December 22, 2013

Journal of Gastroenterology and Hepatology

Volume 29, Issue 1, pages 121–127, January 2014

Hepatology

Fanni Gelley2, Gergely Zadori2, Balazs Nemes2, Matteo Fassan4,Gabor Lendvai1, Eniko Sarvary2, Attila Doros2,  Zsuzsanna Gerlei2, Peter Nagy3, Zsuzsa Schaff1, Andras Kiss1,*

Article first published online: 19 DEC 2013

DOI: 10.1111/jgh.12362

© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

Keywords: HCV receptors;  HCV; liver transplantation;  microRNA;  SVR

Abstract

Background and Aim

Management of hepatitis C virus (HCV) recurrence is a major challenge after liver transplantation. Significant dysregulated expression of HCV receptors (i.e. claudin-1, occludin, tetraspanin CD81, scavenger receptor type B1) has been shown recently during HCV infection. This might facilitate hepatocytic entry and reinfection of HCV. MicroRNAs (miRs) play role in the regulation of gene expression. We aimed to characterize miR expression profiles related to HCV infection and antiviral therapy in adult liver transplant recipients, with special emphasis on miRs predicted to target HCV receptors.

Methods

Twenty-eight adult liver transplant recipients were enrolled in the study. Paired biopsies were obtained at the time of HCV recurrence and at the end of antiviral treatment. MiRs for HCV receptors were selected using target prediction software. Expression levels of miR-21, miR-23a miR-34a, miR-96, miR-99a*, miR-122, miR-125b, miR-181a-2*, miR-194, miR-195, miR-217, miR-221, and miR-224 were determined by reverse transcription–quantitative polymerase chain reaction.

Results

miR-99a* and miR-224 expressions were increased in HCV recurrence samples, while miR-21 and miR-194 were decreased in comparison to normal liver tissue. Increased expressions of miR-221, miR-224, and miR-217 were observed in samples taken after antiviral therapy when compared with HCV recurrence samples. High HCV titer at recurrence was associated with higher level of miR-122.

Conclusions

Samples at recurrence of HCV and after antiviral therapy revealed distinct HCV-related miR expression profiles, with significant dysregulation of those miRNAs potentially targeting mRNAs of HCV receptors. In particular, miR-194 and miR-21 might be involved in the regulation of HCV receptor proteins' expression during HCV infection and antiviral therapy.

Source

By Chris Weller | Dec 20, 2013 02:22 PM EDT

http-content

(Reuters)  People with HIV can now expect to live into their early 70s. But what kind of life will that longevity entail?

Thanks to antiretroviral therapy, a combination of drugs that suppresses the spread of HIV (human immunodeficiency virus) within the body, young patients who are HIV-positive now enjoy a life expectancy that rivals the average American, a new study finds.

Underlying this shining discovery, however, is the sobering question of what state these young patients will live out their remaining years in. Barring the potential development of a cure, HIV management comes with a mountain of side-effects, some of which are devastating conditions on their own. And since each patient’s case is unique, the combination of certain drug therapies, patient background, and interaction with other drugs and risk factors may make antiretroviral therapy (ART) the key to longevity but not necessarily to rejuvenation.

“[It is] nothing short of miraculous, given where we were 20 years ago,” Dr. Mark Smith, president of the California Health Care Foundation, not involved in the study, and who treats people with HIV, told Healthline. “It's a stunning success story for biomedical science and has contributed greatly to our understanding of other viruses and disease processes as well."

Researchers collected data on 23,000 patients as part of the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), each aged 20 years and older. They took a look at death rates across various time periods, finding that life spans increased from 36.1 years in 2000 to 2002 to 51.4 in 2006 to 2007. Extrapolating for today’s advances and current treatment methods, the team estimated that people living with HIV could potentially live into their early seventies, or roughly the equivalent of the average American.

Unfortunately, the news isn’t all good. Whites were significantly more likely to outlive non-whites, and people with no prior drug use had much better chances than people who had used drug intravenously. While a young white HIV patient may live into his or her seventies, drug users typically lived until age 49 and non-whites until age 58. “Across the board, communities of color fare worse than their white counterparts,” Kyle Murphy, assistant director of communications for the National Minority AIDS Council, toldHealthline. “They are diagnosed much later and are less likely to be retained in care or to be virally suppressed.”

Meanwhile, HIV treatment remains a challenge for all. From minor abdominal pain and dizziness to renal failure and HIV-associated neurocognitive disorder, the side-effects of antiretroviral drugs depend on a raft of different factors. If patients don’t follow their drug therapy regimens, they raise their risk of transmitting the disease to others, as it is now less suppressed and can more easily do damage. And despite some theories of “hit hard, hit early” in order to minimize this damage, the costs of facilitating such treatment can run patients into enormous debt.

In the end, however, extending patient life spans is seen by many as a universal good. It means the drug therapies are working. Indeed, certain researchers are skeptical that a cure may never be found, as it means less profit from repeat medication buyers. But on a personal level, it means a great deal. Smith, for instance, has a patient with HIV who is 70 years old.

“He walks his grandkids to school," Smith explained. "The irony is that now I have to worry about the same things I worry about with any 70-year-old — lipids, blood pressure, etc. Five years ago, frankly, I didn't spend a lot of time on mildly elevated blood pressure in people with HIV.”

Source: Samji H, Cescon A, Hogg R. Closing the Gap: Increases in Life Expectancy among Treated HIV-Positive Individuals in the United States and Canada. PLoS One. 2013.

Source

You are receiving this message as a subscriber to the FDA hepatitis electronic list serve. The purpose of the list serve is to relay important information about viral hepatitis-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment.
Please do not reply to this message.

Changes have been made to the Baraclude (entecavir) label to reflect a new protective outer cardboard carton added as secondary packaging for 0.5 and 1 mg tablets, intended to help avoid exposure to light.  The container has been updated with the wording "Protect from Light."

The label reflects the change under 16 HOW SUPPLIED/STORAGE AND HANDLING as follows:

Storage
BARACLUDE Tablets should be stored in a tightly closed container at 25° C (77° F); excursions
permitted between 15–30° C (59–86° F) [see USP Controlled Room Temperature]. Store in the
outer carton to protect from light.

BARACLUDE Oral Solution should be stored in the outer carton at 25° C (77° F); excursions
permitted between 15–30° C (59–86° F) [see USP Controlled Room Temperature]. Protect from light. After opening, the oral solution can be used up to the expiration date on the bottle. The bottle and its contents should be discarded after the expiration date.

The Patient Product Information similarly summarizes the storage information as follows:

How should I store BARACLUDE?

