Showing posts with label IV drug use. Show all posts
Showing posts with label IV drug use. Show all posts

Monday, March 4, 2019

Hepatitis C among intravenous drug users in upper middle-income countries.

Estimating the prevalence of hepatitis C among intravenous drug users in upper middle income countries: A systematic review and meta-analysis
Víctor Granados-García , Yvonne N. Flores, Lizbeth I. Díaz-Trejo, Lucia Méndez-Sánchez, Stephanie Liu, Guillermo Salinas-Escudero, Filiberto Toledano-Toledano, Jorge Salmerón

Published: February 26, 2019

Abstract
Aim
This systematic review and meta-analysis characterizes the prevalence of hepatitis C virus (HCV) infection among intravenous drug users (IDUs) in upper middle-income countries.

Methods
Five databases were searched from 1990–2016 for studies that took place in countries with a GDP per capita of $7,000 to $13,000 USD. The data extraction was performed based on information regarding prevalence, sample size, age of participants, duration of intravenous drug use (IDU), recruitment location, dates of data collection, study design, sampling scheme, type of tests used in identifying antibody reactivity to HCV, and the use of confirmatory tests. The synthesis was performed with a random effects model. The Cochrane statistical Q-test was used to evaluate the statistical heterogeneity of the results.

Results
The 33 studies included in the analysis correspond to a sample of seven countries and 23,342 observations. The point prevalence value estimates and confidence intervals of the random effects model were 0.729 and 0.644–0.800, respectively for all seven countries, and were greatest for China (0.633; 0.522–0.732) as compared to Brazil (0.396; 0.249–0.564). Prevalence for Montenegro (0.416; 0.237–0.621) and Malaysia (0.475; 0.177–0.792) appear to be intermediate. Mexico (0.960) and Mauritania (0.973) had only one study with the largest prevalence. A clear association was not observed between age or duration of IDU and prevalence of HCV, but the data from some groups may indicate a possible relationship. The measures of heterogeneity (Q and I2) suggest a high level of heterogeneity in studies conducted at the country level and by groups of countries.

Conclusions
In this systematic review and meta-analysis, we found that the pooled prevalence of HCV was high (0.729) among a group of seven upper middle income countries. However, there was significant variation in the prevalence of HCV observed in China (0.633) and Brazil (0.396). 

Full-text available online:

Sunday, March 3, 2019

HCV reinfection as a positive indication of high‐risk population treatment access

Recommended Reading
High response and re-infection rates among people who inject drugs treated for hepatitis C in a community needle and syringe programme
We show that it is feasible to recruit people who inject drugs(PWID) from a community-basedneedle and syringe programme (NSP) onto HCV treatment, and achieve over 80% SVR-12 andimpressive treatment adherence.

Commentary
HCV reinfection as a positive indication of high‐risk population treatment access
Gregory J Dore

First published: 25 February 2019
https://doi.org/10.1111/jvh.13092

Strategies to address HCV reinfection and limit its overall impact on HCV elimination are required, but the most important of these is ongoing engagement with high- risk individuals to enable detection of HCV reinfection and its retreatment without stigma and discrimination.

Download full-text article:

Article shared via Twitter by Henry E. Chang‏.

Thursday, January 24, 2019

New evidence shows needle and syringe programmes are highly cost-effective

In The News
New evidence shows needle and syringe programmes are highly cost-effective
Thu, 01/24/2019 - 14:55
Evidence from a new study shows that needle and syringe programmes providing clean injecting equipment are a highly cost-effective way of preventing hepatitis C transmission. New research led by the University of Bristol and London School of Hygiene and Topical Medicine reveals that rolling out these programmes could save millions of pounds in infection treatment costs in the UK. This is the first study to evaluate the cost-effectiveness of needle and syringe programmes in Western Europe.

The researchers used data from three cities with different levels of hepatitis C infection among people who inject drugs—Bristol (45%), Dundee (26%) and Walsall (18%). They estimated the cost-effectiveness of existing needle programmes in each city and their impact on hepatitis C transmission rates. Using mathematical models, they were able to project how hepatitis C transmission would increase if all needle and syringe programmes were stopped for the first ten years of a 50-year time period (2016-2065).

Their findings revealed that in all three cities, current needle and syringe programmes result in lower healthcare and treatment costs than if the programmes were stopped, with estimated cost-savings of £159,712 in Bristol and £2.5 million in Dundee.

Maintaining the needle and syringe programmes was also associated with a lower prevalence of hepatitis C and improvements in quality of life for people who inject drugs. Infections were projected to reduce by 8 per cent in Bristol and Walsall and 40 per cent in Dundee between 2016 and 2065 if needle and syringe programmes were maintained.

Even if hepatitis C treatment rates were to increase or treatment costs were further reduced, needle and syringe programmes would continue to save money, because of their effectiveness in preventing re-infection.

Responding to the findings of the study, Rachel Halford, CEO of The Hepatitis C Trust said: “Needle and syringe facilities are key to preventing the transmission of hepatitis C, yet we know that in many areas provision is insufficient or dropping.

While in recent years the numbers of people being treated and tested for the virus have increased, Public Health England estimates that prevalence has remained broadly stable due to new infections and re-infections. To achieve NHS England’s ambition to eliminate hepatitis C as a public health concern by 2025, we must ensure that numbers of new infections are falling.

This will require sustained investment in prevention initiatives. Now that we have clear evidence for the cost-effectiveness of needle and syringe programmes, there is no excuse for not expanding them significantly.”

You can read a full report of the study’s findings here.
Source: http://www.hepctrust.org.uk/blog/jan-2019/new-evidence-shows-needle-and-syringe-programmes-are-highly-cost-effective

Friday, November 30, 2018

Beyond interferon side effects: What residual barriers exist to DAA hepatitis C treatment for people who inject drugs?

