MSF HIV/TB GuideHOSPITAL LEVEL August 2019

ENGLISH

Published by Médecins Sans Frontières - Southern African Medical Unit (SAMU)

August, 2019

4th Floor, Deneb House, Corner of Main and Browning Roads, Observatory, 7925, Cape Town, South AfricaTel:+27 (0) 21 448 3101Visit the Southern Africa Medical Unit’s website: www.samumsf.org

Our strategies and protocols in HIV/TB management could be disproved or confirmed when confronted with field experience. Keep it in mind when reading this.And please do refer to national protocols before prescribing any treatment.

Please contact alexandra.meyer@joburg.msf.org if you happened to notice any abnormalities or mistakes.

MSF HIV/TB GuideHOSPITAL LEVEL

Contents PageInpatient notes.....................................................................................................................

Advanced HIV – Seriously ill patients: Summary.......................................................................

Advanced HIV – Seriously ill patients: Detail............................................................................

Confusion: Causes................................................................................................................

Confusion............................................................................................................................

Neurological Problems: Clinical presentation............................................................................

Neurological Problems: Interpretation of lumbar puncture results................................................

“Big 3” CNS opportunistic infections.......................................................................................

Diarrhoea in HIV positive patients...........................................................................................

Respiratory Problems............................................................................................................

Patients deteriorating or not improving on TB treatment............................................................

Renal Disease in Hospitalised HIV positive patients..................................................................

Liver Disease in HIV positive patients......................................................................................

Drug Induced Liver Injury (DILI): how to do a TB drug rechallenge.............................................

Aneamia..............................................................................................................................

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INPATIENT NOTES

Name: ………………………………………………………………………….……...

Folder number: ....….………………………………………………………Date of Birth: …………………………………………………………………..........

REFERRED FROM (CLINIC / HOSPITAL) __________________________________

CLINIC PATIENT ATTENDS __________________________________

RELATIVE'S CONTACT NUMBER 1. ______________________________________

2. ______________________________________

ADMISSION RECORD

Previous admissions

DATE ADMITTED DATE DISCHARGED REASON FOR ADMISSION

1.

2.

3.

4

5.

3

Date ____________________________

Time ____________________________

Admitting Doctor ____________________________

History: symptoms, duration, functional status

__________________________________________________________________________________________________ __________________________________________________________________________________________________ __________________________________________________________________________________________________ __________________________________________________________________________________________________ __________________________________________________________________________________________________ __________________________________________________________________________________________________ _______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

Previous opportunistic infections, additional past medical history:

____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

Year of HIV diagnosis: Previous TB - dates of treatment:

basis of diagnosis (circle all that apply): • TB LAM/geneXpert/CXR/abdominal

USS/symptoms/other

Sensitivity: Rif sensitive/Rif resistant/unknown

Current TB - when started:

basis of diagnosis (circle all that apply): • TB LAM/geneXpert/CXR/abdominal

USS/symptoms

Sensitivity: Rif sensitive/Rif resistant/unknown

Adherence:

CD4 counts - give dates and results:

ART - circle one:

ART currently

ART previously

ART naive

ART history:

First line: dates and regimen:

Second line: dates and regimen:

Adherence - circle one:

No interruptions

One interruption

>1 interruption:

Give dates:

Viral load: give dates and results:

Name_____________________________________________

Folder no._____________________________________________

Date of birth________________________________________

TB symptom screen – circle all that apply:

• Cough

• Loss of weight

• Fever

• Night sweats

4

SOCIAL HISTORY________________________________

Smoking / ETOH / Mining _________________________

Occupation ____________________________________

Lives with ______________________________________

General Examination:

BP P Temp Sats Hb HGT

Jaundice / Anaemia / Clubbing / Cyanosis

LYMPH NODES (sites)

SKIN KAPOSI Y / N

MOUTH KAPOSI Y / N

CVS Pulse: Volume regular/irregular JVP

Apex Position: Nature: Normal Diffuse Heaving Tapping

Parasternal heave Thrill

DVT

Auscultation: Oedema

RESPIRATORY Inspection: Chest wall shape Chest movement

Trachea central/deviated to right/deviated to left Percussion

Auscultation

ABDOMEN Tenderness: no/yes – where? Hepatomegaly yes/no

Distention yes/no Bowel sounds: normal/none/high pitched Splenomegaly yes/no

PR Ascites: yes/no Other masses:

CNS GCS: /15 M: /6 V: /5 E: /4 Speech Swallowing

Muscle Wasting Meningism

Involuntary movement Gait

Cranial nerves Bladder function Bowel function Sphincter reflex:

LIMBS MOTOR

Sensation Reflexes Tone Power Cerebellar

UL

R Biceps (C5,6)

Triceps (C6,7)

L Biceps (C5,6)

Triceps (C6,7)

LL

R

Knee (L3,4)

Ankle (L5,S1)

Plantar

L

Knee (L3,4)

Ankle (L5,S1)

Plantar

URINE DIPSTIX: PRENANCY TEST:

PV if indicated: CONTRACEPTION: PAP SMEAR:

MEDICATION

Allergies:

5

Significant results:

___________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

Problem list: Differential Diagnosis:

_________________________________________ _________________________________________________ __________________________________________ __________________________________________________ __________________________________________ __________________________________________________ __________________________________________ __________________________________________________ __________________________________________ __________________________________________________ __________________________________________ __________________________________________________ __________________________________________ __________________________________________________ __________________________________________ __________________________________________________ __________________________________________ __________________________________________________

Management Plan: ____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

Signed: ___________________________ Print name: ____________________________ Date: ___________________

Urine LAM: positive/negative

CrAg: positive/negative

GeneXpert sputum: positive/negative

6

Continuation notes: SIGN & DESIGNATION

(print name)

7

Advanced HIV – Seriously Ill Patients SUMMARY

DANGER SIGNS

• Respiratory rate > 30/min• Temperature > 39°C• Heart rate > 120/min• Systolic BP < 90mm Hg • Saturation < 90%• Moderate/severe dehydration• Unable to walk unaided

• Altered mental state: confusion, strange behaviour, reduced level ofconsciousness

• Any other neurological problem:headache, seizures, paralysis, difficultytalking, cranial nerve problems, rapid deterioration in vision

Often there is more than one cause

• Take a good history• Examine the patient• Focus on respiratory &

neurological systems and ARThistory

Disseminated TB is the most common cause of mortality

1. ART failure

2. Neurological disease – Big 3:• TB • Cryptococcal meningitis• Toxoplasmosis

3. Respiratory Disease – Big 3:• Pneumocystis pneumonia• Pulmonary TB• Bacterial pneumonia

4. Severe Diahorroea

5. Other bacterial infections • Bacterial meningitis• Bacteria• Urinary tract

infection

6. Other non-infectiouscauses • Hypoglycaemia• Renal failure• Abnormal sodium,

potassium• Liver disease• Drug side effects

Basic package of point of care tests • HIV Testing• CD4• Serum CrAg• TB LAM• Rapid malaria test• Glucose• Haemoglobin• Urine dipstick

Additional investigations: Do what is available

Basic TB investigations: • TB LAM (urine) • GeneXpert (sputum)

For either test: treat if positive, but a negative result does not exclude TB

Other TB Investigations:: • Sputum Microscopy • GeneXpert on non-sputum.