  • Store BARACLUDE Tablets or Oral Solution at room temperature, between 59° F to 86° F (15° C to 30° C).
  • Keep BARACLUDE Tablets in a tightly closed container.
  • Do not store BARACLUDE Tablets in a damp place such as a bathroom medicine cabinet or near the kitchen sink.
  • Store BARACLUDE Tablets or BARACLUDE Oral Solution in the original carton, and keep the carton out of the light.

The complete revised label will be posted at Drugs@FDA.

Baraclude is a nucleoside analogue indicated for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

Baraclude is a product of the Bristol-Myers Squibb Company

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Office of Special Health Issues
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Division of Antiviral Drug Products
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---------

Treating HCV Infection in Patients Receiving Hemodialysis

December 17, 2013

Atif Zaman, MD, MPH reviewing Liu CH et al. Ann Intern Med 2013 Dec 3.

Until next-generation drugs become approved for this population, adding low-dose ribavirin to standard peginterferon therapy improves sustained virologic response.

Although the next-generation regimens for hepatitis C virus (HCV) are effective, currently, the standard approved regimen for patients receiving hemodialysis is still peginterferon plus low-dose ribavirin (200 mg/day). The addition of low-dose ribavirin was approved by the FDA in August 2011. However, that approval was based on small studies that were very heterogeneous with regard to treatments, HCV genotypes, and endpoints. Therefore, the efficacy and safety of combination therapy compared with monotherapy in this population is unclear.

In the current open-label, randomized, controlled trial, 205 treatment-naive patients with genotype 1 HCV infection receiving hemodialysis were randomized to receive either peginterferon alone (135 µg weekly) or in combination with ribavirin (200 mg daily) for 48 weeks. Outcomes were sustained virologic response (SVR) rate and adverse event–related withdrawal rate.

SVR was significantly higher in the combination group compared with the monotherapy group (64% vs. 33%, respectively; P<0.001). As expected, significant anemia (hemoglobin level <8.5 g/dL) was higher among the patients receiving ribavirin (72% vs. 6%; P<0.001), who also required higher doses of erythropoietin (P=0.006) for a longer duration (P=0.004). Adverse event–related withdrawal rates were similar in the combination and monotherapy groups (7% and 4%).

COMMENT

In this large treatment study, sustained virologic response was higher with combination peginterferon and ribavirin compared with monotherapy in patients with genotype 1 hepatitis C virus infection receiving hemodialysis. Using the very low dose of 200 mg daily of ribavirin not only achieved an SVR rate comparable to that reported in patients who were not receiving hemodialysis, but also kept the discontinuation rate due to adverse events low. While we wait for the safety and efficacy data of the new HCV regimens in patients receiving hemodialysis, peginterferon plus low-dose ribavirin is a viable option.

Editor Disclosures at Time of Publication

CITATION(S):

  1. Liu CH et al. Pegylated interferon-α2a with or without low-dose ribavirin for treatment-naive patients with hepatitis C virus genotype 1 receiving hemodialysis: A randomized trial. Ann Intern Med 2013 Dec 3; 159:729. (http://dx.doi.org/10.7326/0003-4819-159-11-201312030-00005)

Source

Journal of Hepatology

Article in Press

Sumeet K. Asrani, Jayant A. Talwalkar, Patrick S. Kamath, Vijay H. Shah, Giovanna Saracino, Linda Jennings, John B. Gross, Sudhakar Venkatesh, Richard L. Ehman

Received 12 June 2013; received in revised form 27 November 2013; accepted 9 December 2013. published online 20 December 2013.
Accepted Manuscript

Abstract

Background and Aims

Non-invasive predictors identifying subjects with compensated liver disease at highest risk for transitioning to a decompensated state are lacking. We hypothesized that liver shear stiffness as measured by magnetic resonance elastography is an important non-invasive predictor of hepatic decompensation.

Methods

Among patients with advanced fibrosis undergoing magnetic resonance elastography (2007-11), a baseline cohort and follow up cohort (compensated liver disease) were established. Cause specific cox proportional hazards analysis adjusting for competing risks was utilized to determine the association between elevated liver shear stiffness and development of decompensation (hepatic encephalopathy, ascites, variceal bleeding).

Results

In the baseline cohort (n=430), subjects with decompensated liver disease had a significantly higher mean liver shear stiffness (6.8 kPa, IQR 4.9-8.5) as compared to subjects with compensated liver disease (5.2 kPa, IQR 4.1-6.8). After adjustment for Model for End Stage Liver Disease score, hepatitis C, age, gender, albumin, and platelet count, the mean liver shear stiffness (OR=1.13, 95%CI 1.03-1.27) was an independently associated with decompensated cirrhosis at baseline. Over a median follow up of 27 months (n=167), 7.2% of subjects with compensated disease experienced hepatic decompensation. In the follow up cohort, the hazard of hepatic decompensation was 1.42 (95% CI 1.16 -1.75) per unit increase in liver shear stiffness over time. The hazard of hepatic decompensation was 4.96 (95% CI 1.4-17.0, p=0.019) for a subject with compensated disease and meanLSS value greater then or equal to 5.8 kPa as compared to an individual with compensated disease and lower mean LSS values.

Conclusion

Baseline liver shear stiffness assessed by magnetic resonance elastography is independently associated with decompensated liver disease.

Abbreviations: LSS, Liver shear stiffness, MRE, magnetic resonance elastography, HCV, hepatitis C, MELD, model for end stage liver disease, CI, confidence interval, OR, Odds ratio

Keywords: Non invasive, Outcomes, Natural history, Prognosis, Cirrhosis

Source

Clinical Gastroenterology and Hepatology

Article in Press

Robert J. Wong, Pardha Devaki, Long Nguyen, Ramsey Cheung, Cheryl Cho-Phan, Mindie H. Nguyen

Received 29 July 2013; received in revised form 14 November 2013; accepted 6 December 2013. published online 19 December 2013.
Accepted Manuscript

Abstract

Background & Aims

Assignment of model for end-stage liver disease (MELD) exception points to patients with hepatocellular carcinoma (HCC) who fall within Milan criteria, which began in 2003, increases their priority on liver transplantation waitlists. However, little is known about how this change affected survival of all patients with HCC (transplant eligible and ineligible). We compared long-term survival of HCC patients before and after this change.

Methods

We performed a large population-based cohort study using the Surveillance, Epidemiology, and End Results cancer registry to investigate survival times of patients with HCC before those who met the Milan criteria were given MELD exception points (1998–2003) and afterward (2004–2010), using Kaplan Meier methods. Multivariate Cox proportional hazards models evaluated independent predictors of survival.

