February 15, 2014

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Clinical Infectious Diseases Advance Access published February 12, 2014 Keith M. Rose Mount Sinai Health System St. Luke's Roosevelt Hospital

Hepatitis C is a major cause of morbidity and mortality estimated to affect over 150 to 200 million people worldwide. 1,2,3 Infection with hepatitis C virus (HCV) carries a large clinical impact and high cost burden to health care systems, and is one of the leading contributing causes of end stage liver disease requiring liver transplantation in the US. 4 Advancements have been made in areas of both diagnosis and treatment, improving our ability to detect and treat the disease earlier. This carries the potential benefit of decreasing the morbidity and mortality caused by this disease.
This month's issue of Clinical infectious Diseases features two articles which address the impact of hepatitis C, highlighting both the significant mortality it brings as well as the potential underreporting of the disease. Both of these studies utilize data collected from death certificates and either disease reporting/ surveillance systems, or electronic medical records.

The study by Pinchoff et al entitled "Death among people with Hepatitis C in New York City, 2000-2011'"examined surveillance data for Hepatitis C reporting, and compared it to cause of death data obtained from death certificates from 2000 to 2011 in New York City (NYC). They evaluated the effect of Hepatitis C on age of death, cause of death (COD), as well as the effect of co-infection with HIV compared to the population without these diseases. This was a well designed study taking advantage of New York City having several robust disease surveillance registries that were able to be cross-matched and then compared to mortality data. By doing the study in NYC, they were able to evaluate a large, well defined, and diverse population with a particularly high incidence of this disease.5 This study adds to the literature as it further helps to delineate the natural history of Hepatitis C in the real world.The authors were able to convincingly demonstrate an increased risk of premature mortality (age <65) in patients infected with hepatitis C, stressing the importance again of early identification and potential treatment of this disease.The study also attempted to further evaluate the cause of death in this population from a review of death certificate data. It is very important to understand when and how people are being diagnosed with the disease and ultimately what they are specifically dying from.

There are however some weaknesses in the study that need to be discussed. Unlike a true cohort, this study only captured people who died in NYC. Patients who were diagnosed and treated in NYC would not be included in the COD analysis if they were to die outside of the city limits. Although the study implies that earlier diagnosis and treatment would likely decrease premature mortality, the study was not able to evaluate the subset of people that were treated for hepatitis C, and with what regimen. Overall the study does an excellent job demonstrating the associated mortality with HCV, but causation is much more difficult to prove. Lastly, the utilization of death certificate data may lead to a classification bias with overrepresentation of certain CODs ie HIV/AIDS and cardiovascular causes. 6,7,8

Also in this issue of Clinical Infectious Diseases, Mahajan et al publish their findings from The Chronic Hepatitis Cohort Study (CHeCS). This large cohort of 11,703 patients was formed from a review of electronic medical records from four large healthcare systems from 2006-2010, extracting demographics and data from patients diagnosed with HCV. They found a significantly higher than expected effect of hepatitis C on mortality, with a mortality rate twelve times higher in their cohort compared to the general population. An interesting finding of this study, was the paucity of HCV being listed on death certificates of these individuals. In fact, the majority of deaths, whether liver or non-liver related, did not have hepatitis C listed as a COD. Although this finding was specifically for hepatitis C, it reiterates the importance of proper death certificate completion and accuracy. It also sheds light on the potential impact on other studies such as the article by Pinchoff et al above that utilize death certificate data, to determine the impact on mortality of a certain disease. Potentially the Pinchoff study may be missing large numbers of patient s that died from both hepatic and non-hepatic causes related to Hepatitis C. Clearly those that had hepatitis C listed on their death certificates tended to died younger with a higher incidence of premature death, but the full impact is uncertain if we don't have an accurate representation of the deaths that HCV may have contributed to.

This paper by Mahajan et al also has some limitations, and opens the door for many further questions. This study was done with data from four large academic centers and may not necessarily be extrapolated to all hospital systems. Furthermore it would be interesting to know who completed the death certificates, ie attending versus resident or intern, how often it was completed by a covering physician who may not have known the patient as well, and what specific training, if any the completing physician had received in proper death certificate completion. Lastly it would be useful to know what percentage of patients were being treated for Hepatitis C and the impact this may have had on this subset of the cohort.

It's important to note that both of the above studies are only able to take into account HCV cases that were picked up by surveillance. HCV is often under diagnosed, so we don't know if the findings from these studies would apply to all subjects infected with HCV. We can only address the mortality risk, and associations in those with an established diagnosis of hepatitis C. Many of these cases may have been detected because of liver function test abnormalities or exam findings consistent with liver disease. It's important to also consider that hepatitis C infection is associated with several social factors and behaviors that can increase the risk of death. This comes back to an important question of whether people are dying with hepatitis C or from hepatitis C. To this point, it is also possible that some of the controls who died in both studies may have had HCV, as not everyone who dies is checked for the disease.

