June 18, 2013

Last Updated: Tuesday, June 11, 2013,20:55

Washington: The Ohio State University is working on a new technology, which will pave the way for low-cost electronic devices that work in direct contact with living tissue inside the body.

The first planned use of the technology is a sensor that will detect the very early stages of organ transplant rejection.

Paul Berger, professor of electrical and computer engineering and physics at Ohio State, explained that one barrier to the development of implantable sensors is that most existing electronics are based on silicon, and electrolytes in the body interfere with the electrical signals in silicon circuits.

Other, more exotic semiconductors might work in the body, but they are more expensive and harder to manufacture.

Berger and his colleagues have described a new, patent-pending coating that that they believe will bridge that gap.

In tests, silicon circuits that had been coated with the technology continued to function, even after 24 hours of immersion in a solution that mimicked typical body chemistry.

The researchers submerged the coated test sensors in fluid for up to 24 hours, removed them from the solution, and then ran a voltage across them to see if they were working properly. The tests showed that the oxide coating effectively blocked electrolytes from the solution so the sensors remained fully functional.

Once developed, a device using this technology could detect certain proteins that the body produces when it`s just beginning to reject a transplanted organ. Doctors would insert a needle into the patient`s body near the site of the implanted organ. Silicon sensors on the needle would detect the protein, and doctors would know how to tailor the patient`s dosage of anti-rejection drugs based on the sensor readings.

The work represents a first step toward fabricating devices that could be implanted in the body long-term, Berger said.

Though the current study describes a silicon sensor coated with aluminum oxide, he envisions that other devices could utilize coatings made from other materials such as titanium. Such coatings could even be tailored to boost the performance of sensors or other biomedical devices.

In particular, Berger sees a potential use for coated polymer semiconductors that goes beyond sensing chemicals in the body. He suspects that such semiconductors could replace nerves in the body that have been damaged by disease or injury.

The study was appeared in the journal Electronics Letters.

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More Organ-Donor Testing is Advised

NA-BW882_ORGANS_G_20130618183120

Agence France-Presse/Getty Images

Niraj Desai waits for a kidney to be removed from a donor at Johns Hopkins Hospital. More than 118,000 Americans are waiting for an organ transplant.

June 18, 2013, 7:29 p.m. ET

By TIMOTHY W. MARTIN and LAURA LANDRO

The federal government on Tuesday recommended expanding the number of diseases that organ donors should be screened for, adding hepatitis B and hepatitis C to the list, in an effort to cut down on infections that could unexpectedly occur when a person receives a transplant.

The guidelines released by the Department of Health & Human Services also recommend that a newer, more sensitive and faster test be used to screen for hepatitis as well as for HIV, the virus that causes AIDS, for which donor screening is already recommended.

Currently, even without the new guidelines, potential donors are routinely screened for hepatitis, though with older tests that take longer to produce results. But time is of the essence when it comes to organ transplants.

Organs harvested from deceased donors can only be used for a short period of time, and pathogens like HIV or hepatitis don't immediately show up on tests, evading detection for weeks, if not months. Tests with shorter turnaround times—like the ones recommended in the new guidelines—are better able to screen out infected individuals in time for a transplant.

The guidelines must still be adopted as policy by the federal agencies that contract with United Network for Organ Sharing to operate the national organ-transplantation system.

"We have to make these difficult decisions of what organs can be accepted for transplantation and what risks are acceptable," said Matthew Kuehnert, the director of the office of blood, organ and other tissue safety at the Centers for Disease Control and Prevention, which helped draft the guidelines.

The aim is to help physicians and patients make an informed choice about whether to go ahead with transplantation of a particular donated organ, and enable clinicians to track recipients after donation for signs of an emerging infection, Dr. Kuehnert said.

The number of transplants performed in the U.S. has risen 74% in the past two decades, to 28,051 in 2012 from 16,134 in 1992, according to UNOS. Kidneys, liver and hearts were the most commonly transplanted organs. Demand has increased from Americans needing kidney replacements due to diabetes, chronic hypertension and other illnesses, Dr. Kuehnert said.

Supply hasn't kept up. More than 118,000 Americans are on UNOS's waiting list for an organ transplant.

The new guidelines have some in the transplant community concerned because they could reduce the number of donors, since they might be labeled as having an increased risk for hepatitis, even though they aren't actually infected, said Michael G. Ison, medical director of Northwestern University's transplant infectious-disease service in Chicago. "There's a large deficit of organs," he said.

Only about 1% of all organ transplants lead to an unexpected infectious-disease transmission, the CDC said. But HIV, hepatitis B and hepatitis C have been reported to be unintentionally transmitted in heart, liver, kidney and pancreas recipients, according to the agency.

An estimated 72,000 Americans become infected with viral hepatitis every year, many of them baby boomers who don't realize they have the blood-borne infection. The CDC estimates about 1.2 million Americans have hepatitis B and 3.2 million are infected with hepatitis C.

The newer tests, known as NAT, for nucleic acid testing, detect infections very close to when donors contract them. Hepatitis C, for instance, can be identified 90% faster, from 77 days previously to just 7 days with the newer tests, Dr. Kuehnert said.

Write to Timothy W. Martin at timothy.martin@wsj.com and Laura Landro at laura.landro@wsj.com

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AIDS 2013 June 3 Epub

"Combining first, second and third reinfections, there were 54 reinfections in total"

"Our results demonstrate a high risk of HCV reinfection among HIV-positive MSM who are either treated for or who spontaneously clear their initial HCV infection. As many as 25% of individuals treated for HCV will become reinfected within 2 years. These results emphasize the need for effective sexual education for HIV-positive MSM presenting with primary HCV infection and the implementation of preventative interventions to reduce the risk of reinfection. Given their high risk, we recommend enhanced surveillance of previously infected individuals to enable the early detection and treatment of any reinfections. New UK guidelines have been updated to reflect this by recommending HCV PCR testing every 3-6 months among individuals who remain at risk following incident infection clearance [30]."

Martin, Thomas C.S.; Martin, Natasha K.; Hickman, Matthew; Vickerman, Peter; Page, Emma E.; Everett, Rhiannon; Gazzard, Brian G.; Nelson, Mark

aHIV Department, Chelsea and Westminster Hospital, London, UK, bSchool of Social and Community Medicine, University of Bristol, Bristol, UK, and cSocial and Mathematical Epidemiology Group, London School of Hygiene and Tropical Medicine, London, UK.

Abstract

Objective: Liver disease secondary to hepatitis C virus (HCV) infection in the context of HIV infection is one of the leading non-AIDS causes of death. Sexual transmission of HCV infection among HIV-positive men who have sex with men (MSM) appears to be leading to increased reports of acute HCV infection. Reinfection after successful treatment or spontaneous clearance is reported among HIV-positive MSM but the scale of reinfection is unknown. We calculate and compare HCV reinfection rates among HIV-positive MSM after spontaneous clearance and successful medical treatment of infection.

Design: Retrospective analysis of HIV-positive MSM with sexually acquired HCV who subsequently spontaneously cleared or underwent successful HCV treatment between 2004 and 2012.

Results: Among 191 individuals infected with HCV, 44 were reinfected over 562 person-years of follow-up with an overall reinfection rate of 7.8/100py (95%CI 5.8-10.5). Eight individuals were subsequently reinfected a second time, with a rate of 15.5/100py (95% CI 7.7-31.0). Combining all reinfections, 20% resulted in spontaneous clearance and treatment SVR rates were 73% (16/22) for genotype 1/4 and 100% (2/2) for genotype 2/3.

Among 145 individuals with a documented primary infection, the reinfection rate was 8.0 per 100 person-years (95%CI 5.7-11.3) overall, 9.6/100py (95%CI 6.6-14.1) among those successfully treated and 4.2/100py (95%CI 1.7-10.0) among those who spontaneously cleared. The secondary reinfection rate was 23.2/100py (95%CI 11.6-46.4).

Conclusion: Despite efforts at reducing risk behaviour, HIV positive MSM who clear HCV infection remain at high risk of reinfection. This emphasizes the need for increased sexual education, surveillance and preventative intervention work.

INTRODUCTION

Following the introduction of effective anti-retroviral therapy (ART), liver disease has become the leading non-AIDS cause of death among HIV positive patients in the resource rich world [1]. The majority of liver disease in HIV positive patients is caused by coinfection with the hepatitis C virus (HCV) [1-3]. Coinfection with HIV and HCV is associated with accelerated liver fibrosis, shorter time to progression to cirrhosis and hepatic decompensation when compared to those with HCV monoinfection [4-8].

Over the past decade, an epidemic of sexually transmitted HCVamong HIV positive men who have sex with men (MSM) in Europe, the USA and Australia has been reported [9-17]. Phylogenetic analyses of circulating HCV strains in European countries suggest sexual transmission occurring since the mid-90 s [10,18]. The incidence of HCVinfection among HIV-positive MSM is increasing with recent reports of rates as high as 2-5 per 100 person years [18-21]. Identified risk factors for transmission include ulcerating genital infections, unprotected anal intercourse and high-risk sexual activity such as toy use, group sex, fisting and recreational drug use [9,17,21-23].