Samples: urine, CSF, pus • CXR • Abdominal USS

Lumbar puncture: • Necessary if there is any abnormal

neurology • Request: CrAg, cell count and

differential, protein, glucose, gram stain,geneXpert

• If LP not possible or inevitable delay: serum CrAg, empiric treatment as indicated (see Management - Neurology)

Blood tests: • Creatinine, sodium, potassium• Full blood count• VDRL • Jaundice or hepatomegaly: bilirubin, ALT,• Bacterial infection possible: blood/urine

cultures

Initiate without delay

Start empiric treatment (highlighted) for diseases where clinical suspicion is high, but where there is no diagnostic test available or where diagnostic tests cannot exclude the disease. Start second line ART if CD4 <200 and suspected treatment failure

Emergency Management

Respiratory Disease

Neurological Disease:

Clinical indications for immediate empiric TB

treatment:Hypoglycaemia: • 50 mls of 50% dextrose Dehydration, renal impairment*: • IV fluids, electrolytes • Chronic watery diarrhoea: empiric

treatment for Isospora belli (cotrimoxazole)

• Beware nephrotoxic drugs Liver failure*: • Beware hepatotoxic drugs Severe anaemia (Hb < 5g/dL)*: • Transfuse, oxygen Bacterial infection*: • Empiric IV antibiotics

*See relevant algorithm

Respiratory Danger Signs: RR > 30 or saturation < 90%

• Give oxygen • Empiric treatment for

pneumocystis and bacterialpneumonia

• Empiric treatment for TB ifIndicated

No danger signs: • CXR – treat accordingly • CXR not available, consider empiric

treatment: pneumocystis, bacterial pneumonia, TB

Treat for cryptococcal meningitis: • CSF CrAg positive • Abnormal neurology and serum CrAg

positive, LP not possible or CrAg unavailable

• Fluconazole only if serum CrAg positive,CSF negative.

• Serum CrAg positive LP not available andno abnormal neurology

ccc Treat for CNS TB: • Lymphocytes on CSF, and/or high

Protein ccc Treat for toxoplasmosis: • CD4 < 200; new focal neurology; or other

abnormal neurology and no other diagnosis

Do available investigations while starting treatment

• CNS TB likely• Miliary TB or other CXR evidence

of TB • Clinical presentation strongly

suggests TB; investigations not available or unable to exclude TB

• Clinical condition life-threatening, patient deteriorating, or not improvingafter 3 days of hospitalisation

Definition of ‘seriously ill’:

Do not delay investigations and management

One or more danger signs

Mortality is high:

Common causes of mortality: see box

Investigations DO Immediately

Management

8

ADVANCED HIV – SERIOUSLY ILL PATIENTS DETAIL

DANGER SIGNS

• Respiratory rate > 30/min• Temperature > 39°C• Heart rate > 120/min• Systolic BP < 90mm Hg• Saturation < 90%• Moderate/severe dehydration

• Unable to walk unaided• Altered mental state: confusion, strange behaviour, reduced

level of consciousness• Any other neurological problem: headache, seizures,

paralysis, difficulty talking, cranial nerve problems, rapiddeterioration in vision.

One or more danger signs

Often there is more than one cause Investigations and management focus on these causes

Disseminated TB is the most common cause of mortality: All patients need investigating for TB, and rapid initiation of treatment if indicated

1. ART failure

2. Neurological disease – Big 3:• TB• Cryptococcal meningitis• Toxoplasmosis

3. Respiratory Disease – Big 3:• Pneumocystis pneumonia• Pulmonary TB• Bacterial pneumonia

4. Severe diarrhoea:• Renal failure and abnormal

sodium and potassium levelsare common, and are oftenasymptomatic

5. Other bacterial infections:• ‘Bloodstream’ infections• Meningitis• Urinary tract infections

6. Common non-infectiouscauses: • Hypoglycaemia• Renal failure• Sodium/potassium

abnormalities• Liver disease• Drug side effects: find out all

the medication the patient istaking

Key question 1: is the patient on ART? Patients on ART should be doing well, and not seriously ill:

What has gone wrong?

Key question 2: is the patient taking TB treatment?

Patients on TB treatment should be doing well, and not seriously ill: what has gone wrong? • What is the regimen?

• How long is the patient on ART?< 3 months: TB is very common during this time - ‘unmasking TB’>6 months: is there treatment failure?

ccc

The majority of seriously ill patients nowadays with advanced HIV are failing first line and need rapid switch to second line • If this is not addressed, treating opportunistic infections alone will

not save the patient’s life• Adherence issues must be addressed at the same time as changing

regimen; staying on a failed regimen means the patient will die

Questions to ask: • For how long is the patient on TB treatment?• Was TB proven? Rifampicin sensitive?• Is the admission due to drug adverse effects?• Did the patient improve on TB treatment?

If not – see algorithm ‘Patients deteriorating ornot improving on TB treatment’

• Start with the presentingcomplaint

• Always ask about neurologicaland respiratory symptoms, anddiarrhea

• Ask the 2 key questions (seeright)

Definition of ‘Seriously ill’:

Do not delay investigations and management

Mortailty is high:

Common causes of mortality: see box

• Reassess vital signs• Specifically assess neurological

and respiratory systems, andassess for dehydration

• Look for KS (skin, palate)• Look for CMV retinitis if recent

deterioration in vision

Take a good history

Examine the patient

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ADVANCED HIV – SERIOUSLY ILL PATIENTS (Detailed version continued)

If the patient is to be referred to a higher level of care, do as many investigations as possible at the initial facility, and start management

Investigations: Take sample immediately AND collect results within

Basic package of point of care tests:

These should be available 24/7, and all clinical, nursing and lab staff trained in their

use. • HIV Testing• CD4• Serum CrAg• TB LAM• Rapid malaria test• Glucose• Haemoglobin• Urine dipstick

Chest X Ray

TB: • Miliary TB• Pleural effusion,

pericardial effusion• Lymphadenopathy• Pulmonary infiltratePneumocystis pneumonia:• Ground glass pulmonary

infiltrateBacterial pneumonia: • Consolidation, air

bronchograms

All patients need investigation for TB:

TB LAM: • TB LAM positive: start TB treatment• TB LAM negative: TB is not excluded! Continue

investigations, start empiric TB treatment ifindicated (see Management section)

GeneXpert: • Sputum: spontaneous or induced• Non-sputum samples: urine*, CSF*, ascites* pus

GeneXpert positive: start TB treatment GeneXpert negative: TB is not excluded!

Continue investigations, start empiric TBtreatment if indicated (see Managementsection)

Other investigations for TB:

Sputum microscopy: • If geneXpert unavailable

CXR: see left

Abdominal ultrasound: • Lymphadenopathy• Ascites• Hepatosplenomegaly

Indications for LP: • Any neurological symptoms or signs• Serum CrAg positive• LP should be done before antibiotics are

started unless this will delay the firstdose; the sample can be stored in a fridgeovernight

Baseline investigations: • CrAg• Cell count and differential (lymphocyte

count, neutrophil count)• Protein, glucose• Gram stain for bacteria: Streptococcal

pneumoniae: gram positive cocci inpairs/chains Neisseria meningitidis: gramnegative diplococci

• GeneXpert*

If unable to do an LP or if there is aninevitable delay (eg referral isnecessary for LP), empiric treatmentmay be necessary

See Management section: NeurologicalDisease

Lumbar puncture

Centrifuge urine, CSF, ascites and pus

otherwise sensitivity is very

low.

REMEMBER: All neurological

signs are Danger Signs

Blood Tests

• Creatinine, sodium, potassium• Full blood count• VDRL• Jaundice or hepatomegaly:

bilirubin, ALT, hepatitis B

Does the patient have a bacterial infection?