Results

During 2004–2010, a significantly higher percentage of patients with HCC survived for 5 years compared to 1998-2003 (21.9% vs 13.0%, P<.001). This difference remained significant among all treatment groups (no therapy: 15.2% vs 10.2%, P<0.001; local tumor destruction: 37.6% vs 22.1%, P<0.001; resection: 55.5% vs 39.2%, P<0.001; transplantation: 77.2% vs 73.1%, P =0.12). Multivariate Cox proportional hazards models, inclusive of sex, age, ethnicity, Milan criteria, number and stage of tumor, and time period, showed increased survival of patients during 2004–2010 (hazard ratio [HR], 0.87; 95% confidence interval, 0.83–0.91; P<.001). Compared to non-Hispanic whites, Asians (HR, 0.81; 95% CI, 0.77–0.86; P<.001) and Hispanics (HR, 0.89, 95% CI, 0.84–0.95; P<.001) had longer survival times, whereas blacks had a trend toward shorter survival times (HR, 1.05; 95% CI 0.98–1.13; P=.16).

Conclusions

Patients with HCC who met Milan criteria had significantly longer survival times after implementation of the MELD exception points, regardless of sex or ethnicity. Blacks continued to have the lowest rates of 5 year survival.

Keywords: SEER, racial disparities, liver cancer, resource allocation

Abbreviations: CI, confidence interval, HCC, hepatocellular carcinoma, HR, hazard ratio, MELD, model for end stage liver disease, SEER,surveillance, epidemiology, and end results, TACE, transarterial chemoembolization, UNOS, United Network for Organ Sharing

Source

Clinical Gastroenterology and Hepatology

Article in Press

George N. Ioannou, Lauren A. Beste, Pamela K. Green

Received 14 October 2013; received in revised form 18 November 2013; accepted 2 December 2013. published online 19 December 2013.
Accepted Manuscript

Abstract

Background

& Aims: We investigated the real-world effectiveness of triple therapy regimens against hepatitis C virus (HCV) and compared rates of sustained virologic response (SVR) between telaprevir- and boceprevir-based regimens in a population-based study.

Methods

We analyzed data on all patients in the Veterans Administration (VA) healthcare system who were infected with HCV genotype 1 and began treatment with pegylated interferon, ribavirin, and either boceprevir (n=3696, 83%) or telaprevir (n=759, 17%) from June 2011 through February 2013.

Results

Patients treated with telaprevir were more likely to have baseline characteristics associated with not achieving SVR than patients treated with boceprevir. Fewer than half of patients eligible for short-duration regimens (28 weeks for boceprevir, 24 weeks for telaprevir) successfully completed treatment (37% for boceprevir, 27.5% for telaprevir); ∼25% discontinued early and the remaining patients were treated for longer durations. Of patients who were supposed to complete 48-week regimens, only 35% of boceprevir- and 34% of telaprevir-treated patients completed >44 weeks. The rate of SVR was 51.5% overall, 42.7% among patients with cirrhosis, 56.8% among treatment-naïve patients, 64.2% among prior relapsers, 31.7% among prior partial-responders, and 29.8% among prior null responders. There were no significant differences in rate of SVR between patients given boceprevir or telaprevir, in the entire population or among subgroups. The most important predictors of failure to achieve SVR were IL28B genotype, high viral load, Black race, diabetes, high APRI or FIB-4 scores, low platelet counts, or low levels of low-density lipoprotein cholesterol. Erythropoietin use was not associated with SVR.

Conclusions

In a nationwide analysis of Veterans with HCV genotype 1 infection, rates of SVR are similar for those treated with boceprevir vs telaprevir. However, rates of treatment completion and SVR in real clinical practice are substantially lower than those in clinical trials.

Keywords: DAA, antiviral therapy, population, APRI, outcome, LDL

Source

Tulane researcher gets $2.6M in grants for hepatitis studies

THE ASSOCIATED PRESS  
December 22, 2013 - 9:35 am EST

NEW ORLEANS — Tulane University pathology professor Srikanta Dash has been awarded two National Institutes of Health grants totaling $2.6 million to study why some patients respond and other develop resistance to standard treatments for chronic hepatitis C.

The disease is the most common cause of end-stage liver disease.

Dash, director of Tulane's hepatitis research laboratory, received a $1.4 million, four-year grant from the National Institute of Allergy and Infectious Diseases to explore the mechanisms behind a gene that plays a critical role in whether a patient with hepatitis C responds to antiviral treatment.

The second award is a $1.2 million National Cancer Institute grant to study how chronic hepatitis C develop resistance to interferon therapies.

Source

Centers for Disease Control and Prevention (CDC) sent this bulletin at 12/19/2013 01:50 PM EST

Viral Hepatitis Updates from CDC

MMWR - CDC Guidance for Evaluating Health-Care Personnel for Hepatitis B Virus Protection and for Administering Postexposure Management

The MMWR is an extension of the ACIP 2011 recommendations for evaluating hepatitis B protection among health-care personnel (HCP) and administering post-exposure prophylaxis. The MMWR emphasizes the importance of administering Hepatitis B vaccination for all health-care personnel and provides explicit guidance for evaluating hepatitis B protection among previously vaccinated health-care personnel (particularly those who were vaccinated in infancy or adolescence), and it clarifies recommendations for postexposure management of health-care personnel exposed to blood or body fluids. This new guidance can assist clinicians, occupational health and student health providers, infection-control specialists, hospital and health-care training program administrators, and others in selection of an approach for assessing Hepatitis B protection for vaccinated health-care personnel.
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6210a1.htm

Testing Asian Americans & Pacific Islanders for Hepatitis B – Clinical Summary

Studies have shown that while Asian Americans and Pacific Islanders (AAPI) represent 5% of the total U.S. population, they make up 50% of hepatitis B cases. Nearly 2 in 3 people living with chronic hepatitis B do not know they are infected. Testing for chronic hepatitis B plays an important role in the detection, classification, management and medical care for patients with hepatitis B. This fact sheet outlines who should be tested for Hepatitis B with an HBsAg test, the geographic distribution of chronic hepatitis B infection worldwide, recommended follow-up for a positive HBsAg, and interpretation of serologic tests.
http://www.cdc.gov/hepatitis/HBV/PDFs/HepB-API.pdf

Know Hepatitis B Campaign Materials

Know Hepatitis B a national communications campaign promoting Hepatitis B testing among Asian Americans and Pacific Islanders (AAPIs).  Four languages have been added:  Burmese , HmongKhmer, and Lao to campaign materials already available in Chinese, Vietnamese, Korean, and English. English, Chinese, Korean, Vietnamese and multi-lingual posters are also now available for ordering.

Source

Expert Opin Investig Drugs. 2013 Dec 20. [Epub ahead of print]

Qiu Z, Dai Y.

