ADH_Part_II_Training Slides_ Hub_Spoke_V05_04_June_2022.pptx

Advanced HIV Disease
Management Training
For HealthCare Worker, June 2022

• MODULE 1: Basics of AHD (See section 2 of AHD toolkit)
• MODULE 2:
• MODULE 2II: WHO Clinical Staging
• MODULE 3: TB POC Diagnostics and TB Preventive Therapy
• MODULE 4: Reference Algorithms for AHD Care
• MODULE 5: Other Causes of death in AHD
• MODULE 6: Basic Principles of ART Initiation in AHD
AHD – MODULES FOR HCW IN HUB & SPOKE FACILITIES
CrAg Screening, Pre-emptive therapy and referral of
symptomatic cases of Cryptococcal Meningitis

Module 1: Basics of AHD
ADAVANCED HIV DISEASE (AHD)
PART I

Learning Objectives
By the end of this session, participants will be able to;
• Understand the background, burden and causes of Advanced HIV
Disease (AHD).
• Know the components of the recommended WHO basic package of
care for Advanced HIV Disease (AHD).
• Identify a critically unwell AHD patient
• Understand the hub & spoke AHD model of care as a recommended
approach to implementation of AHD care in resource limited settings.

Antiretroviral treatment (ART) has scaled up dramatically since 2000, reaching almost
20M people living with HIV (PLHIV)
Historical scale up of PLHIV on ART in low- and middle-income countries (LMICs)
Source: WHO/UNAIDS for historical estimates
Note: 2010-2018 ART coverage figures calculated for LMICs using 2019 World Bank Income Classifications and UNAIDS AIDSinfo database, accessed August 29, 2019 (only includes
countries with both ART and PLHIV numbers reported)
Number
of
PLHIV
on
ART
(millions)
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
0.0
5.0
10.0
15.0
20.0
25.0
0%
10%
20%
30%
40%
50%
60%
0.2 0.3 0.4 0.7
1.3
2.0
3.0
4.1
5.3
6.6
8.1
9.7
11.4
13.3
15.1
17.1
19.2
21.4
0.222079963288017
0.26910496486809
0.31682241743506
0.365643551071653
0.41697594113363
0.467517146436913
0.518304653167262
0.58
0.63
Historical LMIC ART Estimates
ART coverage for PLHIV in LMICs
ART
coverage
for
PLHIV
(%)

Annual AIDS-related deaths have declined since the peak in the mid-2000s, but have
plateaued in recent years
Source: UNAIDS 2018 estimates.
1990
1992
1994
1996
1998
2000
2002
2004
2006
2008
2010
2012
2014
2016
2018
2020
0.0 M
0.5 M
1.0 M
1.5 M
2.0 M
Annual
AIDS-related
deaths
Fast-Track Target
Number of AIDS-related deaths, global, 1990–2017 and 2020 target
2017: 940K

Global AIDS-related deaths
Source: UNAIDS 2022 estimates https://www.unaids.org/en/regionscountries/countries/southsudan .
Disaggregated number of AIDS-related deaths, Globally in 2020

South Sudan AIDS-related deaths
Adult and child deaths
due to AIDS
8900 [6000 - 12 000]
Deaths due to AIDS
among adults aged 15
and over
6900 [4600 - 9600]
Deaths due to AIDS
among women aged 15
and over
3900 [2600 - 5600]
Deaths due to AIDS
among men aged 15 and
over
3000 [2000 - 4200]
Deaths due to AIDS
among children aged 0
to 14
2000 [1300 - 2800]

AIDS-related mortality is due to a number of factors
Delayed HIV diagnosis
Delayed enrollment in care and ART initiation
Patient abandoning care and loss-to-follow up
Treatment failure due to non-adherence and drug resistance
 All contribute to HIV disease progression and Advanced HIV Disease
Why has progress in reducing mortality stalled?

Clinically, advanced HIV disease (AHD) is characterized by the presentation of people
living with HIV with weakened immune systems
• HIV infection is characterized by infection of the CD4 lymphocyte cell, the
primary coordinator of the immune system
• HIV select specific clones of CD4 for destruction, this is followed by CD4 depletion
culminating in AHD
• While the body can replace destroyed CD4 cells, over time this ability is
progressively degraded, leading to:
– Decreased numbers of circulating CD4 cells
– Decreased immune function
– Increased susceptibility to infections
• Starting with more frequent common infections and
• Ultimately with unusual infections that a healthy immune system would be able to control
(opportunistic infections)
• While this progressive immune damage usually causes symptoms, often these
symptoms go unnoticed and occasionally patients may have no symptoms at all
Basic Pathogenesis of HIV Infection

AIDS-related mortality is driven by a small number of OIs, including TB and fungal
infections like Cryptococcus
The majority of AIDS-related deaths of hospitalized adults are caused by
opportunistic infections, including:
TB
35%
Cryptococcal Meningitis
18%
Toxoplasmosis
15%
PCP
15%
Severe
bacterial
infections and
other
17%
Source: WHO AHD Guidelines, 2017.