As more studies are done to look at the effect of disease, and ultimately determine what Americans or other populations are dying from, the importance of accurate information on death certificates becomes paramount. Based on their data, Mahajan et al propose that 80,000 Americans died with Hepatitis C in 2010 instead of the reported 16,622 secondary to gross underreporting on death certificates. This huge disparity is unlikely unique to Hepatitis C. Wexelman et al in a survey of residents in NYC found that the majority of residents in NYC felt the death certificate reporting system was inaccurate and often knowingly listed inaccurate CODinformation on death certificates.9 Other studies have also documented the general inaccuracies of death certificates, particularly noting cardiovascular disease being overrepresented. 6,7,8 As less autopsies are being performed, it is becoming more and more important to strive to improve the accuracy and consistency of cause of death reporting.

Increasing education initiatives seem to help, 10 and perhaps with more of these programs we may be moving toward a more reliable system, but this is not the only obstacle. There are system based issues which also need to be further addressed.9 For instance, in the Wexelman et al study, residents reported not being able to enter into the Electronic Death Registration System (EDRS) system what they believed was the true COD for a variety of reasons. These issues seem to be multi-factorial and will ultimately need to be addressed on several levels. However, perhaps it is only when you look at studies like these two well designed, interesting papers on hepatitis C, do you really appreciate the importance of getting this right.

The author has no reported conflicts of interest.

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Liver Int. 2014 Jan 19. doi: 10.1111/liv.12471. [Epub ahead of print]

Everson G, Cooper C, Hézode C, Shiffman ML, Yoshida E, Beltran-Jaramillo T, Andreone P, Bruno S, Ferenci P, Zeuzem S, Brunda M, Le Pogam S,Nájera I, Zhou J, Navarro MT, Voulgari A, Shulman NS, Yetzer ES.

Abstract

BACKGROUND & AIMS: Danoprevir is a hepatitis C virus (HCV) protease inhibitor with activity against genotypes (G)1/G4, which is maintained at lower doses by ritonavir-boosting. We report results of a large, randomized, active-controlled phase IIb study of ritonavir-boosted danoprevir (danoprevir/r) plus peginterferon alpha-2a/ribavirin (P/R) in treatment-naive patients with HCV G1/4 infection.

METHODS: Treatment-naive patients with HCV G1/4 infection were randomized to twice-daily danoprevir/r 200/100 mg (A, n = 92); 100/100 mg (B, n = 93); or 50/100 mg (C, n = 94) plus P/R for 24 weeks; twice-daily danoprevir/r 100/100 mg (D, n = 94) plus P/R for 12 or 24 weeks; or P/R alone (E, n = 44) for 48 weeks. Patients in the response-guided therapy arm (D) with an extended rapid virological response (eRVR2: HCV RNA <15 IU/ml during Weeks 2-10) stopped all therapy at Week 12; non-eRVR2 patients continued all treatment to Week 24. The primary efficacy endpoint was sustained the virological response (SVR24: HCV RNA <15 IU/ml after 24 weeks of untreated follow-up).

RESULTS: SVR24 rates in Arms A, B, C, D and E were 89.1%, 78.5%, 66.0%, 69.1% and 36.4%, respectively, in the overall population; 83.6%, 69.6%, 60.3%, 59.2% and 38.5% in G1a-infected patients, 96.6%, 93.1%, 73.1%, 78.4% and 28.6% in G1b-infected patients and 100%, 87.5%, 100%, 100% and 66.7% in G4-infected patients. Danoprevir/r plus P/R was generally well tolerated compared with P/R alone. There was a higher incidence of serious adverse events in danoprevir-treatment arms, but most were associated with P/R.

CONCLUSIONS: The combination of danoprevir/r plus P/R is efficacious in treatment-naïve patients with HCV genotype 1 or 4 infection.

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

KEYWORDS: danoprevir, hepatitis C virus, response-guided therapy, ritonavir-boosting, sustained virological response

PMID: 24517252 [PubMed - as supplied by publisher]

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Antivir Ther. 2014 Feb 12. doi: 10.3851/IMP2743. [Epub ahead of print]

Degasperi E, Valenti L, Aghemo A, De Francesco R, Rumi M, Soffredini R, Donnici L, Cheroni C, Fargion S, Zanoni V, Orsi E, Colombo M.

