Condition category
Circulatory System
Date applied
10/10/2017
Date assigned
15/05/2018
Last edited
15/05/2018
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Cerebrovascular disease (CBD, e.g. stroke) and cardiovascular disease (CVD, e.g. myocardial infarction and heart failure) are increasing in the general adult population in low income countries, including those in Sub Saharan Africa (SSA). This growing CBD/CVD epidemic intersects with an ageing HIV-infected population in countries such as Malawi where successful scale-up of antiretroviral therapy (ART) has led to a rising HIV prevalence due to increased life expectancy. In Europe and the USA, HIV is associated with a 50% increased risk of CVD. Studies are now urgently needed to find modifiable CVD/CBD risk factors in HIV-infected patients in SSA. In people with chronic viral infection (such as HIV and herpesviruses) products from ongoing virus replication cause inflammation which may lead to damage to the arteries. This arterial damage may then lead to increased risk of CBD/CVD. The main aim of this study is to find out whether ongoing inflammation from uncontrolled chronic viral infection increases the risk of CBD/CVD in HIV-infected patients on ART. The study’s other aims are to find out whether CBD/CVD is more common in people with uncontrolled chronic viral infection and ongoing inflammation.

Who can participate?
Patients aged 35 and over with HIV who are starting ART, and HIV-uninfected adults

What does the study involve?
Participants are interviewed regarding their medical history and risk factors for vascular disease. They also have a physical examination, which includes assessment of blood pressure and a scan of the blood vessels. A 30 ml blood sample is taken for assessment of viral load, Herpeseviruses infection, blood glucose, creatinine, cholesterol and immune markers of inflammation and senescence. Follow-up visits are conducted at months 6, 12, 18, 24, 30 and 36, and include some of the assessments done at the first visit. The first visit takes about 2 hours, while follow-up visits take about 1 hour. Participants are asked to come into the study clinic at any time that they are unwell. The study team help manage their clinical care by providing extra tests that may not be readily available under standard care.

What are the possible benefits and risks of participating?
Participants may benefit from this study by gaining knowledge of their risk factors for illnesses like stroke and heart disease, which may enable them to change their lifestyle or receive medication to reduce that risk. Participants who experience a clinical event are expected to receive improved access to tests and follow-up by the study team, compared to normal standard of care. Participants receive a refund of the cost of travelling to attend study visits. Risks to participants are minimal. However, participants may experience pain and risk of hematoma with blood samples. The amount of blood drawn is within the WHO recommended allowable amounts. Participants may also be inconvenience by spending longer than normal at their ART appointment.

Where is the study run from?
Malawi Liverpool Wellcome Trust (Malawi)

When is the study starting and how long is it expected to run for?
May 2015 to May 2021

Who is funding the study?
GlaxoSmithKline (UK)

Who is the main contact?
Dr Ingrid Peterson
ipeterson@som.umaryland.edu

Trial website

Contact information

Type

Public

Primary contact

Dr Ingrid Peterson

ORCID ID

Contact details

Malawi Liverpool Wellcome Trust
PO 30096
Chichiri
Blantyre
3
Malawi
+265 1874628
ingrid.peterson@lstmed.ac.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

P02161874

Study information

Scientific title

Protocol for a longitudinal, cohort study to evaluate Reactivation of Herpesviruses and Inflammation as Cardiovascular and Cerebrovascular risk factors in Antiretroviral initiators, in an African HIV population (RHICCA)

Acronym

RHICCA

Study hypothesis

Immune activation, and in turn dysfunction, driven by HIV and reactivation of latent herpesvirus infections leads to increased cardiovascular and cerebrovascular risk in adults aged > 35 years in SSA.

Ethics approval

1. University of Malawi College of Medicine Ethics Committee, 05/30/2016, ref: P02/16/1874
2. Liverpool School of Tropical Medicine Research Ethics Committee, 08/10/2016, ref: 16-014

Study design

Single-centre 36-month observational prospective cohort study

Primary study design

Observational

Secondary study design

Longitudinal study

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet

Condition

Cardiovascular and cerebrovascular disease

Intervention

The primary study exposures are HIV infection, CMV reactivation, and markers of inflammation and endothelial dysfunction. HIV tested at baseline in all participants (ART patient and HIV uninfected community controls). HIV status will be assessed yearly by rapid test in HIV-uninfected participants to detect sero-conversion. Reactivated latent herpes viral infections will be assessed by quantification of IgG VZV, CMV and HHV-8 antibodies at baseline in HIV uninfected controls and at baseline and 6 months in HIV infected participants. In all participants, at baseline, 6, 12, 24 and 36 months we will measure soluble markers in plasma , which are associated with systemic inflammation (plasma IL-6, hsCRP), and activation of coagulatory pathways (D-Dimers) and endothelial activation (sICAM-1 and sVCAM-1).