Beyond interferon side effects: What residual barriers exist to DAA hepatitis C treatment for people who inject drugs? 
Annie Madden, Max Hopwood, Joanne Neale, Carla Treloar
Published: November 30, 2018 https://doi.org/10.1371/journal.pone.0207226

Abstract
Recent advances in the efficacy and tolerability of hepatitis C treatments and the introduction of a universal access scheme for the new Direct Acting Antiviral (DAA) therapies in March 2016, has resulted in a rapid increase in the uptake of hepatitis C treatment in Australia. Despite these positive developments, recent data suggest a plateauing of treatment numbers, indicating that more work may need to be done to identify and address ongoing barriers to hepatitis C treatment access and uptake. This paper aims to contribute to our understanding of the ongoing barriers to DAA therapies, with a focus on people who inject drugs. The paper draws on participant interview data from a qualitative research study based on a participatory research design that included a peer researcher with direct experience of both hepatitis C DAA treatment and injecting drug use at all stages of the research process. The study’s findings show that residual barriers to DAA treatment exist at personal, provider and system levels and include poor venous access, DAA treatments not considered ‘core-business’ by opioid substitution treatment (OST) providers, and patients having to manage multiple health and social priorities that interfere with keeping medical appointments such as childcare and poor access to transport services. Further, efforts to increase access to and uptake of DAA hepatitis C treatment over time will require a focus on reducing stigma and discrimination towards people who inject drugs as this remains as a major barrier to care for many people.

Links:
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Combination interventions for Hepatitis C and Cirrhosis reduction among people who inject drugs: An agent-based, networked population simulation experiment

Combination interventions for Hepatitis C and Cirrhosis reduction among people who inject drugs: An agent-based, networked population simulation experiment
Bilal Khan, Ian Duncan, Mohamad Saad, Daniel Schaefer, Ashly Jordan, Daniel Smith, Alan eaigus,
Don Des Jarlais, Holly Hagan, Kirk Dombrowski 

Published: November 29, 2018



Fig 1. Finite state diagram of the HCV model used in the experiments.
Once infected, agents face a series of stochastic and enforced progressions through a series of ever worsening liver function. Throughout the simulation, infected agents who have reached a chronic state (non-acute HCV infected agents) face a small but regular chance of moving directly to cirrhosis, decompensated cirrhosis, or hepatocellular carcinoma. In addition, their Metavir fibrosis level is incremented yearly, moving them gradually from early stage fibrosis to cirrhosis. Once in any of the three severe liver stages, agents face an increasing probability of death due to HCV infection, incremented on a five year basis.
https://doi.org/10.1371/journal.pone.0206356.g001

Full-text article:

Abstract
Hepatitis C virus (HCV) infection is endemic in people who inject drugs (PWID), with prevalence estimates above 60% for PWID in the United States. Previous modeling studies suggest that direct acting antiviral (DAA) treatment can lower overall prevalence in this population, but treatment is often delayed until the onset of advanced liver disease (fibrosis stage 3 or later) due to cost. Lower cost interventions featuring syringe access (SA) and medically assisted treatment (MAT) have shown mixed results in lowering HCV rates below current levels. However. little is known about the potential cumulative effects of combining DAA and MAT treatment. While simulation experiments can reveal likely long-term effects, most prior simulations have been performed on closed populations of model agents—a scenario quite different from the open, mobile populations known to most health agencies. This paper uses data from the Centers for Disease Control’s National HIV Behavioral Surveillance project, IDU round 3, collected in New York City in 2012 to parameterize simulations of open populations. To test the effect of combining DAA treatment with SA/MAT participation, multiple, scaled implementations of the two intervention strategies were simulated. Our results show that, in an open population, SA/MAT by itself has only small effects on HCV prevalence, while DAA treatment by itself can lower both HCV and HCV-related advanced liver disease prevalence. More importantly, the simulation experiments suggest that combinations of the two strategies can, when implemented together and at sufficient levels, dramatically reduce HCV incidence. We conclude that adopting SA/MAT implementations alongside DAA interventions can play a critical role in reducing the long-term consequences of ongoing HCV infection.

Wednesday, November 28, 2018

Australian experience shows high DAA uptake and rapid fall in rates of HCV viraemia among people who inject drugs

Australian experience shows high DAA uptake and rapid fall in rates of HCV viraemia among people who inject drugs
Michael Carter
Published: 28 November 2018

Providing hepatitis C virus (HCV) therapy with direct-acting antivirals (DAAs) to people who inject drugs can achieve rapid reductions in community prevalence of viraemia, according to Australian research published in the Journal of Hepatology. Uptake of HCV treatment increased from 10% to 41% after unrestricted access to DAAs was rolled out in March 2016, and the proportion of viraemic patients fell from 43% to 25%.

The authors believe their findings have significance for the World Health Organization (WHO) target of eliminating HCV as a public health threat by 2030.
Read More:

Wednesday, November 21, 2018

HCV epidemic continues to rise among young adults

Of Interest 
AASLD 2018 The Liver Meeting®:
“Our data demonstrate that people who inject drugs can achieve SVR at comparable rates to non-drug using populations, even if adherence is imperfect,”

We Cured Hepatitis C - Now The Work Begins: Finding Neglected Patients  
One Health System's Efforts to Eliminate Hepatitis C

Real-World Data Show Rising HCV Epidemic Among Young Adults
Cassandra Pardini, PharmD
Results from the largest real-world study analyzing hepatitis C virus (HCV) screening practices determined that, although HCV antibody (AB) screening and confirmatory RNA testing rates are improving, the HCV epidemic continues to rise among young adults.

The study included 17,149,480 patients obtained from 2 national laboratory datasets who were screened between 2013 and 2016 based on an AB test. The study authors defined an active HCV infection as having an HCV RNA+ result following a positive AB test. The study authors added, "AB screening rates, AB+ rates, RNA follow-up testing rates, and RNA+ rates were assessed descriptively by year and stratified by baby boomers 48-71 years old and young adults 18-39 years old, to reflect the evolving disease epidemiology."

Reference: Abstract
Sulkowski MS, Marx S, Manthena SR, Strezewski J, Chirikov VV. National Estimates for HCV Screening and Diagnosis Rates in the United States (2013-2016) Based on Large Real-World Dataset. Presented at AASLD The Liver Meeting 2018. Study number 1565.

Full-Text Article
First published: 6 November 2018 - In Hepatology

Friday, November 16, 2018

HCV Re-infection in People with High-risk Behavior Low

11.15.2018 
HCV Re-infection in People with High-risk Behavior Low
Widespread treatment should be offered to people who inject drugs
by Pippa Wysong
Contributing Writer, MedPage Today 

The overall number of people re-infected with hepatitis C (HCV) after successful treatment with direct-acting agents (DAAs) was small in a large population-based study from Canada, providing more evidence to offer widespread treatment to high-risk populations.

