November 15, 2013

Provided by NATAP

Download the PDF here

"We found that viral load suppression was associated with decreased risk of liver-related eventsÉ..Patients who achieved an undetectable viral load significantly reduced their risk of the composite clinical end point by 27% (hazard ratio [HR], 0.73 [95% CI, 0.66-0.82]) and their risk of death by 45% (HR, 0.55 [95% CI, 0.47-0.60]) relative to patients with a detectable viral load over their entire postindex period. The risk reduction associated with the composite clinical end point measured after a 1-year washout period increased slightly to a reduction of 28% (HR, 0.72 [95% CI, 0.64-0.81]).

----------------------------

The Risk of Long-term Morbidity and Mortality in Patients With Chronic Hepatitis C Results From an Analysis of Data From a Department of Veterans Affairs Clinical Registry

JAMA Intern Med. Published online November 05, 2013

Jeffrey McCombs, PhD1; Tara Matsuda, BA1,2; Ivy Tonnu-Mihara, PharmD2; Sammy Saab, MD3; Patricia Hines, BA4; Gilbert L'Italien, PhD4; Timothy Juday, PhD4; Yong Yuan, PhD4

"We found that viral load suppression was associated with decreased risk of liver-related events using data from a large cohort of real-world patients with HCV at various stages of disease progression while controlling for other risk factors, including genotype.

“Previous research has clearly documented that patients with an undetectable viral load18 or who achieve SVR due to treatment are at significantly lower risk of late-stage liver events and death.14,19 Our results are consistent with these earlier studies. Patients who achieve an undetectable viral load reduce their risk of death by 45% and reduce their risk of our composite end point of liver-related events by 27% relative to those patients whose viral load was detectable over the entire period following their diagnosis. More importantly, very few patients achieve an undetectable viral load without treatment (39 of 97 485 untreated patients)."

"Patients who achieved an undetectable viral load significantly reduced their risk of the composite clinical end point by 27% (hazard ratio [HR], 0.73 [95% CI, 0.66-0.82]) and their risk of death by 45% (HR, 0.55 [95% CI, 0.47-0.60]) relative to patients with a detectable viral load over their entire postindex period. The risk reduction associated with the composite clinical end point measured after a 1-year washout period increased slightly to a reduction of 28% (HR, 0.72 [95% CI, 0.64-0.81])."

"Patients infected with HCV are at risk for progressive liver disease and related complications such as cirrhosis, liver failure, HCC, and death.1,2,5- 7 The primary outcomes specified for this analysis were all-cause mortality and a composite of newly diagnosed cirrhosis (compensated and decompensated), HCC, or a liver-related hospitalization. The time to the composite event was set at the earliest event date for any of the composite events. Because HCV infections commonly go undiagnosed or untreated until complications are observed, sensitivity analysis was conducted in which clinical composite variables were measured using a 1-year postindex washout period during which the clinical events were not counted. The secondary outcomes included the individual elements of the clinical composite analyzed individually.

"Patients with genotype 2 were consistently at lower marginal risk for liver-related events compared with patients with the more common genotype 1, controlling for viral load suppression and other risk factors. The risk reduction for the composite end point was 23% (HR, 0.77 [95% CI, 0.74-0.80]). The risk of all-cause mortality for genotype 2 patients was reduced by 20% relative to genotype 1 patients (HR, 0.80 [95% CI, 0.76-0.84]). Patients with genotype 3 were consistently at higher risk than patients with genotype 1. The estimates of marginal increased risk for those with genotype 3 ranged between 11% for the composite clinical end point (HR, 1.11 [95% CI, 1.07-1.16]) to a 17% increase in the risk of death (HR, 1.17 [95% CI, 1.11-1.24]). Other genotypes were infrequent in the VA patient population and were collapsed into a single category for which the estimated HRs were not generally significant."

"The primary outcomes were time to death and time to a composite of liver-related clinical events. Secondary outcomes included the components of the composite clinical outcome"

"80% of patients were genotype 1. Just over 42% of study sample patients had baseline data for their fibrosis stage at baseline (FIB-4 score), and only 19% had a FIB-4 score higher than 3.25, which is correlated with a Metavir fibrosis stage of F3 to F416 or an Ishak fibrosis stage of F4 to F6.17 The FIB-4 score was not used in the core analysis owing to this high level of missing data. Instead, a sensitivity analysis was conducted using only those patients with baseline FIB-4 scores, and the patient's FIB-4 category was entered as a potential risk factor."

"Sensitivity Analysis: Impact of Fibrosis Stage

Risk models for the composite end point and all-cause mortality were reestimated using only patients with a baseline FIB-4 score (n = 54 420), and FIB-4 stage was entered as a potential risk factor. Several results are noteworthy (Table 5). First, our core estimates of the impact of achieving an undetectable viral load on event risk were very robust (Table 3). If anything, the estimated risk reduction associated with viral load suppression increased when the analysis took into account baseline levels of fibrosis. Second, risk of the composite event and all-cause mortality was monotonically and positively related to the patient's baseline fibrosis level. FIB-4 stage 2 increased risk of the composite event by 47% (HR, 1.47 [95% CI, 1.42-1.54]), while stage 3 HR for the composite event was 3.44 (95% CI, 3.29-3.61). The corresponding HRs for the risk of death were 1.46 (95% CI, 1.37-1.55) for stage 2 and 3.77 (95% CI, 3.55-4.00) for stage 3. In the FIB-4 analyses, each additional year of age was estimated to decrease event risk, but this is likely owing to age appearing in the FIB-4 calculation. Genotype 3 was also associated with lower risk than genotype 1 in the FIB-4 sensitivity analyses, but the estimated HRs were not statistically significant."

------------------------------------------

The Risk of Long-term Morbidity and Mortality in Patients With Chronic Hepatitis CResults From an Analysis of Data From a Department of Veterans Affairs Clinical Registry - pdf attached

JAMA Intern Med. Published online November 05, 2013

Jeffrey McCombs, PhD1; Tara Matsuda, BA1,2; Ivy Tonnu-Mihara, PharmD2; Sammy Saab, MD3; Patricia Hines, BA4; Gilbert L'Italien, PhD4; Timothy Juday, PhD4; Yong Yuan, PhD4

ABSTRACT

Importance The impact of viral load suppression, genotype, race, and other factors on the risk of late-stage liver-related events in patients with hepatitis C (HCV) has been assessed previously using data from small observational cohorts or clinical trials. Data from large real-world practice samples are needed to improve risk factor estimates for late-stage liver events and death in HCV.

Objective To describe the natural history of HCV in real-world clinical practice.

Design, Setting, and Participants Observational cohort study. Patients with a detectable viral load (>25 IU/mL) and a recorded baseline genotype were selected from the Veterans Affairs (VA) HCV clinical registry (CCR), which compiles electronic medical records data from 1999 to present.
Exposures Risk factors included genotype, race, age, sex, and time to achieving an observed undetected viral load.

Main Outcomes and Measures The primary outcomes were time to death and time to a composite of liver-related clinical events. Secondary outcomes included the components of the composite clinical outcome. Outcomes were measured using a time-to-event format and were analyzed using Cox proportional hazards models.

Results A total of 28 769 of 360 857 unique HCV CCR patients met all study criteria. Only 24.3% of patients received treatment, and 16.4% of treated patients (4.0% of all patients) achieved an undetectable viral load. The unadjusted death rates were 6.8 (95% CI, 6.0-7.7) per 1000 person-years for patients who achieved viral load suppression vs 21.8 (95% CI, 21.5-22.2) deaths per 1000 person-years in patients who did not achieve this goal. Cox model results found that achieving viral suppression reduced risk of the composite clinical end point by 27% (hazard ratio [HR], 0.73 [95% CI, 0.66-0.82]) and the risk of death by 45% (HR, 0.55 [95% CI, 0.47-0.64]). Genotype 2 patients were at significantly lower risk, and genotype 3 patients were at higher risk for all study outcomes relative to genotype 1. Black patients were at lower risk for all liver events than white patients.

Conclusion and Relevance Achieving an undetectable viral load was associated with decreased hepatic morbidity and mortality. It remains to be determined whether newer treatment regimens can offer higher response rates with fewer adverse effects in real-world settings.

Hepatitis C virus (HCV) affects approximately 130 to 170 million people worldwide,1,2 and an estimated 3.2 million people in the United States.3 This US estimate may be low because high-risk groups such as the incarcerated and the homeless were not included in the data. Alternative estimates put the number of US patients with chronic HCV at between 5.2 million and 7 million.4

Patients with HCV are at risk of developing liver-related complications such as cirrhosis, liver failure, and hepatocellular carcinoma (HCC).1,2,5- 7 Using data from the US Department of Veterans Affairs (VA), Butt et al8 found that infection with HCV increased the risk of death by 37%.8 Hepatitis C is also the leading indication for liver transplant, and the US incidence of HCC is increasing.9 Davis et al10 used a simulation model to project that 13.1% of US patients living with HCV in 2005 will die of liver-related causes by 2030. Rein et al11 extended this projection to 2060, at which time they estimate that 36.8% of the 2005 HCV cohort will have died due to liver causes.