PLHIV with AHD have low CD4 count and are at high risk for disease
progression, development of opportunistic infections, and death
 For adults and adolescents, and children older than five years,
advanced HIV disease is defined as CD4 cell count <200cells/mm3
or
WHO stage 3 or 4 event
– Includes both ART naïve individuals and those who interrupt treatment and return to care
 All children younger than five years old with HIV are considered as
having advanced HIV disease
WHO Definition of AHD
In spite of increasing access to treatment, the number of people with
advanced HIV at the time of diagnosis remains high and is not declining
very fast, especially among men and
The mortality rate among people with advanced HIV disease is very high
even with access to ART. The risk of death is higher with low CD4 cell
count, especially with CD4 cell count <100 cells/mm3

The approach to the management of patients with AHD is contingent on their clinical
stability (e.g. ‘Ambulatory’ or ‘Critically unwell’) and their ART status
Patient identified as new stage 3 or 4 disease or with CD4 < 200 (ART naïve or experienced)
• Screen for danger signs (Respiratory rate >30, Heart rate >120, Systolic BP <90,
Temperature >39°C, moderate/severe dehydration, Unable to walk unaided,
Saturation <90%, altered mental state/GCS, other neurological problems)
• CRITICALLY UNWELL patient
• Provide urgent labs, supportive
management (e.g. oxygen, IV
fluids)
• Start urgent treatment: (e.g.
antibiotics, TB treatment, etc.).
• Refer to Hospital
PRESENT
ABSENT
• Complete clinical history and
assessment for TB and other
OIs
• Conduct appropriate labs: CD4,
TB LAM, Serum CrAg
Further management is based on two key criteria:
Is the patient ART-naïve or Treatment experienced client returning
to care

Access to the AHD package of care by the patient at the nearest health care facility is
contingent on many factors
Urgency of the diagnosis: If the patient is seriously unwell
Complexity and availability of the tests that need to be performed
The availability and frequency of sample transport and result delivery
mechanisms
Ability of the site to ensure quality control
The knowledge and capacity of different levels of HR to urgently manage
complex cases e.g. cryptococcal meningitis
In-country policies for who can perform specific tests/procedures e.g. LP and
prescribe certain medications

A hub and spoke system:
Involves setting up local networks based
on expertise and infrastructure of health
facilities identified for AHD care (e.g.
Cryptococcal Meningitis care in
hub/regional referral hospitals & district
hospitals).
Provides reliable linkage to appropriate
AHD services, including timely referral
where need be e.g. Referral from spokes
to Hubs of critically unwell recipients of
care
Streamlines and permits easier
coordination and communication by
implementing partners and national
programs to monitor uptake of AHD
services, and to ensure quality.
Hub
Spoke
A “Hub & Spoke” model permits for access to appropriate AHD care based on the severity
of illness (ambulatory, critically unwell)
Spoke
Spoke
Spoke

AHD care for the critically unwell patient hospitalized patients (Hub)
Hubs:
 Definition: Hospital level facilities where comprehensive
packages of AHD care can be implemented with;
 Clinical expertise in management of critically unwell AHD
patients
 Appropriate storage facilities
 Laboratory capacity (timely and reliable laboratory
monitoring e.g. renal function monitoring; basic microbiology
including CSF culture)
 Will serve as referral sites for spokes and will manage patients in
need of hospitalization and regular monitoring e.g. in treatment
of cryptococcal meningitis
1

Diagnosis
Prophylaxis
& pre-
emptive
therapy
Treatment
Adapted
adherence
support
AHD Package for hospitalized patients (Hub)
*Kaposi sarcoma, PCP, Bacterial Sepsis
• Clinical Expertise
• CCM Treatment
• TB treatment
• Other OI
treatment*
• Appropriate ART
timing
• Counselling
• Community-based
support/home visit
• TPT, CPT
• Fluconazole
• CD4
• CrAg – blood /CSF
• TB LAM, Xpert
• LP
• Haematology &
chemistry