Abstract

Introduction: microRNA (miRNA) regulates target gene expression to influence many physiological and pathophysiological processes. The liver-specific miRNA, miR-122, contributes to liver function and plays a very important role in hepatic diseases including the viral hepatitis C (HCV). For this reason, developing an miR-122-related clinical application could be very useful in managing or treating many hepatic disorders. Areas covered: This review introduces the basic concepts of miRNA and miR-122. It also discusses the possibility of miR-122 as a biomarker and summarizes the results of anti-miR-122 treatment from basic research to a Phase IIa clinical trial. Furthermore, the authors discuss the potential opportunities and challenges found in clinical trials with miravirsen. Expert opinion: miR-122 may be a useful biomarker as both a diagnostic and prognostic tool. Furthermore, miravirsen is a novel treatment with great potential for hepatic disease treatment, especially in HCV. However, there is certainly the need for future investigations to better determine whether miR-122 is really specific for liver. It is also important to elucidate whether miR-122 is actually specific for HCV genome and further investigate the therapeutic potential of miravirsen. Only once these studies have been completed can anti-miR-122 treatment potentially enter the clinical practice.

PMID: 24354366 [PubMed - as supplied by publisher]

Source

J Clin Gastroenterol. 2013 Dec 18. [Epub ahead of print]

Bonner JE, Esserman DA, Golin CE, Evon DM.

Abstract

GOALS:: To investigate the role of self-efficacy (SE) during hepatitis C virus (HCV) treatment.

BACKGROUND:: Adherence to chronic HCV treatment is critical. SE is an important predictor of medication adherence in a number of chronic disease populations and medication regimens, but its role during HCV treatment remains unknown.

STUDY:: Data from the prospective Virahep-C study were analyzed to examine relationships between SE and patient-driven deviations (ie, missed doses measured using electronic pill caps, and nonpersistence) from adherence to HCV antiviral treatment. SE was measured using the 17-item HCV Treatment Self-Efficacy scale. This measure provides a global estimate of a patient's confidence to undergo and adhere to HCV treatment, and can estimate SE in 4 underlying domains: communication SE (ie, confidence to communicate with health care provider), physical coping SE (ie, confidence to cope with physical side effects), psychological coping SE (ie, confidence to cope with psychiatric side effects), and treatment adherence SE (ie, confidence to take all medications as prescribed and attend doctor visits). Generalized estimating equations and Cox proportional hazards models were used to assess associations between SE and missed doses and nonpersistence, respectively.

RESULTS:: SE was associated with being in a relationship, educated, privately insured, and less depressed. Higher communication SE at TW24 reduced the risk of missed doses between TW24 and TW48. Higher baseline treatment adherence SE reduced the likelihood of nonpersistence between baseline and TW24.

CONCLUSIONS:: SE's relationship to HCV treatment adherence has promising clinical and research implications.

PMID: 24356458 [PubMed - as supplied by publisher]

Source

J Gastroenterology
DOI 10.1007/s00535-013-0926-7

Shinya Maekawa • Nobuyuki Enomoto
Received: 7 December 2013 / Accepted: 10 December 2013
Springer Japan 2013

Hepatitis C virus (HCV) is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC), and it is estimated that infected individuals total 185 million people worldwide. In Japan, around 2 million are infected with HCV, and more than 20 thousand die from HCV-induced HCC annually. Though viral eradication with antiviral therapies is the most important and effective choice for decreasing HCC-related deaths induced by HCV, complete viral eradication has been quite difficult till recently, especially in patients with genotype-1 HCV infection because of the low response rate to interferon (IFN)-based therapy [1, 2].

In this background, development of novel direct-acting antiviral agents (DAAs) specific for HCV was truly a revolutionary event. In 2011, two first-generation NS3 protease inhibitors (PIs), telaprevir and boceprevir, were firstly approved among all the DAAs for clinical use in USA and Europe for genotype-1 HCV in combination with pegylated-interferon and ribavirin (PR), while telaprevir was approved in Japan in the same 2011 period. As expected, a regimen including telaprevir in combination with pegylated-interferon and ribavirin dramatically improved the sustained viral response (SVR) rate to as high as 80 % in genotype-1 HCV infection. On the other hand, telaprevir has several undesirable problems. Among all, adverse events (AEs) of anemia and skin rash are serious problems of telaprevir, and Grade 3/4 skin disorders, including Stevens–Johnson syndrome and drug rashes with eosinophilia and systemic symptoms, as well as Grade 3 anemia (\8.0 g/dL), might occur [3, 4]. Moreover, cumbersome frequent dosing three times a day (every 7–9 h) could induce poor medication adherence. Under the circumstances, it has been quite stressful for patients as well as clinicians to introduce and monitor this telaprevir-based regimen.

Simeprevir (SMV, TMC435) is classified as a second generation PI with the macrocyclic structure having an advantage in the binding affinity and specificity for NS3 protease compared to the first-generation PI with the linear structure. Due to the difference in the structure, the drugresistance profile is somewhat different from that of telaprevir. Though simeprevir shows cross-resistance with telaprevir at amino acid positions of 155 and 156, most of the resistant mutation occurs at the simeprevir-specific amino acid position of 168 [5]. Though simeprevir is effective in all viral genotypes (genotype 1–6), it has the strongest antiviral activity for genotype-1a and -1b HCV infection. In particular, low AE rate and its patient-friendly once-daily dosing are the important characters of simeprevir aside from its strong antiviral activity. In the international phase II trials of simeprevir in combination with PegIFNa-2a/RBV for treatment-naı¨ve (PILLAR study) [6] and treatment-experienced patients (ASPIRE study) [7] for HCV genotype 1-infected patients, it was demonstrated that simeprevir was generally well tolerated and had a pharmacokinetic profile supporting once-a-day (QD) dosing resulting in high virologic response rates.

In this issue of the Journal of Gastroenterology, Hayashi et al. [8] reported the important results of the phase II Dose and duration Ranging study of Antiviral agent TMC435 in Genotype One HCV treatment-Naı¨ve patients (DRAGON study; TMC435-C215) evaluating once-daily simeprevir with pegylated-interferon and ribavirin therapy for treatment- naı¨ve, high viral-loaded hepatitis C genotype 1-infected patients in Japan. Due to the result of previous phase I study that simeprevir plasma concentration was higher in Japanese healthy volunteers compared with Caucasian volunteers, simeprevir doses of 50/100 mg QD were selected for this study, while simeprevir doses of 150 mg QD were selected in western countries [9]. Through investigating five treatment groups (SMV12/PR24 50 mg, SMV12/PR24 100 mg, SMV24/PR24 50 mg, SMV24/PR24 100 mg, and PR48), it was disclosed that simeprevir-combined groups all achieved high SVR rate (77–92 % compared to 46 % for PR). As to the AEs, simeprevir was well tolerated, and the incidence of anemia and skin rash were similar in their frequency and their grade between all the SMV groups and the PR group. Due to low AEs, therapy discontinuation rate and ribavirin dose reduction was also similar in the SMV groups and the PR group. While an AE of bilirubin elevation was specific to simeprevir, and it reached to grade 3 (2.6–5.0 mg/dL) to 4 ([5.0 mg/dL) in four patients (5 %) leading to the discontinuation of simeprevir in these individuals, the bilirubin level returned to baseline after the end of simeprevir in those patients. Since bilirubin elevation is considered to result from the blockade of bilirubin clearance-associated OATP1B1 and MRP transporters by simeprevir [10], it is considered that the bilirubin elevation by simeprevir does not reflect deterioration of liver function.