The impact of genotype and demographic factors on the clinical course of HCV may be significant. For example, genotype 1 is thought to be highly correlated with disease progression, although Seeff5 casts some doubt on this conclusion. Kallwitz et al12 found that BMI and Hispanic ethnicity were associated with disease progression, while African Americans had a lower rate of disease progression than white patients.

Sustained viral response (SVR) to treatment is associated with decreased liver-related morbidity and mortality. The REVEAL HCV study13 found a significant association between undetectable viral load and liver-related events in Taiwan. Van der Meer et al14 found that the 36% of patients with advanced hepatic fibrosis who achieved SVR had reduced all-cause mortality and reduced incidence of liver-related events compared with those who did not achieve SVR.14 To our knowledge, no previous studies have investigated a wide range of the risk factors associated with mortality and morbidity in a large real-world cohort of patients at all levels of disease progression. The objective of the present research is to use HCV RNA data to quantify the impact of viral load suppression on liver-related morbidity and overall mortality using a large cohort of patients with HCV, including those in the early stages of disease progression, while controlling for the impact of genotype, race, age, sex, and other factors.

METHODS

Data

The data used in this study were taken from the VA clinical case registry (CCR) system for HCV-infected patients. The VA institutional review board approved the study. Potential patients with HCV were identified by the presence of an HCV-related International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code or a positive viral load assessment using the hepatitis C antibody test, the hepatitis C RIBA (recombinant immunoblot assay), or the qualitative hepatitis C RNA test. A local CCR coordinator then manually confirmed or rejected the patient for HCV CCR inclusion. After confirmation, all historical data from the patient's electronic medical record (EMR) were pulled and added to the CCR. The VA EMR system was fully implemented in 1999, and the data period for this study covers the entire period over which EMR data were available from all VA regions from 1999 to 2010.15

An intermediate patient-level analytic database was created consisting of summary variables for each month before and after the patient's CCR enrollment (index date). Summary data were organized as follows:

1. Patient demographic data were recorded (age in months at baseline, sex, race, ethnicity); race and ethnicity data were based on patient self-report.

2. The patient's diagnostic profile was created, consisting of monthly dichotomous variables reflecting the diagnoses recorded each month.

3. Monthly dichotomous variables were created for hospital admissions for any diagnosis and for liver-related diagnoses.

4. Prescription drug data were used to create monthly variables indicating when patients received HCV-related treatment (peginterferon alfa 2a or 2b, interferon alfa 2a or 2b, interferon alfacon-1, boceprevir, or telaprevir). The use of ribavirin alone was not considered to be a drug therapy for HCV.

5. The objective of treatment is to suppress the patient's HCV viral load to undetectable levels. A primary objective of this research was to document the impact of viral load suppression, accounting for the temporal relationship between achieving an undetectable viral load and event date. To achieve this, we calculated the time to the first undetectable viral load test result as our covariate of interest and defined our primary and secondary outcomes using time-to-event formats. This approach is less stringent than measuring time to SVR, the gold standard for measuring treatment response. Time to SVR is significantly more difficult to calculate, requiring the determination of the time at which the patient maintained consistent viral load suppression for a minimum of 6 months following the termination of treatment.

Sample Selection Criteria

To estimate the risk reduction achieved if patients achieved viral load suppression, all patients were screened for a detectable baseline HCV viral load (>25 IU/mL). Study patients were also screened for a recorded genotype within 6 months of their index date. Longitudinal data were then used to measure time-to-outcome events and estimate the impact of achieving an undetectable viral load and other factors on event risk.

Primary and Secondary Outcomes

Patients infected with HCV are at risk for progressive liver disease and related complications such as cirrhosis, liver failure, HCC, and death.1,2,5- 7 The primary outcomes specified for this analysis were all-cause mortality and a composite of newly diagnosed cirrhosis (compensated and decompensated), HCC, or a liver-related hospitalization. The time to the composite event was set at the earliest event date for any of the composite events. Because HCV infections commonly go undiagnosed or untreated until complications are observed, sensitivity analysis was conducted in which clinical composite variables were measured using a 1-year postindex washout period during which the clinical events were not counted. The secondary outcomes included the individual elements of the clinical composite analyzed individually.

Monthly dichotomous variables were created for the outcomes of the study based on recorded diagnostic codes (eg, diagnosis of cirrhosis) and selected CPT-4 codes (Current Procedural Terminology, Fourth Edition) included in data from hospital admissions and outpatient services. Hospitalizations were defined as being liver related if the primary diagnosis for the hospitalization was one of those listed in the eAppendix in the Supplement, building on the fact that all study patients had a positive HCV viral load. Cirrhosis and HCC outcomes were compiled by searching the inpatient, outpatient, and problem lists for ICD-9 codes 571.5, 571.2, and 571.6; and 155, 155.1, and 155.2, respectively.

Decompensated cirrhosis was defined as a diagnosis of cirrhosis and a diagnosis of hepatic coma (70.44, 71.71, 348.3, 348.31, 572.2), portal hypertension (572.3), hepatorenal syndrome (572.4), jaundice (782.4), ascites (789.59), or esophageal varices (456, 456.1, 456.2, 456.21) or a FIB-4 score16 higher than 3.25. The FIB-4 score can also be segmented into 3 categories that have been found to correctly classify nearly 73% of liver biopsies and to have an 82.1% positive predictive value to confirm the existence of significant fibrosis in an HCV-infected cohort.16

Statistical Methods

The time-to-event variables for primary and secondary outcomes were analyzed using Cox proportional hazards models to test the correlation between potential predictors and study end points. Time to first observed undetected viral load was included in the analyses as a time-dependent independent variable to measure the impact of viral load suppression on each primary and secondary liver-related event controlling for genotype, race, age, sex, and other factors. Race and ethnicity were initially included as separate categories, but the significant correlation between race and ethnicity in the VA sample resulted in only race being included in the final model specifications. The impact of a diabetes diagnosis at baseline and any hospital admission in the 6 months prior to the patient's index date were included in our list of risk factors based on statistical significance.

A sensitivity analysis was conducted using only those patients with a baseline FIB-4 score to test if the core results on the impact of viral load suppression, genotype, and other factors were sensitive to controlling statistically for the patient's baseline fibrosis level.

RESULTS

Descriptive Statistics

The HCV CCR database contained information on 360 857 unique patients from which a population of 128 769 patients met all study inclusion criteria, including a detectable viral load and genotype data at baseline. Only 24.3% of patients in the analytic sample received treatment at any time following HCV diagnosis, while only 16.4% of treated patients achieved an undetectable viral load after treatment (Table 1). The mean (SD) postindex period was 6.1 (3.0) years. The VA patients with HCV were predominately men of either white or black race (51.4% and 31.3%, respectively). The mean (SD) age was 52.0 (6.9) years, and close to 80% of patients were genotype 1. Just over 42% of study sample patients had baseline data for their fibrosis stage at baseline (FIB-4 score), and only 19% had a FIB-4 score higher than 3.25, which is correlated with a Metavir fibrosis stage of F3 to F416 or an Ishak fibrosis stage of F4 to F6.17 The FIB-4 score was not used in the core analysis owing to this high level of missing data. Instead, a sensitivity analysis was conducted using only those patients with baseline FIB-4 scores, and the patient's FIB-4 category was entered as a potential risk factor.

Absolute Risk of Liver-Related Events and Death

Table 2 lists data on the absolute risk of the composite event and death across the risk factors of interest in this analysis. There were a total of 35 253 composite events and 15 458 deaths in our sample over a total of 734 829 person-years of data. Significantly higher event rates and death rates were experienced by male patients, white patients, and patients with genotype 3. Higher unadjusted composite event rates were found in treated patients than in untreated patients and in those who achieved viral suppression than in those who did not. However, patients who achieved viral suppression exhibited lower unadjusted death rates, which may reflect the delays in therapy until patient became symptomatic.

Predictors of Liver-Related Events

The factors associated with our primary outcomes are listed in Table 3. Patients who achieved an undetectable viral load significantly reduced their risk of the composite clinical end point by 27% (hazard ratio [HR], 0.73 [95% CI, 0.66-0.82]) and their risk of death by 45% (HR, 0.55 [95% CI, 0.47-0.60]) relative to patients with a detectable viral load over their entire postindex period. The risk reduction associated with the composite clinical end point measured after a 1-year washout period increased slightly to a reduction of 28% (HR, 0.72 [95% CI, 0.64-0.81]).