Spokes - provide AHD care package for ambulatory patients
Spokes:
 Definition: Include primary health care facilities and hospitals
with;
 limited clinical expertise and diagnostic capacity (including
creatinine) for AHD care.
 limited to no storage capacity (including cold chain) for AHD
commodities.
 The spokes will;
 Offer outpatient and routine care to stable AHD patients.
 Refer critically unwell AHD patients in need of in-patient care
and patients with suspected cryptococcal meningitis to hubs
within proximity.
2

• TPT, CPT
• Fluconazole
• CD4
• CrAg – blood
• TB LAM, Access to
Xpert
Diagnosis
Prophylaxis
& pre-
emptive
therapy
Treatment
Adapted
adherence
support
AHD Package for outpatients (Spoke)
Should every
CrAg positive
be referred?
*Accreditation to provide TB diagnostic and treatment services
• TB treatment*
• Continuation of
Crypto care
(Consolidation,
Maintenance
phases)
By who and
where are
patients with
positive RDTs
being
treated?
• Counselling
• Community -
based
support/
home visit

Module 1 Summary
 A significant proportion of AIDS related deaths are attributed to
advanced HIV Disease.
 TB and CCM are the major causes of AIDS related mortality.
 The WHO recommends a basic package of care for Advanced HIV
Disease (AHD) care in at risk patient populations.
 A “hub & spoke model” provides an avenue for the provision of AHD
care services at health facilities in resource limited settings.

Module 2 – Cryptococcal meningitis

By the end of this section, you should be able to:
– Understand the basic pathophysiology and burden of CCM
– Know the management of PLHIV with AHD screening CrAg
positive(Spoke)
– Identify and investigate the symptoms & signs of CCM and
diagnose CMM(Hub)
– Understand the need to refer PLHIV presenting with signs &
symptoms suggestive of CCM (Spoke)
– Understand the optimal timing for starting ART in PLHIV with a
positive CrAg test result(Spoke)
– Administer appropriate treatment for CCM and Manage raised
intracranial pressure(Hub)
– Initiate, restart or switch ART in patients managed for CCM(hub)
Learning objectives

Burden and basic pathophysiology of CCM

• 940, 000 deaths from AIDS related illnesses
worldwide in 20171
• 15 – 20% AIDS related deaths globally are due to
CCM2
• 135, 900 annual deaths dues to CCM in African
LMICs2
Introduction: CCM and AHD
1. UNAIDS 2018 report
2. Rajasingham R, Smith RM, Park BJ, et al. Global burden of disease of HIV-associated cryptococcal meningitis: an updated
analysis. Lancet Infect Dis. 2017;17(8):873–881. doi:10.1016/S1473-3099(17)30243-8

Burden and Mortality of CCM
• Cryptococcal meningitis is one of the leading causes of
meningitis in PLHIV in many LMIC settings
• 40% mortality for patients treated with Amphotericin
B deoxycholate in clinical trial settings at 10 weeks
• Estimated 3-month mortality is 70% in routine care
settings with more available but inadequate
fluconazole monotherapy.

Global burden of disease of HIV associated cryptococcal meningitis: an updated analysis –
Annual incidence of cryptococcal infection
Source: Rajasingham R, Smith RM, Park BJ, et al. Global burden of disease of HIV-associated cryptococcal meningitis: an updated

Global burden of disease of HIV associated cryptococcal meningitis: an updated analysis –
Countries with the highest incidence of CCM
Source: Rajasingham R, Smith RM, Park BJ, et al. Global burden of disease of HIV-associated cryptococcal meningitis: an updated

What is Cryptococcus?
• Cryptococcus is a fungus found in soil throughout the world.
• Spores are inhaled from the environment by humans.
• There is no person-to-person transmission of Cryptococcus.

Cryptococcal infection/disease
• After inhalation, the fungus
can cause an acute lung
infection, or often no
symptoms at all, and stay
dormant in the body for
months to years.
• Reactivation of disease can
occur in immune-suppressed
people (e.g. PLHIV).
• Not all cases of CCM are
reactivations. Some may be
new CCM infections.
 Meningitis (inflammation of the
tissue surrounding the brain) is
the most common form of
cryptococcal disease in PLHIV.
 Encephalitis (infection of the
brain itself) can also occur
together with meningitis.
Adapted from: South African National Department of Health and
NICD/Nelesh Govender
Infection Disease

• Adult HIV/AIDS patients with a
CD4 count < 100 are at highest
risk for reactivation.
• When Cryptococcus
reactivates in the body, it can
cause disease in the brain,
lungs, skin, and bones.
 Cryptococcal meningitis is a
common cause of death among
PLHIV.
 Even when patients are treated
with antiretroviral medications
and anti-fungal therapy, 30 to
70 per cent die from their
cryptococcal disease.
Infection Disease