Following the results of this phase II DRAGON study, treatment dosage of simeprevir was determined as 100 mg QD in Japan, and successive phase III CONCERTO studies for simeprevir/pegylated-interferon/ribavirin therapy have been conducted (CONCERTO-1 for treatment-naı¨ve, -2 for previous null responder, -3 for previous relapser, and -4 for naı¨ve, null responder and relapser). After the completion of those CONCERTO studies with favorable outcomes for simeprevir-based regimens, once-daily simeprevir with pegylated-interferon and ribavirin therapy for high viralloaded hepatitis C genotype 1-infected patients was just recently approved for clinical use in Japan.

Considering the history of HCV therapy, this new therapy of once-daily simeprevir with pegylated-interferon and ribavirin therapy is ideal in its high efficacy and low AEs. Of course, it is true that DAA combination therapies without IFN (IFN-free therapies) would appear in the near future, and that these IFN-free therapies are advantageous in that they are free from IFN-related AEs. However, in terms of DAA-resistant viral mutants, it is considered that these mutant HCVs generally have low replication fitness, and are sensitive to IFN. Therefore, it is speculated that IFN-based DAA therapies compared to IFN-free DAA therapies are safer in preventing the development of multidrug resistant HCVs.

Taken together, the new regimen of once-daily simeprevir with pegylated-interferon and ribavirin therapy would surely be an important milestone in the therapy for high viral-loaded hepatitis C genotype-1 infected patients in the era of DAA therapy.

References

1. Kim MN, Kim BK, Han KH. Hepatocellular carcinoma in patients with chronic hepatitis C virus infection in the Asia- Pacific region. J Gastroenterol. 2013;48(6):681–8.

2. Thomas DL. Global control of hepatitis C: where challenge meets opportunity. Nat Med. 2013;19(7):850–8.

3. Chayama K, Hayes CN, Ohishi W, Kawakami Y. Treatment of chronic hepatitis C virus infection in Japan: update on therapy and guidelines. J Gastroenterol. 2013;48(1):1–12.

4. Kumada H, Toyota J, Okanoue T, Chayama K, Tsubouchi H, Hayashi N. Telaprevir with peginterferon and ribavirin for treatment-naive patients chronically infected with HCV of genotype 1 in Japan. J Hepatol. 2013;56(1):78–84.

5. Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, et al. In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435. Antimicrob Agents Chemother. 2010;54(5):1878–87.

6. Fried MW, Buti M, Dore GJ, Flisiak R, Ferenci P, Jacobson I, et al. Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naive genotype 1 hepatitis C: the randomized PILLAR study. Hepatology. 2013;58(6):1918–29.

7. Zeuzem S, Berg T, Gane E, Ferenci P, Foster GR, Fried MW, et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology. 2013. doi:10.1053/j. gastro.2013.10.058.

8. Hayashi N, Seto C, Kato M, Komada Y, Goto S. Once-daily simeprevir (TMC435) with peginterferon/ribavirin for treatmentnaı ¨ve hepatitis C genotype 1-infected patients in Japan: the DRAGON study. J Gastroenterol. 2013. doi:10.1007/s00535-013- 0875-1.

9. Verloes R, Shishido A. Phase I safety and PK of TMC435 in healthy volunteers and safety, PK and short-term efficacy in chronic hepatitis C infected individuals. Kobe: Abstract O-32 presented at the Japanese Hepatology Congress; 2009. p. 4–5.

10. Huisman MT, Snoeys J, Monbaliu J, Martens M, Sekar V, Raoof A. In vitro studies investigating the mechanism of interaction between TMC435 and hepatic transporters. Poster 278 presented at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), Boston, USA, October 29– November 2, 2010.

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What a Year for Harm Reduction!

Provided by The Huffington Post

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Hilary McQuie
Western Regional Director, Harm Reduction Coalition

Posted: 12/22/2013 9:16 am

Harm reduction is a movement for social justice built on a belief in, and respect for, the rights of people who use drugs. Harm reduction is also a set of practical strategies and ideas aimed at reducing negative consequences associated with drug use. Although those working in harm reduction believe that drug criminalization maximizes harm, the focus of most harm reduction policy and practice is in the borderlands between legalization and prohibition. To quote an old social justice slogan, harm reduction is the art of "building a new society in the vacant lots of the old." And those lots are filling up, due to the hard work of people around the world. Here are 10 of the most important harm reduction developments in North America in 2013:

1. "Needle Exchange" in the US Turns 25

A quarter of a century ago, public health activists started doing needle exchange in Tacoma, WA, San Francisco, CA, and New York, NY. These efforts, now referred to as 'syringe access programs', spread and continued and have been widely recognized as the single most successful HIV prevention intervention. To date, however, they are legally excluded from receiving access to the federal funding enjoyed by all other HIV prevention efforts. Perhaps in 2014, we can report that the federal funding ban for syringe access programs was finally lifted for good.

2. States Decriminalize Syringes to Increase Safe Syringe Access

Syringe access policy varies by state, and this year, community organizing led the Nevada legislature to finally pave the way for syringe access programs and over the counter pharmacy sales by fully decriminalizing syringes, making it one of the strongest state enabling laws for syringe access programming. North Carolina partially decriminalized syringes to protect law enforcement from needlestick injury, but without legalizing their existing syringe access programs, yet.

3. Laws Passed in Six States to End Overdose Epidemic by Providing Antidote

Opioid overdose has surpassed auto accidents as the leading cause of accidental death in the US. New laws were passed this year in six states to encourage health care providers and community programs to widely distribute naloxone to treat opioid overdose incidents. Additionally, new programs started providing naloxone access in Colorado, Vermont, North Carolina, Kentucky, Ohio, New Jersey, Minnesota, and Missouri this year. Naloxone is used in opioid overdoses to counteract life-threatening depression of the central nervous system and respiratory system, allowing an overdosing person to breathe normally. Although traditionally administered by emergency response personnel, naloxone can be administered by minimally trained laypeople, which makes it ideal for treating overdose in people who have been prescribed opioid pain medication and in people who use heroin and other illicit opioids.

4. Opioid Overdose Antidote Provided by Rhode Island Walgreens Pharmacists Directly to Patients

2013 saw a statewide scale up of a collaborative pharmacy practice agreement for naloxone, bringing naloxone to all 26 Walgreens stores in Rhode Island and training 80 Walgreens pharmacists in how to counsel patients on, train in, and dispense naloxone (without a prescription) to anyone who asks for it.