Patients with genotype 2 were consistently at lower marginal risk for liver-related events compared with patients with the more common genotype 1, controlling for viral load suppression and other risk factors. The risk reduction for the composite end point was 23% (HR, 0.77 [95% CI, 0.74-0.80]). The risk of all-cause mortality for genotype 2 patients was reduced by 20% relative to genotype 1 patients (HR, 0.80 [95% CI, 0.76-0.84]). Patients with genotype 3 were consistently at higher risk than patients with genotype 1. The estimates of marginal increased risk for those with genotype 3 ranged between 11% for the composite clinical end point (HR, 1.11 [95% CI, 1.07-1.16]) to a 17% increase in the risk of death (HR, 1.17 [95% CI, 1.11-1.24]). Other genotypes were infrequent in the VA patient population and were collapsed into a single category for which the estimated HRs were not generally significant.

Patient Characteristics

Male sex significantly increased the risk of the composite clinical outcome by 11% (HR, 1.11 [95% CI, 1.04-1.19]) and the risk of death by 58% (HR, 1.58 [95% CI, 1.38-1.80]). Each additional year of age increased the risk of death by 6% (HR, 1.06 [95% CI, 1.05-1.06]) but only increased the risk of the composite outcome by less than 1% (HR, 1.0001 [95% CI, 1.0012-1.0016]). Whites were consistently at higher risk for all late-stage liver events than blacks and other races. A diagnosis of diabetes at baseline and a hospital admission within 6 months prior to the index date were significantly associated with liver-related events.

\Secondary Outcomes

The risk prediction models for the individual late-stage liver events that compose the composite clinical outcome are listed in Table 4. As with the primary outcomes, achieving an undetectable viral load significantly reduced the risk of all clinical events. Other estimates were consistent with the results for the composite event.

Sensitivity Analysis: Impact of Fibrosis Stage

Risk models for the composite end point and all-cause mortality were reestimated using only patients with a baseline FIB-4 score (n = 54 420), and FIB-4 stage was entered as a potential risk factor. Several results are noteworthy (Table 5). First, our core estimates of the impact of achieving an undetectable viral load on event risk were very robust (Table 3). If anything, the estimated risk reduction associated with viral load suppression increased when the analysis took into account baseline levels of fibrosis. Second, risk of the composite event and all-cause mortality was monotonically and positively related to the patient's baseline fibrosis level. FIB-4 stage 2 increased risk of the composite event by 47% (HR, 1.47 [95% CI, 1.42-1.54]), while stage 3 HR for the composite event was 3.44 (95% CI, 3.29-3.61). The corresponding HRs for the risk of death were 1.46 (95% CI, 1.37-1.55) for stage 2 and 3.77 (95% CI, 3.55-4.00) for stage 3. In the FIB-4 analyses, each additional year of age was estimated to decrease event risk, but this is likely owing to age appearing in the FIB-4 calculation. Genotype 3 was also associated with lower risk than genotype 1 in the FIB-4 sensitivity analyses, but the estimated HRs were not statistically significant.

\DISCUSSION

We found that viral load suppression was associated with decreased risk of liver-related events using data from a large cohort of real-world patients with HCV at various stages of disease progression while controlling for other risk factors, including genotype. This study considered a wide range of liver-related events as study outcome variables and measured these outcomes and viral load suppression as time-dependent outcomes over as long as 10 years, depending on each patient's availability of data. Finally, the risk factors studied here were derived from EMR data and included both baseline data (sex, race, genotype) and other time-dependent risk factors (BMI, age) that take full advantage of the temporal relationships between events and patient risk factors.

Previous research has clearly documented that patients with an undetectable viral load18 or who achieve SVR due to treatment are at significantly lower risk of late-stage liver events and death.14,19 Our results are consistent with these earlier studies. Patients who achieve an undetectable viral load reduce their risk of death by 45% and reduce their risk of our composite end point of liver-related events by 27% relative to those patients whose viral load was detectable over the entire period following their diagnosis. More importantly, very few patients achieve an undetectable viral load without treatment (39 of 97 485 untreated patients).

While antiviral therapy can lead to viral eradication and reduced event risk, its effectiveness under real-world clinical conditions is limited by adverse effects and other factors. In this study, only 1 in 4 patients with HCV and a detectable viral load were willing to initiate treatment. Once treated, only a fraction of patients achieved the minimum treatment response of a single undetectable viral load test. Our rate of treatment "success" of 16.4% is consistent with that of other studies. For example, Kramer et al19 documented that the SVR rates achieved using standard antiviral therapy in real-world clinical settings ranged from 14% to 24% for HCV genotype 1 and 37% to 52% for genotypes 2 or 3. In the present study, 16.4% of treated patients achieved viral suppression. The independent role of genotype on the risk of liver-related events has been controversial, mostly because of limited number of patients with nonÐgenotype 1 infection.20,21 Our results are consistent with those of Larsen et al,22 who demonstrated that genotypes 1 and 3 may be associated with greater rates of disease progression than other HCV genotypes. Our results are also consistent with prior observations demonstrating low risk of disease progression in African American patients.23,24 Kallwitz et al12 found that both Hispanics and non-Hispanic whites had a higher risk of cirrhosis than blacks (odds ratios, 1.6 and 2.4, respectively). This study found that incidence rates of HCC were also slightly lower in blacks.

Our sensitivity analysis using baseline FIB-4 scores to define fibrosis stages found these staging variables to be highly predictive of hepatic morbidity and mortality. This supports the expanded use of noninvasive fibrosis staging methods as substitutes for liver biopsy. It is noteworthy that the inclusion of baseline FIB-4 levels into the statistical models eliminated the estimated increase in risk associated with genotype 3 relative to genotype 1. The exact reason for the differential risk effects associated with genotype 3 is unclear but may be related to the higher risk of hepatic steatosis in genotype 3 patients.25- 27

The use of HCV protease inhibitors is associated with a significant increase in SVR rates relative to standard therapy but also with increases in frequency and severity of adverse effects such as anemia, neutropenia, thrombocytopenia, rash, and gastrointestinal events.28 Early reports suggest nonÐinterferon-based therapies will deliver increased SVR rates while reducing associated substantial adverse effects that limit tolerability.29- 33 Clearly, new therapeutic options might offer significant benefits to patients and the health care system if their introduction improves the willingness of patients to initiate therapy and the likelihood that the patient will achieve viral suppression leading to SVR. Natural history data and an understanding of the challenges and expectations from patients are essential to help both providers and patients make informed decisions about when to initiate antiviral therapy and to motivate patient adherence.34

There are several important limitations in our study. First the VA study population differs significantly from the US population, consisting mostly of white and black men. Therefore, results for the risk associated with sex and the catch-all category of "other race" should be viewed with caution. Nevertheless, most US patients with HCV are male,3,4 and VA is the largest provider of care to chronically HCV-infected patients in the United States.35

We did not measure SVR, which requires that an undetectable viral load be maintained for 6 months following the termination of treatment. Instead, we used time to the patient's first undetectable viral load test. It is possible that patients achieving viral load suppression at 1 point can relapse. Nevertheless, our findings are consistent with those of previous studies that even suboptimal therapy is associated with survival benefits.8

The sensitivity of HCV viral load tests has changed over time, presented a challenge in defining an "undetectable" viral load. Many older tests used prior to 2004 have a lower threshold of 600 IU/mL, below which the result would be reported as undetectable. Newer tests are sensitive down to 10 IU/mL. For patients with more sensitive tests, we chose to define reported values under 25 IU/mL as undetectable. This overclassification of cases as being undetectable excluded some patients with baseline detectable viral loads from the study sample. Misclassification of some patients as having achieved viral suppression was much less likely because these measurements were made later in the data period. If viral suppression is based on an older laboratory technology, then some "detectable" postindex test findings would be miscategorized as viral suppression. This created a conservative bias in our estimates of the impact of achieving viral suppression because some patients in this category would have viral loads as high as 600 IU/mL and higher risk.

