UK-CAB 22 – HIV testing and monitoring

13 July 2007

Programme

Background reading

Rapid testing in practice

Adam Wilkinson from THT will present on THT’s 3+ years’ experience of using rapid tests as a first screen for HIV infection.

The Heath Protection Agency document listed below is a key reference:

Towards error-free HIV diagnosis: guidelines on laboratory practice PDF 332 Kb

JV Parry et al, Health Protection Agency HIV Laboratory Diagnosis Forum, published in Commun Dis Public Health 2003; 6(4): 334-50

This covers principles of diagnostic testing and passes some comment on viral load (HIV-1 quantification). Key points from this document:

• Other than unlinked anonymous testing, patients should only be tested for HIV infection with their informed consent, and requests to the laboratory should be signed by the person taking clinical responsibility, to whom the result should be issued.
• There are many possible opportunities for error in the diagnostic process – these, not the assay kits, are the most common sources of error.
• Any screening test may give rise to some weak reactions. In low-risk populations many of these will not be true HIV-positive results. Weak positives in combo tests, unreactive in anti-HIV-only tests, should be tested for p24 Ag and/or HIV RNA to ensure the specimen is not from a seroconverting patient.
• In England and Wales the prevailing approach is to employ at least two different tests following the initial reactive screening test (or an additional screening test with a line immunoassay). The golden rules are: 1) caution with weak reactions in some or all assays; 2) always examine follow-up specimen – it is a critical safeguard against errors, especially against the misidentification of specimens.
• Most commercial screening assays are designed to detect both HIV-1 and HIV-2, but infections with HIV-2 must be distinguished from those with HIV-1 (prognosis, treatment and epidemiology are different). Infections with some rare strains of HIV-1 may be poorly recognised by some screening tests. Submit clinically suspicious anti-HIV negative specimens for more detailed analysis.
• The HIV-1 pandemic involves subtypes of HIV-1 and recombinants between subtypes. Genetic analysis can identify subtype, suggesting the regional origin of infection and (at a higher level of resolution) even direct connections between individuals sharing the same strain. However these analyses have ethical and consensual implications. Section 7 Where necessary, adequately sensitive tests for anti-HIV can be done on body fluids other than serum (e.g. oral fluid, urine). This is useful for testing children, needle-phobic patients and for epidemiological purposes. However, these specimens are far less satisfactory for detection of virus and its components.
• After an exposure to HIV it may take at least six months to rule out transmission, depending on the dose and route of transmission. Post exposure prophylaxis (PEP) may prolong that interval.
• Same-day testing has valuable clinical uses. However, it is only a means of generating a negative result (based on a sensitive screening assay). Positive reactions must be reported provisionally and they should lead to examination of a further specimen.
• Anti-HIV assays are the cornerstone of diagnosis. Other HIV assays have specialised roles.
• HIV diagnosis in infancy requires close liaison between the paediatric and laboratory teams, and good communication between clinician and parents. It may take several months to exclude HIV transmission from mother to baby. Breastfeeding increases the risk of transmission.
• The end point reactivity of an anti-HIV positive specimen often exceeds one in a million; cross contamination is therefore a constant threat to test accuracy.
• Important decisions about the distribution of resources for HIV care are based on numbers of reports to CDSC.
• The clinical team (junior members as well as seniors) need to understand the meaning of the reports so that there is no room for ambiguity.
• Virological monitoring and anti-viral resistance testing is still a developing area.
• HIV-1 quantification, though imprecise, is an important means of monitoring the success of antiviral treatment. For each patient keep to a single commercial assay product and be sure that laboratory and clinical teams agree on the interpretation of the results.
• HIV-1 quantification should be repeated at least six-monthly in the untreated, and according to a more frequent agreed schedule in treated patients.
• HIV treatment involves close liaison between the clinical team and the laboratory with shared objectives and a common understanding of what tests are needed and how they should be interpreted. Frequent contacts are necessary to agree treatment strategies.
• Reliable results can only be obtained on appropriate specimens in good condition.
• Every opportunity should be taken to monitor and improve the quality of HIV testing. This should include internal quality control, internal quality assurance and participation in external quality assurance.

People north of the Border may be interested in this report:

Blood Borne Virus Specialist Testing Laboratories Edinburgh/Glasgow Annual Report PDF 240 kb

Testing: the standard of care and some other useful tests

CD4 count, viral load and resistance testing are basic tests. Dr Simon Edwards will talk in detail about monitoring tests in the afternoon session. The morning session will be a refresher presentation.