Abstract

BACKGROUND: In patients with chronic hepatitis C virus (HCV) infection, an association between IL28B genotype and insulin-resistance (IR), known predictors of sustained virological response (SVR) to PegInterferon (PegIFN) and Ribavirin (Rbv) therapy, has been reported. The aim of this study was to investigate the association of IR and IL28B genotype in two cohorts of well-characterized HCV patients.

METHODS: 480 non-diabetic HCV patients were analyzed: 391 patients who received PegIFN/Rbv in the MIST study, and 89 previously reported patients followed at a Metabolic Liver Diseases center. All were tested for IL28B rs12979860 SNP by RT-PCR and had IR measured by HOMA-IR. Staging of liver disease through liver biopsy was available for all patients.

RESULTS: 164 patients (34%) were IL28B CC. Mean HOMA-IR values did not differ according to IL28B genotype, being respectively 1.14 ± 0.79 in CC vs 1.14 ± 0.78 in CT/TT (p=1.0) in the first, and 2.4 ± 1.0 vs 2.5 ± 1.0 (p=0.7) in the second cohort. HOMA-IR>2 was not associated with IL28B genotype: 16/132 (12%) CC vs 31/259 (12%) CT/TT (p=1.0) in the first cohort, and 16/32 (50%) vs 37/57 (65%) (p=0.18) in the second. This held true also when using different HOMA cut-offs (>2.5, >3.0, >3.5, >4.0). In the MIST cohort, HOMA-IR>2 did not influence treatment outcome, SVR rates being 28/47 (60%) in HOMA-IR>2 vs 214/344 (62%) in HOMA-IR<2 (p= 0.8). IL28B genotype was a strong predictor of SVR: 84% (111/132) in CC vs 51% (131/259) in CT/TT patients (p<0.0001).

CONCLUSIONS: In two cohorts of non-diabetic HCV patients where IL28B genotype predicted treatment outcome, we found no association between IL28B genotype and HOMA-IR.

PMID: 24523350 [PubMed - as supplied by publisher]

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Media Contact:Steve Graff | stephen.graff@uphs.upenn.edu | 215-349-5653

February 14, 2014

People receiving mental health care are up to four times more likely to be infected with HIV than the general population, according to a new study published Feb. 13 in the American Journal of Public Health from researchers at the Perelman School of Medicine at the University of Pennsylvania and other institutions who tested over 1,000 patients in care in Philadelphia and Baltimore. Of that group, several new HIV cases were detected, suggesting that not all patients are getting tested in mental health care settings, despite recommendations to do so from the CDC and the Institute of Medicine.

The study is one of the largest studies to date to estimate HIV prevalence and risk factors among persons receiving treatment in mental health settings and included researchers from the Centers for Disease Control and Prevention (CDC), as well as the University of Maryland and Columbia University Medical Center.

“These findings paint a recent picture of HIV infection rates in the community, and reinforce how important it is to identify patients and get them into appropriate infectious disease care in a timely manner while being treated for mental illness,” said lead author Michael B. Blank, PhD, associate professor in Psychiatry at the Perelman School of Medicine. “With such a high-risk group, it’s imperative to be routinely testing patients to improve care and reduce transmissions to others. Historically, though, HIV testing is often not implemented in mental health care.”

For the study, researchers provided rapid HIV testing to 1,061 individuals (621 men and 436 women) seeking treatment for symptoms, including depression, psychosis, and substance abuse, at university-based inpatient psychiatry units, intensive case-management programs, and community mental health centers from January 2009 to August 2011. About 0.3 percent of the general population is HIV infected, and CDC estimates a much higher prevalence of 1.4 percent in Philadelphia and 1.3 percent in Baltimore, since both cities are HIV epicenters.

The research team found that 4.8 percent of the mental health patients receiving care (51 individuals) were infected with HIV, which is about four times the base rate in each city and about 16 times the base rate for the United States population. Thirteen of the 51 infected patients reported that they did not know they were HIV positive, which represents an important failure in our public health system since they were already receiving ongoing mental health care. These results suggest that even in areas in the U.S. where prevalence is lower those with mental illness may be at substantially higher risk and should be routinely tested.

Results of the study also showed that persons with more severe symptoms of mental illness were at higher risk for being HIV-infected. HIV prevalence was also higher among the groups most likely to be infected in the general population, including African American, gay or bisexual men, and those infected with Hepatitis C, which is often an indicator of past injection drug use.

Previous studies have found that people with serious mental illness are at an increased risk for being infected with HIV, but many were from the 1990s and early 2000s and produced wide variations in risk, most likely because of small sample sizes, differences in sampling frames, and inadequate adjustment for confounding effects of factors associated with the disease. What’s more, the demographics of the HIV epidemic have shifted in the past decade, and the degree to which HIV prevalence among persons with mental illness has changed remains unclear.