For 2 reasons, this study did not estimate or control for the effects of treatment on clinical end points and death. First, viral suppression without treatment was exceedingly rare, consisting of only 39 patients of 97 485 untreated patients. Second, the parameters with which to determine if a patient completed an adequate course of therapy vary by genotype and other factors, such as allowable duration on breaks in treatment. While developing counts of continuous days of therapy has been used by this research team in the past,36 we elected to use viral load suppression as our measure of treatment success. Finally, our study did not capture medical care outside the VA system, such as the Medicare program, which may cloud the relationship between viral load suppression and event risk. For example, viral load suppression is highly correlated with expensive treatment that was not well covered in the Medicare program before Part D became effective in 2006. Even when the treatment is covered, drug copayments and the cost of physician visits for injections constitute a significant financial burden. This suggests that treated patients use the VA system, which likely rolls over into treatment for any future liver-related events. If true, this would result in an underestimate of the impact of viral load suppression on event risk. Fortunately, the problem of missing outcome data does not apply to mortality, where viral load suppression has a larger estimated effect.

Source

Acetaminophen and Alcohol May Be Nephrotoxic

Medscape Medical News > Conference News

Neil Osterweil
November 15, 2013

BOSTON, Massachusetts — The link between acetaminophen (Tylenol and generics) and liver damage is well established, but there is also evidence to suggest that in some asymptomatic patients, therapeutic doses of acetaminophen and light-to-moderate alcohol use can lead to renal disease.

An examination of data from a nationwide health survey found that taken alone, neither light-to-moderate alcohol consumption nor acetaminophen were associated with significant risk for kidney disease. But respondents who reported taking both acetaminophen and drinking lightly or moderately had a more than two-fold higher risk for kidney dysfunction.

"Although individually it may not be harmful to ingest therapeutic doses of acetaminophen and light to moderate amounts of alcohol, we found that combining the two has the potential to be hazardous," said Harrison Ndetan, MSc, MPH, DrPH, from Parker University in Dallas, Texas, at the American Public Health Association 141st annual meeting here.

The findings suggest that primary care practitioners who treat patients with acute and chronic pain should inform them of the potential for kidney problems with concomitant use of alcohol and over-the-counter (OTC) analgesics containing acetaminophen, he told Medscape Medical News.

Pain is among the most common symptoms seen in primary practice, and an estimated 36 million Americans self-medicate with OTC analgesics, of which acetaminophen-containing products are the most frequently used, Dr, Ndetan said.

Acetaminophen has been shown to have nephrotoxic effects when used above recommended doses, and alcohol is known to affect renal filtration protein transporters that can affect acetaminophen metabolism, he said.

Alcohol and Analgesics

To see whether alcohol might exacerbate the renal effects of the drug when both are used in moderation, Dr. Ndetan and colleagues examined data from the 2003-2004 iteration of the National Health and Nutrition Examination Survey (NHANES).

Among more than 10,000 respondents included in the analysis, 38.13% reported mild-to-moderate alcohol consumption, 5.6% reported using therapeutic doses of acetaminophen, and 2.6% reported using both. In all, 1.2% of respondents reported renal dysfunction.

In logistic regression analyses controlling for sociodemographics and health conditions, the authors found that the combination but not acetaminophen or alcohol alone was associated with significant risk for kidney dysfunction (see table).

Table. Risk for Renal Dysfunction, NHANES 2003 - 2004
Variable Odds Ratio 95% Confidence Interval
Therapeutic acetaminophen (1.2 g) 0.91 0.57 - 1.45
Light/moderate alcohol 0.53 0.43 - 0.65
Acetaminophen and alcohol 2.23 1.22 - 4.08

The risk for kidney dysfunction in respondents who mixed acetaminophen and alcohol was greater for older adults, males, blacks, and Hispanics (vs, whites), and those with conditions that may compromise renal function, such as hypertension, diabetes, and obesity.

Jeanmarie Perrone, MD, associate professor of emergency medicine and director of medical toxicology at the University of Pennsylvania in Philadelphia told Medscape Medical News that acetaminophen-induced nephrotoxicty typically manifests as renal insufficiency in about 1% - 2% of patients who present with acetaminophen overdose. Although it is not as well documented as acetaminophen hepatoxicity, it is not all that uncommon.

Dr. Perrone is coauthor of a study of the pathophysiology, clinical presentation, and management of acetaminophen-induced nephrotoxicity. She notes that chronic alcohol use as well as certain drugs (eg, anticonvulsants) are associated with increased activity of the cytochrome P450 (CYP-450) pathway, and that CYP-450 can enhance acetaminophen toxicity (J Med Toxicol. 2008;Mar 4(1):2-6).

The study funding source was not reported. Dr. Ndetan and Dr. Perrone have disclosed no relevant financial relationships.

American Public Health Association (APHA) 141st Annual Meeting: Abstract 290307. Presented November 4, 2013.

Source

Hepatitis C: Patient Warehousing

Randi Hernandez, MS, Associate Editor/Online
Published Online: Friday, November 15, 2013

Aimee Tharaldson of Express Scripts explains why some hepatitis C patients who do not have signs of active disease may want to wait to receive treatment until later this year and early next year, when the FDA is expected to approve sofosbuvir and simeprevir for the treatment of this condition.

 
This video was shot at the 2013 Academy of Managed Care Pharmacy Nexus meeting in San Antonio, Texas.

Source

Liver International

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Original Article

Guillaume Geri1, Marianne Maynard2, Eric Rosenthal3, Hélène Fontaine4, Karine Lacombe5, Laurence Slama6, Cécile Goujard7, Véronique Loustaud-Ratti8,  Jean-François Bergmann9, Philippe Morlat10, Daniel Vittecoq11, Laurent Alric12, Patrice Cacoub1,*, The GERMIVIC Group

DOI: 10.1111/liv.12388

This article is protected by copyright. All rights reserved.

Publication History
Accepted manuscript online: 15 NOV 2013 12:37AM EST
Manuscript Accepted: 9 NOV 2013
Manuscript Revised: 7 NOV 2013
Manuscript Received: 21 SEP 2012

Keywords: hepatitis C virus;  human immunodeficiency virus;  epidemiology;  treatment;  interferon

Abstract

Objective

To determine the characteristics of hepatitis C (HCV)-infected patients in 2010 and compare this survey with those reported in 1995 and 2001.

Patients and methods

Observational multicenter study conducted in 2010 in french internal medicine, infectious diseases and hepatology departments.

Results

1,621 HCV infected patients (mean age 50.1±10.7 years; sex ratio M/F 1.8; genotype 1: 55.7%) were included. Of these, 910 (56.1%) were HIV-HCV co-infected, 463 (40.4%) were asymptomatic and 184 (16.1%) had cirrhosis at inclusion in the study. Positive viremia was found in 1,025 patients (65.5%) at inclusion in the study. A complete pre-treatment evaluation including investigation for HCV RNA, genotype determination and liver fibrosis was performed in 96.5%, 80.5% and 68.7% of the 1,621 patients, respectively. Previous and ongoing HCV treatments were noted in 49.6% and 20.1% of patients, respectively. A sustained virological response (SVR) was observed in 271/801 (38.3%) patients, i.e. 44.1% and 30.7% in co-infected and mono-infected patients, respectively. Cirrhosis was more frequent in the 2010 than in the 2001 and 1995 surveys (16.1% vs. 10.4% and 7.4%, respectively; p<0.0001). A complete pre-treatment evaluation was performed in 57.9% and 50.9% of patients in 2010 and 2001 (p<0.0001). Liver fibrosis evaluation was more frequent in 2010 than in the 2001 and 1995 surveys (68.7% vs. 62.7% and 28.7%, respectively, p<0.0001).

Conclusion

The care of HCV infected patients has changed significantly in “real life” through an improvement of pre-treatment evaluation before antiviral introduction and the increased use of antivirals. New HCV therapy combinations including protease inhibitors are warranted to increase the SVR rate.

This article is protected by copyright. All rights reserved.

Source

3D Printing May Revolutionize Drug R&D

Genetic Engineering & Biotechnology News

Nov 15, 2013 (Vol. 33, No. 20)

Organovo Offers Design Options for Modeling Diverse Tissue Types

Gail Dutton

Organovo_LiverTissue1331515822

A cross-section of bioprinted human liver tissue that has undergone histological staining demonstrates cell viability and density, as well as compartmentalization between the hepatocytes (shown as blue nuclei), endothelial cells (red), and hepatic stellate cells (green).

    Differences between animal models and human tissues have contributed to approximately one dozen failures of late-stage drugs in 2012 alone. Organovo is remedying the situation with an innovative tissue development technology that produces fully functional human tissue for research and therapeutic applications.

    “We can create a number of tissues,” notes Keith Murphy, president and CEO. “Liver, cancer, and kidney tissues are highest on our list.” Created using 3D printing, the resulting tissue models have greater predicative capacity and are available in unlimited quantities for multiple studies, thus enabling drug candidates to be tested on functional human tissue before entering clinical trials.

    To develop tissue, “We create a bio-ink from cell aggregates and locate them precisely, using the Organovo NovoGen Bioprinter™. These are building blocks,” Murphy says. They are composed of approximately 1,000 cells that maintain tissue-specific geometries. These blocks fuse together naturally and build collagen, creating small pieces of tissue that perform like natural tissue.