5. Federal Agencies Declare Support for Peer-Delivered Naloxone Distribution

Under the Bush Administration, officials in the Office of National Drug Control Policy (ONDCP) opposed peer-delivered naloxone. Then Deputy Director Bertha Madras said drug users "aren't likely to be competent to deal with an overdose emergency", and stated that "rescue programs might take away the drug user's motivation to get into detoxification and drug treatment". Obama's White House Office of National Drug Control Policy takes a position 180 degrees from Madras, supports overdose prevention and naloxone programs, and included them in the 2013 Drug Control Strategy. Also this year, the drug treament agency of the federal government, the Substance Abuse and Mental Health Services Administration (SAMHSA) published their long-awaited "Opioid Overdose Prevention Toolkit" which has five components targeting first responders, community members, patients, prescribers, and overdose survivors and their family members. The toolkit provides information on naloxone distribution and prescription and overdose prevention. Peer-delivered naloxone distribution has definitely gone from an underground movement to a mainstream-supported strategy in 2013. Next year, perhaps we can report some funding for this critical yet unfunded lifesaver.

6. Jail-Based Overdose Prevention and Naloxone Distribution Begins

Opiate overdoses are all too common among people released from jail due to decreased tolerance. In March 2013, the Harm Reduction Coalition's Drug Overdose Prevention and Education (DOPE) Project began providing naloxone to inmates of the San Francisco County Jail as they were discharged. The DOPE Project, in collaboration with SFDPH's Jail Health Services, conducts overdose prevention trainings inside the jail, and is able to put naloxone kits in the property of inmates who choose to participate for pick up when they are released. This is the first non-research study in the country to begin providing naloxone directly to inmates as they re-enter the community.

7. Good Samaritan Laws for People Witnessing Overdoses Gain Traction, Law Enforcement Support

Community activists have been working to get Good Samaritan laws passed to protect people from arrest and prosecution for drug possession when they call 911 to report an overdose. Fourteen states have now enacted these laws, as have ninety college campuses. The Florida effort in 2012 was notably initiated by Palm Beach police, a harbinger of change in law enforcement support for harm reduction measures.

8. Newly-Approved Hepatitis C Treatments Move Closer to Making Interferon-Free Cure a Reality for People Who Inject Drugs.

Hepatitis C remains endemic among people who inject drugs, with chronic infection rates of 70% or more among long-term injectors. While new infections have declined dramatically since peaking in the 1980s, due in part to the expansion of syringe access programs, several states report a new wave of hepatitis C infections among younger injectors. While hepatitis C is curable, treatment has traditionally required use of interferon, a drug with significant psychological and physical side effects that does not work for everyone and is difficult to tolerate for many, particularly current and former substance users. In December, the US Food and Drug Administration (FDA) approved a new hepatitis C medication sofosbuvir (Sovaldi, Gilead Sciences, Inc), which can be used without interferon for some people. Other therapies in development offer hope that all people with hepatitis C will have interferon-free treatment options available by the end of 2014.

9. Community Organizes to Mandate Hepatitis C Testing in New York

An estimated 3-4 million people are infected with the hepatitis C virus, and three quarters of them are unaware of it. Baby boomers - those born between 1945 and 1965 - make up over 70% of people with chronic infection, and are at highest risk of liver complications. Following CDC's 2012 recommendation of a one-time hepatitis C test for all baby boomers, a coalition of harm reduction workers, people who use drugs, and other allies passed a bill in New York mandating that doctors inform their patients and offer a hepatitis C test. As better-tolerated treatments with high cure rates become available, this legislation ensures that thousands of lives that may have been lost to liver cancer and other hepatitis C complications are diagnosed and treated.

10. Montreal Approved to Open Four Supervised Injection Sites

There are approximately 90 supervised injection sites worldwide in Europe and Australia, and only one in North America: InSite in Vancouver, British Columbia. After InSite's long legal fight with their conservative government, Canada's Supreme Court ruled in 2009 that the potential denial of health services and the correlative increase in the risk of death and disease to injection drug users outweigh any benefit that might be derived from maintaining an absolute prohibition on possession of illegal drugs on InSite's premises, allowing the facility to stay open indefinitely. In 2009, the site recorded 276,178 visits (an average of 702 visits per day) by 5,447 unique users; 484 overdoses occurred with no fatalities, due to intervention by medical staff. This month, Montreal was given permission to open four injection sites of their own, ensuring that Vancouver's InSite is the first but not the last legal supervised injection site in North America. Perhaps we finally succeed in opening one in the US in 2014.

Hilary McQuie is Regional Director of the Harm Reduction Coalition, and is based in Oakland, CA http://harmreduction.org/

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Killing Pain: Tramadol the 'Safe' Drug of Abuse

Published: Dec 22, 2013

By John Fauber, Reporter, Milwaukee Journal Sentinel/ MedPage Today

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For years following spine surgery, Anthony Fort suffered.

And like many with his condition, the 46-year-old gospel singer and former construction worker used a combination of medications to alleviate his pain.

But as he took more drugs, including narcotic painkillers, Fort was often groggy when awake. When he slept, he gurgled and snored so loudly that his fiancee recorded it so she could convince him he was using too much medication.

On May 18, 2011, he didn't wake up.

According to the Milwaukee County Medical Examiner Office he died of an accidental overdose of opioids.

Tramadol, a "Safe" Pain-Killer

Included in the mix were drugs well-known for their abuse and overdose potential -- hydrocodone and methadone -- and one that the medical world long had thought posed little threat: tramadol.

But doctors -- and the FDA, the agency charged with regulating drug safety -- may have gotten it wrong.

Recent research shows that tramadol has greater potential to be abused and to cause overdoses than was believed when it first appeared on the U.S. market in 1995.

A Journal Sentinel/MedPage Today investigation found that the FDA failed to heed a key piece of research indicating tramadol had the potential to be abused. Instead, the agency recommended not putting tramadol under the Controlled Substance Act. Restrictions on prescribing it are no more stringent than for Lipitor or Viagra.

The Controlled Substance Act places drugs into five progressively restrictive categories based on their abuse potential. At the top of the list are drugs such as heroin. At the other, are some cough medicines with limited amounts of codeine.

In approving tramadol, the FDA decision was based largely on research in which the drug was injected. The FDA also weighed evidence from Europe, where tramadol had been on the market for years.

But the FDA also had research showing that when given to opioid abusers orally in high doses, rather than being injected, it produced opiate-like effects that were similar to oxycodone, the narcotic in OxyContin, one of the most abused drugs in America.

The FDA did ask Ortho-McNeil, the company that marketed the tramadol, to fund a committee of paid consultants who were to watch for abuse problems that might require making it a controlled substance.

That never happened.

