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UK standard of care and some other useful tests Matthew Williams UK CAB Tests and monitoring in HIV infection UK standard of care and some other useful tests Tests and monitoring in HIV infection CD4 count Viral load Resistance Therapeutic drug monitoring

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Tests and monitoring in HIV infection


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cd4 count viral load resistance therapeutic drug monitoring
CD4 count

Viral load

Resistance

Therapeutic drug monitoring

Tests and monitoring in HIV infection
tests and monitoring in hiv infection

CD4 count

Blood test

Used to judge how far HIV disease has advanced

Helps predict the risk of opportunistic infections

Most useful when it is compared with the count obtained from an earlier test.

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CD4 count

CD4 dips on HIV infection from a normal count of 500-1,500 cells in a cubic millimeter (mm3) of blood (a drop, more or less), recovers somewhat, then falls over time down to as low as 0.

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CD4 count

CD4 <200 = greater risk of opportunistic infections (OIs) = “AIDS” = threshold for prophylaxis eg for PCP = bottom of UK threshold for starting combination therapy

CD4 <50 = very great risk of OIs

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CD4 count

CD4 over 350: treatment not recommended

CD4 any count: treatment recommended if “symptomatic”

BHIVA, Treatment of HIV-infected adults with antiretroviral therapy (2006)

Tests and monitoring in HIV infection
cd4 count cd4 count lower in pregnancy temporary drop of 50 cells mm 3
CD4 count

CD4 count lower in pregnancy – temporary drop of 50 cells/mm3

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CD4 count

CD4% - CD4 cells as proportion of all lymphocytes (white blood cells), normally about 40% in adults

CD4% is used to monitor babies and children who have higher CD4 counts

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Viral load

Blood test (can be other serum eg CSF)

Used to judge whether treatment is working (early infection?)

Helps predict the risk of disease progression?

Most useful when it is compared with the count obtained from an earlier test.

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Viral load

After infection, viral load surges to a very high for the first weeks or months

Often 1,000,000+ copies in a millilitre (mL) of blood, when you are very infectious

Viral load falls as the body controls HIV infection then rises over time as immunity is damaged

Tests and monitoring in HIV infection
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Viral load

When you are on HIV treatment, your viral load should be reduced to “undetectable” = <50 copies/mL = 1.7 log10

Tests and monitoring in HIV infection
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Viral load

Blip = 1 viral load test detectable (over 50 copies) – 2 of these may be a trend and indicate “virological failure”

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Viral load

Viral load is usually a PCR (polymerase chain reaction) quantitative (counting) test for HIV RNA - research tests can measure viral load below 50 copies

Other tests: bDNA (branched DNA), NASBA (nucleic acid sequence based amplification)

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Resistance test

Blood test (can be other serum eg CSF)

Used to judge whether treatment will work

Involves interpretation

Two types: genotype and phenotype

Viral load needs to be over 500 copies/mL for the test to work

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Resistance test

Genotype looks at genetic make up of HIV viruses in infection and compares this to what is known about which mutations lead to resistance

Phenotype looks at whether the drugs work in a test tube

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Resistance test

Minority species of resistant virus may be missed by conventional resistance testing (ie if less than 10% of your virus is resistant the test may not pick this up).

In patients without evidence of transmitted resistance, a suboptimal virological response to first-line therapy (<1 log10 copies/mL drop in viral load by 4–8 weeks) should prompt resistance testing at that time.

BHIVA, Treatment of HIV-infected adults with antiretroviral therapy (2006)

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Therapeutic drug monitoring (TDM)

Measures drug levels in the blood - requires blood samples at recorded time intervals after a drug dose

Practical uses for NNRTIs and PIs

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Therapeutic drug monitoring (TDM)

Freely available at low (£45/drug) or no cost (if covered by drug company) from University of Liverpool Department of Pharmacology.

http://www.hiv-druginteractions.org/

http://www.delphicdiagnostics.com/

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Therapeutic drug monitoring (TDM)

Drug levels vary – much evidence of this – recommended dose is based on averages

University of Liverpool TDM audit – 20-25% of children on NNRTIs or PIs using drugs below therapeutic level.

http://www.i-base.info/htb/v7/htb7-6/University.html

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UK standard of care (BHIVA)

All patients should have:

i) a resistance test at diagnosis,

ii) before starting HAART,

iii) if viral load does not drop by <1log10 after 4-8 weeks after starting HAART, (genotype)

iv) after virological failure

Tests and monitoring in HIV infection
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UK standard of care

BHIVA – viral load before and 4-8 weeks after starting treatment (as necessary thereafter)

Tests and monitoring in HIV infection
uk standard of care bhiva cd4 count before treatment as necessary thereafter
UK standard of care

BHIVA – CD4 count before treatment (as necessary thereafter)

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UK standard of care

BHIVA – TDM for management of drug interactions, pregnancy and paediatrics, highly treatment-experienced patients when TDM and resistance test results can be integrated, kidney or liver impairment, transplant patients, drug toxicity, alternative dosing where safety and efficacy has not been established

Tests and monitoring in HIV infection
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Liver enzymes

Kidney function

Urine

Albumin

Bone density

Glucose

Platelets

Red blood count

White blood count

Lipids

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C-reactive protein

DEXA scan

Chest x-ray

Sputum serology

Lactic acid and blood pH

Haemoglobin and iron

Serum urea

Creatine phosphokinase and lactate dehydrogenase

Electrolytes

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Blood glucose

Blood cholesterols and triglycerides

Kidney function

C-reactive protein

Liver enzymes

Anaemia

Lactic acidosis

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Blood glucose

Normal range 4-8 millimoles per litre (µmol/L)

High glucose ?= kidney disease, neuropathy, insulin resistance, cardiovascular disease

Drugs: PIs, tenofovir, AZT?