Look for any of the following: • Temp > 38 degrees or < 35

degrees• HR > 120, or RR > 30• White cell count <4 or > 12• Other causes possible: Acute

onset of symptoms suggestsbacterial infection. In doubt, startantibiotics if seriously ill. Diagnosiscan be reviewed upon furtherresults

• Look for the source (pneumonia,meningitis , UTI): blood streaminfections are also common

• Take blood culture*, using steriletechnique; other relevant tests,e.g. urine dipstick, urine culture

Take before antibiotics are started unless this will delay the first dose.

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ADVANCED HIV – SERIOUSLY ILL PATIENTS (Detailed version continued)

Management: Start without delay Start empiric treatment (highlighted text) for diseases where clinical suspicion is high, but there is no diagnostic test available, there is an unavoidable delay with results, or if diagnostic test cannot exclude the disease. Start second line ART if CD5<200 and suspected treatment failure.

General Management Respiratory disease Neurological disease

Hypoglycaemia: • Give 50mls of 50% dextrose, monitor PoC glucose 4

hourly until hypoglycaemia has resolved for 24 hours.ccc

Dehydration and/or renal impairment: • Intravenous fluids and electrolyte replacement (NaCl or

Ringer’s lactate), at least 3L per day (if tolerated). • Beware nephrotoxic drugs: see renal algorithm.• If chronic watery diarrhoea is the cause, start empiric

treatment for Isospora belli infection.• If vomiting, start regular IV antiemetics

• ccc

Liver impairment: • Beware hepatotoxic drugs; see liver algorithm

• ccc

Anaemia: • HB < 5g/dl: transfuse, give oxygen• HB < 8g/dl and tachypnoea or active bleeding: transfuse• Assess for likely cause: see anaemia algorithm

• ccc

Is bacterial infection likely? • Start empiric antibiotics according to local guidelines• Review all antibiotic prescriptions every 48 hours to

assess if IV drugs can be changed to oral, or if antibioticscan be stopped: see bacterial infection algorithm.

*Amphotericin B plus fluconazole 800mg

**Fluconazole alone; 800mg if CSF CrAg negative, 1200mg If unable to do serum CrAg

Treat as above for 14 days; continue fluconazoleaccording to protocol in MSF/HIV handbook.

3. CXR evidence of TB (see Investigations page - CXR) 4. Seriously ill (any danger signs), orpatient is after 3 days of hospital admission

Respiratory Danger Signs: RR > 30 or saturation < 90%

• Oxygen by face mask or nasal prongs ccc

Start empiric treatment immediately for: • Pneumocystis pneumonia: cotrimoxazole (480mg/4kg

body wt/d, plus prednisone initially 40mg bd)• Bacterial pneumonia: see local guidelines• TB: if immediate investigations positive, or empiric

treatment indicated (see below) • ccc

Evidence of respiratory disease but no Danger Signs: • CXR if available: see Investigations: CXR

• ccc

CXR not available: consider empiric treatment for: • Pneumocystis pneumonia (dyspnoea, dry cough)• Bacterial pneumonia (acute onset, crepitations)• TB: if investigations positive, or empiric treatment

indicated

1. CNS TB is likely:• Neurological symptoms/signs with evidence of TB

elsewhere or clinical presentation is suggestive2. Clinical presentation strongly suggests TB, and investigations not available or cannot exclude TB

• Peripheral lymph nodes• Night sweats, weight loss, fever, cough • Pleural effusion, pericardial effusion or ascites and

no other more likely cause 3. CXR evidence of TB (see Investigations page - CXR) 4. Seriously ill (any danger signs), or patient is deteriorating, or is not improving after 3 days of hospital admission

Clinical indications for immediateempiric TB treatment:

Treat for Cryptococcal meningitis (CCM)* • CSF CrAg positive• Serum CrAg positive, and LP not possible or unavoidable delay,

and any neurological symptoms/signs• No CrAg available and any neurological symptoms/signsccc

Treat positive serum CrAg, and not for CCM** • Serum CrAg positive and CSF CrAg negative• Serum CrAg positive, and LP not possible or unavoidable delay,

and no neurological symptoms/signs • ccc

Treat for CNS TB (TB treatment plus prednisone 1.5mg/kg): • Suggestive LP (mostly lymphocytes, and/or high protein)• Neurological symptoms or signs with evidence of TB elsewhere, or

clinical presentation suggestive • CSF geneXpert positive

• ccc

Treat for Toxoplasmosis (cotrimoxazole 960mg/8kg body wt) CD4 < 200 or unkown and new onset neurology: • Focal neurology (eg hemiplegia)• Altered mental state, or new headache and no alternative

diagnosis • ccc

Treat for Bacterial Meningitis (see local guidelines): • Acute onset of meningitis symptoms • Meningococcal meningitis: non-blanching petechiae• CSF: neutrophil predominance and/or CSF microscopy shows

bacteria on gram stain, and/or high protein• ccc

If there is no evidence to support bacterial meningitis (neutrophils in CSF) and an alternative diagnosis found (for example CCM), antibiotics can be stopped.

ccc

If LP not available or unavoidable delay – and any neurological symptoms or signs: • Acute onset of symptoms: treat for bacterial meningitis• Serum CrAg positive or not available: treat for CCM• Treat CNS TB and/or toxoplasmosis: see above

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Bacterial sepsis: • Common cause of acute confusion• Fever, raised white cell count, low blood pressure• Look for the source: respiratory and urinary tract

infections are common• Start antibiotics immediately

Neurological causes

Metabolic – multiple causes: • Hypoglycaemia• Hypotension• Hypoxia• Hyponatraemia, hypernatraemia• Hypercalcaemia• Renal failure• Liver failureLook for and correct the cause of all metabolicabnormalities

Encephalitis – inflammation of brain:

See ‘neurological problems’ algorithm

In addition to ‘altered mental state’ there may be other symptoms: • Fever• Focal neurology• Signs of the underlying cause, for example

disseminated TB

• LP is normal unless there is also meningitis

Most common causes: The ‘big 3’ neurological opportunistic infections: • Cryptococcal disease• TB – tuberculomas• Toxoplasmosis

When to start empiric treatment for toxoplasmosis: • CD4 known or likely to be < 200 and abnormal

neurology: hemiplegia or other focal neurology, confusion, reduced level of consciousness, or any other form of altered mental state

Medical Causes

Drugs: • Efavirenz, isoniazid, steroids• Alcohol and drugs: intoxication, withdrawal• Change or stop all implicated drugs

HIV encephalopathy – treatment is ART: • Cognitive problems• Behavioural problems & low mood• Motor problemsPsychiatric Disease• Psychosis• Depression

• Useful to ask if there have been previous episodes

Confusion: causes

Diagnoses of exclusion: Exclude neurological and medical causes – using available investigations and clinical assessment

This algorithm is for all forms of ‘altered mental state’: • Confusion• Reduced level of consciousness• Disorientation• Strange behaviour• This algorithm can also be used for convulsions – which can also be caused by neurological or medical abnormalities

Meningitis – inflammation of meninges: • An altered mental state can also occur with meningitis• Meningism, fever, may have focal neurology• CSF may show cells and high proteinCauses:• Cryptococcal: subacute• TB: subacute• IRIS to either of above• Bacterial Meningitis: acute• Neurosyphilis: subacute• Viral meningitis is rare: a lymphocytic CSF in patients

with advanced HIV should be treated as TB meningitis

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What do you mean by ‘confusion’? • Reduced consciousness • Confused speech • Disorientation in time/space • Agitation/aggression • Psychosis – hallucinations – delusions -

delirium

Examination: General: • Fever • Hypotension • hypoxia • jaundice Neurological: • Glasgow Coma Score – evaluate whether

improvement/deterioration • Meningism • Focal Neurology: document neurological

examination • Fundoscopy: papilloedema, opportunistic

infection for example CMV?