Both CDC and the Institute of Medicine recommend routine HIV screening be conducted in all clinical settings, including mental health settings, to increase identification of those infected and strengthen access to care. However, little progress has been made toward integrating HIV testing into mental health care, said Blank.

“There are barriers to testing, be it funding, system-level barriers or access to rapid HIV testing, that need to be addressed in order to have a wider adoption,” said Blank, who also serves as the co-director of the recently-established Penn Mental Health AIDS Research Center, alongside co-author David S. Metzger, PhD, director of the HIV/AIDS Prevention Research Division at Penn Medicine, and chair of Psychiatry Dwight L. Evans, MD.

“The results of this important study highlight the need for research into integrated treatments for people with complex, co-occurring conditions like HIV and mental illness,” said Dr. Evans.

The health care system’s approach to these patients may also play a role in the health disparities that are observed in them. Mental illness and HIV often times go hand in hand; however, today’s system is not fully equipped to treat these co-morbidities in tandem. In order to achieve optimal outcomes, patients would be better served with a more integrated approach, rather than today’s fragmented one.

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Medicines Made in India Set Off Safety Worries

By GARDINER HARRIS FEB. 14, 2014

NEW DELHI — India, the second-largest exporter of over-the-counter and prescription drugs to the United States, is coming under increased scrutiny by American regulators for safety lapses, falsified drug test results and selling fake medicines.

Dr. Margaret A. Hamburg, the commissioner of the United States Food and Drug Administration, arrived in India this week to express her growing unease with the safety of Indian medicines because of “recent lapses in quality at a handful of pharmaceutical firms.”

India’s pharmaceutical industry supplies 40 percent of over-the-counter and generic prescription drugs consumed in the United States, so the increased scrutiny could have profound implications for American consumers.

F.D.A. investigators are blitzing Indian drug plants, financing the inspections with some of the roughly $300 million in annual fees from generic drug makers collected as part of a 2012 law requiring increased scrutiny of overseas plants. The agency inspected 160 Indian drug plants last year, three times as many as in 2009. The increased scrutiny has led to a flood of new penalties, including half of the warning letters the agency issued last year to drug makers.

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Ranbaxy, one of India’s biggest drug manufacturers, pleaded guilty to felony charges and paid a $500 million fine last year. Adnan Abidi/Reuters

Dr. Hamburg was met by Indian officials and executives who, shocked by recent F.D.A. export bans of generic versions of popular medicines — like the acne drug Accutane, the pain drug Neurontin and the antibiotic Cipro — that the F.D.A. determined were adulterated, suspect that she is just protecting a domestic industry from cheaper imports.

“There are some people who take a very sinister view of the F.D.A. inspections,” Keshav Desiraju, India’s health secretary until this week, said in a recent interview.

The F.D.A.'s increased enforcement has already cost Indian companies dearly — Ranbaxy, one of India’s biggest drug manufacturers, pleaded guilty to felony charges and paid a $500 million fine last year, the largest ever levied against a generic company. And many worry that worse is in store.

“If I have to follow U.S. standards in inspecting facilities supplying to the Indian market,” G. N. Singh, India’s top drug regulator, said in a recent interview with an Indian newspaper, “we will have to shut almost all of those.”

The unease culminated Tuesday when a top executive at Ranbaxy — which has repeatedly been caught lying to the F.D.A. and found to have conditions such as flies “too numerous to count” in critical plant areas — pleaded with Dr. Hamburg at a private meeting with other drug executives to allow his products into the United States so that the company could more easily pay for fixes. She politely declined.

India’s drug industry is one of the country’s most important economic engines, exporting $15 billion in products annually, and some of its factories are world-class, virtually undistinguishable from their counterparts in the West. But others suffer from serious quality control problems. The World Health Organization estimated that one in five drugs made in India are fakes. A 2010 survey of New Delhi pharmacies found that 12 percent of sampled drugs were spurious.

In one recent example, counterfeit medicines at a pediatric hospital in Kashmir are now suspected of playing a role in hundreds of infant deaths there in recent years.

One widely used antibiotic was found to contain no active ingredient after being randomly tested in a government lab. The test was kept secret for nearly a year while 100,000 useless pills continued to be dispensed.

More tests of hospital medicines found dozens more that were substandard, including a crucial intravenous antibiotic used in sick infants.

“Some of the fake tablets were used by pregnant women in the post-surgical prevention of infections,” said Dr. M. Ishaq Geer, senior assistant professor of pharmacology at the University of Kashmir. “That’s very serious.”