    Printed tissue has similar cellular density to native tissue and incorporates multiple cell types and the key architectural and functional features—such as intercellular tight junctions and microvasculature—that are present in native tissue. Unlike traditional tissue engineering, 3D printed tissue is free of scaffolds, and any hydrogel components are temporary. When they are gone, they leave behind 100% cellular tissues. Currently, printed tissues are supplied in multiwell plates, slices, or blocks.

    “There are limitations, however,” Murphy cautions. “Our ability to make tissue thicker than about one millimeter is restricted by our ability to deliver nutrients and oxygen to the cells. Today, nobody can integrate the small vessels and capillaries needed for thicker tissue. Therefore, we’re not making whole organs,” he stresses, although doing so may become possible eventually.

    Organovo is working toward that. Already, it has developed a linear artery from human cells and is working to create branched blood vessels. “We hope this will provide a way to perfuse tissues,” Murphy says. “We’re still a couple steps away.”

    Models for Drug Development

    The ability to print 3D human tissue offers significant benefits in drug development and holds promise for therapeutics. Improving the models used for drug testing reduces the failure rates and can eliminate some surprise failures. 3D printing delivers better models because they use human cells and are highly reproducible. It also has the advantage of providing ample quantities and improved longevity for sometimes scarce tissue.

    Organovo’s liver tissue model, for example, survives approximately six days, while normal liver tissue survives about two days. Organovo is currently testing longer time points and plans to release data on performance at 30 days and beyond.

    Because the tissue can be designed, it offers the potential for knockouts as well as the ability to be patient-specific for various disease models. It also enables predictive modeling based on genetic profiles of multiple people, thus helping drug developers select nonresponders before clinical trials begin.

    Printed tissues’ greater predictive capabilities are based upon the structure that can be designed. “Fibrosis, for example, is difficult to research in animal and cellular models,” Murphy says. That’s partially because, in a co-culture of the best current model, the cells randomly originated in a Petri dish are oriented differently than cells in the human body. Printing the underlying cell type with the epithelial cell type on top delivers tissue more similar to what actually is in the human body, he explains. “That premise works for anything with a multilayered structure.”

    Models for Therapeutics

    3D printed tissues also may be used therapeutically. For example, heart tissue may be printed to repair (rather than replace) a heart, or veins may be printed to eliminate the need to transplant a patient’s vein from the leg to the heart for bypass surgery. Because autologous cells may be used, the risk of transplant rejection and the need for immunosuppressant drugs may be avoided. “The simpler applications are only a few years from clinical studies,” Murphy says.

    Partnerships

    Organovo has partnered with Oregon Health & Science University to study tumors using bioprinted tissue. “Researchers typically don’t have access to a whole tumor,” Murphy explains. But, by placing a bioprinter onsite, researchers can print as much tissue as needed to study multiple drug regimens. Organovo’s researchers work closely with their partners, developing custom tissues for drug discovery, preclinical disease modeling, and ADME-Tox studies.

    In late September, Organovo announced a collaborative research agreement with Roche involving liver toxicity. In addition, the company has an agreement with United Therapeutics for undisclosed work. “We also have agreements for tissue engineering with academic institutions,” Murphy says. “Longer term, we want to partner with pharma to help take drugs through development to the clinic. We also plan to develop some of the tissues alone and with partners, using bioprinters as research tools and for direct manufacture.”

    Organovo

    Location: 6275 Nancy Ridge Drive, Suite 110, San Diego, CA 92121

    Phone: (858) 224-1006

    Website: www.organovo.com

    Principal: Keith Murphy, President and CEO

    Number of Employees: 35

    Focus: Organovo uses 3D printing technology to design and develop structurally and functionally accurate human tissue models with improved properties and predictive capabilities. The tissues have applications in medical research and therapeutic interventions.

    Source

      Provided by Healio

      November 15, 2013

      WASHINGTON — Combined sofosbuvir and ribavirin therapy to treat established recurrent hepatitis C infection after liver transplant has proven successful in preliminary results, according to research presented by Michael R. Charlton, MD, in a late-breaking abstract at The Liver Meeting.

      The ongoing single-arm, open-label interferon-free pilot study enrolled 40 naive and treatment-experienced patients with recurrent HCV infection of any genotype after liver transplantation. The patients received up to 24 weeks ofsofosbuvir and ribavirin with a primary endpoint of sustained virologic response 12 weeks after completion of treatment.

      All patients were negative at end of treatment, and preliminary results show SVR4 in 77% of patients.

      “I don’t think SVR4 is enough in this patient population, and we absolutely have to see SVR12,” Charlton, of Mayo Clinic in Rochester, Minn., said. “These are really preliminary data, but they are extremely encouraging.”

      Disclosure: Charlton reports no relevant financial disclosures.

      For more information:

      Charlton MR. #LB-2: Sofosbuvir and Ribavirin for the Treatment of Established Recurrent Hepatitis C Infection After Liver Transplantation: Preliminary Results of a Prospective, Multicenter Study. Presented at: The Liver Meeting 2013; Nov. 1-5, Washington.

      Source

      Hepatitis C Viral Suppression Reduces Liver Morbidity, Death

      Medscape Medical News > Conference News

      Miriam E. Tucker
      November 15, 2013

      Washington, DC — Achieving an undetectable hepatitis C viral load is associated with decreased liver morbidity and death, a large observational study using Veterans Affairs (VA) data finds.

      "New therapies are needed to increase treatment rates and increase treatment effectiveness," said Jeffrey McCombs, PhD, from the University of Southern California School of Pharmacy in Los Angeles.

      Dr. McCoombs presented the results here at The Liver Meeting 2013. The findings were simultaneously published online inJAMA Internal Medicine.

      Dr. McCombs and his team used electronic medical records data from the VA National Clinical Case Registry for hepatitis C virus from 1999 through 2010, which includes 360,857 patients.

      A total of 128,769 people met the selection criteria with a detectable viral load (>25 IU/mL) at baseline and their viral genotype recorded.

      Patients were 97% male, 51% white, and 31% black, with an average age of 52 years. The majority of patients, 79%, were infected with hepatitis C genotype 1, 12% with genotype 2, and 8% with genotype 3.

      Twelve percent also had diabetes and 16% had a prior hospital admission.

      Primary outcomes were time to death and time to a composite liver event, including compensated and decompensated cirrhosis, hepatocellular carcinoma, or liver-related hospitalization.

      Dr. McCombs explained that the time from undetectable viral load to first event was used instead of sustained viral response — the gold standard of treatment success — because it is much easier to obtain. Viral response requires the determination of the time at which the patient maintained consistent viral load suppression for a minimum of 6 months following the termination of treatment.

      Only 1 in 4 Treated

      In all, just 24% of patients had been treated previously for hepatitis C, and only 16% of those treated achieved an undetectable viral load.

      Of the entire study population, only 4% achieved an undetectable viral load.

      Overall, viral load suppression reduced the risk for future liver events by 27% and death by 45%.

      "This verifies earlier findings that viral load reduction through treatment can significantly reduce the risk of adverse patient outcomes," Dr. McCombs said.

      Male sex significantly increased the risk for the composite clinical outcome by 11% and the risk for death by 58%. Both diabetes and prior hospital admissions increased these risks as well.

      Compared with whites, black patients had a 35% lower risk for the composite endpoint and a 28% lower risk for death. And compared with patients who had hepatitis C genotype 1, those with genotype 2 were at lower risk: 23% for the composite event and 20% for death.

      “This has left me, and many clinicians, in the odd position of feeling that patients are either too healthy or too sick for hepatitis C treatment.” Dr. Mitchell Katz

      In an accompanying article, JAMA Internal Medicine deputy editor Mitchell Katz, director of the Los Angeles County Department of Health Services, writes, "The authors demonstrate that patients who do achieve viral suppression, which almost always required  treatment, fared significantly better."

      He adds, "The critical issue going forward is whether the new drugs that have been released (eg, hepatitis C protease inhibitors) or are likely to be approved soon (eg, hepatitis C nucleotide polymerase inhibitor) can achieve sustained viral suppression in a high percentage of patients without serious adverse effects."

      Can these treatments "be made available without breaking the bank of safety net health systems across the country that care for large numbers of patients with hepatitis C?" Dr. Katz questions. "I certainly hope so," he writes.

      Dr. Katz also notes that the low rate of treatment seen in the VA database probably reflects the fact that current treatments aren't very effective in clearing the infection and have serious adverse effects.