Immediately look for and correct life- threatening

• Hypoglycaemia • hypoxia • hypotension • malaria

Investigate for opportunistic infections: • Cryptococcal disease • TB

Always look for TB: • Neurological TB and TB IRIS are common • If on TB treatment: diagnosis proven, drug

sensitive?

Investigate for CNS TB: • CSF GeneXpert – but negative result cannot rule

out TB meningitis

Look for TB elsewhere: • Urine LAM • GeneXpert: sputum, urine • other samples: ascites, pleural fluid • CXR

Confusion

Look for other medical problems – initial investigations: • HB, white cells, platelets • Na, K, creatinine • Liver function tests • RPR

Neurological investigation – Lumbar Puncture: Do all investigations available to you:

• Cell count and differential • Gram stain for bacteria • Pandy (protein) • CrAg • RPR (note that rapid syphilis test is not validated for

CSF) • GeneXpert on centrifuged CSF

Causes (see opposite page): • Neurological • Medical • Psychiatric

History: • Most recent CD4 count: CD4 > 200,

opportunistic infections such as toxoplasmosis and cryptococcal disease unlikely

• ARV history – including adherence & viral loads

• TB history • Onset – acute or chronic? • Previous episodes: what was the cause? • Other neurological symptoms: seizures,

headache, fever • Other non-neurological symptoms: e.g. severe

diarrhoea can result in electrolyte problems and renal failure

Medication: • Efavirenz, isoniazid, corticosteroids • Alcohol, other drugs

History and examination Investigations

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Global neurological dysfunction (‘encephalitis’): • Altered mental state • Reduced level of

consciousness • Confusion

See also ‘confusion’ algorithm

Meningism: • Neck stiffness • Photophobia • Headache

Be suspicious of meningitis even if there is only one of these symptoms If bacterial meningitis possible and LP cannot immediately be done: • Immediate Dexamethasone 8mg IVI plus Ceftrixone

2mg IVI (Dexamethasone prior to, or at the same time as ceftriaxone)

Acute focal neurology:

• Hemiplegia • Cranial nerve

abnormalities • Abnormal

movements • Ataxia, other

cerebellar signs

Seizures:

• May occur with any neurological problem

• HIV positive patients with even one seizure must be investigated as below

• Prevent further seizures: sodium valproate 300mg bd, increase to 500mg bd

Other relevant symptoms:

• Fever • Wasting • Other symptoms

or signs of TB

Emergency Investigations:

• Glucose • Rapid malaria test – endemic

areas

Lumbar Puncture: • Cell count and differential • Gram stain • Pandy (protein) • CrAg

• RPR (if available; note rapid

test is not validated for CSF)

• GeneXpert: centrifuged CSF

HIV and ART investigations:

• CD4 count • Viral load if on ART > 3 months

Always take a full HIV and ART history!

Emergency Management:

• Hypoglycaemia: 50mls of 50% dextrose IVI and look for and correct the underlying cause

• Malaria: start treatment immediately with artensunate: continue to look for additional causes – malaria may not be the only cause of an altered mental state in a patient with a low CD4 count

Other investigations:

Serum CrAg : • CD4 < 100

TB is a major cause of neurological problems in advanced HIV: • TB LAM • geneXpert: sputum, urine, other body

fluids • Imaging: CXR, abdominal ultrasound

Empiric treatment of TB should be started for all patients with CD4 counts < 200 and

neurological disease if there is no other definitive diagnosis

Look for non-neurological causes Confusion, reduced level of consciousness, any other alteration in mental state: Look for metabolic abnormalities: • Hypoglycaemia • Electrolyte abnormalities • Renal impairment • Liver disease

Neurological Problems: Clinical Presentation

Investigations

14

Normal Viral Bacterial TB Cryptococcal

CD4 count Any Any Any – often low Low, usually < 100

Onset

acute acute Sub-acute Sub-acute

appearance Clear Clear Often turbid Clear Clear

Cells < 5 lymphocytes no neutrophils See note*

Lymphocytes Usually < 100 *See note below: lymphocytes In advanced HIV mean TB, not viral meningitis*

Cell count high, mostly neutrophils However: • If antibiotics

are given before LP is done, cell count may fall, and bacteria are unlikely to be seen

Lymphocytes Variable, may be several hundreds However: • Cell count may

also be normal • In early TBM,

neutrophils can predominate

Very variable, may be raised with mostly lymphocytes, often normal

Protein (High = Pandy +ve)

Normal Normal Usually high Usually high Normal or high

Glucose Normal Normal Usually Low Usually Low Normal or slightly low

Special tests

Microscopy to look for bacteria: low sensitivity, but gives definitive diagnosis

GeneXpert on centrifuged CSF (note: negative GeneXpert does not rule out TB)

CrAg: sensitivity and specificity very high

As can be seen, there is a lot of overlap between findings in different types of meningitis

*Viral meningitis:

• Most viral meningitis is self-limiting and is caused by viruses such as enterovirus • This causes a rapid onset meningitis, with rapid recovery - most patients are not admitted to hospital because

they recover rapidly at home • As a general rule: a lymphocytic CSF in hospitalised HIV positive patients is TB meningitis and not “viral

meningitis”

Neurological problems: Interpretation of lumbar puncture results

15

Toxoplasmosis • Reactivation of latent

disease, causing space occupying lesions

• Any abnormal neurology: focal symptoms, any type of altered mental state

Cryptococcal meningitis

• Headache, meningitis symptoms, or altered level of consciousness

• Focal neurology: ophthalmoplegia and visual disturbance are common

Neurosyphilis

In general: • most strokes are caused by

hypertension and diabetes • most strokes cause hemiplegia,

and there may also be a facial nerve palsy (mouth droops on one side)

In HIV patients: • patterns of focal neurology may

be caused by TB or toxoplasmosis

• All HIV positive patients with focal neurology need investigations and empiric treatment if appropriate; plus blood sugar and blood pressure.

Remember Trypanosomiasis in endemic areas: CSF microscopy for parasites

Investigations: • LP - Lymphocyte

predominance, high protein, low glucose

• However LP may be normal • GeneXpert may be positive

on centrifuged CSF • Look for evidence of TB

elsewhere: TB LAM, sputum microscopy, CXR, abdominal USS

Investigations:

• CD4 low (usually <100) • CSF CrAg positive

Investigations: • Toxoplasmosis IgG positive

(if available) • This shows previous

exposure, cannot confirm that there is reactivation

Tuberculosis

• Meningitis • Tuberculomas: space

occupying lesions – causing encephalitis symptoms and focal neurology

Malaria

Bacterial meningitis

• Rapid malaria test positive

• Blood film positive if rapid test not available

• Malaria may not be the only cause of an altered mental state in a patient with a low CD4 count

• Positive CSF VDRL • Rapid test positive

on blood, with suggestive clinical presentation

• Note rapid test is not validated for CSF

• Raised WCC on CSF with > 80% neutrophils

• Organisms may be seen on microscopy

• If LP is done after antibiotics, organisms rarely seen and cell count may be reduced

Treatment: • Amphoterocin B and

fluconazole

• Measurement of opening pressure and therapeutic LPs are essential

• Full protocol: see

MSF guideline

Treatment: • Treat if CD4 < 200 and any

neurological symptoms • cotrimoxazole

400mg/80mg 1 tablet for each 8kg body weight, given in 2 divided doses for 1 month

• Half the dose for 3 months, then continue normal prophylaxis dose.