Investigations of the deaths are continuing, but convictions of drug counterfeiters in India are extremely rare.

Satish Reddy, president of the Indian Pharmaceutical Alliance, said Indian drug manufacturers were better than the F.D.A. now contends. “More rigorous enforcement is needed, for sure, but this impression that India is overrun with counterfeits is unjustified,” Mr. Reddy said.

But Heather Bresch, chief executive of Mylan, which has plants in the United States and India, said regulatory scrutiny outside the United States was long overdue. “If there were no cops around, would everyone drive the speed limit?” Ms. Bresch asked. “You get careless, start taking risks. Our government has enabled this.”

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Dr. Margaret A. Hamburg, the head of the Food and Drug Administration, is in India this week to express her concerns. Associated Press

For Dr. Hamburg, the trip is part of a long-running effort to create a global network of drug and food regulators to help scrutinize the growing flood of products coming into the United States, including 80 percent of the seafood consumed in the United States, 50 percent of the fresh fruit, 20 percent of the vegetables and the vast majority of drugs.

She has gone to conclaves of regulators from Europe and elsewhere to coordinate policing, but Indian officials have so far not attended such meetings.

Many of India’s drug manufacturing facilities are of top quality. Cipla, one of the industry’s giants, has 40 plants across the country that together can produce more than 21 billion tablets and capsules annually, and one of its plants in Goa appeared just as sterile, automated and high tech on a recent tour as those in the United States.

Cipla follows F.D.A. guidelines at every plant and on every manufacturing line, and the company exports more than 55 percent of its production, said Yusuf Hamied, the company chairman.

But Benjamin Mwesige, a pharmacist at the Uganda Cancer Institute in Kampala, said in an interview in July that the institute had stopped buying cancer drugs from India in 2011 because it had received shipments of drugs that turned out to be counterfeit and inactive, with Cipla labels that Mr. Mwesige believed were forged.

He became suspicious when doctors began seeing chemotherapy patients whose cancer showed none of the expected responses to the drugs — and who also had none of the usual side effects. The drugs that had been prescribed were among the mainstays of cancer treatment — methotrexate, docetaxel and vincristine. Laboratory tests confirmed that the drugs were bogus, and Mr. Mwesige estimated that in 2011 20 percent of the drugs that the institute bought were counterfeit.

Enforcement of regulations over all is very weak, analysts say, and India’s government does a poor job policing many of its industries. Last month, the United States Federal Aviation Administration downgraded India’s aviation safety ranking because the country’s air safety regulator was understaffed, and a global safety group found that many of India’s best-selling small cars were unsafe.

India’s Central Drugs Standard Control Organization, the country’s drug regulator, has a staff of 323, about 2 percent the size of the F.D.A.'s, and its authority is limited to new drugs. The making of medicines that have been on the market at least four years is overseen by state health departments, many of which are corrupt or lack the expertise to oversee a sophisticated industry. Despite the flood of counterfeit drugs, Mr. Singh, India’s top drug regulator, warned in meetings with the F.D.A. of the risk of overregulation.

This absence of oversight, however, is a central reason India’s pharmaceutical industry has been so profitable. Drug manufacturers estimate that routine F.D.A. inspections add 25 percent to overall costs. In the wake of the 2012 law that requires the F.D.A. for the first time to equalize oversight of domestic and foreign plants, India’s cost advantage could shrink significantly.

Some top manufacturers are already warning that they may leave, tough medicine for an already slowing economy.

“I’m a great nationalist, an Indian first and last,” Dr. Hamied said. “But companies like Cipla are looking to expand their businesses abroad and not in India.”

American businesses and F.D.A. officials are just as concerned about the quality of drugs coming out of China, but the F.D.A.'s efforts to increase inspections there have so far been frustrated by the Chinese government.

“China is the source of some of the largest counterfeit manufacturing operations that we find globally,” said John P. Clark, Pfizer’s chief security officer, who added that Chinese authorities were cooperative.

Using its new revenues, the F.D.A. tried to bolster its staff in China in February 2012. But the Chinese government has so far failed to provide the necessary visas despite an announced agreement in December 2013 during a visit by Vice President Joseph R. Biden Jr., said Erica Jefferson, an F.D.A. spokeswoman.

The United States has become so dependent on Chinese imports, however, that the F.D.A. may not be able to do much about the Chinese refusal. The crucial ingredients for nearly all antibiotics, steroids and many other lifesaving drugs are now made exclusively in China.

Denise Grady contributed reporting from Kampala, Uganda, and Hari Kumar from Srinagar, Kashmir.

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