But the key to eliminating HCV is to get treatment to HCV-infected people who have high-risk behaviors quickly to reduce the number of people living with infection. This in turn would reduce the passing on of the disease to others who have cleared the virus from treatment, said Naveed Janjua, PhD, senior scientist with the British Columbia Centre for Disease Control.

In fact, the study, published in the Journal of Hepatology, found evidence that people who inject drugs (PWID) who continued to use opiate agonist therapy after successful cure with direct-acting antiviral therapies (DAAs) had lower re-infection rates than PWID who had no opiate-agonist therapy or supports.
Read More: https://www.medpagetoday.com/reading-room/aga/lower-gi/76361

Saturday, November 10, 2018

The Liver Meeting® People with Hepatitis C Who Actively Inject Illegal Drugs Have High Rates of Hepatitis C Treatment Adherence and Cure

People with Hepatitis C Who Actively Inject Illegal Drugs Have High Rates of Hepatitis C Treatment Adherence and Cure

SAN FRANCISCO – Preliminary data from a new study presented this week at The Liver Meeting® – held by the American Association for the Study of Liver Diseases – found that people who inject drugs who are infected with the hepatitis C virus have high rates of hepatitis C treatment adherence (completion of their treatment), and sustained virologic response. Based on these findings, researchers conclude these patients should be included in HCV treatment programs.

Hepatitis C virus, commonly called HCV, is a liver disease that ultimately can cause cirrhosis (scarring of the liver), liver cancer and liver failure. HCV is mainly contracted when a person comes in contact with an infected person’s blood.

People who inject drugs, such as opioids, are at high risk to acquire and transmit HCV, but many are excluded from HCV treatment programs due to concerns about their ability to follow their treatment plans. The ANCHOR Study, conducted by researchers at the Institute of Human Virology at the University of Maryland, evaluated HCV treatment in patients who have chronic HCV, opioid use disorder and ongoing injection drug use. They looked at rates of treatment adherence, treatment completion and sustained virologic response (commonly called SVR) as benchmarks. This is an ongoing study, and data will be updated in the future.

“The ANCHOR study was developed in an attempt to understand if people who inject drugs can be effectively treated with direct-acting antivirals,” explains Elana Rosenthal, MD, co-director, DC PFAP Hepatitis Clinical Research Program, University of Maryland, and the study’s co-author. “Many insurance companies impose restrictions requiring treatment of or abstinence from drugs and alcohol prior to initiation of HCV medication. We wanted to specifically evaluate treatment of the highest risk population, people with ongoing injection drug use, to evaluate if they could be cured with standard treatment using direct-acting antivirals.”

Beyond these restrictions, insurance companies often deny access to HCV treatment for people who inject drugs based on an assumption that they will not follow their treatment plans, says Dr. Rosenthal. “However, this assumption is based on stigma and not medical science. Therefore, we wanted to evaluate if people who inject drugs could have sufficient adherence to HCV treatment to achieve cure.”

Of the 100 participants enrolled in the study, 76 percent were male, 93 percent were black, and 51 percent were unstably housed. Their median age was 57 years. At the study screening, 58 percent of the participants reported they injected opioids at least daily.

Patients received HCV treatment with sofosbuvir/velpatasvir over 12 weeks. Medication was dispensed monthly in 28-pill bottles. Sixty out of 66 patients who reached week 24 of their treatment received a second bottle of medication before running out, and 58 patients received a third bottle of medication before running out. At the fourth week of HCV treatment, 62 patients had their HCV viral load checked, and 59 had a HCV viral load of less than 200 IU/mL.

Two patients received four weeks of treatment, two patients received 8 weeks of treatment, three received between 8 and 12 weeks of treatment, and 59 received 12 weeks of treatment. Of the 59 patients who completed 12 weeks of treatment, 28 finished treatment one to seven days after the anticipated end date; nine finished between eight and 14 days late; and nine patients finished more than 14 days late.

Of the 58 patients who attended an office visit at week 24 of their treatment, 52 achieved SVR (which is marked by no detectable HCV in the blood for 12 or more weeks), giving an overall cure rate of 89.7 percent. This high rate of cure was significantly associated with having an HCV viral load of less than 200 at week four, and with taking 12 weeks of treatment. The researchers also found that finishing treatment late did not impact SVR, even in those completing treatment more than 14 days late. Preliminary data from the study indicates that people who inject drugs who also have HCV and are continuing injection drug use have high rates of adherence and completion in their therapy programs and achieve SVR – even with imperfect adherence.

“Our data demonstrate that people who inject drugs can achieve SVR at comparable rates to non-drug using populations, even if adherence is imperfect,” explains Dr. Rosenthal of the study’s findings. “Therefore, there is no justification for excluding people who inject drugs from being treated. In fact, people who inject drugs should represent a unique high-priority population, because injection drug use remains the primary reason for ongoing HCV transmission in the U.S. Therefore, treatment of people who inject drugs will help prevent new cases of HCV.”

Editor’s note: This press release contains updated data that is not reflected in the published abstract but will be presented at The Liver Meeting®.

Dr. Rosenthal will present these findings at AASLD’s press conference in Room 312-314 at the George R. Moscone Convention Center in San Francisco on Saturday, Nov. 10 from 4 – 5:30 PM. The study entitled “High Svr in PWID with HCV Despite Imperfect Medication Adherence: Data from the Anchor Study,” will be presented on Monday, November 12 at 8:00 AM in Hall D. The corresponding abstract (number 0018) can be found in the journal, HEPATOLOGY (link is external).

About AASLD
AASLD is the leading organization of clinicians and researchers committed to preventing and curing liver disease. The work of our members has laid the foundation for the development of drugs used to treat patients with viral hepatitis. Access to care and support of liver disease research are at the center of AASLD’s advocacy efforts.
Press releases and additional information about AASLD are available online at www.aasld.org.

Wednesday, November 7, 2018

4 Good Reasons to Worry about Hep C

In Case You Missed It
November 7, 2018

4 Good Reasons to Worry about Hep C
Andrew Bowser
Nov 6, 2018

The challenge of successfully treating infection with the hepatitis C virus (HCV) has been significantly reduced in this era of highly effective direct-acting antiviral (DAA) agents; however, there are still important issues for clinicians to be aware of, according to liver disease expert Mitchell L. Shiffman, MD.

“They're not challenges. You just need to be concerned about them,” Dr. Shiffman said in a presentation at the recent American College of Gastroenterology (ACG) meeting in Philadelphia.