• There is should be a rapid response to treatment, there should be a clear clinical response within 14 days

Treatment: • Treat for CNS TB if any

abnormal neurology and evidence of TB elsewhere, or CD4 < 200.

• CNS TB and toxoplasmosis cannot be distinguished on clinical grounds; treat for both if CD4 < 200

• Treatment: TB treatment plus steroids: prednisone 1.5mg/kg/day for 6-12 weeks, depending on clinical response

“Big 3” CNS opportunistic infections: Look for all of these in all patients

Other common infectious causes

Cerebral Vascular Accident (stroke)

Other HIV-related causes

CMV - CD4 < 100: • Treat for CMV encephalopathy if altered

mental state in the presence of CMV retinopathy. Treatment is valganciclovir.

Patients not improving on treatment for toxoplasmosis/CNS TB:

Both of the following are clinical diagnoses to consider in patients not responding to

treatment. Diagnosis is generally not available (CT/MRI). Treatment is ART and palliative care.

Progressive multifocal encephalopathy (PML) - CD4 < 200:

• Multiple progressive white matter lesions n brain: cognitive, motor, visual problems

• Most survivors - severe neurological deficits Primary CNS Lymphoma - CD4 < 50:

• Rapidly fatal

16

What is diarrhoea? • > 3 stools per day • Decreased consistency: ‘takes the

shape of the container’ • Associated symptoms: fever,

abdominal pain, vomiting

Acute vs Chronic: • Acute - < 2 weeks

• Chronic - > 2 weeks

Inflammatory vs Non-inflammatory: Small bowel - non-inflammatory: • Large volume watery diarrhoea: no blood

or mucous Large bowel – inflammatory: • Frequent small volume stools, with blood

and mucous ( WBC on microscopy)

Does the patient have advanced HIV: is CD4 < 200? • Chronic watery diarrhoea is common - caused by

parasite opportunistic infections: Isospora belli, Cryptosporidium

• Dehydration, renal impairment and severe hypokalaemia are common

• WHO stage 4: need effective ART – change to second line if suspect first line failure

Complications: • Dehydration, hypovolemic

shock • Acute kidney injury • Electrolyte abnormalities • Bacteraemia, septic shock

Causes: Infectious: • Viral • Bacterial • Parasites • Mycobacteria: disseminated TB

Diarrhoea in HIV positive patients

3 questions

Chronic diarrhoea

Acute diarrhoea Non-inflammatory:

• Viruses: norovirus, rotavirus • Bacterial: toxin secreting – be alert for

cholera (large volume of rice water stools) • Nausea and vomiting, abdominal cramps

Inflammatory: • Bacteria: Salmonella, shigella,

Campylobacter, E coli, C difficile • Parasites: amoebic dysentery

• Fever, abdominal cramps common • More severe illness: gut mucosa damaged

Investigations: • Creatinine and electrolytes • Stool microscopy if available:

bacteria or parasites found?

Treatment: • Fluid and electrolyte

replacement • Most acute diarrhoea is non-

inflammatory and self-limiting, antibiotics not needed

Antibiotics if bacterial cause or amoebic dysentery: • Fever > 38 degrees • Severe dehydration • Bloody diarrhoea • Mucous, or WBC on microscopy

Which antibiotics: • Ciprofloxacin 500mg x 12 hourly for 3

days • Add metronidazole for 10 days if bloody

diarrhoea or amoebae seen

Non-inflammatory: • CD4 < 200: isospora belli,

cryptosporidium are common WHO stage 4 diseases

• Giardia Lamblia • Vomiting, weight loss,

malnutrition common

Inflammatory: • Parasites: amoebic dysentery,

strongyloides, Giardia lamblia • CD4 < 100: CMV (rare) – look

in eyes to see if there is CMV retinopathy

Investigations: • Creatinine and electrolytes

– renal impairment and hypokalaemia common

• Stool microscopy if available: parasites found?

• 2 or more stool samples may be necessary: parasites are shed intermittently; negative stool does not rule out parasite causes

Treatment: • Fluid and electrolyte

replacement

Anti-parasite treatment: Inflammatory: • metronidazole for amoebiasis (7 days) or strongyloides

(10 days) Non-inflammatory: • Giardiasis is common, treat with metronidazole for 3

days, or single dose tinidazole (2g) • Empiric treatment for Isospora belli: cotrimoxazole 480mg

dose: 1 tablet for each 8kg of body weight per day in divided doses – for 10 days

• Followed by prophylaxis 480mg x 2 tablets per day • Cotrimoxazole hypersensitivity: ciprofloxacin, 500mg bd

for 10 days Some patients have recurrent episodes, despite immune restoration: treat with cotrimoxazole plus ciprofloxacin for 10 days, then maintenance cotrimoxazole 480mg 2 tablets bd

17

Clinical presentation • Dyspnoea • Cough; productive or dry? • Fever

Respiratory danger signs: • Respiratory rate > 30 • Hypoxia: oxygen saturation < 90% • Haemoptysis

Initial assessment

Emergency management • Oxygen via face mask or nasal prongs if RR > 30 or hypoxia • Initiate antibiotics immediately if bacterial pneumonia suspected • Look for pneumothorax Haemoptysis: • codeine or other opiate for cough suppression (do not ask

patient to give sputum samples) • start empiric TB treatment • check Hb; ensure Hb stays > 8 (or >10 if haemoptysis >

250ml/day)

Acute onset: days

Look for alternative/additional causes

*Pneumocystis pneumonia

• CD4 count generally < 200 • Progressive dyspnoea: often dry cough • Very high respiratory rate (> 40) and hypoxia are

common • Sudden deterioration: pneumothorax is

common and life-threatening • Auscultation: crepitations or may be normal • CXR: ‘ground glass’ infiltrate; look for

pneumothorax Treatment: • Cotrimoxazole 480mg 1 tablet for each 4kg of

body weight, in 3-4 divided doses (if 48 kg, 4 tablets 3 x day)

• Hypoxia: prednisone - 40mg twice daily x 5 days – then: - 40mg once daily x 5 days – then: - 20mg once daily x 11 days

Subacute onset: up to 2 weeks

Look for Kaposi’s Sarcoma

• CD4 often < 200, often higher • Look for KS lesions on skin, palate • CXR: ‘lines and nodules’ –

reticulonodular pattern, radiating from the hilar regions May be bloody pleural effusion

Treatment: • Fast track for ART, chemotherapy

Chronic lung disease

• All CD4 counts • Chronic dyspnoea, chronic cough, chronic

hypoxia • CXR: post TB destructive lung disease –

fibrosis, cavities, bronchiectasis on CXR • Comparison with previous CXRs shows this is

chronic: treat TB if proven, avoid empiric treatment on the basis of CXR alone

* = in red, the “big 3” respiratory diseases! They may co-exist, always look for all 3

Respiratory Problems

All patients are TB suspects

*Tuberculosis: investigations

• Pulmonary TB; any CD4 count • Sputum for geneXpert (microscopy if not

available) • TB LAM if CD4 known or considered < 100 • Other investigations as indicated: eg

pleural tap, LN FNAB Infection control: • surgical mask for patients not needing

oxygen; move to TB isolation area) • Open windows!