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Blood cholesterols and triglycerides

Low-density lipoproteins (LDLs) or "bad" cholesterol, and high-density lipoproteins (HDLs) or "good" cholesterol – ratio is key measure

Insulin resistance, metabolic syndrome, cardiovascular disease

Drugs: PIs, AZT, efavirenz

Tests and monitoring in HIV infection
blood cholesterols and triglycerides total cholesterol target level under 5 2 mol l 4 6 4 mol l
Blood cholesterols and triglycerides

Total cholesterol

Target level under 5.2 µmol/L (4-6.4 µmol/L)

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Blood cholesterols and triglycerides

Cholesterol – CV risk cannot be judged on cholesterol levels alone, HDL:LDL ratio, lifestyle, BMI, age and other factors are important

Smoking!

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Blood cholesterols and triglycerides

Triglycerides

Fasted levels <2.2 µmol/L normal, 2.2–4.4 µmol/l borderline, >11 µmol/L very high

Each +1.1 µmol/L increased the risk of a heart attack by about 25% in men and 60% in women

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Urine

Dipstick test

Protein – kidney (tenofovir) << mostly albumin

Glucose – insulin resistance (PIs), kidney (tenofovir, indinavir?, atazanavir?)

Bilirubin – liver ( X atazanavir)

Sensitive but not specific

Tests and monitoring in HIV infection
kidney function urine dipstick test or blood test first test and is indicative but inconclusive
Kidney function

Urine dipstick test or blood test = first test and is indicative but inconclusive

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Kidney function

Serum creatinine (blood, not very specific or sensitive)

Creatinine clearance (blood and/or urine samples over 24 hours)

Calculated creatinine clearance (1 blood sample) – also called estimated glomular filtration rate (eGFR)

Creatinine clearance can increase in pregnancy

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Kidney function

Different formulas to calculate GFR

http://en.wikipedia.org/wiki/Glomerular_filtration_rate

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C-reactive protein

Risk of diabetes, hypertension and CV disease

Low risk: <1mg/L

High risk: >3mg/L

Drugs: PIs?, AZT?

C-reactive protein is a plasma protein produced by the liver (so, another blood test...)

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C-reactive protein

C-reactive protein is also marker of inflammation from infection but seems to be a reliable marker for CV disease in HIV regardless of HAART

http://gateway.nlm.nih.gov/MeetingAbstracts/102261383.html

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Liver enzymes

AST, ALT, ALP, GGT and bilirubin

Many conditions, some specific indications, complicated by hepatitis B and C coinfection, pharmacological agents (all kinds) and food

Drugs: ritonavir, nevirapine, efavirenz, tipranavir, atazanavir, indinavir, d4T - most ARVS and many other drugs may affect the liver

Tests and monitoring in HIV infection
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Liver enzymes

ALT (alanine aminotransferase)

Normal range 7-30 units/L W, 10-55 units/L M

May be more reliable sign of liver damage

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Liver enzymes

AST (aspartate aminotransferase)

Normal range 9-25 units/L W, 10-40 units/L M

Unreliable sign of liver damage

Pregnancy may decrease AST

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Liver enzymes

ALP (alkaline phosphatase)

Normal range 30-100 units/L W, 45-115 units/L M

Non-specific sign of liver damage

Atazanavir and indinavir can raise ALP

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Liver enzymes

GGT (gamma glutamyl transferase)

Normal range >50 units/L W, >65 units/L M

Can be specific sign of liver damage

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Liver enzymes

Interpretation requires experience and the whole picture

ALP+ GGT normal = bone disease?

ALP+ GGT+ = bile ducts? liver damage?

10 x ALT/AST = viral hepatitis? ARVs?

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Liver enzymes

Bilirubin

Direct (unconjugated) 0-7 µmol/L

Total 0-17 µmol/L

Bilirubin levels slightly higher in males than females, black Africans.

Drugs: atazanavir, indinavir

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Liver enzymes

Bilirubin

Jaundice clinically detectable at levels above 40 µmol/l.

Exception: with atazanavir (or ritonavir) if bilirubin levels around 60-70 µmol/l

Tests and monitoring in HIV infection
liver enzymes bilirubin jaundice other enzymes may show no outward sign
Liver enzymes

Bilirubin ++ jaundice

Other enzymes ++ may show no outward sign

Tests and monitoring in HIV infection
liver enzymes q what is the most liver damaging over the counter otc medicine
Liver enzymes

Q: what is the most liver-damaging over-the-counter (OTC) medicine?

