- Hepatitis C Elimination in People With HIV Is Contingent on Closing Gaps in the HIV Continuum
- Study Population
- Study Setting
- Data Collection
- Study Definitions
- Statistical Analyses
- Current hepatitis C virus testing guidelines miss too many cases, study suggest
- Viral Hepatitis C
- Hepatitis C Symptoms
- Hepatitis C Diagnosis at Johns Hopkins
- Blood Tests
- Liver Biopsy
- Hepatitis C Treatment at Johns Hopkins
Hepatitis C Elimination in People With HIV Is Contingent on Closing Gaps in the HIV Continuum
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Bolstered by the high efficacy of hepatitis C virus (HCV) treatment, the World Health Organization has called for HCV elimination by 2030. People with HIV (PWH) have been identified as a population in which elimination should be prioritized.
We examined progress in HCV elimination through the HCV care continuum among patients infected with HIV/HCV receiving HIV care at Johns Hopkins Hospital in Baltimore, Maryland, United States. Patients with HIV care visits in at least 2 consecutive years were followed through December 15, 2018, for referral to HCV care, treatment initiation, and cure.
Among 593 HIV/HCV-coinfected individuals, 547 (92%) were referred for HCV care, 517 (87%) were evaluated for HCV treatment, 457 (77%) were prescribed HCV treatment, 426 (72%) initiated treatment, and 370 (62%) achieved HCV cure. In multivariable analysis, advanced liver disease (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.17–1.
88) remained significantly positively associated with HCV treatment initiation. Conversely, being insured by state Medicaid (HR, 0.75; 95% CI, 0.61–0.92), having an HIV RNA >400 copies/mL (HR, 0.29; 95% CI, 0.18–0.49), and having missed 1%–24% (HR, 0.72; 95% CI, 0.54–0.97), 25%–49% (HR, 0.66; 95% CI, 0.49–0.89), and ≥50% of HIV care visits (HR, 0.39; 95% CI, 0.25–0.
60) were significantly negatively associated with HCV treatment initiation.
HCV infection can be eliminated in PWH. However, HCV elimination requires unrestricted access to HCV treatment and improved methods of retaining people in medical care.
care continuum, hepatitis C, HIV, treatment
HIV and hepatitis C virus (HCV) share similar modes of transmission. As such, people with HIV (PWH) have high rates of HCV infection .
PWH coinfected with HCV suffer markedly worse health outcomes, including accelerated rates of liver disease progression to cirrhosis, end-stage liver disease, and hepatocellular cancer (HCC) [2, 3].
In the interferon era, rates of HCV cure were also significantly lower and associated with major side effects, thus limiting the benefit of HCV treatment in HIV-infected populations [4–7].
With the advent of oral HCV direct-acting agent (DAA) therapies of short duration with minimal side effects, rates of HCV cure are >95% in both HIV-infected and uninfected populations . DAA therapies improve quality-of-life measures and reduce rates of end-stage liver disease and HCC [9–11]. Increased uptake of DAA treatment can also reduce HCV transmission, resulting in fewer new HCV infections and reinfections .
Bolstered by the potential impact of DAAs, the World Health Organization (WHO) has endorsed elimination of HCV as a public health threat by 2030 [13, 14].
Specifically, the WHO targets are a 90% reduction in new infections and a 65% reduction in hepatitis-related mortality by 2030 (relative to 2015) .
Key milestones to accomplish these goals include diagnosis of 90% of HCV-infected individuals and HCV treatment in 80% of infected individuals.
Understanding that eliminating HCV in the 71 million people infected globally will take coordinated and strategic efforts, the concept of HCV micro-elimination in specific populations has growing support [14, 15]. With micro-elimination, large national or global goals are broken into smaller and more easily achievable treatment and prevention goals using targeted methods for individual subpopulations.
Globally, there are an estimated 2.3 million PWH coinfected with HCV . Similar to the WHO targets for HCV, in 2014, the Joint United Nations Program on HIV and AIDS (UNAIDS) established elimination targets for HIV infection.
The 90-90-90 targets are that, by 2020, 90% of PWH will know their status, 90% of these will receive antiretroviral therapy (ART), and 90% of these will be virally suppressed; this program provides the infrastructure and foundation to layer HCV elimination in PWH.
In this study, we characterize the ongoing barriers and facilitators to HCV care in HIV-infected populations in the oral DAA era as a bridge to developing appropriate strategies for HCV micro-elimination in HIV-infected populations.
This analysis included individuals receiving HIV care at the Johns Hopkins HIV clinical practice who are also enrolled in ongoing prospective observational cohort studies of HIV and HIV/HCV clinical outcomes. The HIV clinical cohort has previously been described .