Reinfection with HCV following either treatment or spontaneous clearance has been demonstrated in animal models, people who inject drugs (PWID) and, more recently, HIV positive MSM [24-27]. Among PWID, weak evidence exists to suggest that individuals who spontaneously clear HCV monoinfection are at lower risk of developing chronic reinfections. This lower risk may in part be explained by the development of partial immunity leading to a higher probability of spontaneous clearance of reinfection. However, study results are highly heterogeneous and conflicting results may in part be explained by variable testing intervals during follow up [24,28]. One retrospective study in the Netherlands revealed an alarmingly high HCV reinfection rate of 15.2 per 100 person years among HIV-positive MSM who had previously been treated for acute HCV infection [29]. No studies to date have investigated the rate of reinfection among HIV-positive MSM in the UK, and whether there are differing reinfection rates among those who spontaneously clear their infections and those who are successfully treated.

We therefore calculated and compared the HCV reinfection rate among individuals who had either been treated for acute or chronic HCV infection, or who had spontaneously cleared their HCV infection within a cohort of over 8000 HIV infected individuals attending clinic at Chelsea and Westminster Hospital in London, UK.

Methods

Study population

All HIV-positive MSM who had a positive HCV antibody result between January 2004 and April 2012 who attended the dedicated HIV clinic at Chelsea and Westminster Hospital were identified. Individuals were excluded if their primary documented mode of transmission was via contaminated blood products or injecting drug use. The following subgroups were extracted for inclusion within the study:

Successfully treated HCV infection with results indicating a sustained viral response (SVR) defined as undetectable viral replication 24 weeks following end of treatment and at least 1 subsequent HCV PCR measurement. Spontaneously cleared HCV infection with evidence for undetectable HCV PCR for at least 24 weeks following infection and at least 1 subsequent HCV PCR measurement.

Spontaneously cleared or treated HCV infection who were subsequently reinfected with a different HCV genotype from their previous infection but within the 24- week period required to formally reach SVR.

Data Collection

All HCV PCR results subsequent to the first identified HCV infection were collected. Basic HIV infection and patient characteristics were collected from medical files

including age, HIV viral load, CD4 lymphocyte subset count, anti-retroviral therapy (ART) details, HCV genotype and peak ALT levels. Behavioural data was not routinely collected at the centre and was therefore unavailable for our study.

Case definitions

HCV reinfections were defined as any newly detectable HCV PCR following SVR for treated infections or 24 weeks after spontaneous clearance. In addition, cases were defined as reinfection if patients had detectable HCV viraemia within 24 weeks of end of treatment or spontaneous clearance if there was an HCV genotype switch.

Patients were subdivided depending on whether it was possible to determine that the initial infection was their primary infection (shown by a negative HCV antibody within a year prior to positive HCVantibody detection), or that the nature of the initial infection was uncertain (no previous antibody result available or previously HCV antibody positive).

Data analysis

For those individuals who underwent HCV antiviral treatment, the commencement of follow-up was taken from the end-of-treatment date. For those who spontaneously cleared their HCV infection, start of follow-up was the midpoint between the last positive and first negative HCV PCR. The date of reinfection for all patients was taken as the midpoint between the last undetectable HCV PCR and the first positive HCV PCR.

Reinfection rates were calculated by dividing the number of reinfections by the total number of patient-years of follow-up. Kaplan-Meier survival curves were created to assess the proportion reinfected over time. Comparisons of median testing intervals, age and peak ALT levels were performed using Kruskal-Wallis rank test. Analysis of proportion of patients on ART was performed using Fisher's exact test. Equality of variances were assessed using Bartlett's test. All statistical calculations were performed using Stata 10.0.

Results

858 individuals were identified with a positive HIV and HCV antibody result. Of these, 191 HIV-positive MSM with HCV who fulfilled our inclusion criteria were identified, representing 562 patient years of follow up. Among these patients, 145 had a documented primary infection and 46 had uncertain initial infection details. The stratification of patients is summarized in Fig. 1. Among the 145 who had either spontaneously cleared or had been successfully treated for their primary HCV infection, there were 400 person-years of follow-up with a median follow-up time of 2.1 years. The median testing intervals during follow up were 105 and 173 days among those successfully treated and those who spontaneously cleared their primary infection, respectively. The difference in testing interval was statistically significant (p<0.0001). The median age of patients included was 41 years. Group characteristics and follow-up details are summarised in Table 1.

Of the 145 patients with documented primary infection, 32 reinfections occurred yielding a HCV reinfection rate of 8.0/100py (95% confidence interval (CI) 5.7-11.3). Among the 114 who had been successfully treated for their primary HCV infection, 27 reinfections occurred at a reinfection rate of 9.6/100py (95% CI 6.6-14.1). 25% of patients treated for HCV virus infection became reinfected within 2 years of follow up. Among the 31 individuals who spontaneously cleared their primary HCV infection, 5 reinfections occurred yielding a reinfection rate of 4.2/100py (95% CI 1.7-10.0). The difference in reinfection rate between those treated successfully and those who spontaneously cleared their primary infections did not reach significance (p1/40.15). The Kaplan-Meier curve giving proportion of patients free from reinfection is shown in Fig. 2 for the two groups. 17 of the 32 reinfected patients spontaneously cleared or were successfully treated of which 8 had a subsequent second reinfection over 34 person-years of follow-up yielding a second reinfection rate of 23.2/100py (11.6-46.4). Median follow-up time per patient following second reinfection was 1.5 years.

There was no evidence of a difference in CD4 cell count, age, use of ART or peak ALT during primary infection between patients who underwent reinfection and those who did not or between those who were treated and those who spontaneously cleared their infection. Use of ART during follow-up was high (89%) and did not differ between groups (p1/40.11). Peak ALT levels did not significantly differ between primary infection and primary reinfection. However, peak ALT among patients who were reinfected was significantly higher than peak ALT during follow-up of patients who had no reinfection (median 253 vs 41 U/L, p<0.0001).

When including those with uncertain incident infection details, the overall reinfection rate was similar at 7.8/100py (95% CI 5.8-10.5). Among the 191 patients there were 44 reinfections of whom 7 (16%) spontaneously cleared their infection. 17 were successfully treated and the remainder failed therapy [6], opted out of treatment [1] or are pending final SVR results [13].

24 patients had available HCV PCR results following successful treatment or spontaneous clearance of their first reinfection. Among these patients there were 8 second reinfections yielding a second-reinfection rate of 15.5/100py (95% CI 7.7-31.0). From these 8, 4 (50%) spontaneously cleared their infection, one opted out of treatment developing chronic infection and three were treated with results pending. From the four patients who spontaneously cleared their second reinfection, 2 patients underwent a third reinfection: one was successfully treated and the other is pending SVR. A summary of the eight patients who were reinfected more than once is shown in Fig. 3.

Combining first, second and third reinfections, there were 54 reinfections in total. 32 (59%), 1 (2%), 2 (4%), 7 (13%) and 12 (22%) were genotype 1, 2, 3, 4 and unknown genotype respectively. From the 54 reinfections, 11 patients (20%) spontaneously cleared HCV. Among patients who spontaneously cleared their reinfections, the median time to achieve undetectable viraemia was 43 days (IQR 28-76.5) and the median number of positive HCV PCRs per infection was 1 (IQR 1-3). A total of 63% (34 of 54) of those with reinfection underwent treatment. Following reinfection, the median period until treatment was initiated was 57 days (IQR 38-112). The SVR rate among reinfections was 73% (16 of 22) for genotype 1/4 and 100% (2 of 2) for genotype 2/3. 10 patients are pending SVR results.

Discussion

Our results demonstrate a high risk of HCV reinfection among HIV-positive MSM who are either treated for or who spontaneously clear their initial HCV infection. As many as 25% of individuals treated for HCV will become reinfected within 2 years. These results emphasize the need for effective sexual education for HIV-positive MSM presenting with primary HCV infection and the implementation of preventative interventions to reduce the risk of reinfection. Given their high risk, we recommend enhanced surveillance of previously infected individuals to enable the early detection and treatment of any reinfections. New UK guidelines have been updated to reflect this by recommending HCV PCR testing every 3-6 months among individuals who remain at risk following incident infection clearance [30].

Our rate of reinfection among spontaneous clearers was lower than treated individuals (4.2/100py vs 9.6/100py); however, the evidence for a difference lacked power (p=0.15) and may have been influenced by different median testing intervals in the two groups (105 vs. 173 days, p<0.0001) therefore providing only weak evidence for protective immunity [24,28]. The rate of reinfection among spontaneous clearers was high overall and this group should therefore be followed up with regular HCV PCR testing as for individuals who have been previously treated for their HCV infection.

SVR rates for individuals treated for their HCV reinfection were generally high (73% for genotype 1+4 and 100% for genotype 2+3). The majority of reinfections were treated in the acute phase of the infection (median time to treatment following first positive HCV PCR was 43 days) and SVR rates were consistent with studies treating acute HCV infections in HIV-positive MSMs [31].