Emerging Danger

Now, after 18 years of less restrictive treatment, the U.S. Drug Enforcement Administration has proposed putting tramadol under the Controlled Substances Act. While that has not been done on the federal level, 10 states already have done so on their own.

An analysis by the Journal Sentinel and MedPage Today revealed that tramadol use has increased dramatically since 2008, rising from 25 million prescriptions that year to nearly 40 million in 2012, according to data from IMS Health, a market research firm.

In 2011, the drug was linked to 20,000 emergency department visits around the country.

In Florida alone, there were 379 overdose deaths involving tramadol in 2011, up from 106 in 2003.

In Milwaukee County, 20 people died of a drug overdose involving tramadol from 2010 through October 2013, according to records from the Medical Examiner's Office. In most of those cases, tramadol was one of several opioids that had been taken.

In May of 2011, Fort was found in bed not breathing by his fiancee, Latrice Wells Odom.

She said Fort started taking tramadol about 9 months before he died.

"I said, 'I don't like what it's doing to you,'" she said. "He said, 'Baby, I'm in so much pain.'"

Fort had been taking narcotic painkillers after injuring his back at a construction site several years earlier, Wells Odom said. A beam fell on his back, leading to surgery and the placement of 10 screws and a rod in his spine.

She said he never thought the tramadol might be dangerous.

"Tony's thing was, the doctor gave it to him so it must be safe," she said.

Tramadol was first introduced in Germany in 1977.

Evidence Overlooked

Data from Germany had suggested it was only about one-tenth as potent as morphine when injected. Other data showed that after years of use in Germany and other countries there was very little abuse of the drug.

However, in the early 1990s, researchers at Johns Hopkins University did a study in which high doses of the drug were given orally to opioid abusers. Taken that way, tramadol acted much differently than when injected.

At very high doses it produced opiate-like effects that were similar to high-dose oxycodone.

Taken by mouth, the drug is transformed in the liver to a metabolite known as M1, which is able to attach to and activate opioid receptors in the brain. It is that substance that is believed to produce the desirable, opiate-like effect.

In 1994, Ortho-McNeil, part of the R.W. Johnson Pharmaceutical Research Institute of Johnson & Johnson, sought approval from the FDA to sell Ultram, its brand name version of the drug in the U.S.

The Johns Hopkins study never was published but the company said it was provided to the FDA when it was reviewing the approval for tramadol.

"That paper certainly was accurate," said Thomas Kosten, MD, an addiction specialist and professor of psychiatry at Baylor College of Medicine. "You take enough of it, you can get high from it."

Sharon Walsh, PhD, an opioid researcher at the University of Kentucky College of Medicine, said the research provided important evidence that tramadol had the potential to be abused.

Given the findings of the Hopkins study, it is unlikely the FDA would approve tramadol today as a nonscheduled drug, said Walsh, director of the university's Center for Drug and Alcohol Research.

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But in the early 1990s, when the FDA approved the drug, abuse of opioids such as heroin and morphine often was done by addicts who injected the drugs. In the years that followed, dramatic increases in abuse of pill-form opioids such as OxyContin and Vicodin would plague the country.

Following the Money

Journal Sentinel/MedPage Todayinvestigations have showed that opioid companies paid millions of dollars to doctors and nonprofit medical societies that pushed for more liberal use of the drugs in treating chronic, noncancer pain. Yet, rigorous studies never have shown that the drugs are safe and effective when used that way.

Morgan Liscinsky, a spokeswoman for the FDA, said she could not comment on the agency's decision-making process that led to the drug's approval as a noncontrolled substance. As tramadol's public health and abuse risks became more fully recognized, the FDA now has recommended making it a controlled substance, she said.

Liscinsky noted that, at the time, the FDA's advisory committee unanimously said the drug should not be put under the Controlled Substances Act.

Yet there was concern that abuse of the drug might occur in the U.S., which was why the FDA asked an "independent steering committee," to monitor the drug as part of the FDA's marketing approval. Ortho-McNeil paid for the committee's work and also paid consulting fees to its members.

Sidney Schnoll, MD, PhD, a former member of the committee, said he could not remember how much the committee members were paid. In total, the program cost Ortho-McNeil about $15 million a year, said Schnoll, now an executive with Pinney Associates, a Bethesda, Md. company that works with drug and opioid companies.

From early on, Ortho-McNeil's marketing plan for tramadol meant keeping it off the controlled substances list where it would have difficulty competing against other narcotic painkillers such as Tylenol 3 and Tylenol 4, Schnoll said in a 2009 interview. Both Tylenol products contain codeine and are schedule 3 drugs.

The interview was done with two professors, one from the University of Florida and one from Rensselaer Polytechnic Institute in New York, as part of a project at University of Michigan Substance Abuse Center.

"There were equally good products that were cheaper on the market," he said, according to a transcript of the interview. "So they really wouldn't have much of the market. They wanted to see if it would be possible to get the drug onto the market as a noncontrolled substance."

After a decade, the eight-member Ortho-McNeil committee dissolved itself in December 2005, without ever having recommended that tramadol be put under the Controlled Substances Act.

"There was absolutely nothing independent about this group," said Andrew Kolodny, MD, a New York addiction specialist and advocate of tighter controls on opioids.

In an email, Pam Van Houten, a spokeswoman for Johnson & Johnson, said no one from the company was on the committee and only committee members were allowed to attend its deliberations and monthly meetings. Van Houten did, however, add that there were occasional circumstances when company officials were invited to committee meetings.

Moreover, Van Houten said the committee's funding always was disclosed.

Tramadol "Trending"

Walsh, the University of Kentucky researcher, and others have done their own studies on oral tramadol showing that experienced opioid abusers like it as much or more than oxycodone.

In a 2012 study, they gave up to 400 mg of tramadol, about four times the normal single dose, and oxycodone to nine opioid abusers.

On the next day, the test subjects sat at a computer. They were told they would be given the drugs again in increments if they clicked a mouse to earn it. The mouse clicking progressively increased for each additional increment of the drug. To get all the drug, they would have to click the mouse 7,800 times.

Five of the nine test subjects clicked the mouse at least 5,300 times to get the high-dose tramadol, compared with only one who did so to get the high-dose oxycodone.

"That was really surprising to us," said lead author Shanna Babalonis, PhD, an assistant professor of behavioral science at the University of Kentucky.

The likability of oral tramadol can be seen in the large numbers of people who have used it recreationally.

In 2011, 2.6 million people ages 12 and older used tramadol for nonmedical purposes, according to the DEA. The DEA said the drug is most commonly abused by addicts, chronic pain patients, and health professionals.

Over the years, there had been indications that the drug was being abused, but Ortho-McNeil has fought efforts to make tramadol a controlled substance.