• NO person – person
transmission
NB:
This is a ‘time lapse
diagram showing
infection spreading
within the same
patient

How to prevent cryptococcal meningitis in PLHIV
with AHD

Preventing Cryptococcal Meningitis
Training Objectives:
 Describe the importance of preventing cryptococcal meningitis
 Understand the advantages and disadvantages of primary
prophylaxis
 Understand how to screen for cryptococcal antigen in blood or
serum
 Understand how to administer pre-emptive treatment for CrAg
positive antigenemia using fluconazole

Preventing Cryptococcal Meningitis: Pre-emptive fluconazole treatment for CrAg positive
PLHIV
Cryptococcal disease is common among HIV/AIDS patients and is
responsible for a large number of deaths, especially among those
with CD4 count <200 cells/μl.
Antifungal therapy is costly and often not available. Even when
antifungal therapy is given, patients who already have cryptococcal
meningitis often do poorly because they are diagnosed late.
Patients are most at risk for getting sick from Cryptococcus before
they are started on ART (when their CD4 counts are low) and
immediately after starting ART (due to cryptococcal IRIS).
Why is preventing cryptococcal meningitis important?

One strategy to prevent cryptococcal meningitis deaths is
to treat all HIV/AIDS patients with a CD4 count <200 with
low-dose fluconazole, such as 200 mg daily.
This strategy has been shown to decrease the number of
cases of cryptococcal disease, but has not consistently
been shown to decrease rates of death.
There are also several concerns about widespread use of
fluconazole including cost, drug resistance, drug adverse
events
Primary prophylaxis

 Cryptococcal screening paired with pre-emptive treatment of
those who screen positive is another strategy to prevent deaths
from cryptococcal meningitis.
 CrAg can be detected in the blood weeks to months before the
patient develops symptoms of disease.
 Patients found to be CrAg positive are more likely to develop
meningitis. The presence of CrAg is highly predictive of the
development of CCM.
 CrAg is negative in people without active disease, but may remain
positive for months after disease, even when treatment is
successful.
Cryptococcal screening

Decision-Making Guide for Cryptococcal Screening: CrAg screening in practice: reflex vs
provider initiated
 Reflex screening: When you order a CD4 count test, the laboratory
will automatically perform a cryptococcal antigen test on all
patients whose CD4 count is <200.
o Cost effective
o Prevents repeat patient visits
 Provider-initiated screening: The provider orders a cryptococcal
antigen test if the CD4 count result is <200.
o Patients with a positive CrAg test will need to be contacted
urgently to return to the clinic for follow-up

Decision-Making Guide for Cryptococcal Screening: CrAg screening in practice: reflex vs
provider initiated
 Irrespective of screening approach, the patient should be
assessed for symptoms of meningitis.
o If the patient has any symptom of meningitis (e.g. headache,
confusion) he or she will need a lumbar puncture and should
be referred to a hub facility.
o ALL CrAg positive recipients of care should be offered LP

Preventing Cryptococcal Meningitis: Pre-emptive fluconazole treatment for CrAg positives
 Instead of treating everyone with a CD4 count < 200 (i.e. primary
prophylaxis), patients with low CD4 counts can be screened for CrAg and
treated with fluconazole if they test positive.
 Screening and primary prophylaxis are not recommended for children,
given the low incidence of CCM in this age group.
 The benefit of this strategy is that it minimises unnecessary treatment of
patients who are at lower risk of getting sick from Cryptococcus.
 This decreases costs and concerns about drug resistance, side effects,
and safety.

Decision-Making Guide for Cryptococcal Screening
Principles for pre-emptive fluconazole treatment
Identify patients at risk (CD4 count less than 200)
1
Test for cryptococcal antigen before onset of meningitis
symptoms
2
Treat
• Treat: Oral fluconazole 800mg daily for 2 weeks, followed by
consolidation and maintenance therapy as for treatment of
CCM.
• Stop: After suppressed VL<1,000 copies/mm3
& CD4 ≥ 100 for
at least 1 year, or CD4 ≥200 cells/mm3
for at least a year if
viral load not available.
3
Prevent cryptococcal meningitis-related deaths
4

Symptoms and signs of cryptococcal meningitis
- When to refer a patient from spoke
recognizing clinical features of Cryptococcal disease
in Hub