Our spontaneous clearance rate of reinfection (11 of 54 reinfections, 20%) is consistent with spontaneous clearance rates of primary HCV infection in HIV-positive MSM (5-40%) [32-36]. The true spontaneous clearance rate of reinfection is likely to be higher, though, as spontaneously cleared infections may have been missed due to variable testing intervals (median 112 days, IQR 62-224). This study provides the first large cohort estimates of spontaneous clearance of HCV reinfection among HIV-infected individuals and supports monitoring for spontaneous clearance of reinfection before initiating treatment as for primary infection with HCV.

Our reinfection rate following treatment for HCV infection (9.6/100py 95% CI 6.6-14.1) is comparable to that found by Lambers et al (15.2/100py 95% CI 8.0- 26.5) [29]. Strengths of our study in comparison to Lambers et al. are the considerably larger sample size (191 patients and 562 person-years follow-up vs 56 patients and 72 person-years follow-up), the inclusion of spontaneous clearers in the analysis and the analysis of individuals who subsequently had multiple reinfections. The higher incidence of reinfection found by Lambers et al. may be explained by their inclusion of patients who underwent reinfection with the same genotype but different phylogeny within the 24 weeks required for definitive SVR and also shorter testing intervals during follow up (median 91 days, IQR 58-130 vs. 112 day, IQR 62-224) [28].

Limitations of our study include its retrospective nature, the absence of behavioural data and the lack of phylogenetic analysis to prove reinfection in cases where reinfection was with the same genotype. The true reinfection rate in our cohort is likely to be higher for the following reasons: (i) the testing interval post primary infection was variable and long in comparison to the duration of possibly missed spontaneous clearances; (ii) we excluded patients who developed recurrent viraemia within the 24 weeks required for SVR whereas previous phylogenetic studies have shown a proportion of these 'relapses' to, in fact, be true reinfections.

Unfortunately, it remains difficult, as in previous studies, to definitively say that the reappearance of viraemia following treatment is not the emergence of a non dominant quasispecies or superinfection after treatment of a dominant HCV strain [32,37]. However, we believe the re-emergence of viraemia is most likely to represent reinfection in our study, supported by the long duration to reinfection in most cases with multiple negative HCV PCR results between infections and the excellent response of reinfection to treatment. Finally, the patients included in our study were all from a single HIV clinic and as such our results may not be representative of other areas in London, the UK or Europe.

In conclusion, our results show high HCV reinfection rates for HIV positive MSM who have previously cleared the infection either spontaneously or through treatment. We recommend enhanced surveillance of patients who have cleared HCV infection to allow the early detection and treatment of any reinfection. In addition, we recommend directed education and prevention interventions to HIV positive MSMs with HCV infection. Future work will include evaluation of interventions and prospective studies to evaluate further protective immunity in this population.

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The Lancet, 15 June 2013

Kris V Kowdley, Eric Lawitz, Israel Crespo, Tarek Hassanein, Mitchell N Davis, Michael DeMicco, David E Bernstein, Nezam Afdhal, John M Vierling, Stuart C Gordon, Jane K Anderson*, Robert H Hyland, Hadas Dvory-Sobol, Di An, Robert G Hindes*, Efsevia Albanis*, William T Symonds, M Michelle Berrey, David R Nelson, Ira M Jacobson

Gilead submitted their New Drug Application (NDA) to the FDA this past Spring for several uses, indications of Sofosbuvir (GS7977) including for gt1 with SOF+Peg/Rbv for 12 weeks duration of therapy and also for Gt2/3 with SOF+Rbv for 12 weeks. As well Janssen submitted their NDA for Simeprevir (protease)+Peg/Rbv this past Spring. Boehringer Ingelheim will soon follow in step with their NDA submission for Faldaprevir (protease)+Peg/Rbv. FDA approvals are expected later this year or soon thereafter. Next year by the end of 1st half 2014 several more NDA submissions are expected including by Abbott for their 4-drug IFN-free regimen of ABT450/r(protease)+ABT267(NS5A)+ABT333(non-nuc)+/-Rbv for 12 weeks duration of therapy for Gt1; also Gilead is expected to submit their NDA for their IFN-free regimen of Sofosbuvir+GS5885(Ledipasvir)+/- Rbv for 12 weeks for Gt1; as well, BMS is expected to submit several NDAs for several different combinations including for their potent first-in-class NS5A BMS052 (Daclatasvir). Of note 3 IFN-free & Rbv free studies have been conducted but they were relatively small phase 2 studies: Daclatasvir+Sofosbuvir in treatment-naives & separate study in boceprevir & telaprevir failures with 100% SVR rates, and the COSMOS Study of Simeprevir+Sofosbuvir for 12 weeks in null responders with a 96% SVR rate. By the end of this year both Simeprevir+Sofosbuvir are expected to be approved by the FDA but not for this indication, i.e. not to be used together in this 2-drug combination which is IFN & Rbv free because the study was relatively small, it was not a phase 3 study. This is unfortunate for patients who would like to use this regimen & for those who might need such a regimen. Of note, there are many additional IFN-free regimens in research & development now using 2-4 potent HCV orally administered antivirals by Boehringer Ingelheim, Merck, Vertex, Roche, Janssen, BMS, Achillion and in collaboration with big pharma Presidio & Idenix. Some of these oral antivirals are 2nd generation meaning they are more potent & effective against resistant virus. These ongoing or soon to start studies will include 2-4 different oral HCV drugs, will be 12 week regimens & be IFN-free and are a few years away, maybe 2-3 additional years away. What we need is to conduct HCV screening projects that include linkage to care, we need federal, state & city support to conduct these studies, as it is estimated that as many as 75% of HCV-infected individuals remain undiagnosed

COSMOS Study: SVR4 results of a once daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype 1 null responders
http://www.natap.org/2013/CROI/croi_34.htm

EASL: Sustained Virologic Response With Daclatasvir Plus Sofosbuvir ± Ribavirin (RBV) in Chronic HCV Genotype (GT) 1-Infected Patients Who Previously Failed Telaprevir (TVR) or Boceprevir (BOC) - (04/27/13)

AASLD/2012: High Rate of Sustained Virologic Response With the All-Oral Combination of Daclatasvir (NS5A Inhibitor) Plus Sofosbuvir (Nucleotide NS5B Inhibitor), With or Without Ribavirin, in Treatment-Naive Patients Chronically Infected With HCV GT 1, 2, or 3 - (11/13/12)

EASL: SAFETY AND EFFICACY OF INTERFERON-FREE REGIMENS OF ABT-450/r, ABT-267, ABT-333 +/- RIBAVIRIN IN PATIENTS WITH CHRONIC HCV GT1 INFECTION: RESULTS FROM THE AVIATOR STUDY - (04/25/13)

Gilead Reports Interim Data From Phase 2 LONESTAR Study

from Jules: this ATOMIC Study is the forerunner for the NEUTRINO Study which is the phase 3 study for this very same regimen of SOF+Peg/rbv in gt1/4/5/6.

HERE in this link is the Phase 3 NEUTRINO data reported at EASL:

EASL: Treatment With Sofosbuvir + Peginterferon + Ribavirin for 12 Weeks Achieves 90% SVR12 in Treatment-Naïve Genotype 1, 4, 5, and 6 HCV-Infected Patients: The NEUTRINO Study - (04/27/13)

Here are NATAP EASL & CROI/HCV Reports--

EASL: New Oral HCV Drugs at EASL - Report 4A

Summary from EASL 2013 for Hepatitis C - New HCV DAAs on their way soon: what do the phase III studies tell us? - written by Jurgen K. Rockstroh M.D., Professor of Medicine University of Bonn, Germany (05/16/13)

New HCV Drugs - EASL & Beyond - (05/11/13)

EASL 48th Annual Meeting
April 24th - 28th 2013
The Netherlands, Amsterdam

HCV at CROI - (03/17/13)

Summary

Background

The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV.

Methods

For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800 000 IU/mL vs ≥800 000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01329978.

Results

We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5).

In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77-96) in cohort A, 97 patients (89%, 82-94) in cohort B, and by 135 (87%, 81-92) in cohort C.

We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0·94), or in cohort C (p=0·78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug-anaemia and neutropenia-were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event.

Interpretation

Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis.

Funding

Gilead Sciences.