History: • Duration of onset, additional

symptoms Examination: look for • lymph nodes • pleural effusion • wasting • skin lesions

Investigations: • All patients are TB suspects! • Investigate for TB • CXR for all patients as soon as

possible • Pleural effusion: diagnostic tap,

therapeutic tap if large and causing respiratory distress

*Bacterial pneumonia

• Occurs with any CD4 count • Auscultation: Bronchial breathing

and crepitations • CXR: Pulmonary infiltrate or

consolidation; empyema may occur (purulent pleural effusion, mostly neutrophils)

Treatment: • Antibiotics • Ceftriaxone 1g: change to oral

antibiotics (co-amoxyclav) after 1-2 days, when clinical improvement shown

• Duration of antibiotics: 5-7 days

Don’t Forget – Respiratory Emergencies: • Pulmonary embolism • Pneumothorax (common

complication of pneumocystis pneumonia)

• Haemoptysis • Empyema

18

Not drug sensitive TB:

• DR TB • MAC

2. Was TB proven? • How? • When? • Drug sensitive?

3. TB medication history: • When started? Regimen? • Detailed adherence history:

from folder, patient, family

4. ART history: • On HAART? • When started, which regimen • Detailed adherence history:

from folder, patient, family • CD4 and VL history

Drug sensitive Tb proven, therapeutic level of drugs too low: • Dose too low • Malabsorption:

Chronic diarrhoea, vomiting • Rifampicin levels sub

therapeutic

Poor adherence is a common cause: • Poor adherence - why?

Timeline always important: when started, when stopped, when restarted: • Poor adherence: virological failure? • Recently started ART: IRIS • Not taking ART prior to admission, but

prescribed because history of non-adherence not known: IRIS

• If poor adherence – why?

Additional diagnosis:

• Original TB diagnosis correct, but now something extra

Adverse drug effects: • TB meds • ART • Cotrimoxazole • Efavirenz • Others

Alternative diagnosis:

• Original diagnosis of TB not correct

• New OI: eg pneumocystis, cryptococcal disease • Other HIV related problem • HIV unrelated problem

If cause cannot be found: • Retake history… anything missed? • Re-examine patient– again and again

• Infection: viral, bacterial, parasite, fungal Infections may be acute or chronic

• Malignancy: for example KS, lymphoma, lung cancer • Organ failure: cardiac, renal, liver, blood, chronic lung

disease … and look for the cause • Other chronic disease: eg diabetes, • Drugs, alcohol, smoking, traditional medication

If not proven or no sensitivity testing • Send all possible samples • GeneXpert very helpful: sputum, CSF, urine

1. Evolution of illness: • Pattern of

improvement/deterioration

• Initial improvement on TB treatment? • No improvement at all? • Improved with TB treatment, deteriorated

when ART started?

• This is a common reason for admission • Patients on TB treatment should be improving, and not need

hospital admission • It is important to find the reason patients are not doing well,

and correct the cause • Many of these patients have disseminated TB, and non-

specific symptoms It always important to review the initial diagnosis, as per algorithm

Patients deteriorating or not improving on TB treatment

2. Consider specific causes

1. Essential background information 2.

19

Acute Kidney Injury: • Dehydration • Sepsis • Nephrotoxic drugs :

particularly tenofovir, rifampicin, cotrimoxazole

Often there is more than one cause

Clinical presentation • Kidney disease is often missed: it is often asymptomatic or presents with general symptoms, eg fatigue, nausea • Oedema is a very late sign, and is not seen with HIVAN: its absence does not exclude significant renal disease • The commonest presentation of renal disease is an incidental finding of elevated serum creatinine • Strongly suspect and look for renal disease in all patients with the risk factors in bold listed above • Chronic renal disease may present with anaemia – due to reduced production of erythropoietin

Chronic kidney disease:

• Hypertension and diabetes are major risk factors for chronic kidney disease

• Chronic kidney disease means patients are more vulnerable to acute kidney injury: ie acute on chronic kidney injury

Creatinine

All patients needing hospital admission should have creatinine checked The definition of normal depends on age, weight and gender. Creatinine clearance is more useful. Normal creatinine clearance is > 50ml/min

A useful note: • If creatinine < 100 µmol/L , and weight > 50kg, and age < 50 years and the for

patient is not pregnant, the creatinine will be within normal range

Sodium and Potassium

Abnormal sodium and potassium are common in kidney disease and may be life-threatening

Severe hypokalaemia is common in chronic diarrhoea and acute severe diarrhoea Potassium may be very high in chronic kidney disease

Urine dipsticks

• Protein and blood indicate renal disease. This can be associated with a urinary tract infection (UTI) but findings usually include white blood cells and nitrites

• Always follow up with another dipstick after treatment of a UTI to ensure resolution of the abnormal dipstick findings

• WBC +/- bacteria – show urinary tract infection

Urine microscopy

Renal ultrasound • Shows general anatomy, can suggest underlying HIVAN (large or normal echogenic kidneys), or end-stage kidney disease (small kidneys), but cannot give further information about the underlying cause

Renal Disease in Hospitalised HIV positive Patients

Investigations

HIVAN (HIV associated nephropathy)

• If detected early, HIVAN is

reversible • However it may progress

to chronic kidney disease

Use the CKD-EPI formula to calculate GFR, now considered the most accurate Free app will calculate offline: go to any of usual app stores, type in CKD-EPI and choose

the one with the orange kidney icon. On opening the app, select the top option, “CKD-EPI Creatinine 2009 Equation”

20

Causes :

Hypo-perfusion - reduced blood flow to kidney: • Hypovolaemia • Other causes of

hypotension, for example sepsis and cardiac failure

REVERSIBLE IF CORRECTED EARLY

Correct the underlying cause : • Severe diarrhoea is a

common cause : correct with fluids, and electrolytes

If not corrected rapidly : • Acute tubular necrosis

develops – see next box

Causes:

Ischaemia • Pre-renal failure not

corrected

Toxins: • Tenofovir • Rifampicin • Amphotericin B • Aminoglycosides • NSAIDS

REVERSIBLE IF CORRECTED EARLY

• Correct the underlying

cause • Fluid and electrolyte

replacement if hypovolaemia

• Stop all nephrotoxic drugs

Causes: • Drug hypersensitivity Most common: • Rifampicin • Cotrimoxazole

Others: • Antibiotics: cephalosporins • NSAIDS • Traditional medicines

REVERSIBLE IF CORRECTED

EARLY

• Stop all implicated drugs: do not re-challenge

• The only exception is rifampicin if there is absolutely no alternative, and there is no doubt about TB diagnosis … re-challenge, frequent creatinine monitoring

General management: • Correct dehydration rapidly – 500 – 1000 ml bolus of crystalloid over 30 mins,

followed by 3 litres normal saline IV in 24 hours, plus oral fluids if tolerated • Correct electrolyte abnormalities, and correct the underlying cause • Look for sepsis : treat infections promptly • Stop all nephrotoxic drugs : for example, change tenofovir to another NRTI • Treat other co-morbidities causing renal disease : eg diabetes, hypertension