All patients with signs and symptoms of CCM should be referred to a Hub: Recognizing
Cryptococcal disease
• Symptoms:
– Headache
– Fever
– Change in mental status (ranging
from confusion to lethargy to
coma)
– Double vision (and other cranial
nerve deficits)
– Neck stiffness
– Sensitivity to light
– Nausea and vomiting
 Signs
— Seizures
— VIth
cranial nerve palsy
— Reduced level of consciousness
— Meningism
— Papilloedema (blurred optic disk
margin on fundoscopy)
• See CCM and signs and symptoms of meningitis posters
• Refer to Cryptococcus_Screening for OI among PLHIV_CDCfactsheet

Additional CCM presentations
Chest X-ray of
cryptococcal infiltrate
Cryptococcal skin
lesions

Differential diagnoses
TB meningitis is the most common
1
Cerebral Malaria
2
Meningoencephalitis caused by other organisms
(mycobacterial, viral, bacterial, Toxoplasma gondii, neurosyphilis
etc.) – see other modules for details
3
Space-occupying lesions (lymphoma, T. gondii, abscess, etc.)
4
HIV encephalopathy
5
Other conditions (toxic, metabolic, autoimmune, intracranial
bleed, etc.)
6

Please see lumbar puncture (LP) workshop for symptoms and signs and initial routine laboratory test
results for HIV-associated meningo-encephalitis
CSF parameters
• CSF samples for PLHIV presenting with meningoencephalitis need a
basic CSF analysis with WCC and differential, CSF protein and glucose
— CSF opening pressure not useful to distinguish meningitis cause but
often elevated in CM patients (it can be normal)
— CSF WCC is of limited use for PLHIV: it may be below 10 cells/ul or
10-500 cells/ul
— CSF glucose levels may be normal or low
— CSF protein levels may be normal or slightly elevated
— Low CSF WBC may be a poor prognostic sign

Diagnostic methods
• CrAg LFA
– Cryptococcal antigen Lateral
Flow Assay
– High specificity (99%) and
sensitivity (99%)
– Rapid (10 minutes)
– Easy to perform
– Assays include: FDA approved
IMMY & Biosynex CryptoPS
• Culture – Gold Standard
 Can only grow if you
have live organism
 Positive within 72 hours
 CSF should be cultured
for fungi using
Sabouraud medium for:
o 5 days at 300
C to 350
C
in aerobic conditions
(for 1st
episode)
o 14-21 days if relapse
episode
• India Ink stain (microscopy)
– Performed on CSF
– High specificity
– Low sensitivity (60-80%)
– India ink is also used when
cultured to identify the organism
that is growing
1
2
3

CrAg LFA, Culture, and India Ink
Illustration of CrAg LFA dipstick tests
CSF culture with C. neoformans growth
India Ink stain with C. neoformans visible
1 2
3

Laboratory diagnosis/findings of cryptococcal meningitis
 LP: CSF lymphocytic (Note that is often
acellular in HIV), raised protein (0.5 – 1),
reduced glucose.
 Gram stain/India ink: spherical yeasts,
halo. Is 80% sensitive
 Blood cultures: cryptococcaemia.
 Biopsy: skin (ulcerated papules indicate
dissemination), lymph node
Cryptococcus staining positive with India ink
Ulcerated skin lesions due to disseminated
cryptococcal disease

Laboratory diagnosis/findings of cryptococcal meningitis: Culture/Histology
 Gold standard for diagnosis of cryptococcal
meningitis.
 48 – 72 hrs ordinary media/SAB 30 – 35 0
C.
 Creamy (sometimes mucoid) colonies
 Urease+
 Selective media:
 Niger seed, caffeic acid, dopamine
 Canavanine glycine bromothymol blue (CGB)
agar – distinguish C gattii (blue, glycine) from
neoformans
 Histology:
 Budding spherical capsulated yeast.
 Stains: Grocott Methamine Silver.
 Capsulate stain: mucicarmine (pink)
Positive fungal culture with Cryptococcus colonies
CGB agar distinguishing C gattii from C Neoformans
Mucicarmine stain of capsulated Cryptococcus yeast

Case scenario based discussions

Case Study 1: Asymptomatic Presentation of Cryptococcal Meningitis
• Highlights the potential treatment complications associated
with cryptococcal meningitis
• Patient history and initial presentation
 A 40-year old man is referred to your clinic after a two-week
hospital stay with PCP, where he was treated with
cotrimoxazole and steroids, and made a good recovery.
 He is newly diagnosed with HIV with a CD4 count of 11.
 Upon presentation to the clinic, he has no headache, no
fever, confusion, or neck stiffness. However, he has severe
oral candidiasis, one Kaposi’s sarcoma (KS) lesion on his
back, and nerve pain in his feet.
Adapted from: South African National Department of Health and NICD/Nelesh Govender
1