Introduction

For previously untreated patients with chronic hepatitis C virus (HCV) genotype-1 infection, the standard of care is one of two HCV protease inhibitors-telaprevir or boceprevir-in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin for up to 48 weeks.1 Duration of treatment is defined by patients' on-treatment response; the dosing schedules for both drugs allow the shortening of treatment duration to 24-28 weeks in patients with no liver cirrhosis who achieve and maintain undetectable HCV RNA in the first 8 weeks of treatment.2, 3 The potential to shorten duration of treatment is important because it can reduce the occurrence of the serious side-effects associated with peginterferon and ribavirin (headache, fever, cytopenia, autoimmunity disorders, and depression).4, 5 Unfortunately, many patients do not qualify for shortened regimens and need 48 weeks of treatment.6, 7 Data beginning to emerge since the approval of the protease inhibitors suggest that discontinuation rates from these regimens have been high.8-11 Other limitations of treatment with the available protease inhibitors are their low barrier to resistance,12 potential for drug interactions, and complex regimens with high pill burdens. Thus, a clear need exists for a shorter, simpler, better tolerated, and effective regimen with a high barrier to resistance for treatment-naive patients with chronic HCV infection.

Sofosbuvir (formerly known as GS-7977; Gilead Sciences, Foster City, CA, USA) is a selective, pangenotypic nucleotide inhibitor of NS5B-directed HCV RNA replication. In another phase 2 trial,13 43 (91%; 95% CI 80-98) of 47 treatment-naive patients with HCV genotype-1 receiving 400 mg sofosbuvir in combination with peginterferon and ribavirin for 12 weeks followed by 12 weeks of peginterferon and ribavirin had sustained virological response at post-treatment week 12 (SVR12).13 These results, along with the rapidity of the recorded on-treatment virological suppression (nearly all patients had undetectable concentrations by week 4) and the lack of viral breakthrough in this trial and other studies of sofosbuvir, including the exploratory ELECTRON phase 2 trial,14 indicate the need to assess shorter durations of treatment with sofosbuvir plus peginterferon and ribavirin in the treatment of patients with chronic HCV. The ATOMIC trial was designed to assess whether a 12-week treatment regimen of sofosbuvir plus peginterferon and ribavirin is as effective as a 24-week regimen. Additionally, we explored whether or not 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by an additional 12 weeks of sofosbuvir monotherapy or sofosbuvir and ribavirin offers any benefit compared with the 12-week regimen of sofosbuvir plus peginterferon and ribavirin.

Methods

Study design and participants

We did this randomised, open-label phase 2 study at 42 centres: 41 in the USA and one in Puerto Rico. Study screening began on March 23, 2011, with the last patient enrolled on Sept 21, 2011; the last patients' final follow-up visit was on Aug 27, 2012. Eligible patients were at least 18 years of age, had not been treated previously for HCV infection, and had chronic genotype 1, 4, 5, or 6 HCV infection with serum HCV RNA concentrations of 50 000 IU/mL or greater. Exclusion criteria included histological evidence of cirrhosis (patients had to have had a liver biopsy done within 36 months of entry) or other clinically important chronic liver disease, a body-mass index of 18 kg/m2 or lower, or co-infection with hepatitis B or HIV. Patients with a history of psychiatric illness were eligible if approved by a psychiatrist or licensed mental health professional.

Before enrolment and before any procedures were done, written informed consent was obtained from all patients. The study was done in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. A safety review committee consisted of a group of Pharmasset employees (including a clinical scientist, safety scientist, medical monitor, medical advisor, and chief medical officer) who met on a monthly basis to review the ongoing safety of the study; additionally, a group of four external members (including the committee chairman) were available on an as-needed basis.

Randomisation and masking

Using an interactive web-based response system, we randomly allocated patients with HCV genotype-1 in a 1:2:3 ratio to cohorts A, B, or C. Randomisation was stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800 000 IU/mL vs ≥800 000 IU/mL). Patients with genotype 4, 5, or 6 (or indeterminate genotype) were enrolled into cohort B. This study was an open-label study. For the study to have been blinded, patients in cohorts A and C would have had to receive placebo injections for 12 weeks after the conclusion of their planned dosing. We decided that the potential benefits of blinding did not warrant the risk and inconvenience to patients. Patients as well as individuals providing study treatment, assessing outcomes, or analysing data were not masked to group assignment at any point during the study.

Procedures

Individuals in cohort A received sofosbuvir 400 mg orally once daily, peginterferon 180 μg subcutaneously once a week, and ribavirin orally as a divided weight-based daily dose (ie, patients <75 kg received 1000 mg and those ≥75 kg received 1200 mg) for 12 weeks. Patients in cohort B received the same drugs at the same doses for 24 weeks. Patients in cohort C received the same regimen as individuals in cohort A followed by an additional 12 weeks of sofosbuvir monotherapy for half the patients, or sofosbuvir plus ribavirin for the other half (with patients randomly allocated to these subcohorts). Patients in cohort A who did not achieve a rapid virological response (defined as HCV RNA <15 IU/mL at week 4) continued to receive sofosbuvir plus peginterferon and ribavirin for an additional 12 weeks. After completion or early discontinuation of treatment, patients were followed up off-treatment until week 24.

We measured plasma HCV RNA concentrations using the COBAS AmpliPrep/COBAS Taqman HCV test (Roche; Indianapolis, IN, USA) with a limit of detection of 15 IU/mL. We defined virological breakthrough as the presence, during treatment, of detectable HCV RNA in serum samples after previous documentation of HCV RNA concentrations lower than 15 IU/mL; we defined virological rebound as a greater than 1 log10 increase in HCV RNA from the lowest point while on treatment. Relapse was defined as presence of detectable HCV RNA at any time during the 24-week post-treatment follow-up after documentation of HCV RNA less than 15 IU/mL in serum samples at the end of treatment. We discontinued treatment in patients who did not respond by week 12 (ie, <2 log10 decrease in HCV RNA) or who had confirmed viral breakthrough or rebound at any time during the trial.

We monitored patients for virological breakthrough during the 12-24 weeks of treatment and for relapse after treatment discontinuation. We did a confirmatory HCV RNA test in any patient with virological breakthrough and all treatment was discontinued if breakthrough was confirmed. Blood samples were obtained at each study visit for population sequencing of the NS5B-encoding region with a detection limit of 15-25% of the viral population. Samples were sequenced by dideoxy sequencing (DDL Diagnostic Laboratory; Rijswijk, Netherlands) at baseline for all patients, and at failure timepoints for those who had virological breakthrough or relapse.

For virological failures, phenotypic analysis of NS5B was done by Janssen Diagnostics BVBA (Beerse, Belgium), with a replicon-based HCV assay containing the NS5B regions of HCV derived from plasma sequences from patients and quantitatively measured differences in sofosbuvir susceptibility compared with corresponding baseline samples or respective wild-type reference replicon.

Safety was assessed by review of adverse events and concomitant drugs, blood samples for serum tests and haematological assessments, and physical examinations including vital signs and electrocardiograms. Patients with decreases in haemoglobin concentrations to lower than 100 g/L during treatment received reduced peginterferon or ribavirin dosing. The use of erythropoiesis-stimulating agents was not allowed.

Statistical analysis

The primary efficacy endpoint of the study was sustained virological response 24 weeks after discontinuation of all treatment (SVR24). The intention-to-treat analysis included all patients who were enrolled and received at least one dose of study drug. The primary analysis compared the proportion of patients in each treatment group with HCV RNA concentrations lower than 15 IU/mL (or undetectable) at week 24 after the end of treatment. We calculated point estimates and two-sided 95% CIs of between-group differences in SVR24 using stratum-adjusted Mantel-Haenszel proportions. Secondary endpoints were the proportion of patients with undetectable HCV RNA at all timepoints throughout the study (eg, rapid virological response and SVR12) with point estimates and exact 95% CIs.

We estimated that a sample size of 50 patients and 100 patients or a sample size of 75 patients and 100 patients would be sufficient to achieve 90% power to detect a 30% or 25% difference in SVR24 rates between two treatment groups with the χ2 and a 5% two-sided significance level. We used SAS (version 9.2) for all statistical analyses.

Role of the funding source

The sponsor of the study contributed to recruitment of patients, trial management, data collection, statistical analyses, and the writing and review of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results

We screened 588 patients with HCV genotypes 1, 4, and 6, of whom 332 were eligible and enrolled in the study (figure 1). No patients with HCV genotype 5 were enrolled into this study. Characteristics of patients were much the same between groups at baseline, with a mean age of about 50 years and most patients being men, being white, and carrying a non-CC IL28 B genotype (table 1).

Because efficacy results for patients in cohort C who were randomly allocated into two subgroups for the second 12 weeks of treatment-those who received sofosbuvir monotherapy (cohort C1) and those who received sofosbuvir plus ribavirin (cohort C2)-were very similar, their data were pooled when assessing efficacy. However, we analysed the two subcohorts separately when assessing adverse events.

Patients in all groups had rapid and substantial reductions in HCV RNA after beginning treatment (table 2). At the end of the first week of dosing, median decreases in HCV RNA in all three cohorts were greater than 4·5 log10 IU/mL. By the second week of treatment, 79% of patients (259 of 328) receiving treatment had undetectable HCV RNA, a proportion that increased to 99% (323 of 326 patients; 97% by intention-to-treat analysis [323 of 332 patients]) at week 4 of treatment. One patient in cohort A did not have undetectable HCV RNA by week 4. Because of an administrative error, this patient did not receive an extra 12 weeks of treatment as specified by the protocol, but did achieve SVR24.