      He explains that he often feels he is "between a rock and a hard place" when it comes to treating patients with hepatitis C. For patients who are healthy, despite their infection, it may be worthwhile to wait for better treatments, whereas patients with severe liver damage may not be able to tolerate the adverse effects of treatment; for those patients, it is unclear whether suppressing the virus would even improve their outcomes.

      "This has left me, and many clinicians, in the odd position of feeling that patients are either too healthy or too sick for hepatitis C treatment," writes Dr. Katz. "It undoubtedly explains why in this VA cohort only 24% of patients had received treatment at any time."

      Sustained Viral Response

      During the question-and-answer period at the meeting, audience members questioned the study's methods, given its assumption that the patients are all at equal risk going in, which may not be the case.

      "Especially when you have relatively low response rates, there's a big difference between those who do and don't respond, before you ever treat them," said Andrea Branch, MD, from the Icahn School of Medicine at Mount Sinai, New York.

      She urged Dr. McCombs and his team to compare long-term outcomes in the relapsers with those in patients who actually achieve a sustained viral response.

      "That gives you a chance to look at people who have the physiology necessary to respond to treatment with dramatic suppression of virus, but who remain viremic afterward," she explained.

      Dr. Branch said other studies have shown that the patients who first suppress the virus, but then relapse and don't achieve a sustained viral response, tend to have long-term outcomes, such as liver cancer and mortality, similar to those in patients who do achieve a sustained response, even though they become hepatitis C load positive again.

      "I think it's really important when doing outcomes to tease out patients who never suppress the virus with those who are capable of suppressing it," even if they later relapse, stressed Dr. Branch. "It's a marker of those healthy enough to respond to therapy by becoming viral-load negative. Those people are different from the population who don't become viral-load negative."

      But, she added, "as more and more people have a sustained viral response, this will become less of an issue because the more potent the antiviral drugs, the less significant the underlying physiology in achieving viral suppression."

      Dr. McCombs replied that the VA dataset would allow for this analysis.

      "I would very much encourage you to do that and would be very interested in what you find," Dr. Branch said.

      This study was funded by Bristol-Myers Squibb. Dr. McCombs received salary and travel support under the terms of the research grant between Bristol-Myers Squibb and the University of Southern California. Dr. Branch has received research support from Gilead Sciences, the National Institute of Drug Abuse, and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Katz has disclosed no relevant financial relationships.

      The Liver Meeting 2013: American Association for the Study of Liver Diseases (AASLD). Abstract #246. Presented November 5, 2013.

      JAMA Intern Med. Published online November 5, 2013. Abstract Editorial

      Source

      Experts Agree: We Can No Longer Ignore the Burden of Liver Disease

      Received via email November 15, 2013

      Caring Ambassadors Program

      The Liver Cancer Roundtable held their inaugural meeting last week in Washington, DC. The Roundtable attendees included leading academic experts in liver cancer, patient advocates, and representatives from HHS, NIH, and the CDC. Dr. Douglas LaBrecque, who co-chairs the Roundtable and has been spearheading a year-long global effort to raise awareness about liver cancer for the World Gastroenterology Organization, was encouraged by the two-day event. "This was a remarkable gathering of national and international experts," LaBrecque stated. "The results of their passionate and enthusiastic discussions will provide the basis for a first draft of a National Action Plan for the prevention, diagnosis, care, and treatment of liver cancer."

      Every 30 seconds, one individual dies from liver cancer (HCC). Globally, HCC is the second deadliest cancer in men and number 3 overall. Together with liver cirrhosis, it results in 1.75 million deaths per year. One in twelve of the world's population is affected by chronic hepatitis B or C, which cause 80-85 percent of all the world's HCC. 25-40 percent of those infected with viral hepatitis will die of the resulting cirrhosis or HCC. This is especially disturbing given that both hepatitis B and C are preventable and treatable. New drugs, just approved for hepatitis C, will cure close to 100 percent of patients infected with hepatitis C. A highly effective vaccine has been available to prevent hepatitis B since 1982. In the US, HCC is one of the very few cancers which has an incidence that is rising instead of falling, and it is the fastest rising cause of cancer death in the US. Yet, there is no US, much less global, policy or action plan to address HCC. The majority of countries don't even have a policy to address hepatitis B and C. Universal birth and full 3 dose vaccination for hepatitis B should be a global priority, but 25% of the world's children are still unvaccinated.

      Given the number of individuals that HCC impacts in the US and worldwide, liver cancer has received very little attention from those organizations that are in a position to effect real change. The WHO's Millennium Health Goals stress HIV, tuberculosis, and malaria as the critical global infections; hepatitis doesn't even make their list of 'neglected infections'. This inattention to viral hepatitis is alarming, given that it results in significantly more deaths than HIV, tuberculosis, or malaria. The WHO's policies have a very real impact; the WHO itself spends 500-800 times more per death per year on HIV, tuberculosis, and malaria than they do on viral hepatitis. The US President's Emergency Plan for AIDS Relief (PEPFAR) program has spent 63 billion dollars on HIV, tuberculosis, and malaria in low resource countries over the past eight years. The Global Fund to Fight AIDS, Tuberculosis, and Malaria has allocated 22.9 billion dollars to these diseases since 2002. Other philanthropic organizations, including the Gates Foundation, have spent tens of billions more. In the US, the NIH designates over 3 billion dollars per year to HIV, but only 160 million to all of viral hepatitis. The CDC will spend 1.3 billion on HIV/AIDS this year and only 30 million on all of viral hepatitis, which represents a significant increase from the 19 million dollars that were allocated in previous years.

      Lorren Sandt co-chairs the Roundtable with Dr. LaBrecque. "I have been working to put together a Roundtable on liver cancer for the better part of a decade," said Sandt. "I am greatly encouraged by the amazing group that we had in the room and the progress that we were able to make in just a couple of days."

      "How and why the US and the world have continued to ignore this ongoing health crisis escapes and astounds me," said LaBrecque. "It will take a massive, coordinated global effort to reverse this critical assault on world health, similar to the successful campaign mounted to reverse the onslaught of HIV/AIDS. HIV currently affects 34 million individuals globally. In contrast, hepatitis B and C chronically infect close to 600 million individuals globally. It is well past time that viral hepatitis receive the attention that it deserves in order to reduce the number of needless deaths from HBV, HCV, and liver cancer."

      For more information, please contact Lorren Sandt at 503-632-9030.

      Douglas LaBrecque, MD, is an Emeritus Professor of Internal Medicine at the University of Iowa, founder and 30 year chair of their Liver Section, and Chair of the Liver Section of the World Gastroenterology Organization.

      Lorren Sandt is the Executive Director of the Caring Ambassadors Program, a non-profit patient advocacy organization that has been working to improve the lives of individuals with viral hepatitis since 1999.

      “Empowering people to be ambassadors for their own health since 1997”

      Source: CaringAmbassadors.org

      A Promising Interferon-Free Regimen for HCV Genotype 1 Infection

      SUMMARY AND COMMENT | GASTROENTEROLOGY

      November 15, 2013

      Atif Zaman, MD, MPH Reviewing Lawitz E et al., Lancet 2013 Nov 5;

      In a phase II trial, a single-tablet, all-oral regimen of sofosbuvir and ledipasvir achieved nearly 100% sustained virologic response in both treatment-naive and treatment-experienced patients.

      The FDA should soon approve the interferon-based regimen of sofosbuvir plus peginterferon and ribavirin for the treatment of hepatitis C virus (HCV) genotype 1 infection. Response rates of 90% have been achieved with only 12 weeks of therapy in treatment-naive patients without cirrhosis. The next step in the evolution of therapies for HCV genotype 1 infection is the development of interferon-free regimens.

      In this phase II, open-label, randomized trial, investigators evaluated sofosbuvir (a nucleotide polymerase inhibitor; 400 mg) plus ledipasvir (an HCV NS5A inhibitor; 90 mg) in a single combination tablet taken daily with or without ribavirin (1000–1200 mg daily). In one cohort, 60 treatment-naive patients without cirrhosis were randomized to receive sofosbuvir plus ledipasvir alone for 8 weeks or 12 weeks or with ribavirin for 8 weeks. In a second cohort, 40 patients who had previously failed protease inhibitor–based therapy were randomized (stratified by presence or absence of cirrhosis) to receive sofosbuvir and ledipasvir with or without ribavirin for 12 weeks.

      In all five treatment groups, rates of sustained virologic response (SVR) were between 95% and 100%. SVR rates were similar with 8 and 12 weeks of therapy. Only two patients (2%; one treatment-naive and one treatment-experienced) had viral relapse after stopping therapy. HCV genotype (1a or 1b), IL28B genotype, black race, and high baseline viral load did not affect SVR. The incidence of adverse events was low; the most common ones were headache, nausea, and anemia.