Asymptomatic Presentation of Cryptococcal Meningitis
• Patient management:
 Baseline bloods are ordered. CrAg test is requested by the
clinician: positive
 Patient is called back to clinic urgently and now has mild headache
 Patient is referred and admitted to hospital for further
management for suspected cryptococcal meningitis
 Lumbar puncture performed: CSF CrAg test positive
• Medication prescribed:
 AmB d 1 mg/kg/day IV with appropriate pre-hydration, and oral K
& Mg supplementation.
 5-FC 100mg/day PO for 1/52, followed by Fluconazole 1200mg for
1/52

Patient management of CCM: In patient care and discharge
• Patient progress:
 On day four of hospital admission, the patient’s creatinine is
too high, which means his kidneys are failing. He is given
fluids and the dose of AmB d is adjusted (Refer to Job aid –
Use of AmB Deoxycholate).
 High dose Fluconazole with Ambisome is the regimen for
intensive phase, consolidation, and maintenance phases for
treatment of CCM, doses needs to be adjusted if there is
evidence renal impairment
 The AmB d causes him to develop thrombophlebitis
(inflamed veins due to a chemical reaction with
amphotericin B) and he has become anaemic.
 He completes the 1st
week of AmB d and fluconazole 1200
mg/daily for the 2nd
week and is discharged on fluconazole
800 mg/daily for two months (consolidation phase of CCM
treatment).

Patient management: AHD care post hospital discharge
• Patient progress:
 At his post-hospital discharge clinic visit, the patient is doing well
and does not complain of headaches.
 He is offered TPT and CPT: He expresses concerns about the many
medicines he has to take!
 He is started on ART 4 – 6 weeks after initiating Crypto treatment
(ABC, 3TC, DTG) in view of his creatinine levels (kidney failure).
 After 2 months of consolidation phase of treatment, he is
continued on fluconazole 200 mg/day (Maintenance phase of
CCM treatment)
What concerns and considerations do you have and want to
make respectively as you plan his post-discharge care?

Refer to Section 5, sub-section IV - ‘AHD Care Post Hospital
Discharge”
 Maintenance Phase:
 1 year of Fluconazole
 Criteria to stop after a minimum of 1 year of
maintenance phase is
o VL<1,000 copies/mm3
& CD4 ≥ 100 for 6 months
o or CD4 ≥200 if viral load not available
 He is offered TPT and CPT: Pill burden is a concern and could
affect his adherence to the treatment he is provided. Explore
options for fixed dose combinations e.g. CTX/INH/B6 .

• Discussion points:
 AHD patients often have multiple OIs, so it is important to look
for CCM.
 Initiation of ART at initial admission with PCP was indicated.
 AmB d can have serious side effects that need to be monitored
and managed including kidney failure, low potassium,
abdominal discomfort, infusion reactions, phlebitis, anemia,
and low white blood cell count.
 Adjust the dose for both AmB d and Fluconazole in case of
renal impairment.

 L-AmB has a better side effect profile than AmB-d.
 IV rehydration and K/Mg supplementation are required in use
of both L-AmB and AmB-d.
 Management of anaemia is dependent on severity. (e.g. Blood
Transfusion is indicated for severe anaemia )
 Thrombophlebitis (Refer to poster “Safe administration of
Amphotericin B”).

 Fluconazole can interact with some ART medications, and this
is an important consideration when starting ART.
 If the PLHIV is female, counsel and educate on the risk for
teratogenicity on and following 5-FC use.
 Though rare, PLHIV should be monitored closely for signs of
liver damage including right upper quadrant abdominal pain,
nausea/vomiting, or jaundice (yellowing of the skin and eyes).

Case Study 2: Symptomatic Presentation of Cryptococcal Meningitis (Hub)
 A 49-year-old, newly-diagnosed HIV-infected man
presents at your clinic. He has been having watery
diarrhoea for one month and has lost 10 kg over the
past two months.
 He lives by himself and drinks one bottle of wine and
two glasses of brandy per day.
 He reports no headache, fever, confusion, neck
stiffness, or sensitivity to light. However, he is very
wasted, mildly dehydrated, and has oral candidiasis.
2

Symptomatic Presentation of Cryptococcal Meningitis
• Patient management
 Baseline bloods are ordered.
 A stool sample is taken.
 The patient is advised to return to the clinic in two weeks to
begin ART if
• Medications prescribed
 Nystatin mouth wash
 Cotrimoxazole two tabs/day
 Vitamin B complex two tabs/day
 Thiamine 200mg/day (in view of alcohol history and possible
malabsorption)
 Vitamin C 100mg/day