We recorded high rates of SVR12 and SVR24 in all three groups (table 2). We noted no difference in the proportions of patients achieving SVR24 between cohorts A and B (p=0·94) or between cohorts A and C (p=0·78), suggesting no additional benefit of treatment durations of longer than 12 weeks.

Of the 11 patients with genotype 4 HCV, nine (82%, 95% CI 48-98%) achieved both SVR12 and SVR24. We recorded no virological failure in these 11 patients-the other two patients were lost to follow-up at the end of treatment. All five of the patients with genotype 6 HCV achieved SVR12 and SVR24 (100%, 48-100%).

Factors shown to be associated with reduced response to treatment did not seem to greatly affect response to this regimen: rates of SVR24 for patients with high baseline HCV RNA (≥800 000 IU/mL) were 89% in cohort A (40 of 45 patients), 90% in cohort B (81 of 92 patients), and 87% in cohort C (110 of 127 patients); rates of SVR24 for patients carrying non-CC IL28B genotypes were 87% in cohort A (34 of 39 patients), 90% in cohort B (80 of 89 patients), and 88% in cohort C (96 of 116 patients); and rates of SVR24 for patients with bridging fibrosis versus those without bridging fibrosis were 100% (all seven patients) versus 87% (19 of 23 patients) in cohort A, 88% (15 of 17 patients) versus 89% (96 of 108 patients) in cohort B, and 83% (19 of 23 patients) versus 88% (116 of 132 patients) in cohort C.

No patients had viral breakthrough during treatment. Of the 11 patients who had a return of detectable HCV RNA after stopping treatment, seven relapsed after completing their assigned treatment regimen (table 2). Of these seven patients, relapse occurred by post-treatment follow-up week 4 in four patients, by follow-up week 8 in two patients, and by follow-up week 12 in one patient. All but one patient who had viral relapse carried a non-CC IL28B allele. The slightly fewer number of individuals achieving SVR12 than those receiving SVR24 in each group was not because of relapse but because of patients lost to follow-up after 12 weeks. The rate of relapse did not seem to be higher in patients who received ribavirin dose reductions during treatment (data not shown). The remaining four patients who had virological failure did not complete their assigned course of treatment. All four achieved undetectable HCV RNA during treatment, but had detectable viraemia within 8 weeks after early treatment discontinuation.

Changes in the NS5B polymerase in clinical isolates from the 11 patients who either relapsed after a full course of treatment or after early discontinuation were assessed by population sequencing. We detected neither the Ser282Thr or Met289Leu mutations at the time of virological failure. We detected no change in susceptibility to sofosbuvir compared with their corresponding baselines or in the wild-type 1b Con-1 replicon with any of the 11 patients at the time of relapse.

Most patients (97-99%) had at least one adverse event during the study. The most common adverse events were those consistent with the known safety profile for peginterferon and ribavirin: fatigue, headache, and nausea, with most of these adverse events rated by treating clinician as mild in severity (table 3). 30 patients had adverse events leading to discontinuation of any study drug. The proportion of patients with genotype-1 who discontinued any study drug because of an adverse event was greater in cohort B than in either of the other two cohorts (18% vs 5-6%; three [6%] of 52 patients in cohort A, 19 [18%] of 106 patients in cohort B, and seven [5%] of 155 patients in cohort C). The most common adverse events that led to the discontinuation of any study drug-anaemia and neutropenia-are associated with peginterferon and ribavirin treatment. Anaemia leading to dose modification or interruption seemed to be more common in cohort B (25 [20%] of 125 patients) and cohort C2 (17 [23%] of 75 patients) than it was in cohort A (five [10%] of 52 patients) and cohort C1 (eight [11%] of 75 patients), which might be a consequence of the longer treatment duration with ribavirin. Adverse events that led to treatment discontinuation in more than two patients were neutropenia, nausea, and anxiety (four patients for each), and anaemia (three patients).

13 treatment-emergent serious adverse events were reported in 12 patients: two (4%) in cohort A, six (5%) in cohort B, and four (3%) in cohort C (two each in cohorts C1 and C2). Nine serious adverse events were thought to be unrelated to study drug treatment (arrhythmia, ischaemic colitis, chest pain, acute cholecystitis, cholelithiasis, alcohol poisoning, road-traffic accident, costochondritis, and hip arthroplasty). Four serious adverse events-anaemia, autoimmune hepatitis, pyelonephritis, and pancytopenia-were reported as related to peginterferon and ribavirin (but unrelated to sofosbuvir). Two of the 13 serious adverse events (automimmune hepatitis and chest pain) led to permanent discontinuation of study drug. Subsequent testing confirmed that the case of autoimmune hepatitis was an undiagnosed pre-existing disorder. No patients died during the study period.

Across all treatment groups, we recorded a decrease in neutrophils, haemoglobin, platelets, and lymphocytes, consistent with the known effects of peginterferon and ribavirin (figure 2). The most common grade 3 or 4 laboratory abnormality was neutropenia (table 4). Recovery of neutrophil counts to baseline values occurred promptly after discontinuation of peginterferon in patients continuing on sofosbuvir or sofosbuvir plus ribavirin (figure 2). Additionally, we detected rapid increase of haemoglobin and lymphocyte counts to baseline values in patients receiving sofosbuvir monotherapy; improvement of these indices occurred at a slower rate and to a lesser extent in the group randomised to receive sofosbuvir plus ribavirin (figure 2). Although mean serum ALT concentrations decreased in all cohorts B, C1, and C2 (figure 2) during the first 12 weeks of treatment, we saw further improvements after discontinuation of peginterferon at week 12.

Discussion

Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending sofosbuvir treatment beyond 12 weeks. Furthermore, patients in the groups receiving longer durations of peginterferon generally had higher rates of adverse effects without an attendant increase in efficacy.

The uniformly high rates of SVR24 with sofosbuvir plus peginterferon plus ribavirin also suggest that there would be no need to tailor either the treatment duration or regimen to individual patients on the basis of early response or baseline characteristics. Protease inhibitor regimens (approved in April, 2011) use response-guided treatment to shorten treatment duration from 48 weeks to 24-28 weeks in patients who fulfil predefined criteria for early response.2, 3 Our results indicate that response-guided treatment might not be needed for treatment with sofosbuvir. Moreover, on the basis of our findings, other factors previously shown to be predictive of response to treatment-IL28B CC versus non-CC genotype, high versus low baseline viral load, and genotype 1a versus genotype 1b-are of doubtful use with this sofosbuvir regimen. Although all but one patient who relapsed carried non-CC IL28B alleles, the predictive value of this index for response seems insufficient to base treatment decisions on. However, the small numbers of patients in some of these subgroups do not allow definitive conclusions.

The advent of direct-acting antivirals has been accompanied by concerns about the development of drug resistance.7 In phase 3 trials of the protease inhibitors telaprevir and boceprevir, resistance-associated mutations were detected in up to 75% of patients who did not achieve SVR.12 More than 90% of patients who had virological failure in these trials were shown to harbour drug-resistant variants.12 Our findings seem to lend support to the claim that sofosbuvir has a high barrier to resistance. We detected no virological breakthrough or treatment-emergent resistance in this trial. Relapse after treatment was rare, and no patients who had relapse showed the presence of the signature Ser282Thr mutation in population sequencing.

Sofosbuvir-based treatment seemed to be safe and well tolerated. Most of the adverse events and laboratory abnormalities seen during this study were characteristic of peginterferon or ribavirin. Patients in cohort C who received sofosbuvir monotherapy after 12 weeks of triple therapy showed prompt improvement in haemoglobin and neutrophil values towards baseline values, suggesting little or no haematological toxicity that could be ascribed solely to sofosbuvir. Patients in the third cohort who received sofosbuvir and ribavirin combination treatment after 12 weeks of triple therapy also showed improvement in haematological indices, although recovery was slower, consistent with the effect of ribavirin.

In terms of its rate of response, resistance profile, and safety characteristics, sofosbuvir plus peginterferon plus ribavirin for 12 weeks seems to compare favourably with those seen with present standard-of-care treatments for treatment-naive patients with HCV genotype-1 (panel).

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

Panel

Research in context

Systematic review

We consulted a review of treatment of hepatitis C in adults,14 which systematically assessed a large body of evidence concerning outcomes of clinical trials of approved drug regimens for the treatment of hepatitis C virus (HCV). We searched PubMed in December, 2012, using the search term "HCV treatment", searching for studies written in English. We also consulted treatment guidelines for hepatitis C.1, 15

Interpretation

For previously untreated patients with genotype-1 hepatitis C infection, standard-of-care treatment is one of the recently approved (April, 2011) protease inhibitors-telaprevir or boceprevir-plus peginterferon and ribavirin. Our findings lend support to the phase-3 assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis. Furthermore, the exploration of the combination of sofosbuvir with other direct-acting antiviral agents is warranted.