While first- and second-line therapy for HCV is very effective, there are still a small number of DAA treatment failures that can be very challenging to manage, said Dr. Shiffman, liver disease expert at Bon Secours Liver Institute of Richmond, Va.

Other issues that should be on the radar:
Monitoring for chronic hepatitis B reactivation
Treatment of active drug users
Managing patients with end-stage renal disease

Read on to learn more about these key issues and comments on each Dr. Shiffman made at ACG.

Friday, October 12, 2018

Case study of needle exchange programs in the Central Appalachian region of the United States

Qualitative case study of needle exchange programs in the Central Appalachian region of the United States
Stephen M. Davis , Danielle Davidov, Alfgeir L. Kristjansson, Keith Zullig, Adam Baus, Melanie Fisher
Published: October 12, 2018 https://doi.org/10.1371/journal.pone.0205466

Due to overwhelming need, PWID are often in the dark regarding the precise outcomes that will be experienced during their next injection. Will it be the sought-after high or a disappointing low? Will it be a fatal overdose or a ‘near-miss’? Similarly, the two West Virginia needle exchange programs described in this case study have been forced to take a shot in the dark and open NEPs in the absence of model programs, adequate funding, and other resources, due to overwhelming need in their small communities. Despite these challenges, such programs have enjoyed robust community support, and have creatively navigated unexpected problems and challenges to effectively implement needle exchange programs in their communities. However, surging participant volumes amidst ongoing funding challenges coupled with location and transportation barriers make the future trajectory of such programs difficult to predict. Additionally, the efficacy of these programs in preventing transmission of blood borne viruses may be compromised from the legal conundrums created by paraphernalia laws and policing behaviors that may promote needle sharing that is the primary risk for acquiring HCV among PWID. Future studies should investigate these potential barriers to using clean needles in people who inject drugs residing in smaller, less populous areas of the United States.

Abstract
Background
The Central Appalachian region of the United States is in the midst of a hepatitis C virus epidemic driven by injection of opioids, particularly heroin, with contaminated syringes. In response to this epidemic, several needle exchange programs (NEP) have opened to provide clean needles and other supplies and services to people who inject drugs (PWID). However, no studies have investigated the barriers and facilitators to implementing, operating, and expanding NEPs in less populous areas of the United States.

Methods
This qualitative case study consisted of interviews with program directors, police chiefs, law enforcement members, and PWID affiliated with two NEPs in the rural state of West Virginia. Interview transcripts were coded inductively and analyzed using qualitative data analysis software. Final common themes related to barriers and facilitators of past program openings, current program operations, and future program plans, were derived through a consensus of two data coders.

Results
Both NEPs struggled to find existing model programs, but benefited from broad community support that facilitated implementation. The largest operational barrier was the legal conundrum created by paraphernalia laws that criminalize syringe possession. However, both PWID and law enforcement appreciated the comprehensive services provided by these programs. Program location and transportation difficulties were additional noted barriers. Future program operations are threatened by funding shortages and bans, but necessitated by unexpected program demand.

Conclusion
Despite broad community support, program operations are threatened by growing participant volumes, funding shortages, and the federal government’s prohibition on the use of funds to purchase needles. Paraphernalia laws create a legal conundrum in the form of criminal sanctions for the possession of needles, which may inadvertently promote needle sharing and disease transmission. Future studies should examine additional barriers to using clean needles provided by rural NEPs that may blunt the effectiveness of NEPs in preventing disease transmission.

Thursday, October 4, 2018

At-Risk Teens and Young Adults Overlooked During Opioid Crisis Too Few Tested for Hepatitis C, Research Suggests

SAN FRANCISCO – Teens and young adults who have injected drugs are at risk for contracting hepatitis C, but most aren’t tested and therefore don’t receive life-saving treatment, according to a national study being presented at IDWeek 2018. The study of more than 250,000 at-risk youth found only one-third of those with diagnosed opioid use disorder (OUD) were tested for hepatitis C.

AT A GLANCE
Injection drug use increases the risk of contracting hepatitis C, but few teens and young adults are tested, according to a large national study presented at IDWeek.

The study of more than 250,000 youth determined only one-third of those with documented opioid use disorder were tested for hepatitis C.

Hepatitis C treatment was recently approved for teens, making it even more important that they get tested so they can be treated.

The Centers for Disease Control and Prevention seeks to eliminate HCV transmission among injection drug users. These data suggest that goal may not be attainable without substantial effort to improve testing rates.

This study is the first to look at opioid use and hepatitis C testing in at-risk youth. “We’re missing an opportunity to identify and treat young people who are at risk for this deadly infection,” said Rachel L. Epstein, MD, MA, lead author of the study and a post-graduate research fellow in the section of infectious diseases, Boston Medical Center. “Screening for OUD and other drug use, and then testing for hepatitis C in those at high risk, can help us do a better job of eliminating this serious infection, especially now that very effective hepatitis C medications are approved for teenagers.”

An infection of the liver, hepatitis C killed more than 18,000 Americans in 2016, making it the most common cause of death from a reportable infectious disease, according to the Centers for Disease Control and Prevention (CDC). It can be spread by sharing needles used to inject drugs. Health care providers may not test young people they suspect of misusing opioids because the drugs are available in pill form, which does not increase the risk of infection with hepatitis C. But studies show many youths who misuse prescription oral opioids eventually begin injecting them.

Results of the study suggest that current guidelines -- which only recommend testing those with known injected drug use or other specific risk factors – underestimate who is at risk for hepatitis C.

In 2017, the Food and Drug Administration (FDA) approved the first direct-acting hepatitis C medications for teens. These medications can cure a person with hepatitis C infection in two to three months. Without treatment, people may develop liver failure, liver cancer, or chronic liver disease (cirrhosis) many years after being infected.

For the study, researchers analyzed electronic medical records for 269,124 teens and young adults (13-21 years old) who visited one of 57 Federally Qualified Health Centers, which provide health care to diverse and underserved communities across 19 states, between 2012 and 2017. Of the 875 who had diagnosed OUD, 36 percent were tested for hepatitis C, and of those, 11 percent had been exposed to hepatitis C and 6.8 percent had evidence of chronic hepatitis C infection.

Overall, 6,812 (2.5 percent) who visited the health centers were tested for hepatitis C and of those, 122 (1.8 percent) tested positive for hepatitis C. Researchers found those most likely to be tested for hepatitis C were African American youth, those with any substance use disorder, and those 19-21 years old.