For this analysis, participants were required to be receiving HIV care and to have evidence of HCV viremia (detectable HCV RNA) in the oral DAA era. Receipt of HIV care was defined as having at least 1 HIV care visit in 2 consecutive years between January 1, 2013, and December 31, 2016.
Individuals who met these criteria were followed through March 31, 2018, for ascertainment of HCV treatment status and through December 15, 2018, for ascertainment of HCV treatment outcome status.
The Institutional Review Board of the Johns Hopkins University School of Medicine approved the research study, and all participants provided written informed consent.
The Johns Hopkins HIV clinical practice provides HIV care to a predominantly inner-city population with high rates of current and previous injection drug use.
The co-located viral hepatitis clinic provides comprehensive care, including testing, evaluation, treatment, pharmacy prior authorization, and support for patient assistance program (PAP) applications for patients who have been denied insurance treatment coverage.
HCV care is provided within the HIV care infrastructure, which is structured as multidisciplinary teams. Clinicians, nurses, and social workers work together to provide longitudinal care to defined groups of HIV patients.
HIV providers refer patients to HCV care providers, who evaluate, prescribe, and treat hepatitis infections. A limited number of HIV providers treat HCV infection in their coinfected HIV continuity patients.
In the state of Maryland, where the Johns Hopkins Hospital is located, the Department of Health (DOH) has established criteria for HCV therapy paid for by Maryland Medicaid after approval of a prior authorization application.
During the study period, payment for HCV therapy by Maryland Medicaid was restricted to patients with METAVIR stage ≥F2 liver disease .
At the Johns Hopkins HIV clinical practice, providers prescribe DAAs through the specialized Johns Hopkins Hospital outpatient pharmacy team, which navigates the process of prior authorization and written appeals of insurance denials.
For patients denied by insurance, a dedicated team handles PAP applications to enable access to free HCV treatment. A subset of patients also accessed HCV therapy through clinical trials that were ongoing during the study period.
In addition to sociodemographic characteristics and laboratory values, data on referrals for HCV evaluation, scheduling, attendance at HCV and HIV appointments, HCV treatment prescription, and HCV treatment initiation and completion dates were extracted from the electronic medical record and supplemented through chart review.
Additional information on HCV therapy prescription, start, and completion was extracted from pharmacy records. Death information was obtained using a combination of medical records and the National Death Index (NDI).
Most study participants (527/593, 89%) had additional survey data collected using audio computer-assisted interview software (ACASI) at study visits, which was used to assess recent drug use and hazardous alcohol consumption.
Sustained virologic response (SVR), also referred to as HCV cure, was defined as at least 1 HCV RNA result undetectable at 15 IU/mL after previous evidence of achievement of SVR confirmed through chart review. A genotype switch in pre- and post-treatment virus was also considered evidence of HCV reinfection .
Liver disease staging was assessed by liver elastography (FibroScan, EchoSens, Paris, France), FibroTest, and FIB-4 (calculated from the patient’s age, AST and AST levels, and platelet count) [19, 20]. Fasting liver stiffness measurements >12.5 KPA by elastography, FibroTest >0.79, or FIB-4 score >3.25 was considered evidence of cirrhosis. The cutoffs of >7.
9 KPA by elastography or a FibroTest ≥0.48, which are accepted by the Maryland DOH, were considered evidence of ≥F2 liver disease . Recent drug use was defined as self-reported use (collected through ACASI at study visits) of any illicit substances, including heroin or cocaine, in the prior 3 months.
Hazardous alcohol use was defined as a score of ≥4 for men and ≥3 for women on the AUDIT-C, as reported by ACASI at study visits [21, 22].
The study population was characterized with respect to demographics and risk behaviors at study baseline using descriptive statistics. Study baseline was the first HIV care visit (or the first study visit for data collected by ACASI) on or after January 1, 2013.
To evaluate the HCV care continuum, the proportion of the study population referred for HCV care, attending HCV care, prescribed HCV treatment, initiating HCV treatment, and achieving SVR were calculated over the study period. Factors associated with HCV treatment initiation were evaluated among all participants in the study.
Participants entered the analysis at study baseline and exited at either March 31, 2018, or HCV treatment initiation (whichever came first). Time from study baseline was used as the time scale for the analysis.
Time-fixed covariates of interest were anchored at study baseline and included sex, race, HIV transmission risk group, insurance, HCV genotype, fibrosis stage, history of alcohol abuse, tobacco use, psychiatric diagnoses, depression, prior HCV treatment, and current liver disease stage.