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

Sofosbuvir-based combination treatment also seemed to be effective in patients with HCV genotypes 4 and 6; however, the small numbers of patients in the study with genotype 4 and 6 preclude any definitive conclusions. Nor do our data allow us to address whether 12 weeks of treatment is sufficient for patients with these genotypes, because all patients with genotypes 4 or 6 received 24 weeks of triple therapy. However, we saw no breakthrough or relapse in any patient with HCV genotype 4 or 6. The only two patients (both genotype 4) who did not achieve SVR24 were lost to follow-up.

This study was limited by its exclusion of patients that are historically more difficult to treat-namely, those with cirrhosis and advanced liver disease. Ongoing phase 3 trials (NCT01497366, NCT01641640, NCT01542788, and NCT01604850) of sofosbuvir include patients with cirrhosis. We have planned future studies to examine the effectiveness of this agent in patients who have failed to respond to telaprevir-based or boceprevir-based combination treatment.

Our findings suggest that simple, short sofosbuvir-based regimens are effective for patients with HCV genotypes 1, 4, and 6. Further study of this agent in phase 3 studies are warranted and ongoing.

Source

HIV Care Not Reaching the Young

By Michael Smith, North American Correspondent, MedPage Today

Published: June 18, 2013

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points

  • Note that this analysis of surveillance data demonstrated that roughly a quarter of Americans with HIV had a suppressed viral load (<200 copies/ml).
  • Be aware that significant age disparities existed, with younger individuals at particular risk of not having access to care.

Younger age is a barrier to successful HIV care, researchers reported.

In an analysis of surveillance data, there were disparities by age at each step of the so-called "continuum of care," according to Irene Hall, PhD, of the CDC, and colleagues. And in the youngest group analyzed -- those ages 13 through 24 -- only 41% were diagnosed and only 31% were linked to care.

People under 45 also were significantly less likely to have suppressed HIV, the goal of antiretroviral therapy, Hall and colleagues reported online in JAMA Internal Medicine.

"Increasing the percentage of young persons diagnosed and receiving continuous care is critical to addressing HIV" in the U.S., Hall and colleagues concluded.

Previous analyses have shown that -- of the more than 1.1 million Americans with HIV -- more than 200,000 don't know it, fewer than half are in regular care, and fewer than 30% have the virus under control, Hall and colleagues noted.

To get updated estimates that would take into account variation between subgroups, they turned to 2009 data from the National HIV Surveillance System to determine HIV prevalence and the proportion linked to care.

They used the CDC's Medical Monitoring Project to discover the proportion of HIV-positive people who were retained in care, prescribed antiretroviral therapy, and achieving viral suppression.

Overall, they estimated that 1,148,200 people had HIV that year, including 18% who had not yet been diagnosed. Of the entire group, an estimated 44% were black, 19% were Hispanic or Latino, and 33% were white.

Most -- some 61% -- were 35 through 54, 7% were 13 through 24, 15% were 25 through 34, 14% were 55 through 64, and 4% were 65 or older. Men made up 76% of the population and an estimated 52% of them had infections attributed to sexual contact between men.

Hall and colleagues also reported that:

  • 82% of the overall group had been diagnosed as having HIV infection
  • 66% were linked to care
  • 37% were retained in care
  • 33% were prescribed antiretroviral therapy
  • 25% had a suppressed viral load

But there were differences by age at every step the continuum of care, they reported, although not all variances reached statistical significance.

Those 25 through 34, and 35 through 44, had numerically lower rates for all aspects of care than older HIV-positive people and significantly lower rates of viral suppression (at P<0.001 for both) when compared with those 55 through 64, who formed the reference group for the analysis.

Improving participation in the HIV care continuum will require insights from the "rapidly growing" field of implementation science, commented Katerina Christopoulos, MD, and Diane Havlir, MD, both of the University of California San Francisco.

Implementation science, they argued in an accompanying commentary, will help bridge the gap between research and the real world, but finding out how to translate what works in research may not be easy.

"Put simply, we may know what works but not how to do it," they wrote.

The HIV community is already trying to find ways to overcome bottlenecks in the care continuum, they noted. "Achieving an AIDS-free generation will be within reach if, and only if, these efforts succeed," they concluded.

Hall and colleagues cautioned that the numbers on linkage to care and retention in care might be underestimates.

The study had support from the CDC.

Hall and other authors made no disclosures, according to the journal.

Editorial author Christopoulos reported financial links with Bristol-Myers Squibb.

Primary source: JAMA Internal Medicine
Source reference:
Hall HI, et al "Differences in human immunodeficiency virus care and treatment among subpopulations in the United States" JAMA Intern Med 2013; DOI: 10.1001/jamainternmed.2013.6841.

Additional source: JAMA Internal Medicine
Source reference:
Christopoulos K, Havlir DV "Overcoming the human immunodeficiency virus obstacle course" JAMA Intern Med 2013; DOI: 10.1001/jamainternmed.2013.7943.

Source

Also See: HIV: Viral Suppression Less Common in Young Adults

Posted by: Bridgette P. LaVictoire on June 18, 2013.

The HIV Organ Policy Equity Act (HOPE Act) passed late last night. The bill had bipartisan support, and its passage was praised by Senator Barbara Boxer (D-CA) and Senator Tom Coburn (R-OK). The legislation would lift “the federal ban on research into organ donations from HIV-positive donors to HIV-positive recipients.”

Following the passage of the HOPE Act, Senator Boxer stated “I applaud the Senate for moving to end this outdated ban on research into organ donations between HIV-positive individuals. This legislation offers hope for thousands of patients who are waiting for transplants by allowing scientists to research safe and effective ways to transplant these organs and save lives.”

She was joined in praising its passage by Senator Coburn, who is a medical doctor. Senator Coburn stated “The passage of the HOPE Act is an encouraging step forward for HIV-positive individuals who need organ transplants. By lifting these arcane federal regulations, we give hope by allowing doctors and scientists to explore potentially transformative research into organ donations between HIV-positive patients.”

The bill was “sponsored by Senators Tammy Baldwin (D-WI), Rand Paul (R-KY), Richard Burr (R-NC), Michael Enzi (R-WY), Elizabeth Warren (D-MA), Mark Kirk (R-IL), Dianne Feinstein (D-CA), Mary Landrieu (D-LA), Brian Schatz (D-HI), Richard Blumenthal (D-CT), Roy Blunt (R-MO), Mark Pryor (D-AR) and Carl Levin (D-MI).”

The bill would, eventually, allow for the transplantation of HIV-positive organs into the bodies of those who already suffer from the disease. There are, currently, thousands of HIV-positive individuals who are in need of organ transplants, but the ban on researching the feasibility of the transplants is banned by federal law.

According to Senator Boxer’s office, the HOPE Act would establish a standardized review process overseen by the Health and Human Services Secretary. HHS would “evaluate the process of medical research into the procedures.” If they find that the research shows that it is possible to safely and successfully transplant organs from HIV-positive donors to HIV-positive recipients, then the HHS Secretary will be able to direct the Organ Procurement and Transplantation Network to set up procedures for these transplantations to occur.

The HOPE Act overturns the ban on HIV-positive organ donation and research first put into place as part of the Organ Transplant Amendments Act of 1988. The OTAA is now woefully out of date “thanks to advances in antiretroviral therapy.” Because of those therapies, HIV-positive individuals are living longer lives, and because they are living longer lives, they are faicing chronic conditions such as liver and kidney failure.

In the early days of HIV/AIDS, information regarding the disease was still being gathered, and a lot of misinformation was available.  During that time, people thought that the disease could be passed through casual contact.  For medical personnel, the disease, which is passed through bodily fluids, resulted in numerous changes in how they handled patient care including and especially around situations involving blood and saliva.  Bans on blood donation by gay men, which are still in place in the United States, came into effect after several cases of people contracting the disease thanks to contaminated blood.

Boxer’s office notes that “There are currently more than 100,000 patients on the active waiting list for organ transplants in the United States and about 50,000 people are added to the list each year – but fewer than 30,000 transplants are performed annually. Tragically, many patients die while waiting for a transplant.” One study has pointed out that allowing organ transplants from HIV-positive donors to HIV-positive recipients would have the effect of increasing the donation pool by about 500 to 600 donors a year, saving hundreds of lives.

A long list of medical associations support the bill “including the American Medical Association, American Society of Transplant Surgeons, American Society of Transplantation, Association of Organ Procurement Organizations, American Academy of HIV Medicine, American Society for the Study of Liver Disease, the Human Rights Campaign, National Minority AIDS Council, HIV Medicine Association, National Coalition for LGBT Health, Infectious Diseases Society of America, Gay and Lesbian Medical Association, United Network for Organ Sharing, The AIDS Institute, amfAR (American Foundation for AIDS Research), Lambda Legal, the Treatment Access Group (TAG), and AIDS United.”

Focus on passing the HOPE Act now shifts to the House where it has been supported by a bipartisan group headed up by Representatives Lois Capps (D-CA) and Andy Harris (R-MD).

Source

When the big C in cancer could mean a cure

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Millions of radioactive micro-spheres travel through blood vessels to the liver and deliver their payload at the site of the tumour.