Useful references:

BHIVA 2005 HIV treatment guidelines for adults PDF 488 Kb

Blood tests – CD4 (T cell) test, viral load, chem. Screen AIDSmeds

Resistance tests AIDSmeds – includes pictures of test results

Understanding resistance and resistance tests HIV i-Base

3. Yellow Card scheme

The MHRA and the Commission on Human Medicines (CHM) run the UK’s adverse drug reaction reporting scheme called the Yellow Card Scheme. This receives reports of suspected adverse drug reactions (ADRs) from healthcare professionals. More recently the scheme was extended to included direct reporting by patients.

MHRA – Yellow Card Scheme

The MHRA and its predecessor organisations have collected reports of suspected adverse drug reactions through the Yellow Card Scheme for over 40 years. Since the establishment of the Yellow Card Scheme over 500,000 UK reports have been collected. Yellow Card reports apply to prescription medicines, herbal remedies and over-the-counter (OTC) medicines. There is currently a special emphasis on reporting ADRs for medicines used in HIV treatment.

There are 5 Yellow Card Centres whose role focuses on follow-up of reports in their areas as this has been shown to improve follow-up rates (reporters may request follow-up by MHRA if they would prefer this):

• Yellow Card Centre Mersey, Freepost, Liverpool L3 3AB.
• Yellow Card Centre Wales, Freepost, Cardiff CF4 1ZZ.
• Yellow Card Centre Scotland, 51 Little France Crescent, Old Dalkeith Road, Edinburgh EH16 4SA.
• Yellow Card Centre Northern and Yorkshire, Freepost, Newcastle-upon-Tyne NE11BR.
• Yellow Card Centre West Midlands, Freepost, Birmingham B18 7BR.

Monitoring HIV infection and treatment in the 2nd decade of HAART

The new Bloomsbury Clinic (UCL) blood test protocol and patient information sheet was circulated on the UK CAB list (email dated 5 April 2007).

The key innovation here is – as a general but not binding rule – annual viral load for people not on treatment, and annual CD4 count for people on treatment.

Viral tropism

Tropic means movement response. [from Middle English tropik, Old French tropique, Latin tropicus, from Latin, of a turn, Greek tropikos, turning]

Viral tropism means the way the virus responds to external stimulus in order to attach to and infect cells.

Scientists studying HIV-1 discovered as early as the 1989 that different forms of HIV use different coreceptors to attach to cells. The most commonly-transmitted strains of HIV use the CCR5 coreceptor, and the most common strains that develop in late-stage infection use CXCR4. Therefore, many researchers refer to strains of HIV as follows:

R5 = HIV strains which use the CCR5 coreceptor

X4 = HIV strains which use the CXCR4 coreceptor

• during the early stages of infection HIV is mainly targets macrophages using the CCR5 coreceptor (called M-tropic)
• during later stages of infection HIV isolates are T-cell tropic and use the CXCR4 coreceptot (T-tropic)

There are also R5X4 strains of HIV which can use either of these receptors.

Viral tropism is important for a new class of drugs called CCR5 inhbitors. These are a kind of entry inhibitor (like T-20) and stop HIV binding to cells by blocking the CCr5 coreceptor.

Viral tropism can be tested for. The tropism test that you need to take before using a CCR5 inhibitor only works if your viral load is over 500 copies/mL.

General overview

The Buzz: A New Era in HIV Treatment: The Entry Inhibitors The Body

Although a little out-of-date this has a good diagram of how coreceptors help HIV to bind to a cell’s surface and an explanation of tropism.

HIV virus components and concepts

X4/R5

CCR5

CXCR4

Coreceptors

Binding

Viral tropism and HIV treatment

HIV resistance mutations common but CXCR4 rare among untreated US gay men Aidsmap

CXCR4, dual or mixed tropic HIV does not reduce response to HAART Aidsmap

The immune system – AIDS.gov

Maraviroc

HIV may use different coreceptors in blood and brain HIV i-Base

Maraviroc results in R5/X4 mixed/dual tropic patients: unexpected safety data shows possible immunological effect HIV i-Base

HIV tropism: diagnostic tools and implications for disease progression and treatment with entry inhibitors NATAP

Financial support

The UK-CAB receives unrestricted funding from some pharmaceutical companies towards the direct costs of holding four meetings each year. This funding supports the travel and accommodation costs for members to attend from outside London, plus the cost of catering.

The content, programme and agenda for meetings is decided by the UK-CAB steering group in consultation with the wider membership. Funding is unconnected to meeting content.

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