• Start with looking for acute kidney injury (marked AKI) : this is reversible if treated rapidly • Look for the underlying causes: dehydration, sepsis and drugs • First ask if there is PRE-RENAL kidney injury? This is common, and reversible if treated early • Next ask if there is ACUTE TUBULAR NECROSIS? Also common, and reversible if treated early • Always ask if HIVAN is likely? Reversible with effective ART • Always look for diabetes and hypertension

Pyelonephritis AKI: • Fever, flank pain • Leucocytes and proteinuria

on dipstick • Treat with antibiotics and

intravenous fluids: 10-14 days of antibiotics necessary, change to oral when there is a clinical response

Glomerulonephritis: • Acute AKI • or Chronic

Clinical presentation: Any of the following: • Proteinuria • Red blood cells in urine • Oedema • Hypertension

Many causes: • Including hepatitis B,

syphilis, diabetes

Often co-exists with other causes of renal impairment

• Proteinuria (must be present for diagnosis; urine dipstick essential ) • No hypertension: but may occur in

patients with existing hypertension • No oedema: It is a salt-losing condition • Often low CD4 counts but may occur at

any CD4 count

Treatment: • Effective ART: if failing first line, switch to

second line • ACE inhibitor to reduce proteinuria;

normal blood pressure is not a contraindication

• Avoid nephrotoxic drugs

Uncommon cause of renal impairment: • Obstruction to urine outflow

Most likely causes: • Urethral obstruction: prostatic

hypertrophy in older men • Ureteric obstruction: Cervical carcinoma,

abdominal lymphadenopathy in disseminated TB, cervical carcinoma

HIVAN

PRE-RENAL AKI

RENAL: DAMAGE IS WITHIN KIDNEY ITSELF

POST-RENAL

Acute Tubular

Necrosis (ATN) AKI

Acute Interstitial Nephritis AKI

Other

Renal disease in hospitalised HIV positive patients:

21

Liver Disease in HIV positive patients

Are there Liver Danger signs?

Clinical presentation

Most common causes

Jaundice is a liver danger sign: • Refer all patients with jaundice to

Hospital

Confusion or reduced consciousness: these are signs of severe liver disease, due to: • hypoglycaemia• Hepatic encephalopathy• sepsis

Other danger signs commonly co-exist:

• Temperature > 39°C• Heart rate > 120/min• Systolic BP < 90mm Hg• Unable to walk unaided

• Jaundice• Hepatomegaly• RUQ pain, vomiting• Ascites

•

•

•

There may be more than one cause! Most common: • Drug induced liver injury (DILI)

• Viral hepatitis:o acute (A,B)o chronic (B,C)

• Toxins: traditional medications,alcoholic hepatitis

• Bacterial sepsis (jaundice)• Malaria (jaundice)

Other causes:• TB and TB IRIS are common causes

of hepatomegaly, often tender• right heart failure causes

tender hepatomegaly +/- raisedtransaminases, raised bilirubin

• schistosomiasis causes chronic liverdisease and portal hypertension,

Common causes of DILI:

Prophylaxis or treatment doses of: • Cotrimoxazole• Fluconazole (less common)

TB medication:• Rifampicin, isoniazid, pyrazinamide

ART:• Nevirapine, Efavirenz:

Usually within first 2-8 weeks,Efavirenz can also cause late DILI -after many months

• Lopinavir, ritonavir, atazanavir*

*note: Atazanavir commonly causes benign‘cosmetic’ jaundice (high unconjugated

bilirubin with normal liver enzymes): bilirubin transport problem: it is not a danger to the

patient

What do the liver tests show?

Transaminases (ALT and AST): • markers of inflammation• raised in DILI, viral hepatitis• ALT is most important marker for DILI

Cholestatic enzymes (GGT and ALP): • markers of obstruction• sometimes raised in DILI• raised in TB, TB IRIS

High bilirubin: • raised in many types of liver disease

The most important test of how well the liver is working is blood glucose:

• The liver regulates blood glucoselevels, and can make glucose

• Hypoglycaemia is common in liverdisease, and is rapidly fatal

• Check random blood sugar in allpatients with liver disease, andregular monitoring (3- 4 x day) untilliver disease has resolved

•

• confusion or reduced consciousness • Liver disease may be found incidentally

if ALT is requested

22

History and examination • haemoglobin

• TB LAM• Serum CrAg

Important points on history:

Drugs: • TB treatment• Cotrimoxazole• ART – don’t forget late DILI due to EFV• Any traditional medicines?

• Any history of viral hepatitis?

• Alcohol history

Important points on examination: • Jaundice• Confusion, reduced consciousness• Liver flap

• Hepatomegaly, splenomegaly• Ascites

Signs of chronic liver disease: • Spider naevi• Gynaecomastia• Palmar erythema

•

Investigations

Point of care investigations:

• RBS – urgent!!• CD4• Hepatitis B (A, C)• Rapid malaria test• Glucose• Haemoglobin

Lab investigations:

• Bilirubin, ALT, GGT (AST, ALP give no additional information)

• Ascitic tap: cell count, protein, glucose, Xpert,gram stain

• Creatinine, sodium, potassium• Full blood count• TB investigations are commonly indicated

Management

Severe DILI: stop all drugs TB drugs: for rechallenge protocol, see next algorithm If the patient is severely ill with TB: start alternative TB treatment with a backbone of TB drugs that are safer for the liver: • Ethambutol• Levofloxacin or moxifloxacin (ciprofloxacin if no alternative)• Kanamycin (streptomycin if no alternative). Do not give aminoglycoside if renal

impairment – ie creatinine clearance < 50; give ethionamide instead if available: ifunavailable give aminoglycoside 3 x week, monitor creatinine 2-3 x per week

If the patient is not severely ill with TB: • Stop all TB treatment for 1-2 weeks while DILI settles; do not give the backboneART: • Stop ART until DILI has settled• Never rechallenge with nevirapine: change to protease inhibitor or dolutegravir• Rechallenge with efavirenz only if there is a more likely cause of DILI (eg recent start of

TB treatment), and if mild DILI; otherwise change to PI. If late EFV DILI suspected, neverrechallenge, change to protease inhibitor or dolutegravir

• Remember to check VL, to determine if regimen switch is neededCotrimoxazole:• Stop, do not rechallenge. Do not change to dapsone (can also cause DILI)

All patients: • Avoid alcohol• Avoid liver toxic drugs, including

traditional medicines

Hepatitis B: • TDF and 3TC reduce replication of

hepatitis B virus• Continue TDF if switch to second

line ART: standard second lineregimen becomes AZT/TDF/3TC plusPI or DTG

Hepatitis C: • Use local protocols

Treat other causes: • Treat TB; steroids for IRIS• Treat schistosomiasis: praziquantel

40mg/kg single dose

Severe DILI: definition One or more of the following: • ALT > 120 IU/l in a symptomatic patient (nausea/vomiting, abdominal pain)• ALT > 200IU/l times normal in an asymptomatic patient• Bilirubin >40 µmol/l (> 2.3 mg/dl)

•

• •

Normal values (minor variations between labs): • ALT ≤ 40 IU/L• bilirubin ≤ 17 µmol/l (1.0mg/dl)

Liver disease cont.