Jill Margo

PUBLISHED: 8 hours 17 MINUTES AGO | UPDATE: 3 hours 30 MINUTES AGO

“Cure” is a big word in cancer medicine and oncologists use it with considerable caution. If they can find a way of curing even a tiny percentage of people considered incurable, it is regarded as a huge advance.

Scientists on the cusp of a cure have to resist the temptation of overstating their position.

Although Australian oncologists have cured a small number of patients with liver cancer, they shrink back from calling their treatment curative.

They use an innovative Australian therapy which involves placing tiny radioactive spheres in the liver. These spheres deliver high doses of radiation to the cancerous tumours.

“The conservative point of view at this stage is that we are not sure it is curative for a small number of patients,” says Peter Gibbs, an oncologist at the Royal Melbourne Hospital and an associate professor at the Walter and Eliza Hall Institute of Medical Research.

“We certainly do have patients where this treatment has shrunk the liver tumours to the point where they could be surgically removed and some of these people have gone on to survive long-term. In a small percentage of patients it does appear to be curative.”

Gibbs says the “poster girl” for this therapy is a woman who was first treated in 2002 at the Royal Melbourne Hospital.

She had five liver tumours which disappeared after therapy and have still not come back.

These tumours were secondaries from her colorectal cancer.

After the primary cancer in her colon was surgically removed, she was referred to Gibbs to have the liver secondaries treated.

“I am very confident that she is cured,“ he says.

“It’s a guess but probably in 3, 4 or 5 per cent of patients, this treatment may control and cure the cancer. We just don’t know.”

Selective internal radiation therapy

This therapy, known as selective internal radiation therapy, or SIRT, confines the radiation to the liver so adjoining tissues are not damaged.

The spheres are introduced through the groin and sent into the liver via the circulatory system.

Each one is one-third the diameter of a strand of hair and remains active for three days.

SIRT is at present used in about 300 patients a year in Australia. In addition to liver secondaries from colorectal cancer, it is also used on primary liver cancer that can develop in people with hepatitis or cirrhosis.

It is now a last line of treatment, proven to be moderately effective at controlling cancers when all else has failed.

But work is under way to see if it will have a bigger impact if it is given early in the treatment cycle.

Last year the American Journal of Clinical Oncology published results of a small pilot study, using SIRT in combination with chemotherapy as a first line of treatment.

The study involved 20 patients.

Six to eight months later, the tumours that received the combination therapy were 60 per cent smaller compared with the tumours which received only the chemotherapy.

Now a study involving 500 patients with inoperable liver metastases from a primary colorectal cancer is being conducted in 100 leading hospitals across the world.

The study aims to test if this first line combination of SIRT and chemotherapy is more effective than chemotherapy alone.

Recruitment is complete and first results should become public in 2015.

Liver cancer is more common in men than women and the incidence rises with age.

In Australia, the average age of diagnosis is 66.

SIRT is expensive, with treatment costing around $14000. Health insurers provide cover only when it is used to treat liver secondaries from colorectal cancer.

Gibbs says there definitely is a group of patients in whom the combination treatment shrinks their tumours to point where they can be surgically removed.

In some this may be life-extending, in some it may lead to a cure.

Gibbs points out, however, that the primary focus of the new global study is on patients living longer with acceptable side effects.

The hope is that a small percentage will be cured.

Rather than making a small difference in a big number of people, which is typical of most new cancer therapies, Gibbs says this is likely to make a big difference in a small number of people.

When an inaudible time bomb finally goes off

For 40 years, Bozidar Drulovic has lived with a time bomb.

As a doctor, he made a conscious decision not to let it rule his life, but now he concedes he could have paid more attention to it.

As an intern in Belgrade in the 1970s, he was operating on an abscess in a patient known to have Hepatitis B. Something happened, perhaps a needle-stick injury, and he was infected.

“A short while later, I knew I had a 90 per cent chance of developing cancer during my life,” he says.

Drulovic, now 64 and a general practitioner in Melbourne, lives a full and rich life with his wife, two children and grandchildren.

He has always played sport and does not drink or smoke.

Fortunately, his hepatitis was indolent and apart from blood tests to check liver function, very occasionally he would have a scan too.

About three years ago a scan turned up a 3.5 centimetre lesion, which the report said was probably a haemangioma, a non-cancerous dense collection of dilated blood vessels.

The diagnosis was so appealing that against his better judgement, Drulovic accepted it.

He put it to the back of his mind and last year, in a bid to improve his fitness, he put himself on diet and successfully shed 14 kilograms.

Drulovic acknowledges that had he not been a doctor, he probably would have sought specialist opinions earlier.

As he was still working ten hours a day, he was not that surprised that his energy levels were not as high as he would have liked.

Then, in February this year, there was a sudden pain in his liver. It subsided after half an hour but was enough for him to ask a work colleague to do an ultrasound on him the next day.

The result didn’t look good. There was a 10-centimetre tumour which was bleeding and looked like a cancer. If it was, its size and position would make it inoperable.

A biopsy returned dead tissue but malignant cells were found, meaning cancer was present in his liver.

“But I was mentally OK because, after so many years of waiting, I was ready for it,“ says Drulovic.

He now sought expert opinion and found there were only two options: chemotherapy or selective internal radiation therapy, SIRT. As chemotherapy was minimally effective and highly toxic, he opted for SIRT.

First he underwent a trial with a test dose to check there was no leakage of radiation to his lungs, stomach or other structures.

This was essential as the dose is 30 times higher than that used in external radiation.

In mid-April Drulovic had the full treatment. “It was ok. Afterwards I had no pain, no temperature, no vomiting and no side effects. But the first week was rough.

“I was asleep for two hours and awake for two hours, night and day.”

By late May he was back at work and says the only after-effect is having less energy than he would expect.

The tumour takes between two to six months to shrink and although he has no shrinkage yet, his liver function tests give good reason for hope.

“If a tumour is inoperable, SIRT is an excellent alternative. It was the only option for me and I didn’t hesitate for a second.”

Drulovic is gaining weight, is pain-free and describes himself as realistic rather than optimistic.

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Opinion: Alternative healing or quackery?

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A man receives a reiki treatment. While alternative therapies can be valuable, some cross the line, according to Dr. Paul Offit.

By Dr. Paul Offit, Special to CNN

updated 9:19 AM EDT, Tue June 18, 2013

Editor's note: Dr. Paul Offit is chief of the division of infectious diseases at the Children's Hospital of Philadelphia and author of the book "Do You Believe in Magic? The Sense and Nonsense of Alternative Medicine." He previously has taken on the anti-vaccine movement.

(CNN) -- It used to be called "fringe" or "unconventional" medicine -- or simply quackery. Today, it's called "alternative," "complementary," "holistic" or "integrative."

And it has moved into the mainstream. Hospitals now have dietary supplements on their formularies (list of stocked medications); offer reiki masters to cancer patients; or teach medical students how to manipulate healing energies.

Forty-two percent of hospitals offered some form of alternative therapies to their patients, according to a 2010 survey of 5,800 facilities. When asked why, almost all responded "patient demand."

Further, private practitioners encourage megavitamins, dietary supplements, acupuncture, chiropractic, homeopathy and naturopathy.

Although nontraditional therapies can be valuable, sometimes a line is crossed. So how can you tell if your alternative healer is a quack? Here are a few red flags:

The therapist offers medicines that don't work instead of those that do

Steve Jobs, for example, suffered from a neuroendocrine tumor of the pancreas. With early surgery, Jobs had a 95% chance of recovery. But Jobs chose acupuncture, herbal remedies, and bowel cleansings instead, and died as a consequence.

Homeopaths have recommended their products (which are diluted to the point that active ingredients aren't there anymore) for treatable diseases such as cancer, malaria, cholera and AIDS.

In 2006, a 6-year-old boy with severe asthma was treated with a homeopathic remedy instead of the bronchodilator that would have saved his life. In Canada, homeopathic vaccines, which have no chance of preventing illness, are worrisomely popular.

Also, naturopaths' objections to the contrary, many studies have shown that garlic doesn't lower low-density-lipoprotein cholesterol (bad cholesterol), chondroitin sulfate and glucosamine don't treat arthritis, and saw palmetto doesn't treat prostatic enlargement; in each of these cases, conventional treatments are available that actually do work.

Warning: Men's natural sex supplements may not be

The therapist doesn't tell you about the dangers of alternative therapies

Alternative medicine is perceived as more natural and less harmful than conventional medicine. But medicine is medicine, and any drug or therapy that has a positive effect can have a negative effect.

For example, at least 86 people have died when acupuncture needles have lodged in hearts, lungs or livers or inadvertently transmitted viruses like hepatitis A, hepatitis B, or HIV. Chiropractic manipulations have killed at least 26 people, virtually all by ripping the vertebral artery in the neck.

