
The HELIX-2 trial is the second study in HCV-infected patients to commence under a non-exclusive collaboration agreement between Idenix and Janssen established in January 2013. The HELIX-1 trial of samatasvir in combination with simeprevir was initiated in May 2013 and is ongoing.
For additional information about this study, please visit www.clinicaltrials.gov
For more information please contact:
Rein Piir, EVP Corporate Affairs & IR, mobile: +46 708 537 292
Simeprevir is an NS3/4A protease inhibitor jointly developed by Medivir and Janssen R&D Ireland for the treatment of chronic hepatitis C infection in combination with other antivirals in HCV genotype 1 & 4 infected subjects with compensated liver disease, including cirrhosis.
Simeprevir was approved for the treatment of genotype 1 hepatitis C in September 2013 in Japan and in the USA and Canada in November. A Marketing Authorisation Application was submitted to the European Medicines Agency (EMA) in April 2013 by Janssen-Cilag International NV seeking approval of simeprevir for the treatment of genotype 1 or genotype 4 chronic hepatitis C. To date, more than 3,700 patients have been treated with simeprevir in clinical trials.
TMC647055 is a potent non-nucleoside hepatitis C polymerase inhibitor with broad genotypic coverage. TMC647055 is in phase II clinical development and is developed by Janssen R&D Ireland to treat chronic hepatitis C virus infections. TMC647055 is being investigated in combination with other DAA agents in all oral interferon-free regimens. There have been no treatment-emergent serious adverse events reported in the program.
About Samatasvir (IDX719)
Samatasvir is an NS5A inhibitor with low picomolar, pan-genotypic antiviral activity in vitro. To date, samatasvir has been safe and well-tolerated after single and multiple doses of up to 150 mg in healthy volunteers up to 14 days duration, and in HCV-infected patients up to 12 weeks duration. There have been no treatment-emergent serious adverse events reported in the program. Samatasvir has demonstrated potent pan-genotypic antiviral activity in HCV-infected patients with mean maximal viral load reductions up to approximately 4.0 log10 IU/mL across HCV genotypes 1-4 in a proof-of-concept, three-day monotherapy study.
Medivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir, a novel protease inhibitor for the treatment of hepatitis C that is being developed in collaboration with Janssen R&D Ireland. The company is also working with research and development in other areas, such as bone disorders and neuropathic pain. Medivir has also a broad product portfolio with prescription pharmaceuticals in the Nordics.
For more information about Medivir AB, please visit the Company’s website: www.medivir.com
Medivir is a collaborative and agile pharmaceutical company with an R&D focus on infectious diseases and a leading position in hepatitis C. We are passionate and uncompromising in our mission to develop and commercialize innovative pharmaceuticals that improve people’s health and quality of life.