23

Drug Induced Liver Injury (DILI): how to do a TB drug rechallenge

‘Backbone’ drugs • Ethambutol• Levofloxacin or moxifloxacin: ciprofloxacin if no other

quinolone available• Kanamycin (streptomycin if no alternative).

o Avoid aminoglycoside if possible if renalimpairment – ie creatinine clearance < 50

o give ethionamide instead if available: ifunavailable give aminoglycoside 3 x week,monitor creatinine 2-3 x per week

TB treatment stopped

Day 1 of rechallenge: • add isoniazid• continue ethambutol• continue quinolone• stop aminoglycoside

Day 1 of rechallenge: Start ‘triple therapy’ with isoniazid and two backbone drugs: • isoniazid• ethambutol• quinolone• Avoid aminoglycoside due to adverse effects

Patient severely ill with TB: • start alternative TB treatment with a ‘backbone’ of

TB drugs that are safer for the liver

Patient is not severely ill with TB: • stop all TB treatment, do not give the backbone

drugs

Diagnosis of DILI

Start rechallenge when: • ALT < 100 IU/L with no symptoms of liver disease• and biluribin is normal

Never rechallenge if there are symptoms of severe liver failure (confusion, hypoglycaemia, clinical concern

of coagulopathy): patient will need an alternative regimen for the duration of TB treatment, using drugs

usually reserved for drug-resistant TB

Normal values (minor variations between labs): • ALT ≤ 40 IU/L• bilirubin ≤ 17 µmol/l (1.0mg/dl)

use correct dose for weight for all rechallenge drugs

Check TB Diagnosis: • TB proven? Rifampicin sensitivity proven? If not, request Lam/Xpert on sputum/non-sputum samples• If TB not proven, clinical response to TB treatment (weight gain, symptoms resolving, anaemia improving, CXR

improving then TB diagnosis can be assumed to be correct

Isolated jaundice (bilirubin >40 µmol/l (> 2.3 mg/dl)and ALT < 120 IU/L – seenote at top of page 3

24

Day 3: check ALT (and bilirubin if initially raised)

Day 4: if ALT /bilirubin unchanged • Add rifampicin• continue isoniazid• continue ethambutol• stop quinolone

Day 7: check (and bilirubin if initially raised)

Day 8 – if ALT/bilirubin unchanged: • Add PZA*• continue rifampicin• continue isoniazid• continue ethambutol

Day 11: check ALT (and bilirubin if initially raised)

Day 12 – ALT/bilirubin unchanged: • Congratulations, all TB drugs are rechallenged!• However there is still a risk of recurrence of DILI check ALT (and bilirubin if initially

raised) at least weekly for the next 4 weeks• Restart ART 1-2 weeks after all TB drugs rechallenged• Do not rechallenge cotrimoxazole. Do not change to dapsone (can also cause DILI)

• Ensure patient has correct duration of TB treatment: ie total 2 months RHZE and 4months of RH: this includes time on TB treatment prior to DILI

• If longer duration required (eg CNS TB) adjust accordingly

ALT and or bilirubin increased, see box

below

ALT and or bilirubin increased, see box

below

ART rechallenge: • Never rechallenge with nevirapine: change to protease inhibitor or dolutegravir• Rechallenge with efavirenz only if there is a more likely cause of DILI (eg recent start of

TB treatment), and if mild DILI; otherwise change to PI. If late EFV DILI suspected, neverrechallenge, change to protease inhibitor or dolutegravir

ALT and or bilirubin increased, see box

below

*PZA rechallenge:• not necessary if patient is

already in the continuationphase!

• can be omitted if the patientdoes not have severe TB(miliary TB, TBM for example),and it is possible to give RHEonly on a long term basis:however total duration of TBtreatment needs to beprolonged from 6 months to 9months

give as RHZE

give as RH plus E

DILI cont.

25

At any stage during rechallenge if ALT > 120 IU/L or bilirubin > 40 µmol/l (> 2.3 mg/dl):

• Stop the drug added last, and restart the last backbone drug that was stopped (eg if this occurred when rifampicin stopped onday 8 – stop rifampicin and restart quinolone). There should be 3 TB drugs at all times in the rechallenge regimen

• Repeat ALT/bilirubin after 3 days

1. If ALT and bilirubin have returned to the levels at the start of the rechallenge:• Continue with the next drug in rechallenge regimen• If ALT/bilirubin remain unchanged after 3 days, continue with rechallenge of any remaining drugs• If ALT/bilirubin remain unchanged when all other drugs are rechallenged, try a further rechallenge with the drug which failed the

rechallenge

2. If ALT and bilirubin have not returned to the levels at the start of the rechallenge:• Repeat ALT/bilirubin after a further 3 days

3. Follow 1 or 2 above depending on ALT and bilirubin levels

Important notes: • if at any time during the rechallenge, patient develops symptoms of liver disease (nausea, vomiting, right upper quadrant pain)

stop all rechallenged drugs, and return to backbone regimen or no backbone, depending on whether the patient is severely ill ornot with TB

• If at any time the patient develops symptoms of severe liver failure (confusion, hypoglycaemia, clinical concern ofcoagulopathy), stop all rechallenge drugs, and never rechallenge further: patient will need an alternative regimen for theduration of TB treatment, using drugs usually reserved for drug-resistant TB

seek advice with any rechallenge that is unsuccessful for one or more drugs

Note - isolated jaundice (bilirubin >40 µmol/l (> 2.3 mg/dl) and ALT < 120 IU/L: • Rifampicin is the most likely cause• Stop rifampicin, continue HZE and add moxifloxacin or other quinolone• Stop cotrimoxazole if GGT or ALP are also elevated, or not available• rechallenge rifampicin when bilirubin is normal

DILI cont.

26

↓ Red cell production

↑ Red cell destruction

Lack of raw materials Bone marrow not working

• Anaemia of chronic disease: both HIV and TB cause bone marrow suppression;anaemia responds to treatment with ART and TB treatment. This is the mostcommon cause of anaemia in HIV positive patients

Drugs: AZT, cotrimoxazole - also common causes of anaemia due to bone marrow suppression: • Anaemia due to AZT is most likely within the first 6 months and at low CD4 counts• Switch AZT if other NRTIs are available; if possible, check patient is virologically

suppressed before changing one drug in a regimen• Stop prophylactic cotrimoxazole• If cotrimoxazole is for treatment of opportunistic infections, see if there is an alternative

available; primaquine and clindamycin for pneumocystis pneumonia, pyrimethamine,clindamycin and folinic acid for toxoplasmosis; ciprofloxacin for isospora belli diarrhoea.

Nutritional deficiency: • Malabsorption (eg chronic diarrhoea) or poor diet causing –

o Iron deficiencyo Folate deficiency

• Note this is rarely the most important cause in HIV patients=> always look for other causes

Lack of erythropoietin: • Occurs in severe, chronic renal failure• Acute kidney injury does not cause of anaemia• All patients should have creatinine on admission

Think about the following:

• Malaria• Cotrimoxazole• Rifampicin: consider if severe anaemia occurred after starting TB treatment.

Anaemia responds rapidly to stopping rifampicin. As alternatives torifampicin are rarely available, restart rifampicin with close monitoring ifanaemia resolves rapidly. If it does not improve, rifampicin is not the cause.Cotrimoxazole is the more likely cause if the patient is taking both drugs.

• Sickle cell disease – common in some countries

Blood loss – may be readily visible: haemoptysis, haematemesis, malaena. May be clinically silent – always think of the following: Kaposi’s sarcoma: • GIT bleeding is common and is often chronic and not seen by the patient or

medical staff• Always look at the palate, and all of the skin (undress the patient)

Hookworm: • Endemic in many countries: albendazole 400mg single dose

Obstetric and Gynaecological causes: • Ectopic pregnancy, miscarriage• Cervical cancer

Blood loss

Anaemia

27

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