      COMMENT

      The results of this small phase II study are impressive. A daily regimen of the single combination tablet of sofosbuvir and ledipasvir with or without ribavirin for 8 to 12 weeks achieved nearly 100% sustained virologic response in both treatment-naive and treatment-experienced patients with genotype 1 hepatitis C virus. This high SVR rate did not seem to be affected by known predictors of negative response. Phase III trial results are eagerly awaited.

      EDITOR DISCLOSURES AT TIME OF PUBLICATION

        Disclosures for Atif Zaman, MD, MPH at time of publicationSpeaker’s bureauBristol-Myers Squibb; Genentech; Gilead; Kadmon; Merck; Salix; Vertex

        CITATION(S):

        Lawitz E et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): An open-label, randomised, phase 2 trial. Lancet 2013 Nov 5; [e-pub ahead of print]. (http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2962121-2/abstract)

      Source

      Also See: Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial

      United States to allow transplants of HIV-infected organs

      ’Positive-to-positive’ transplants would create new pool of donors for infected patients.

      Sara Reardon

      13 November 2013

      1.14170

      The United States banned organ donations by people with HIV 25 years ago.

      WILL & DENI MCINTYRE/SPL

      The United States is poised to overturn its ban on accepting organs from HIV-positive donors, a move that would lead to organ transplants between infected patients.

      Legislation approved by the US House of Representatives on 12 November seeks to end the 25-year prohibition on HIV-infected organs. It also directs the government to develop guidelines for the subsequent study of ‘positive-to-positive’ transplants.

      Researchers say that such procedures could help to ease the overwhelming demand for donor organs in the United States. More than 120,000 people are waiting for new hearts, lungs, kidneys and other organs — a list that includes people with HIV, who are living longer thanks to antiretroviral drugs and other medical advances. Roughly one-quarter of HIV patients in the United States also have hepatitis C, which in its advanced form can be treated only by liver transplant.

      “Any potential source of new donors should be looked at,” says transplant surgeon Peter Stock of the University of California, San Francisco. One recent study suggests that allowing donations from otherwise healthy people with HIV could make an additional 500‒600 organs available for transplant each year1.

      The Senate approved the legislation, known as the HIV Organ Policy Equity Act, in June, and President Barack Obama is expected to sign it into law. But it may be some time before any transplants are performed. First, the federal Organ Procurement and Transplantation Network will need to develop ethical and clinical standards to guide medical research on positive-to-positive transplants. Dorry Segev, a transplant surgeon at Johns Hopkins University in Baltimore, Maryland, who lobbied for the bill, guesses that this may take up to a year.

      Promising precedent

      Such transplants are not without precedent, however. Elmi Muller, a transplant surgeon at the University of Cape Town in South Africa, has pioneered positive-to-positive kidney transplants, conducting 26 since 2008.

      “I felt that where these patients didn’t have much option, there was not much to lose,” says Muller. Approximately 20% of South Africa’s population is infected with HIV, but those who need new kidneys are usually not even considered for dialysis — much less transplant surgery. Until antiretroviral drugs became widely available a few years ago, HIV-positive South Africans were not expected to live very long.

      In the past five years, only two of Muller’s 26 transplants have failed, adding weight to her argument that the benefits of the procedures outweigh their risks. Yet Muller says her research also highlights the need for continued study of the safety and efficacy of transplants from HIV-positive donors. For example, although the organ recipients in her study are generally healthy, a few of their donor kidneys show structural changes that may be caused by HIV — and Muller does not know whether the changes are harmful.

      There are also concerns about ‘superinfecting’ a HIV-positive patient with a second strain of the virus carried by a donor organ, particularly if that strain is resistant to antiretroviral drugs. And it is not clear how immune-boosting antiretroviral drugs will interact with the drugs that transplant patients take to prevent their bodies from rejecting donor organs. High, possibly toxic, doses of immunosuppressant medication may be required to prevent organ rejection in a recipient who is also taking antiretroviral drugs. Some research suggests that HIV-infected individuals seem to be more likely to reject new organs2.

      Despite those caveats, researchers are hopeful that investigating positive-to-positive transplants will yield valuable clinical insights into the functioning of HIV and the human immune system. Says Stock, “There is just so much to learn.”

      Nature doi:10.1038/nature.2013.14170

      References

      1. Boyarsky, B. J. et al. Am. J. Transplant. 11, 1209–1217 (2011). Article PubMed ISI ChemPort

      2. Stock, P. G. et al. N. Engl. J. Med. 363, 2004–2014 (2010). Article PubMed ISI ChemPort

      Source

      Also See: Congress Passes HIV Organ Policy Equity Act (HOPE Act)

      10 months on proposal on Hepatitis-C yet to be approved

      SHABIR AHMAD

      SRINAGAR, Nov 14: Despite the concerns expressed by the health experts over the spread of hepatitis-C in Kokernag area of south Kashmir last year health authorities seem to have ignored the issue which, experts fear could take an ugly turn in the years to come.

      Last year alarm bells rang in the health department after hundreds of people were tested positive for hepatitis-C. Even the concerned LMA and minister for public enterprise, Peerzada Mohammad Syed had admitted that 33 percent population of the area was infected. Following the reportage of the spread of the infection in the area the government dispatched a team of doctors from SKIMS and directorate health services to the area for screening and treatment of the people. A noted gastroenterologist of the state, Dr M S Khuru also visited the area. Khuru after a thorough study on the spread of infection in the area submitted a report to the government cautioning against ignoring the issue. On the basis of the report of Dr Khuru, director health services sent a proposal of 10 crore rupees to the government.

      SKIMS authorities after their study also submitted a proposal of 25 crores to the central government for the treatment of affected and prevention of further infection.

      However, official sources said that the none of the proposals sent by the director health and SKIMS has been approved so far.

      “I had sent a detailed report to the government giving them the actual estimate of the things. I had mentioned everything in the report as to how the situation will take ugly turn in future if steps are not taken to prevent the further infection. I don’t think I have left anything unwritten in the report.

      Despite that I held multiple meetings with the director who too seemed to be concerned about the situation in the area. I had even suggested the setting up of three centers one in Kokernag, Anantnag and Srinagar for the checkup of the infected people but I think that has not taken off yet,” Dr Khuru told Kashmir Times.

      He warned that if the government does not take any measures to prevent the spread of infection at this point of time the situation in the area after 20 years will be grim. “I was supposed to wake up the government and I did that,” Khuru said.

      He said that the government has approved the proposal or the further prevention of the disease without wasting even days but irony is it that a year has passed nothing suggested by the experts has taken off yet.

      Director SKIMS, Dr Showkat Zargar, said that they have also forwarded a proposal to the government which has not been approved yet. “After the screening of the people of the area we had sent a proposal of 25 crores to the central government but the same has not been approved,” Dr Zargar said.

      On being asked about his announcement that SKIMS will treat the infected people free of cost, he said, “Yes I had announced that but I did not know such a huge population will be tested positive.

      At least 50 percent of samples collected by our team were found positive. So it was not possible for us treat all those. It needs crores of rupees which have written to the government,” Dr Zargar said.
      He also seconded Dr Khuru saying the situation could get alarmed in future if measures are not taken to prevent it now.

      People of the area complain that nothing has been done by the authorities except screening of the people.

      “It was only after the issue was highlighted by the press some teams of doctors came to the area and screened the people. Nothing was done beyond screening in Maham and Sona Brari villages,” said a local social activist and PDP leader, Abdul Rahim. He said that the issue seems to be no issue for the government now. “I recently talked to director health services who clearly told me that the chapter has been closed by the government,” Rather said.

      Rahim said that authorities seem to have also ignored the concerns expressed by the experts like Dr Khuru.

      Source

      Laparoscopic liver resection: 5-year experience at a single center

      Surg Endosc. 2013 Nov 7. [Epub ahead of print]

      Long TC, Bac NH, Thuan ND, Dat LT, Viet DQ, Chuong LC.

      Department of General Surgery, University Medical Center at Ho Chi Minh City, Ho Chi Minh City, Vietnam, trancongduylong@yahoo.com.

      Abstract

      BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer, especially in the Association of Southeast Asian Nations (ASEAN) region, where the prevalence of hepatitis virus infection is high. Liver resection is a potentially curative and popular therapy for HCC. Laparoscopic surgery using minimally invasive techniques potentially brings benefits to patients who need liver resection for HCC. This study aimed to evaluate the effectiveness, safety, and benefits of laparoscopic liver resection for HCC with long-term follow-up evaluation.