“The issue is complicated by the fact that not enough at-risk youth are screened for opioid or other drug use for a variety of reasons, including lack of time, comfort level between clinician and patient, and privacy and stigma concerns,” said Dr. Epstein. “And even when drug use is identified, there’s a belief that youth are less likely to test positive for hepatitis C, which isn’t necessarily the case as we show in our study. Clearly, this is an overlooked group that is at high risk.”

In addition to Dr. Epstein, co-authors of the study are: Jianing Wang, MSc, Kenneth Mayer, MD, Jon Puro, MPH, C. Robert Horsburgh, MD, Benjamin P. Linas, MD, MPH and Sabrina A. Assoumou, MD, MPH.

About IDWeek
IDWeek 2018TM is the annual meeting of the Infectious Diseases Society of America (IDSA), the Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA) and the Pediatric Infectious Diseases Society (PIDS). With the theme “Advancing Science, Improving Care,” IDWeek features the latest science and bench-to-bedside approaches in prevention, diagnosis, treatment, and epidemiology of infectious diseases, including HIV, across the lifespan. IDWeek 2018 takes place Oct. 3-7 at the Moscone Center in San Francisco. For more information, visit www.idweek.org.

Thursday, September 20, 2018

Overwhelming evidence shows hepatitis C treatment effective for people who inject drugs

Overwhelming evidence shows hepatitis C treatment effective for people who inject drugs
University of New South Wales
Researchers are calling on an end to discriminatory health and illicit drugs policies, based on overwhelming evidence that new hepatitis C therapies are effective at curing the virus in people who inject drugs.

The Kirby Institute research, being presented tomorrow at the 7th International Symposium on Hepatitis Care in Substance Users in Cascais, Portugal and published in The Lancet Gastroenterology and Hepatology, provides the strongest evidence-base to date to support the removal of restrictions to accessing hepatitis C therapy based on recent drug use.

Globally, more than one in three people who have injected drugs in the past year are living with hepatitis C. New therapies for hepatitis C can cure the virus in more than 95% of people, however in many countries the treatment is inaccessible to people who inject drugs, due to restrictions on treatment reimbursement related to an individual's recent drug use. In addition, many clinicians are hesitant to prescribe hepatitis C therapy to people who use or inject drugs, as there are concerns about adherence and the chance of reinfection.

"The results of our research show that the response to hepatitis C therapy among people who inject drugs was very favourable. Across almost 40 studies worldwide, involving more than 3,500 people with recent or ongoing drug use, hepatitis C was cured in almost 9 out of 10 people," said Dr Behzad Hajarizadeh, from the Viral Hepatitis Clinical Research Program at the Kirby Institute, and lead author on the study. "We conducted a systematic review, which means we examined all the available evidence from studies conducted globally on this topic. It means we can be very confident about these results."

"People should not be denied life-saving treatments, simply because of their recent drug use," said Associate Professor Jason Grebely from the Kirby Institute. "Policies that deny hepatitis C treatment for people who use or inject drugs are unacceptable; they are driven by discrimination as opposed to evidence. I hope our research will encourage countries to overturn these policies and allow treatment to all people living with hepatitis C, regardless of current or previous drug use. In fact, given high prevalence rates, people who inject drugs really should be prioritised for treatment." Associate Professor Grebely is also President of the International Network of Hepatitis in Substance Users (INHSU).

Australia has offered broad access to hepatitis C treatment through its Pharmaceutical Benefits Scheme (PBS) since March 2016, and as a result, is already seeing significant reductions in hepatitis C among people who inject drugs. A Kirby Institute analysis found that prevalence of active hepatitis C infection among people attending needle and syringe programs declined from 43% to 25% between 2015 to 2017, coinciding with the PBS listing.

"The World Health Organisation has set a target to eliminate hepatitis C by 2030," said Associate Professor Grebely. "Our data provides robust evidence to inform global clinical guidelines, and we hope it will improve public health policy for hepatitis C treatment for people who use drugs internationally. This will bring us closer to the ambitious goal of global elimination."

The 7th International Symposium on Hepatitis Care in Substance Users is taking place in Portugal, where illicit drug use has been decriminalised since 2001. On Tuesday, researchers, politicians and international advocates gathered at the Portuguese National Parliament for a joint action policy day. Led by INHSU, delegates from key hepatitis C research and advocacy organisations signed the 'Global Declaration to Eliminate Hepatitis C in People Who Use Drugs', in which they called on world political leaders to adopt the United Nations goal of hepatitis C elimination by 2030. The Declaration outlines seven actions to close the "gap between the global impact of hepatitis C on the health and well-being of people who use drugs and the limited access to evidence-based services effective for the prevention, diagnosis and treatment of hepatitis C infection".

"Endemic stigma and discrimination, which paints people who use drugs as undeserving of health care and treatment, is the fuel driving severe health disparities. Our communities are disproportionately impacted by hepatitis C. To reach global hepatitis C elimination targets, it is imperative to reverse this trend by countering prejudice with evidence, and most importantly for decision-makers and medical professionals to heed the evidence."

- Judy Chang, Executive Director, International Network of People Who Use Drugs

"These data provide strong evidence that direct-acting antiviral therapy is effective in people who use or inject drugs. We must work towards the removal of restrictions against access and reimbursement to therapy for hepatitis C infection among people with ongoing drug use that are still in place in some countries. We have the tools to eliminate hepatitis C, but we will never reach the WHO elimination targets unless we prioritize people who use or inject drugs."

- Michael Ninburg, President, World Hepatitis Alliance
Journal The Lancet Gastroenterology & Hepatology
https://kirby.unsw.edu.au/news/overwhelming-evidence-demonstrates-hepatitis-c-treatment-effective-people-who-inject-drugs
https://www.eurekalert.org/pub_releases/2018-09/uons-oes091918.php

Friday, August 17, 2018

HCV elimination among people who inject drugs. Modelling pre- and post–WHO elimination era

Research Article
HCV elimination among people who inject drugs. Modelling pre- and post–WHO elimination era 
Ilias Gountas , Vana Sypsa, Sarah Blach, Homie Razavi, Angelos Hatzakis
Published: August 16, 2018
https://doi.org/10.1371/journal.pone.0202109

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Abstract
Background
Elimination of hepatitis C virus (HCV) among people who inject drugs (PWID) is a costly investment, so strategies should not only focus on eliminating the disease, but also on preventing disease resurgence. The aims of this study are to compute the minimum necessary antiviral therapies to achieve elimination with and without the additional expansion of harm reduction (HR) programs and to examine the sustainability of HCV elimination after 2030 if treatment is discontinued.