• Results:
 CD4 count: 9 cells/μl
 Cryptococcal antigen (CrAg) reflex test : positive

• Patient progress
 The patient did not return to your clinic to start
fluconazole or ART. Three months later, he presents to the
hospital with a headache, neck stiffness, and confusion.
 A lumbar puncture shows that his intracranial pressure is
very high (45 cm H2O), and that his spinal fluid contains
Cryptococcus (CrAg positive).
 Daily therapeutic LPs are performed to reduce his
intracranial pressure, and his creatinine, potassium, and
magnesium are monitored.
 He is started on AmB d and Fluconazole with pre-
hydration and oral K+
and Mg supplementation.

 Despite appropriate management, the patient dies on day
five of admission

• Discussion points
 On his return visit, the patient had markers of severe
cryptococcal meningitis: altered mental status and raised
opening CSF pressure.
 Although some patients with low-level cryptococcal
antigenaemia may clear the infection with ART alone, many
patients have a delay in starting ART (either due to other
medical conditions such as TB or issues with access to care).
 This patient should have been prescribed fluconazole at his
intake visit (followed by ART one to two weeks later) in order
to prevent his silent cryptococcal disease from progressing to
meningitis.

 A delay in presentation can lead to severe meningitis with high
mortality (up to 50 per cent).
 The positive CrAg is also an emergency, and efforts to find the
patient and bring him into care were needed. Clinic should
have mechanisms to provide timely appointments and trace
patients to initiate appropriate management.
 There would be value in conducting point of care CD4.
 Liver enzymes: history of alcohol use, fluconazole.

Case Study 3: Previous Cryptococcosis
 A 37-year-old woman comes to your clinic for the first
time with a CD4 count of 19.
 She recently moved to Juba City from Torit Town,
leaving behind her medications and transfer letter.
 She reports no headache, fever, confusion, or neck
stiffness, and there are no positive findings upon
examination.
3

Previous Cryptococcosis
• Patient management
 Baseline bloods are ordered.
 The patient is asked to complete readiness classes and
return to the clinic in two weeks to begin ART.
 A CrAg test result comes back positive (ordered by the
clinician) and the patient is called back to clinic urgently
for assessment.
 Recommendation: LP should be offered to CrAg positive
recipients of care.

• Medication prescribed
 Fluconazole 800mg/day for two weeks
 Cotrimoxazole two tablets/day
 Vitamin B complex two tablets/day
 At her two-week follow-up visit, the patient is doing well.
Her sister brings the patient’s original medications and clinic
transfer letter.
 You learn that the patient had previously been prescribed
fluconazole 200mg/day, cotrimoxazole, and vitamin B
complex.

 CrAg can be present for up to two years after an episode of
cryptococcosis. A patient with previous cryptococcal disease and a
positive screening test needs to be evaluated for disease
recurrence.
 A patient with previous cryptococcosis should remain on
fluconazole secondary prophylaxis until they meet specific CD4
and Viral Load criteria following treatment
 Patients who have had previous cryptococcal disease are at risk of
relapse of disease, especially if they have stopped taking their
fluconazole secondary prophylaxis.

 Patients who have had previous cryptococcal disease are at
increased risk of cryptococcal Immune Reconstitution
Inflammatory Syndrome (IRIS) when starting ART.
 Any patient with a history of cryptococcosis who presents
with a headache should be treated as if he or she has
recurrent disease, persistent or recurrent raised ICP or IRIS
until proven otherwise.

Lumbar Puncture procedure & Opening pressure (OP)
CSF opening pressure not useful to distinguish meningitis cause but often
elevated in CM patients (can be normal)

ADH_Part_II_Training Slides_ Hub_Spoke_V05_04_June_2022.pptx

Safe use of Liposomal AmB + Flucytosine (5FC) Regimen for Induction phase of CCM Treatment
WHO Guidance: 1 week AmB + 5FC is recommended for the induction phase of Symptomatic Cryptococcal Meningitis (CCM)
treatment as the Gold Standard for LMICs
Liposomal AmB + 5FC Safe Administration:
Drug L - AmB 5FC
Dosing • 3-4 mg/Kg daily (L-AmB). *Not to be confused with
other formulations of Amphotericin B.
• See 5FC dosing
guide in section
below
Supplementatio
n needed
• *Oral Potassium, Magnesium (and IV Normal Saline
with KCl unless contraindicated)
• None
Safety
Monitoring
• Infusion related reactions (especially during the first
dose).
• Renal function (creatinine, urea & electrolytes),
haematology: To be done minimum at Days 1,4,7 of
treatment and then once stable after treatment has
ceased.
*Refer to “Safe L-AmB administration” Workshop
• Full Blood Count
(FBC) at Days 1,
7, 10 for Hb/
Neutrophils/
Platelets
Side Effects and Management:
Drug
AmB • Inform/alert nearest clinician if: Muscle pain, shaking chills, painful urination, abdominal pain, jaundice,
seizures, irregular heart beat, black stools, or coffee coloured vomit.
• Other medications may be necessary to prevent or reduce these side effects e.g. antihistamines,
antipyretics.
Management:
 Ensure adequate hydration
 If creatinine remains high or increases despite adequate hydration, switch to 2nd
line
induction regimen: 2 weeks fluconazole + 5FC. Adjust 5FC dose as needed.
 Avoid nephrotoxic drugs such as Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
including ibuprofen and aminoglycosides
5FC • Neutropenia and anaemia: Manage with 5-FC dose adjustments/or blood transfusion
• Renal impairment: 5-FC dose adjustment may be required during treatment.
• REFER to “WORKSHOP – Safe administration of 5FC and Fluconazole
Weight of Patient Quarterly 6 hour dosing (mg) 500mg tablets
30 - 39 kg 500-1000-500-1000 1-2-1-2
40 - 49 kg 1000 2-2-2-2
50 - 59 kg 1000-1500-1000-1500 2-3-2-3
60 - 69 kg 1500 3-3-3-3
70 - 79 kg 1500-1200-1500-2000 3-4-3-4
NB: Women of child bearing age on 5FC should be linked to a reproductive health clinic. 5FC is a FDA Pregnancy Category C drug.
*1 week L-AmB (3-4
mg/kg/day) + 5-FC
(100mg/kg/day)
Then 1 week
Fluconazole 1200 mg
daily
**Until CD4 cell count ≥100
cells/mm3
and viral load (VL) <1000cpm.
If VL not available, until
stable/adherent to ART, CD4
count ≥200 cells/mm3
Induction Phase Consolidation Phase
8 weeks
Fluconazole
800 mg daily
Maintenance Phase
**At least 1 year
Fluconazole
200 mg daily

Module 2 Summary
 Cryptococcal infection and disease are a significant cause of morbidity and
mortality in AHD.
 Screening and early diagnosis of CCM is crucial for timely initiation of appropriate
anti-fungal therapy.
 CrAg LFA test kits provide for a rapid screening test in PLHIV with AHD.
 Treatment of CCM is 3 phases (Induction, Consolidation, Maintenance) and
necessitates hospital-based care. AmB is the mainstay of CCM treatment
 Pre-emptive treatment of CrAg positives is 2 weeks of fluconazole 800mg daily,
followed by consolidation and maintenance phases as for CCM treatment.
 All CrAg positives should be offered LP as a significant proportion have sub-clinical
meningitis.
 Clinical expertise in CCM management requires training including proactive patient
monitoring, management of treatment-related side effects and complications of
CCM.

https://forms.gle/Hh9EYsxFYCRB3eTw8
Each Participant Should ensure to
fill the form in the link below

ACKNOWLEDGEMENTS
This toolkit was developed through a collaborative process involving a
coalition of partners (The World Health Organization, Clinton Health Access
Initiative, Centers for Disease Control & Prevention, St George’s University of
London, United States Agency for International Development, Médecins Sans
Frontières, Elizabeth Glaser Pediatric AIDS Foundation, International AIDS
Society, National Institute for Communicable Diseases South Africa, National
Institute for Medical Research Tanzania, Joint United Nations Program on
HIV/AIDS, Infectious Disease Institute Uganda, U.S. President’s Emergency Plan
for AIDS Relief, The Global Fund, Bill & Melinda Gates Foundation, Global Health
Impact Group, Coalition Plus, Medical Mycology Society of Nigeria and
Lighthouse Malawi) and made possible through the Unitaid Advanced HIV
Disease Initiative.

ADH_Part_II_Training Slides_ Hub_Spoke_V05_04_June_2022.pptx

More Related Content

Similar to ADH_Part_II_Training Slides_ Hub_Spoke_V05_04_June_2022.pptx (20)

More from yakemichael (20)

Recently uploaded (20)

ADH_Part_II_Training Slides_ Hub_Spoke_V05_04_June_2022.pptx

Editor's Notes