HALT (Hepatitis and Latent Tuberculosis) studies
Department of Health Policy Research Programme 015/0306
Effectiveness of Testing for, and Treatment of, Hard-to-Reach Groups for Hepatitis B Virus and Hepatitis C Virus in England (HALT: Hepatitis)
Hard-to-reach groups are defined by lifestyle factors that render engagement with healthcare services problematic; they include homeless persons, people who inject drugs and ex-prisoners. These groups are vulnerable to a range of infectious diseases, often due to living conditions, exposure to injecting drug use, alcoholism, chaotic lifestyle factors, and generally poor physical and psychiatric health. Exposure to, and prevalence of tuberculosis, Hepatitis B virus (HBV) and Hepatitis C virus (HCV), amongst the hard-to-reach is known to be high. Additionally, the same factors that increase exposure can also create barriers to passive presentation for diagnosis and adherence to treatment, both from the groups themselves and within the healthcare system. Thus support mechanisms are often needed to help people through the clinical process after they test positive for an infection.
Peer support and accompanied referrals can be effective measures to improve engagement with clinical services among difficult populations, although there is very little published literature surrounding this approach (particularly in developed countries), within hard-to-reach populations and in the field of hepatitis.
Evaluate the cost-effectiveness of measures to improve active case finding and case holding in hard-to-reach groups for a) HCV infection and b) HBV infection.
Intervention: peer support and accompanied referrals.
Baseline: normal NHS care.
Hard-to-reach individuals who have given informed consent will be screened for HCV, HBV and HIV on mobile screening vans using point-of-care tests. Those who test positive for HIV will be referred to normal care. Those who test positive for HCV or HBV will have venous blood drawn for a second level of testing. Individuals positive for HCV will be randomised to either normal care or the intervention arm. Those positive for HBV will all be placed in the intervention arm. All enrolled participants will be followed up until either completion of their clinical referral or the end of the study.
Primary outcome measures:
Successful engagement with clinical services for HCV (attending three appointments at the Hepatitis Clinic).
Cost effectiveness evaluation of the interventions.
Secondary outcome measures: Successfully reaching a sustained virological response (SVR; an undetectable viral load for 6 months after the end of treatment) against HCV.
Successful engagement, reaching a full clinical diagnosis, or commencing treatment for HBV.
Proportion of hard-to-reach with adequate immune response to HBV vaccine. Factors influencing lack of vaccine uptake
HALT LTBI study: Multi-site, unblinded, randomised trial of prophylactic daily rifampicin/isoniazid vs. weekly rifapentine/isoniazid for latent tuberculosis infection (LTBI)
Although surveillance systems from western European countries generally indicate a decline in tuberculosis (TB) case rates over the last few decades, there are certain areas with a decreasing pace of reduction or even an increasing rate over recent years. A major obstacle to the control of TB is poor adherence with lengthy and complicated treatment regimens for active (usually 6-9 months) and latent TB infection (LTBI) (3-6 months). The development of novel treatment strategies with more potent antimycobacterial activity could lead to shorter and simpler regimens, easier to adhere for patients, especially in the LTBI group where patients are healthy, with poor awareness of illness and are at a high risk of discontinuing preventive treatment early.
NICE guidelines, which form the basis of TB management in the UK, do not recommend LTBI treatment in people over 35 years, as the risk of adverse events (mainly liver toxicity) was considered to be too high when balanced across the lifetime risk of developing active TB. However, due to epidemiologic changes in the UK TB patients’ profile, this risk may have risen in the last decade. Elimination requires a focus on sterilising the pool of latently infected individuals from which future TB cases would be generated.
However, the pool of latently infected individuals from which future TB cases would be generated, includes adults aged over 35 years. US, Dutch and Spanish guidelines recommend LTBI treatment with careful monitoring for individuals at risk for developing TB, irrespective of age. A recent paper by Sterling et al (NEJM 2011) described a 12-dose regimen of rifapentine/isoniazid with a low rate of drug-related hepatotoxicity (0.4%) in a group of 3986 LTBI patients with a median age of 36 years (IQR 25-47). Completion rates of this regimen could not be evaluated beyond this study, as these patients had their treatment given under directed observed treatment.
In this study, we will
compare the UK standard regimen for LTBI with three months of daily
rifampicin/isoniazid, including those patients older than 35 and less than 65,
with that described in Sterling’s trial. If a better adherence to treatment and
similar rate of adverse events are demonstrated, this study could offer an
option to first-choice treatment for LTBI in the UK, both by adding a new
regimen and extending it to a larger population.
Primary objective: To assess completion rates of two different LTBI treatment regimens (daily rifampicin/isoniazid vs. weekly rifapentine/isoniazid).
· Secondary objectives:
-To assess frequency of adverse events (AE) when individuals are treated for LTBI.
-To build an integrated transmission-dynamic and health economic model to assess the cost-effectiveness of the interventions, as well as cost per quality adjusted life year.
Phase IV, unblinded, randomised, multi-site UK trial
Individuals who present with latent tuberculosis infection (LTBI) at TB clinics and who agree to preventative therapy and give their written informed consent to take part will participate in the trial. Recruited individuals will be randomised to receive either a daily combination of rifampicin/isoniazid (standard practice) vs. a weekly combination of rifapentine/isoniazid (experimental practice) for three months, without Directly Observed Therapy (DOT).
The primary outcome will be treatment completion assessed using self-report, pill counts, a validated questionnaire, and urine tests for Isoniazid metabolites; Secondary outcomes will include: (1) frequency of AE, which will be assessed by a standardised interview procedure and blood tests, including liver function tests (LFT) at baseline and at each visit, utilising a validated grading procedure; (2) cost per quality adjusted life year, using EQ-5D test at baseline and at each visit.
Primary: Completion of treatment regimen.
Secondary: frequency of AE related to treatment for LTBI and cost-effectiveness of the interventions.
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