In 2006, the company argued that by making it a controlled substance, doctors would be less likely to prescribe it for chronic pain. It cited concerns about the stigma attached to opioids and what it called "opiophobia." The comments were made in a document filed with the FDA in response to an inquiry by the World Health Organization over whether tramadol should become a scheduled narcotic internationally.

Van Houten, the company spokesperson, said the company is reviewing the DEA's proposal to put tramadol under the Controlled Substances Act.

She said the company no longer actively promotes its tramadol product, Ultram, in the U.S.

"Tramadol has been and remains an important medicine used to treat moderate to moderately severe pain in adults," Van Houten said.

DEA Petitions

In 2005, the DEA received four petitions to put tramadol under the Controlled Substances Act in the U.S., three that asked that it be a schedule 3 drug.

Last month, the DEA recommended that it be put under schedule 4 of the act.

Similar concerns about tramadol abuse and overdoses have been raised recently in Great Britain.

In February, the country's Advisory Council on the Misuse of Drugs noted that deaths in which tramadol was mentioned on the death certificate nearly doubled between 2008 and 2011. Prescriptions for tramadol in England also increased from 5.9 million in 2005 in 11.1 million in 2012.

The council recommended that tramadol become a scheduled drug, which would make it a crime to use it or deal it without a prescription. It also said doctors should be given training regarding the drug's possible misuse by patients and the serious complications it can cause.

In the U.S., those who most often prescribe are likely to be on the front line of medicine.

A MedPage Today/Milwaukee Journal Sentinel analysis of IMS Health prescription data shows that over the last 2 years, the top prescribers of tramadol have been family practice doctors, internal medicine physicians, osteopaths, nurse practitioners, and physicians assistants.

More than two-thirds of tramadol prescriptions from 2012 through October, 2013 were written by those health professionals.

Walsh, the University of Kentucky opioid researcher, said she believes that many doctors who prescribe tramadol take their direction from whether a drug is a scheduled narcotic.

"I suspect they don't know about its abuse potential," she said.

Two years after Anthony Fort's death, his former fiancee still has the recording of his loud snoring and gurgling that she made on the day he died.

She was going to play it back to him later in hopes that it would make him realize that the medications he was taking were affecting his sleeping.

After making the recording, she went to the store. She said she only was gone about a half hour.

"I wanted him to listen to it because it scared me," she said. "But it was too late."

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"Co-infections and HIV beget each other": Dr Dilip Mathai

Sun, 2013-12-22 08:35 — editor

Dr. Dilip Mathi

By Shobha Shukla, Citizen News Service – CNS

HIV in today's context is a chronic condition of the human immune system. HIV is a retrovirus and the infection leads to a progressive reduction in the number of CD4+ T-helper cells (so called because CD4 glycoprotein is found on their surface) which are an essential part of the human immune system. They are the main targets of HIV which destroys infected CD4 cells leading to an overall weakening of the immune system, said Dr Dilip Mathai, Dean, Apollo Institute of Medical Sciences and Research, and former Head of Medicine Department, Christian Medical College (CMC), Vellore.Professor (Dr) Dilip Mathai, Dean, Apollo Institute of Medical Sciences and Research

Dr Mathai was speaking with Citizen News Service (CNS) at 6th National Conference of AIDS Society of India (ASICON 2013). Dr Mathai added: Normal values for CD4 cells are 500-1200 cells/mm3. When CD4 cells become depleted, the body is left vulnerable to a wide range of infections that it would otherwise have been able to fight. Lower numbers of circulating CD4+ T-cells indicate a weakening of the immune system and advancement in the progression of HIV disease.

The goal of anti-retroviral therapy (ART) in HIV is to bring down the viral load and increase the CD4 cell count so that the body reconstitutes its immune system AND increases the CD4 count to a manageable level of 500 and more.

Co-infections and HIV beget each other. As the HIV infection progresses, it interferes more and more with the immune system, making the affect person more prone to contract infections, including opportunistic infections (OIs) that do not usually affect people who have strong immune systems. Co-infections like hepatitis B, hepatitis C, TB and pneumonia, among others, can cause a transient increase (which is called a blip) in the viral load and decrease the CD4 cell count, thus lowering the body’s ability to kill the co-infecting bacteria or virus. This can perpetuate other infections. For example, cure of TB depends both on drugs and the body’s defence mechanism to annihilate the TB bacilli. But if the CD4 count is very low and the viral load increases then the body defence against TB is not so good. The anti TB drugs help in decreasing the total number of TB bacilli, but to annihilate them completely requires the body’s defence mechanism for the drugs to penetrate the cells where the bacilli are. No wonder then that a lot many people living with HIV (PLHIV) die of TB and not of HIV.

In PLHIV there is not only the danger of acquiring co-infections but also the problem of eliminating them. HIV may be controlled through ART but co-infections can damage the body organs. Every co-infection (including HIV) has an effect on inflammation. This inflammation can take its toll of the blood vessels and affect the heart as coronary artery disease is the product of an inflammation. Another problem with co-infections is that some of them may not be systemic like cytomegalia virus of the eye, lung or bone marrow, and can damage the affected organ. In fact, for PLHIV, Hepatitis C and/or TB can be more worrisome for survival than even HIV. Then again diseases that can suddenly flare up, like chicken pox, can disseminate and be fatal in those who are immune compromised, like PLHIV. In a normal competent host chances of dissemination are very low. There can also be co-morbidities like diabetes, stroke, and renal problems as HIV can affect the heart, the kidney, and have secondary effect on the bones.

Thus there is a wide spectrum of diseases and issues to be dealt with for prevention, treatment, and management of HIV—TB and HIV, Hepatitis C/B and HIV, liver disease and HIV, kidney disease and HIV, nutrition and HIV, heart disease and HIV, to name a few. Doctors and other healthcare personnel need to be trained and also kept updated so that they are competent enough to handle their HIV patients well and not let them die of HIV related OIs. So a multi-disciplinary approach is needed—general physicians, specialists, paediatricians, gynaecologists, nurses, psychologists-- all holding hands and working together to ensure that PLHIV have the same quality of life as any other person.

Detecting and diagnosing new cases, enrolling them into care/treatment, retaining them in care and making them adhere to therapy and behavioural change-- all are equally important in controlling the HIV pandemic. There is no point in diagnosing if one cannot treat them; there is no point in holding them in care if they are not willing to be engaged to reach out to the others. We have to reach out to all, especially the young and other vulnerable populations, educating them about the hazards of unsafe sex which increases risk of HIV and other sexually transmitted diseases. In the absence of a cure, the disease will continue to be transmitted if people do not change their risk seeking behaviour like chemical dependence, unsafe sex, injecting drug use, among others.

(This article is based upon a CNS interview with Professor (Dr) Dilip Mathai, Dean, Apollo Institute of Medical Sciences and Research)

- Asian Tribune -

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