Tests and monitoring in HIV infection
liver enzymes q what is the most liver damaging over the counter otc medicine a paracetamol
Liver enzymes

Q: what is the most liver-damaging over-the-counter (OTC) medicine?

A: Paracetamol

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Liver enzymes

WHO's top 10 liver-damaging medicines

Paracetamol, troglitazone, valproic acid, d4T, halothene, 3TC, ddI, amiodarone, nevirapine, cotrimoxazole

The ABCs of liver disease, Edwin J Bernard, NAM

http://www.aidsmap.com/files/file1000630.pdf

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Liver

PT time – Prothrombin Time

Also called INR - International Normalized Ratio

Evaluate the ability of blood to clot properly

Not an enzyme test

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Liver

PT time – Prothrombin Time

Monitor anti-coagulants?, bleeding disorders, before surgery

Normal range 11-13.5 seconds

1.5-2 times normal = too slow but no consensus on calibration of test as marker of over-fast clotting

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Liver

PT time – Prothrombin Time

INR = (Pt test /PT normal) ISI

ISI = International Sensitivity Index for tissue factor (1-1.4)

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Anaemia

Iron, B12, B6, folic acid, red blood count, heamoglobin (HGB), mean corpuscular haemoglobin (MCH), heamocrit (HCT), mean corpuscular volume (MCV)

Drugs: AZT (pregnant?)

Tests and monitoring in HIV infection
anaemia haemocrit normal ranges 40 52 m 35 35 w low haematocrit anaemia
Anaemia

Haemocrit

Normal ranges 40-52% M 35-35% W

Low haematocrit = anaemia?

Tests and monitoring in HIV infection
anaemia haemoglobin normal ranges 11 5 to 16 5g w 13 18g m per 100ml blood low haemoglobin anaemia
Anaemia

Haemoglobin

Normal ranges 11.5- to 16.5g W 13-18g M per 100mL blood

Low haemoglobin = anaemia?

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Anaemia

Mean corpuscular volume

Larger = anaemic, B6, B12, folic acid deficiency?

Smaller = anaemic, iron deficiency?

AZT (and smoking) can increase MCV without causing anaemia

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Anaemia

Red blood count (total erythrocytes)

Normal range 3.8-5 W 4.5-6.5 M billion per litre or million per cubic millimitre of blood (1012/L).

Low count = anaemia? but not sensitive or specific = probably a first test

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The rest...

Blood chemistry

http://www.aidsmeds.com/articles/CSTest_4730.shtml

http://www.aidsmeds.com/articles/CBCTest_4729.shtml

A-Z tests

http://www.aidsmap.com/cms1031936.asp

http://www.labtestsonline.org.uk/

Hepatitis C coinfection – liver and diagnosis

http://www.i-base.info/guides/hepc/livertests.html

http://www.i-base.info/guides/hepc/hcvtesting.html

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Tests to avoid during pregnancy

Amniocentesis

Chorionic villus sampling

Fetal scalp sampling

Cordocentis

Percutaneous umbilical cord sampling

Internal fetal labour monitoring (external ultrasound and fetal monitoring OK)

Tests and monitoring in HIV infection
plebotomy having blood taken a cruel and unusual punishment or nice chat with the nurse
Plebotomy (having blood taken)

A cruel and unusual punishment - or nice chat with the nurse?

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Blood count reference ranges

Red blood count (RBC) 3.8 to 5 W 4.5-6.5 M million per mm3

White blood count (WBC) 4-11 per mm3

Haemoglobin (HGB, Hg) 11.5-16.5 W 13-18 M g per 100mL

Neutropils 2-7.5 per mm3

Lymphocytes 1.3-4 per mm3

Platelets 150-440 per per mm3

Mean corpuscular volume (MCV) 80-97

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Blood count reference ranges

CD4 400-1,600 per mm3

CD4% 32-68%

CD8 140-1000 per mm3

CD4:CD8 ratio 0.9-6

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Sampling

Biggest causes of odd results are ‘sampling error’, ‘processing error’ or ‘sample contamination’

wrong tube, wrong person's sample, cross-contamination, sample too hot/cold/old, wrong reagent, wrongly set up equipment, not reading instructions, misreading output...

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Results

One result is rarely conclusive

ANY unusual or unexpected results should ALWAYS be retested before making a treatment decision

“Normal” is a difficult word – tests refer to reference ranges, can mean doctor/nurse is happy with results even though high/low

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Sensitive v specific

Sensitivity = reacts positively

Specificity = reacts positively in right circumstances

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Sensitive v specific

Sensitivity = rule in

Sensitivity refers to the proportion of people with disease who have a positive test result

Specificity = rule out

Specificity refers to the proportion of people without disease who have a negative test result.

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Sensitive v specific

SnNout: when a sign, test or symptom has a high Sensitivity, a Negative result rules out the diagnosis.

SpPin: when a sign, test or symptom has a high Specificity, a Positive result rules in the diagnosis.

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Sensitive v specific

Many “rapid” tests are highly sensitive but not specific enough to be definitive – prone to sample contamination

Urine dipstick tests

Fingerprick tests

Tests and monitoring in HIV infection