Time-varying covariates of interest included CD4 count, HIV viral load, ART use, hazardous alcohol or illicit drug use, and missed HIV care visits. For time-varying covariates, values were carried forward and updated when new values were available.
Missed HIV visits was calculated as the proportion of missed HIV visits over the total scheduled HIV visits, was accumulated from 1 year before study baseline, and was updated at each CD4 or viral load measure. A sensitivity analysis was conducted using number, instead of proportion of missed visits.
Cox proportional hazard models were used to evaluate factors associated with treatment initiation. Hazard ratios and 95% confidence intervals are reported. Covariates that were statistically significant (P < .05) in the univariable analysis and race were included in the multivariable model. As engagement in HIV care was found to be important, an additional analysis was conducted comparing the characteristics between those engaged and not engaged in care using descriptive statistics. Two or more missed visits in the year before study baseline was defined as being poorly engaged in care . All analyses were performed using SAS, version 9.4 (SAS Institute Inc., Cary, NC), and Stata, version 14.2 (StataCorp LLC., College Station, TX).
Of 2884 HIV-infected patients enrolled or in ongoing follow-up between January 1, 2013, and December 31, 2016, 672 had a diagnosis of HCV at study entry.
Among the 2111 patients who did not have a diagnosis of HCV, 2010 (95.2%) were tested for anti-HCV and/or HCV RNA. Overall, 2783 (96.
5%) patients were tested for HCV with anti-HCV and/or HCV RNA or had a diagnosis of HCV at study entry.
There were 978 patients with HIV visits in at least 2 consecutive years between January 1, 2013, and December 31, 2016, who had ever tested anti-HCV-positive, of whom 602 (62%) had a detectable HCV RNA during the study period. Of these 602 people, 9 (1%) had evidence of spontaneous HCV clearance and were excluded.
Among the remaining 593 individuals, the median age was 53.9 years, and the majority were male (68%), black (89%), had a history of injection drug use (73%), and had a psychiatric diagnosis (58%) (Table 1).
Twenty percent reported illicit drug use (including heroin and cocaine) in the preceding 3 months, and 45% received medication-assisted treatment for opioid use disorder with methadone (31%) or buprenorphine (15%). A clinical history of hazardous alcohol use was documented in 51%.
AUDIT-C, 14% of 527 patients with ACASI interview data available had evidence of current hazardous alcohol use. The majority were prescribed antiretroviral therapy (93%), but only 78% had HIV suppression to
Current hepatitis C virus testing guidelines miss too many cases, study suggest
Electron micrographs of hepatitis C virus purified from cell culture. Scale bar is 50 nanometers. Credit: Center for the Study of Hepatitis C, The Rockefeller University.
A review of blood samples for nearly 5,000 patients seen at The Johns Hopkins Hospital Emergency Department suggests that federal guidelines for hepatitis C virus (HCV) screening may be missing up to a quarter of all cases and argues for updated universal screening.
A report on the study is published online ahead of print in the journal Clinical Infectious Diseases.
Currently, the U.S. Centers for Disease Control and Prevention (CDC) recommends one-time HCV testing for all adults born between 1945 and 1965, or for those with risk factors such as injection drug use, HIV or use of clotting factors.
But up to one-quarter of infections could remain undiagnosed, according to results of the new study, and the authors say that universal one-time testing of all U.S. adults seeking care at inner-city emergency rooms might identify many more people who have the virus, getting them into management and treatment.
Better screening would also reduce the risk of spreading the infection to others.
In November 2015, The Johns Hopkins Hospital expanded its testing for HCV to all eligible Emergency Department adults 18 and older who have their blood drawn as part of routine clinical care and are not known to be HCV antibody-positive.
Johns Hopkins Bayview Medical Center adopted this expanded testing protocol in February 2016.
The Johns Hopkins team specifically found that nearly 14 percent of patients among the 5,000 tested positive for HCV, one-third of whom were unaware they were infected.
“Hpatitis C has a very long clinical arc, so if you get infected, you may not have obvious signs of illness for five to 10 years. Ultimately, it eats away at the liver in many people and can cause liver cancer,” says senior study author Thomas C. Quinn, M.D.
, professor of medicine and pathology at the Johns Hopkins University School of Medicine. “This is an infection that can now be cured if detected early, rendering people noninfectious and thereby preventing the dire consequences that are associated with the virus.
However, we found a large proportion of undocumented, undiagnosed hepatitis C infection in the population attending this ED.”
Many people with risk factors injection drug use don't disclose their risk information to emergency department staff, so universal testing, “in addition to the CDC recommendations, is the only way to identify as many HCV infections as possible,” adds lead study author Yu-Hsiang Hsieh, Ph.D., an associate professor in Johns Hopkins' Department of Emergency Medicine.