      METHODS: This cohort study with 5-year results of total laparoscopic hepatectomy for HCC was conducted in one center. Patients with HCC were selected for laparoscopic liver resection by the same team. The operation also was performed by one team of surgeons. The follow-up protocol was similar to that for open surgery. The patients were scheduled to return for examination every 2 months after the operation. The data for the patients were collected and analyzed using SPSS software.

      RESULTS: From January 2008 to December 2012, 173 enrolled patients with HCC underwent laparoscopic liver resection. The male-to-female ratio was 3:1. The mean age of the patients was 56 years (range 16-83 years). The follow-up period for 130 patients was 21.6 ± 16.0 months (range 0-60 months). The mean tumor size was 3.73 cm (range 2-10 cm). The stages of HCC according to the Barcelona Clinic Liver Cancer (BCLC) categorization were as follows: 0 (6 %), A1 (59.5 %), A2 (6.9 %), A4 (2.9 %), and B (27.2 %). Four patients required conversion to other techniques (2.3 %) because of the potential for major bleeding and tumor perforation. The types of resection were resection of one segment (segments 2, 3, 4, 5, 6, 7, and 8; 43.8 %), resection of two segments (posterior sector, anterior sector, segments 5 and 6, and left lateral sector; 47.9 %), resection of three segments (left and central liver; 4.7 %), and four segments (right liver; 3.6 %). The mean operation time was 112 ± 56 min (range 30-345 min), and the median blood loss was 100 ml (range 20-1,200 ml). The mean hospital stay was 6.5 ± 2.0 days (range, 3-19 days). No perioperative mortality occurred. The overall survival rates were 94.2 % at 1 year, 87 % at 2 years, 72.9 % at 3 years, 72.9 % at 4 years, and 72.9 % at 5 years. The mean overall survival time was 49.7 ± 2.1 months (range 45.5-53.9 months). The disease-free survival rates were 79.1 % at 1 year, 60 % at 2 years, 57 % at 3 years, 52 % at 4 years, and 26.3 % at 5 years. The mean disease-free survival time was 38.9 ± 2.6 months (range 33.9-44.0 months).

      CONCLUSION: Laparoscopic liver resection for HCC is feasible, safe, and effective, with good oncologic results. Major and anatomic hepatectomy are possible with improved skill and experience. Laparoscopic liver resection is a promising treatment option with minimally invasive benefits for HCC patients.

      PMID: 24196550 [PubMed - as supplied by publisher]

      Source

      Heroin Addiction Warps Brain's Ability to Change

      Published: Nov 14, 2013

      By Cole Petrochko, Staff Writer, MedPage Today

      Action Points

      • Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

      SAN DIEGO -- Years of heroin addiction alter gene expression and brain plasticity, researchers reported here.

      In a study of heroin abusers' post-mortem brains, longer duration of heroin use was associated with changes in the shape and packaging of DNA in the brain in the ventral and dorsal striatum, areas of the brain associated with drug addiction, according to Yasmin Hurd, PhD, of the Icahn School of Medicine at Mount Sinai Hospital in New York, N.Y., and colleagues.

      The DNA of these patients' brains became more "open" to gene expression and overactive, which may mean that a treatment that helps "close" this gap and reduce overactivity may help temper addiction, Hurd told MedPage Today during an oral presentation at the Society for Neuroscience meeting.

      Healthcare costs due to opioid abuse total around $50 billion each year, according to Hurd, and opioid abuse in particular costs 2.5 times that of other medical disorders.

      She also noted that "many new heroin users were first prescription opioid users," which is already a source of discussion for CDC and FDA.

      The authors "studied the human striatum to characterize epigenetic marks and genes related to synaptic plasticity, dysregulation of which is a core feature of substance use disorders," This was done through a post-mortem analysis of a collection of 31 heroin users' brains and 13 matched controls.

      In the ventral striatum, they saw a "significant impairment of genes related to glutamatergic neurotransmission, as well as chromatin remodeling enzymes," which they said contributed to drug-induced synaptic plasticity of the striatum.

      In the dorsal striatum, they saw no significant differences in gene expression of glutamate-related markers or in histone H3 acetylation, but noted a significant positive correlation between acetylation and years of heroin use, which "suggested that chronic heroin use leads to hyperacetylation of histone H3 that contributes to the observed gene expression impairments," as well as the drug-related synaptic plasticity.

      Additionally, the epigenetic changes in DNA were associated with the "heroin-related glutamatergic dysregulation in the striatum."

      They were also surprised to find that there was an inverse relationship between the openness of DNA and heroin overdose, implying that the mechanisms at work in overdose are different from those involved in addiction, Hurd noted.

      Hurd cautioned that much of this research is ongoing, and that pharmacologic or other treatment targets are, at best, being looked at in animal models.

      In a model of mice allowed to self-administer heroin, "the degree of the activation of glutamatergic genes related to the amount of heroin they took," she noted, so perhaps those animals and those people who have been taking heroin for a longer time and larger amount may need a longer treatment.

      "Is a person injecting heroin for 10 years going to need the same degree of treatment as someone in their first year of drug abuse?," she posed as a future research target, cautioning that addiction is -- at least presently -- a life-long problem.

      "We want to see if we can re-normalize the brain and see if we can give them a chance if they relapse again," she said.

      The study was supported through an NIH grant.

      The authors declared that they had no conflicts of interest.


      Primary source: Society for Neuroscience
      Source reference: Hurd YL, et al "Impairments of chromatin remodeling and gene expression in the striatum of human heroin abusers" SFN 2013; Abstract 257.20/LL11.

      Source

      Primary Care New HIV Treatment Focus

      Published: Nov 14, 2013 | Updated: Nov 15, 2013

      Download Complimentary Source PDF

      By Michael Smith, North American Correspondent, MedPage Today

      Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

      166151281

      Action Points

      • Evidence-based guidelines for the management of patients infected with human immunodeficiency virus were prepared by an expert panel of the HIV Medicine Association of the Infectious Diseases Society of America and replace those published in 2009.
      • With fewer complications and increased survival, HIV-infected persons are increasingly developing common health problems that also affect the general population. Some of these conditions may be related to HIV infection itself or its treatment.
      • The changes include recommendations on initial evaluation and immediate follow-up, removal of recommendations for long-term complications, and a new section on metabolic comorbidities.

      Doctors caring for HIV-positive patients should increasingly focus on preventive care for the common health problems that affect the general population, according to new guidelines.

      As the long-term prognosis for people with HIV continues to improve, they are at risk for such things as diabetes and high cholesterol, according to the 2013 guidelines from the HIV Medicine Association of the Infectious Diseases Society of America.

      Some common health problems are exacerbated by HIV or HIV care, but others are simply the result of living long enough to get them, according to guidelines lead author Judith Aberg, MD, of the New York University School of Medicine in New York City, and her colleagues.

      "In many HIV practices now, 80% of patients with HIV infection have the virus under control and live long, full lives," Aberg said in a statement.

      "HIV specialists need to provide the full spectrum of primary care to these patients, and primary care physicians need a better grasp of the impact HIV care has on routine healthcare," she said.

      "As with primary care in general, it's about prevention."

      The new guidelines, published online and in the January issue of Clinical Infectious Diseases, replace those from 2009, in which physicians were urged to focus on helping their patients adhere to sometimes difficult treatment regimens.

      Adherence remains an issue, Aberg said, "but adherence is about more than just taking [antiretroviral therapy] regularly -- it's also about receiving regular primary care."

      Since 2009, new anti-HIV drugs, some of them in new classes, have entered the clinic, the authors noted, and patients have "fewer complications and increased survival."

      Changes include:

      • Patients with controlled HIV should have tests for viral load every 6 to 12 months, rather than every 3 to 4 months as previously recommended.
      • Patients should be offered vaccination against pneumococcal infection, influenza, varicella, and hepatitis A and B, as indicated.
      • Expanded recommendations on the initial evaluation and immediate follow-up of patients have replaced an earlier discussion of the best way to diagnose HIV.
      • A section on metabolic comorbidities, including diabetes, high cholesterol, and osteoporosis, replaces separate guidelines on dyslipidemia.
      • The new guidelines also expand the section on other sexually transmitted diseases, including a new recommendation for annual screening for trichomoniasis in women and yearly screening for gonorrhea and chlamydia for people at risk.

      Clinicians also need to ask regularly -- in "an open, nonjudgmental manner" -- about patients' sexual histories and any risky behaviors, such as the use of illicit drugs, the guidelines note.

      Usually, HIV patients receive care from either a specialist or a primary care physician, Aberg noted, and the new guidelines are intended to ensure that both groups are aware of issues that arise in the other camp.

      The work was supported by the Infectious Disease Society of America.

      Aberg reported financial links with AbbVie, Janssen (Tibotec), Merck, ViiV, Kowa, Gilead, and Wyeth/Pfizer.

      Source