Method
We considered two types of epidemic (with low (30%) and high (50%) proportion of PWID who engage in sharing equipment (sharers)) within three baseline chronic HCV (CHC) prevalence settings (30%, 45% and 60%), assuming a baseline HR coverage of 40%. We define sustainable elimination strategies, those that could maintain eliminations results for a decade (2031–2040), in the absence of additional treatment.

Results
The model shows that the optimum elimination strategy is dependent on risk sharing behavior of the examined population. The necessary annual treatment coverage to achieve HCV elimination under 45% baseline CHC prevalence, without the simultaneous expansion of HR programs, ranges between 4.7–5.1%. Similarly, under 60% baseline CHC prevalence the needed treatment coverage varies from 9.0–10.5%. Increasing HR coverage from 40% to 75%, reduces the required treatment coverage by 6.5–9.8% and 11.0–15.0% under 45% or 60% CHC prevalence, respectively. In settings with ≤45% baseline CHC prevalence, expanding HR to 75% could prevent the disease from rebounding after elimination, irrespective of the type of the epidemic. In high chronic HCV prevalence, counseling interventions to reduce sharing are also needed to maintain the HCV incident cases in low levels.

Conclusions
Harm reduction strategies have a vital role in HCV elimination strategy, as they reduce the required number of treatments to eliminate HCV and they provide sustainability after the elimination. The above underlines that HCV elimination strategies should be built upon the existing HR services, and argue for HR expansion in countries without services.

Friday, May 11, 2018

MMWR: Access to Syringe Services Programs — Kentucky, North Carolina, and West Virginia, 2013–2017

Centers for Disease Control and Prevention
Morbidity and Mortality Weekly Report (MMWR)
Weekly / May 11, 2018 / 67(18);529–532

Access to Syringe Services Programs — Kentucky, North Carolina, and West Virginia, 2013–2017
Danae Bixler, MD1; Greg Corby-Lee2; Scott Proescholdbell, MPH3; Tina Ramirez4; Michael E. Kilkenny, MD5; Matt LaRocco6; Robert Childs, MPH7; Michael R. Brumage, MD4; Angela D. Settle, DNP8; Eyasu H. Teshale, MD1; Alice Asher, PhD


The Appalachian region of the United States is experiencing a large increase in hepatitis C virus (HCV) infections related to injection drug use (IDU) (1). Syringe services programs (SSPs) providing sufficient access to safe injection equipment can reduce hepatitis C transmission by 56%; combined SSPs and medication-assisted treatment can reduce transmission by 74% (2). However, access to SSPs has been limited in the United States, especially in rural areas and southern and midwestern states (3). This report describes the expansion of SSPs in Kentucky, North Carolina, and West Virginia during 2013-August 1, 2017. State-level data on the number of SSPs, client visits, and services offered were collected by each state through surveys of SSPs and aggregated in a standard format for this report. In 2013, one SSP operated in a free clinic in West Virginia, and SSPs were illegal in Kentucky and North Carolina; by August 2017, SSPs had been legalized in Kentucky and North Carolina, and 53 SSPs operated in the three states. In many cases, SSPs provide integrated services to address hepatitis and human immunodeficiency virus (HIV) infection, overdose, addiction, unintended pregnancy, neonatal abstinence syndrome, and other complications of IDU. Prioritizing development of SSPs with sufficient capacity, particularly in states with counties vulnerable to epidemics of hepatitis and HIV infection related to IDU, can expand access to care for populations at risk.

Discussion 
During 2013–2017, the number of operational SSPs increased from one to approximately 50 in Kentucky, North Carolina, and West Virginia. Visits to SSPs by clients who inject drugs also increased. In Kentucky and North Carolina, this increase followed changes in laws permitting access to sterile injecting supplies; in West Virginia, SSPs were never prohibited under state law. In North Carolina, any group can start an SSP after notifying the state health department; Kentucky requires a lengthy approval process for local health departments before offering syringe services. This paper demonstrates that increasing access to SSPs is possible with community support using a variety of models if SSPs are not prohibited by law.

The increase in client visits to SSPs by persons who inject drugs represents an unprecedented opportunity to improve access to care for this highly stigmatized population. In addition to increased access to sterile needles, syringes, and injection paraphernalia (5), comprehensive syringe services programs should also improve access to medication-assisted treatment, counseling, and social support to address substance use disorder (6); naloxone and lay naloxone training to prevent fatal overdose (7); the full range of contraceptives, including long acting reversible contraceptives to prevent unintended opioid-exposed pregnancy; prenatal care and medication-assisted treatment to reduce harm from substance use disorder in pregnant women and their infants (8); vaccination; and HCV, HIV, and hepatitis B virus (HBV) screening and treatment (5). State and local health departments that are actively addressing the health effects of the opioid crisis might consider a formal evaluation process to improve service quality and access for persons who inject drugs, including those attending SSPs. Process evaluation indicators for SSPs should include number of clients, number of syringes distributed, number of syringes returned, availability of services in hours per week, summary statistics on HIV, HBV, and HCV testing, and number and type of services (e.g., patient-centered family planning services and naloxone) and referrals provided (e.g., medication assisted treatment, prenatal care, HIV, and hepatitis treatment) (9). Evaluation should also include health indicators such as rates of hepatitis, HIV, fatal and nonfatal overdose, unintended pregnancy and neonatal abstinence syndrome, and initiation and retention in drug treatment. CDC has published a framework to guide evaluation of public health programs (10), which might be useful for evaluating access to essential services at the community level for persons who inject drugs.

The findings in this report are subject to at least six limitations. First, data were self-reported from SSPs and are therefore subject to bias. Second, because some programs do not collect identifying information, the total numbers of clients served is estimated. Third, at the time of this analysis, North Carolina was in its first year of implementation, and limited data are available. Fourth, no data were obtained for SSPs operating underground (i.e., outside the legal framework). Fifth, growth of SSPs and service integration in these states is rapid, and the most recent data on SSPs should be sought through the state or local health department or harm reduction coalition. Finally, these data cannot be used to evaluate quality of service delivery and whether service delivery is adequate to meet the needs of the population.