Dietary supplements also have unseen harms. For example, kava can cause severe and occasionally fatal liver damage; blue cohosh can cause heart failure; nutmeg can cause hallucinations; comfrey can cause hepatitis; monkshood can cause heart arrythmias; wormwood can cause seizures; stevia leaves can decrease fertility, concentrated green tea extracts can damage the liver, bitter orange can cause heart damage, and Aristolochia, found in Chinese herbs, can cause kidney failure and bladder cancer.

Because dietary supplements and herbs aren't regulated by the Food and Drug Administration, most people don't know about these problems.

The therapist makes a fortune off your misfortune

Perhaps no one is more susceptible to quackery than parents of children with autism: a disorder without a clear cause or cure.

Bogus treatments have included ion-exchange machines, lymphatic drainage massage, electrical or magnetic stimulation, Rife machines, hyperbaric oxygen chambers, intravenous immunoglobulins, and stem-cell transplantation. Some of these same therapies are offered for "chronic" Lyme disease and cancer.

Dramatically different disorders, identical cures. All quite expensive and all without any chance of actually working.

Docs should know about kids and alternative medicine

The therapist promotes 'magical thinking'

Reiki masters who claim they can manipulate healing energies; chiropractors who claim that all diseases are caused by misaligned spines; homeopaths who claim that their highly diluted potions contain even a single molecule of an active ingredient; acupuncturists who claim that healing can only be achieved by balancing yin and yang; or naturopaths who claim that a drug found in nature is different from a drug synthesized by a pharmaceutical company (when they have the exact same molecular structure) are appealing to our sense of magic.

And although the notion of something beyond our level of understanding is attractive, current gaps in medical knowledge aren't going to be filled by energy fields, acupuncture meridians, or the notion that all things natural must be good for you.

"Isn't it enough to see that a garden is beautiful," wrote Douglas Adams in "The Hitchhiker's Guide to the Galaxy," "without having to believe that there are fairies at the bottom of it, too."

Like conventional therapies, alternative remedies shouldn't be given a free pass. They should be held to the same high standards of safety and efficacy. And where scientific studies don't exist, we should insist that they be performed. Otherwise, we'll continue to be susceptible to the worst kinds of quackery.

Complementary and alternative medicine: Evaluate treatment claims

The opinions expressed in this commentary are solely those of Dr. Paul Offit.

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HIV: Viral Suppression Less Common in Young Adults

Medscape Medical News

Joe Barber Jr, PhD

Jun 17, 2013

Substantial differences in each step of the continuum of care for HIV exist in relation to age, according to the findings of a retrospective study.

H. Irene Hall, PhD, from the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, and colleagues published their findings online June 17 in JAMA Internal Medicine.

In the study, the researchers used data from the CDC's National HIV Surveillance System to determine the prevalence of undiagnosed HIV infection among people at least 13 years old, and linkage to care was estimated using data from 14 states. Among the 1,148,200 people estimated to be infected with HIV in 2009, 18% had not been diagnosed, 34% were not linked to care, 63% were not retained in care, 67% were not receiving ART, and 75% had not achieved viral suppression.

In total, 44% of HIV-infected people were black compared with 19% for Latinos and 33% for whites. No significant ethnicity or sex-related differences were noted for any steps of the continuum of care, except men who were infected with HIV through heterosexual contact. They were less likely to achieve viral suppression than those who were infected through male-to-male sexual contact (19% vs 27%; P < .04).

Compared with people aged 55 to 64 years, those aged 25¬ to 34 and 35 to 44 years were less likely to be aware of their infection or linked to care. Specifically, people aged 55 to 64 years (36%) were more likely to achieve viral suppression than those aged 25 to 34 years (15%; P < .001) or 35 to 44 years (22%; P < .001).

In addition, among people prescribed ART, adults aged 55 to 64 years (86%) were more likely to achieve viral suppression than those aged 25 to 34 years (70%) or 35 to 44 years (73%).

The limitations of the study included the use of linkage of care data for only 14 states, the use of retention of care data for only 4 months, and a lack of data for certain ethnic groups.

"Individuals, health care providers, health departments, and government agencies must all work together to increase the numbers of people living with HIV who are aware of their status, linked to and retained in care, receiving treatment, and adherent to treatment," the authors write.

In a related commentary, Katerina A. Christopoulos, MD, MPH, and Diane V. Havlir, MD, from the Department of Medicine, University of California, San Francisco, and San Francisco General Hospital, stressed that additional efforts are needed to ensure the health of all persons infected with HIV. "If we are to meet the goals of the National HIV/AIDS Strategy, then the ultimate end point to which the cascade aspires is not just the absence of viremia but the presence of health for all sectors of society affected by HIV," Dr. Christopoulos and Dr. Havlir write. "Achieving an AIDS-free generation will be within reach if, and only if, these efforts succeed."

Dr. Christopoulos receives grant support from Bristol-Myers Squibb. The authors and Dr. Havlir have disclosed no relevant financial relationships.

JAMA Intern Med. Published online June 17, 2013.

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MENAFN - - 6/18/2013 7:45:03 AM

Isotechnika Pharma Receives Additional Funding From the Government of Canada for the Preclinical Development of NICAM 440-02 as an Anti-Hepatitis C Agent

EDMONTON, Alberta, Jun 18, 2013 (Menafn - GLOBE NEWSWIRE via COMTEX) --Isotechnika Pharma Inc. ("Isotechnika" or the "Company") today announced that it has received additional funding from the National Research Council Industrial Research Assistance Program ("NRC-IRAP") for its Non-Immunosuppressive Cyclophilin Antagonist Molecules ("NICAMs") program.

NRC-IRAP continues to play an instrumental role in networking the NICAM program with key global partners and previously assisted Isotechnika in late-stage screening of several NICAM compounds, including evaluation of anti-hepatitis C virus ("HCV") activity.

These evaluations have also been funded by the U.S. National Institutes of Allergy and Infectious Disease ("NIAID"), a part of the U.S. National Institutes of Health ("NIH"), and have led to the identification of a lead NICAM compound - 440-02 - for development as an anti-HCV agent.

The current project will further define the scope of 440-02 activity by studying its actions on several HCV genotypes and in combination with other anti-viral agents. This work will be conducted by the Scripps Research Institute in the laboratory of Dr. Philippe Gallay, a renowned HCV and human immunodeficiency virus ("HIV) researcher focused on the interplay between cyclophilin and viruses.

"Despite improvements in treatment, HCV remains a significant unmet medical need as the current standard of care does not work for everyone and can produce problematic side effects, which at times may lead to the discontinuation of treatment. Cyclophilin inhibitors target host rather than viral protein, and, as a result, may complement the direct-acting antiviral drugs by increasing the barrier to viral resistance and broadening the genotype treatment profile," commented Isotechnika's President and CEO, Dr. Robert Foster. "We are excited to work with the Scripps Research Institute, and Dr. Gallay in particular, as we continue to advance preclinical development of those NICAMs with the best potential to expand orally administered HCV treatment options for a broader population of patients."

About Non-Immunosuppressive Cyclophilin Antagonist Molecules

NICAMs are an emerging novel class of multifunctional macrocycle drugs showing promise as antiviral, anti-inflammatory and cytoprotective agents. NICAMs inhibit cellular molecules called cyclophilins, and have garnered considerable attention as a novel treatment for a wide range of cyclophilin-mediated conditions comprising viral, cardiac, neurological, and inflammatory diseases. This includes treatment of infectious diseases through the ability of NICAMs to inhibit viral replication.

About the NRC Industrial Research Assistance Program

NRC-IRAP is Canada's premier innovation assistance program for small- and medium-sized enterprises. It is a vital component of the NRC, a cornerstone in Canada's innovation system, regarded world-wide as one of the best programs of its kind.

About the National Institute of Allergy and Infectious Diseases

NIAID conducts and supports research - at NIH, throughout the United States and worldwide - to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

About the National Institutes of Health

The NIH, American's medical research agency, includes 27 institutes and centers and is a component of the U.S. Department of Health and Human Services. It is the primary U.S. federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

About Isotechnika Pharma Inc.

Isotechnika is a biopharmaceutical company focused on the discovery and development of immunomodulating therapeutics designed to offer key safety advantages over currently available treatments. Its lead drug, voclosporin, is a calcineurin inhibitor, and is targeted at the estimated US3.0 billion market for this class of immunosuppressants. The U.S. Food and Drug Administration has cleared Investigational New Drug Applications to evaluate Isotechnika's voclosporin in renal transplantation (phase 3) and lupus nephritis (phase 2b). Isotechnika trades on the Toronto Stock Exchange under the symbol "ISA". More information on Isotechnika can be found at www.isotechnika.com or www.sedar.com.

We seek Safe Harbour.

CONTACT: For further information:
Dr. Robert Foster
President & CEO
780-487-1600 (x247)
rfoster@isotechnika.com

Dr. Daniel Trepanier
Director, New Drug Development
780-487-1600 (x236)
dtrepanier@isotechnika.com

Leonard Zehr
Managing Director
Kilmer Lucas Inc.
905-906-6908
leonard@kilmerlucas.com

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