“We found high prevalence rates of HCV even in young adult patients, suggesting we need to expand testing beyond the baby boomer cohort,” Hsieh says. “Urban EDs should consider expanding CDC HCV testing recommendations to permit more robust identification of patients with unknown HCV status.”
For the study, the researchers examined blood samples from 4,713 patients older than 17 presenting to The Johns Hopkins Hospital's Emergency Department between June and August 2013. Of these patients, 652 (13.
8 percent) were HCV antibody-positive, meaning they either had HCV currently or at a prior time, and 204 (31.3 percent) of those who tested positive had undocumented HCV infection.
Patients born between 1945 and 1965 had an HCV prevalence of about 25 percent compared with adults born outside this range, who had an HCV prevalence of 7 percent. These baby boomers also had a higher prevalence of undocumented HCV—about 7 percent versus 2.
6 percent in other adults tested. Non-African-American men and women as young as 18 to 34 (born between 1979 and 1995) had a high HCV prevalence of up to 7.6 percent.
Among the 204 Emergency Department patients with undocumented HCV infection, 128 (63 percent) were in the 1945 to 1965 birth cohort, 45 (22 percent) were injection drug users and 10 (5 percent) were known to be infected with HIV.
Further assessments by the researchers found that 99 (49 percent) would be diagnosed birth cohort testing alone, with an additional 54 (26 percent) identified modified CDC risk-based testing ( injection drug use or known HIV status).
“Had we established an emergency room HCV testing program with just these guidelines, 51 patients (25 percent) with undocumented HCV would not have been identified during our study period,” Hsieh says.
“Given an estimated 7,727 unique ED patients with HCV infection in a one-year period, birth cohort testing would identify 1,815 undocumented infections, but universal testing would identify an additional 526 cases.”
The results also underscore the need for federal and state HCV management and treatment resources to support emergency departments and HCV patients, Quinn and Hsieh say. “It sounds easy to do HCV testing for every eligible patient, but it takes a lot of effort,” Hsieh says.
In the near future, the investigators hope to examine the cost-effectiveness of different HCV screening approaches in the emergency department setting, including universal testing and CDC-recommended birth cohort testing. But with a projected 3.2 million people infected with HCV in the U.S. alone, it's critical for all of these patients to be identified, treated and cured, say the researchers.
“It's not often that we get to say we can cure a medical condition,” says Hsieh. “So when we can, we should implement protocols that allow us to easily identify those in need.”
Viral Hepatitis C
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Viral hepatitis refers to infections caused by viruses that affect the liver. Viral hepatitis includes five distinct diseases, caused by five different viruses. The different viruses are called by a letter name:
Hepatitis C Symptoms
Hepatitis C may develop without any signs or symptoms, or symptoms may be nonspecific and short-lived.
There are three phases of hepatitis C, and symptoms may differ depending on the stage.
Early in the disease, called the prodromal phase , symptoms may include:
Joint pain or arthritis
Symptoms of the next phase, the preicteric phase , include:
Myalgia (muscle pain)
Nausea and/or vomiting
Abdominal pain and/or diarrhea
Dark urine and light stool color
During the icteric phase :
Jaundice (yellowing of the skin and whites of the eyes) develops
Other symptoms may subside
Anorexia, nausea and vomiting may worsen
Irritated skin lesions may develop
Hepatitis C Diagnosis at Johns Hopkins
Often, patients with hepatitis C do not experience any symptoms. Many are diagnosed after routine blood works shows abnormal liver enzymes. Sometimes, patients are tested because of their risk factors, such as exposure to needles or a history of blood transfusions.
To diagnose hepatitis C, we may run the following tests:
The hepatitis C antibody is found in almost every patient with hepatitis C. However, the antibody takes weeks or even months to develop, so if you are tested early after exposure, a false negative may result.
If the blood test is positive for hepatitis C antibody, we will confirm the findings with a sensitive test that can detect even minute amounts of hepatitis C in the blood. This test is called a PCR-based test.
During a biopsy, some of your liver tissue is removed and sent to a pathology lab for analysis. A liver biopsy is an invasive procedure that carries some risk but allows your doctor to determine the exact nature and severity of your condition.
Sometimes, a biopsy can be helpful when deciding how to treat the disease. For example, if the biopsy is close to normal, you may decide to postpone treatment. If the biopsy shows extensive disease, you may choose to begin treatment immediately.
Hepatitis C Treatment at Johns Hopkins
Thanks to advances in medication options, many patients with hepatitis C can be cured. Learn more about treatment for hepatitis C at Johns Hopkins.