SSPs can be implemented through a variety of models and by a variety of agencies and organizations including those in rural areas. Demand for syringe services is growing rapidly in these three states with underserved populations of persons who inject drugs, representing an opportunity to implement, evaluate, and improve access to evidence-based services known to reduce the considerable morbidity and mortality associated with injection drug use.

Full report -  https://www.cdc.gov/mmwr/volumes/67/wr/mm6718a5.htm?s_cid=mm6718a5_w

Thursday, April 26, 2018

Strategies for Reducing Opioid-Overdose Deaths — Lessons from Canada

April 26, 2018
N Engl J Med 2018; 378:1565-1567
DOI: 10.1056/NEJMp1800216

Perspective
Strategies for Reducing Opioid-Overdose Deaths — Lessons from Canada
Evan Wood, M.D., Ph.D.

Audio Interview with Dr. Evan Wood on actions taken by Canada to reduce opioid-overdose deaths.
Listen Here.....

As the United States faces this unprecedented epidemic, there are lessons to be learned from Canada, which has taken bold action on a number of fronts with the aim of reducing deaths related to fentanyl, fentanyl analogues, and other opioids. For instance, in March 2016, the Canadian government made the overdose-reversal drug naloxone available without a prescription. Although naloxone is also increasingly available in many regions of the United States, laws in 14 states provide no immunity from criminal prosecution for health care providers who prescribe or distribute it to laypersons. Furthermore, in 36 states, existing laws make possession of naloxone without a prescription illegal.

The Canadian government has also passed legislation aimed at facilitating the development of medically supervised injection facilities, where people who use drugs can inject opioids they buy on the street under the supervision of health care staff. Although research has found that supervised injection facilities can reduce rates of fatal overdoses by more than 30% in communities with high rates of drug use1 and can help facilitate greater uptake of addiction treatment, there are few, if any, such programs in the United States. In recent months, however, public health officials in several U.S. cities, including San Francisco, Seattle, and Philadelphia, have endorsed plans to open pilot supervised injection programs to address increasing rates of overdose deaths.

Thursday, April 12, 2018

#ILC2018 Testing & Treatment of HCV infection for people who use drugs: Where To Next?

The International Liver Congress 2018 
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Following presentation shared today by @HenryEChang.



Linkage to care specialist facilitates access to HCV treatment for people who inject drugs

Linkage to care specialist facilitates access to hepatitis C treatment for people who inject drugs

European Association for the Study of the Liver

12 April 2018, Paris, France: A prospective, longitudinal study involving more than 1,000 people who inject drugs has identified a promising role for linkage to care specialists in facilitating rapid access to hepatitis C treatment. The study, which was conducted in Texas, USA, ensured that individuals newly diagnosed with hepatitis C were contacted by a linkage to care specialist within 48 hours of being referred to the service, thereby ensuring that almost 50% of patients referred to a medical practitioner made it to their first appointment and that 60% of those seen were initiated on treatment.

'We have a major problem with injection drug use in the USA', explained Zohha Alam from the Austin Hepatitis Center in Texas, USA. 'At least 75% of new hepatitis C virus (HCV) infections result from injection drug use, and it is often difficult to engage with the users and ensure that HCV infection is both diagnosed and treated'.

The prospective study, which was presented today at The International Liver Congress™ 2018 in Paris, France, evaluated 1,038 patients who were screened and entered into an electronic database in Austin between January and October 2017. A total of 503 individuals were found to be HCV RNA positive and were referred to the linkage to care service. Of those referred, 398 (79%) were contacted within 48 hours by a linkage to care specialist who provided education and linked the individual to a care provider. Of the 249 individuals referred to a medical practitioner, 116 (47%) attended their first appointment, and 69 (59%) had initiated HCV therapy at the time of the analysis.

'Linkage to care is the missing link in the treatment of chronic HCV infection', said Zohha Alam. 'Our study demonstrates a promising role for linkage to care specialists in engaging with people who inject drugs and, importantly, connecting those individuals with HCV care providers'.

The importance of increasing the number of HCV-infected individuals screened and linked to care was highlighted in another study presented at The International Liver Congress™ 2018. The study by a team from the CDA Foundation's Polaris Observatory in Lafayette, Colorado, USA, used data from 53 countries in Europe to forecast the current and future burden of HCV in the region and to estimate the levels of HCV diagnosis and treatment required to achieve World Health Organization (WHO) Global Health Sector Strategy Goals for Hepatitis by 2030.1

'Based on our analysis', said Sarah Robbins from the Polaris Observatory, 'we predict that given the current standard of care for the next 15 years, the total HCV-infected population in Europe would increase by an estimated 1% by 2030 and that, in order to meet WHO goals, the number of individuals diagnosed annually would need to increase to at least 800,000 by 2022, with 900,000 being treated each year by 2025. Improving linkage to care coupled with increased access to DAA therapy is needed to achieve such goals'.

Unfortunately, progress towards establishing national policies to support the necessary scale-up of HCV diagnosis and treatment to achieve these goals remains slow, according to the results of a third study presented in Paris. The 2017 Hep-CORE study, which was conducted in 25 European countries, found that an approved national hepatitis C strategy and/or action plan was in place in just 12 (48%) of those countries. Hepatitis C treatment was reported to be available in non-specialist settings in five (20%) countries, although treatment was available in prisons in 18 (72%) countries. Although an improvement from 2016, 52% and 32% of countries in the 2017 Hep-CORE study still restrict access to direct-acting antiviral agents based on the degree of fibrosis and/or current injecting drug use, respectively.

'HCV can be cured in more than 95% of patients', said Prof. Markus Cornberg from the Hannover Medical School, Germany, and EASL Governing Board Member. 'However, in order to prevent complications such as HCC, patients first need to be identified and treated accordingly. Screening and linkage to care are fundamental if WHO elimination targets are to be achieved, and the data presented here are important in improving these measures'.

1. World Health Organization. Global Health Sector Strategy on Viral Hepatitis 2016-2012. June 2016. Available from: http://www.who.int/hepatitis/strategy2016-2021/ghss-hep/en/. Last accessed: February 2018.

Wednesday, April 4, 2018

Experiences of liver health related uncertainty among people who inject drugs living with hepatitis C

Experiences of liver health related uncertainty and self-reported stress among people who inject drugs living with hepatitis C virus: a qualitative study
Stelliana Goutzamanis, Joseph S. Doyle, Alexander Thompson, Paul Dietze, Margaret Hellard,
Peter Higgs and on behalf of the TAP study group

BMC Infectious Diseases
https://doi.org/10.1186/s12879-018-3057-1
Received: 4 August 2017
Accepted: 21 March 2018
Published: 2 April 2018

Abstract
Background
People who inject drugs (PWID) are most at risk of hepatitis C virus infection in Australia. The introduction of transient elastography (TE) (measuring hepatitis fibrosis) and direct acting antiviral medications will likely alter the experience of living with hepatitis C. We aimed to explore positive and negative influences on wellbeing and stress among PWID with hepatitis C.

Methods
The Treatment and Prevention (TAP) study examines the feasibility of treating hepatitis C mono-infected PWID in community settings. Semi-structured interviews were conducted with 16 purposively recruited TAP participants. Participants were aware of their hepatitis C seropositive status and had received fibrosis assessment (measured by TE) prior to interview. Questions were open-ended, focusing on the impact of health status on wellbeing and self-reported stress. Interviews were voice recorded, transcribed verbatim and thematically analysed, guided by Mishel’s (1988) theory of Uncertainty in Illness.

Results
In line with Mishel’s theory of Uncertainty in Illness all participants reported hepatitis C-related uncertainty, particularly mis-information or a lack of knowledge surrounding liver health and the meaning of TE results. Those with greater fibrosis experienced an extra layer of prognostic uncertainty. Experiences of uncertainty were a key motivation to seek treatment, which was seen as a way to regain some stability in life. Treatment completion alleviated hepatitis C-related stress, and promoted feelings of empowerment and confidence in addressing other life challenges.

Conclusion
TE scores seemingly provide some certainty. However, when paired with limited knowledge, particularly among people with severe fibrosis, TE may be a source of uncertainty and increased personal stress. This suggests the need for simple education programs and resources on liver health to minimise stress.

Excerpt:
--Noninvasive tests for fibrosis
Recently, the therapeutic landscape of hepatitis C has drastically changed. Non-invasive fibrosis assessment tools, such as transient elastography (TE) (an ultrasound like device which determines liver stiffness by measuring wave velocity [9]) and highly effective interferon-free direct acting antiviral (DAA) medications are now considered standard of care [10, 11]. These advances have made the elimination of hepatitis C as a public health threat a real possibility, particularly in Australia, where DAAs are widely accessible and heavily subsidised [12, 13]. However, such advances may also alter the individual experience of living with hepatitis C....

-Throughout the trial, research nurses experienced in hepatitis C and working with PWID provided participants with information and explanation of TE results.
Most participants had been diagnosed with hepatitis C many years prior to interview as having “non A, non B” hepatitis or when “Hep C wasn’t even invented”, but had only recently been told their level of fibrosis through the TAP study. Throughout the trial, research nurses experienced in hepatitis C and working with PWID provided participants with information and explanation of TE results. Many participants also received consultation regarding their hepatitis C from other healthcare providers, outside of the TAP study. Despite the consultation with research nurses following their liver assessment; most participants either did not understand or missed key information regarding their TE results, which ignited feelings of stress.

Participant:
I didn’t know anything about it, [doctors] were like: ‘liver cancer and liver all these things’ and I got really freaked out. (Score: P15, low-level fibrosis)

Approximately half the participants were unclear about the true meaning of TE results, implications of the result and how to manage their fibrosis. Participants were often left feeling frustrated or perplexed when their perceptions of liver health or treatment options did not align with their doctors’, particularly with their liver specialists:

Participant:
What I understood from [the liver specialist] is that a third is damaged. Well I’m like; ‘can’t you cut a third off?’ Just get rid of that broken bit, it’s simple for me! Then I don’t need to live with the stress. And they’re like; ‘it doesn’t work like that’. That doesn’t make sense to me. (Score: P1, high-level fibrosis)

Read the full article: https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-018-3057-1

Friday, March 30, 2018

Potential geographic "hotspots" for drug-injection related transmission of HIV and HCV and for initiation into injecting drug use in New York City, 2011-2015, with implications for the current opioid epidemic in the US

Potential geographic "hotspots" for drug-injection related transmission of HIV and HCV and for initiation into injecting drug use in New York City, 2011-2015, with implications for the current opioid epidemic in the US
D. C. Des Jarlais , H. L. F. Cooper, K. Arasteh, J. Feelemyer, C. McKnight, Z. Ross

For HIV, the lack of potential hotspots is further validation of widespread effectiveness of efforts to reduce injecting-related HIV transmission. Injecting-related HIV transmission is likely to be a rare, random event. HCV prevention efforts should include focus on potential hotspots for transmission and on hotspots for initiation into injecting drug use. We consider application of methods for the current opioid epidemic in the US.
Published: March 29, 2018
https://doi.org/10.1371/journal.pone.0194799

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Abstract
Objective
We identified potential geographic “hotspots” for drug-injecting transmission of HIV and hepatitis C virus (HCV) among persons who inject drugs (PWID) in New York City. The HIV epidemic among PWID is currently in an “end of the epidemic” stage, while HCV is in a continuing, high prevalence (> 50%) stage.

Methods
We recruited 910 PWID entering Mount Sinai Beth Israel substance use treatment programs from 2011–2015. Structured interviews and HIV/ HCV testing were conducted. Residential ZIP codes were used as geographic units of analysis. Potential “hotspots” for HIV and HCV transmission were defined as 1) having relatively large numbers of PWID 2) having 2 or more HIV (or HCV) seropositive PWID reporting transmission risk—passing on used syringes to others, and 3) having 2 or more HIV (or HCV) seronegative PWID reporting acquisition risk—injecting with previously used needles/syringes. Hotspots for injecting drug use initiation were defined as ZIP codes with 5 or more persons who began injecting within the previous 6 years.

Results
Among PWID, 96% injected heroin, 81% male, 34% White, 15% African-American, 47% Latinx, mean age 40 (SD = 10), 7% HIV seropositive, 62% HCV seropositive. Participants resided in 234 ZIP codes. No ZIP codes were identified as potential hotspots due to small numbers of HIV seropositive PWID reporting transmission risk. Four ZIP codes were identified as potential hotspots for HCV transmission. 12 ZIP codes identified as hotspots for injecting drug use initiation.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0194799