Intervention type

Other

Phase

Drug names

Primary outcome measure

1. Carotid intima media thickness (cIMT) is assessed by ultrasonography at baseline and 24 months
2. Carotid femoral pulse wave velocity (PWV) is assessed using a Vicorder at baseline, 6, 12, 18, 24, 30 and 26 months

Secondary outcome measures

All secondary outcomes are reviewed by an Endpoint Review Committee, comprised of medical experts. Retrospective assessment of outcomes deceased cases is done by medical record review, or by verbal autopsy if the individual died > 4 weeks after hospital discharge (or with no hospital admission). Verbal autopsy is conducted using a standardized WHO assessment tool
1. Stroke is measured at all occurrences by clinical assessment with standard protocols with MRI confirmation
2. Myocardial infarction (MI) is measured at all occurrences by clinical assessment with standard protocols, and ECG confirmation
3. Unstable angina is measured at all occurrences by clinical assessment with standard protocols, and ECG confirmation
4. Peripheral vascular disease (PVD) is measured at baseline, 6, 12, 18, 24, 30 and 36 months by calculation of ankle brachial pressure index (ABPI), which is assessed by sphygmomanometer and doppler ultrasound. A change of >0.15 ABPI from baseline is considered clinically significant PVD
5. All cause death or vascular death is measured at all occurrences. For deaths occurring within 4 weeks of hospital admissions, cause of death will be assessed by medical record review using standardized protocols. Deaths occurring >4 week post hospital discharge (or with no hospital admission) will be assessed by verbal autopsy
6. Immune Reconstitution Syndrome [IRIS] vasculopathy is measured at all occurrences within 6 months of the baseline visit. It is defined as a vascular event (ex. stroke, MI or unstable angina) accompanied by a decrease in viral load >1 log10 copies from baseline

Overall trial start date

27/05/2015

Overall trial end date

31/05/2021

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Aged => 35 years
2. Resident in Blantyre
3. HIV-infected patients must further be ART-naïve or initiated ART <10 days prior to enrolment
4. Initiating standard first-line ART (in Malawi this is: TDF/3TC/EFV)
5. Adult controls must further be HIV uninfected

Participant type

Mixed

Age group

Adult

Gender

Both

Target number of participants

HIV-infected participants initiating ART: 800; HIV uninfected participants: 190

Participant exclusion criteria

1. Clinical history of CVD/CBD
2. Pregnant
3. Critically ill or have symptomatic anaemia at enrolment
4. Enrolled in an intervention study

Recruitment start date

17/05/2017

Recruitment end date

31/05/2020

Locations

Countries of recruitment

Malawi

Trial participating centre

Malawi Liverpool Wellcome Trust
PO 30096, Chichiri
Blantyre
3
Malawi

Sponsor information

Organisation

GlaxoSmithKline

Sponsor details

980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom

Sponsor type

Industry

Website

Funders

Funder type

Industry

Funder name

GlaxoSmithKline

Alternative name(s)

GlaxoSmithKline plc., GSK

Funding Body Type

private sector organisation

Funding Body Subtype

corporate

Location

United Kingdom

Results and Publications

Publication and dissemination plan

The study protocol is currently under review for publication with BMJ Open.

Results will be primarily presented in tables and graphs to show the results of the study analyses for all study objectives. Study results will also be summarized in high-quality scientific abstract and manuscripts. Results will be disseminated in several formats in order to reach a variety of audiences. The trialists will present the results to the ART Clinic Staff, the HIV Unit of the Malawian Ministry of Health, QECH’s Department of Medicine, local scientific conferences as well as to Master of Public Health students in the College of Medicine as lectures.

IPD sharing statement
Participant level data for sub-analyses will be available upon request conditional upon approval by study committee approval of proposed sub-study. Please contact Ingrid Peterson (idpet2@gmail.com) or Laura Benjamin (L.Benjamin@liverpool.ac.uk).

Intention to publish date

31/05/2021

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes