Transcript Module IV Session 1 Intro and Management

Module IV: Paediatric ART
Treatment
An Introduction to Antiretroviral Therapy
Key questions:
• What are ARVs?
• Why do we give ARVs to HIV infected children
and adolescents?
• How do ARVs reduce the replication of HIV?
• What are the different ARV drug classes and
types?
• What factors affect success of ART in children?
Why do we give ARVs to HIV infected
children and adolescents?
To reduce the HIV related morbidity & mortality of
children and improve survival and quality of life.
What do ARVs do?
• Suppress HIV replication and prevent disease
progression.
• Restore and/or preserve the immune system
reducing the risk of opportunistic Infections.
• Promote optimal growth and development
Why do we learn about the structure and
life cycle of the Virus?
• Understanding the structure helps us to know
structures in the virus that helps it multiply in
the human cell
• Understanding the Life cycle helps us to know
how the virus multiplies, where the ARV drugs
work and how they are classified
Structure Of Human Immunodeficiency Virus
HIV STRUCTURE
Envelope Proteins
Envelope
gp120
Enzymes
gp41
2.Reverse Transcriptase
Matrix Protein
p17
Core Proteins
RNA
HIV Core protein’s
1.P24 surrounds protein Core
converts viral single-stranded RNA
into double stranded (DNA)
3.Integrase. Integration of the viral
p24
DNA into the host’s chromosomal
RT
DNA.
Integrase
4.Protease splits generated macro
Protease
proteins into smaller viral proteins
which are then incorporated into
the new viral particles
HIV life cycle shows where the ARVs work
INFECTING
VIRUS
HIV
RNA
INTEGRASE
REVERSE
TRANSCRIPTASE
S. S.
HIV
DNA
REVERSE
TRANSCRIPTION
D. S.
HIV
DNA
HIV
mRNA
INTEGRATION
PR
RIBOSOMES
HIV
LIFE
CYCLE
HIV
precursor
proteins
O
TE
AS
E
HIV
RNA
ASSEMBLY
HIV
RNA
Insertion
in Host
Genome
HIV LG. PROTEINS
NEW
VIRUS
Steps in HIV life cycle
1. Fusion and entry into human cell.
2. Reverse Transcription RNA-DNA.
3. Integration into host genome
4. Transcription and Translation of virus components
5. Budding and maturation of new virus particles
Video of Life cycle
What are the different classes of ARVs?
• Nucleoside Reverse Transcriptase Inhibitors (NRTI)
• Non- Nucleoside Reverse Transcriptase Inhibitors
(NNRTI)
• Protease Inhibitors (PI)
• Integrase Inhibitors
• Fusion Inhibitors (FI)
Which three classes are commonly used in Uganda?
Nucleoside Reverse Transcriptase
inhibitors (NRTI)
Single Drugs:
• Zidovudine (AZT)
• Stavudine (D4T)
• Lamuvudine (3TC)
• Didanosine (DDI)
• Abacavir (ABC)
• Tenofovir
• Emtricabine
• Zaltacibine
Fixed Dose Combinations
• AZT/3TC/NVP (Douvir N)
• AZT/3TC (Combivir or Duovir)
• D4T/3TC/NVP (triomune)
• D4T/3TC
• AZT/3TC/ABC(Trizivir)
• ABC/3TC(Epzicom)
• Tenofovir/Emtricabine(Truvada)
Non Nucleoside Reverse Transcriptase
Inhibitors
Nevirapine (NVP)
Efavirenz (EFV)
Delarvirdine (DLV)
Protease Inhibitors
lopinavir/ritonavir (Kaletra/ Aluvia)
Ritonavir
Lopinavir
Atazanavir
Darunavir
Saquinavir
Nelfinavir
Indinavir
New Classes
Entry/ Fuzion Inhibitors
• T20/ Fuzeon / Enfuvertide
Integrase Inhibitors
• Raltegravir
Principles of Paediatric Antiretroviral Therapy
• Initiate therapy with at least three drugs in a potent
regimen
• Include at least two new agents when changing a
therapy.
• Avoid using drugs previously used in a failing regimen
(recycling) unless you have done resistance testing
• Keep doses at the upper end of dosing range
• Check children’s weights and adjust drug dosages at
each visit
• Maximize adherence to ART
• Rationally sequence drugs to preserve future treatment
options
What factors affect the success of ART?
Drug
Virus
10 OR 20
Resistance
Potency
Patient
Toxicity /
Interaction
Clinician,
Nurse,
Counsellor
NonAdherence
Activity:
Do you know the basics about ARVs?
• Let us practice with a T/F quiz competition
Management of ART
Key questions:
• When should HIV+ve children be started on ART?
• What 1st line regimens are used to start ART?
• When do we substitute drugs in the 1st line regimen?
• How do we monitor children on ART?
• How do we make a decision to switch from a 1st line
to 2nd line regimen?
• What 2nd line ARV regimens are used in Uganda?
• How can we identify an Immune Reconstitution
Inflammatory (IRIS) event?
When are children supposed to start ART?
1. Determine eligibility for ART
– Clinically
– Immunologically
2. Determine the readiness of the child to start ARVs
–
–
–
–
–
–
Disclosure if appropriate
Adherence counseling
Social life and current responsibilities
Being in and out of school
Family support
Availability of trusted treatment supporter (Buddy)
3. Do a Pre-treatment (Baseline) Assessment
–
–
–
–
–
–
Full clinical assessment for infections & clinical staging
Neuro developmental assessment (include Tanner staging)
Weight, length/height, head circumference
Do Hb
CD4+ count
Viral load (where available)
4. Identify and prepare the main parent/caregiver
– Educate on giving the child ARVs and continuing with home
care
– Counsel on caring for and living with an HIV infected child
Comparing 2006 and 2010 guidelines- What has
changed?
2006
2010
Immune
marker
Age-specific recommendation to initiate ART
<12
m
12 to 35 m
CD4 percent
All
<20%
<20%
<15%
CD4
count/mm3
All
<750 cells
<350 cells
<200
cells
TLC/mm3
All
<3000 cells
<2500 cells
<2000
cells
Immune
marker
Age-specific recommendation to
initiate ART
Clinical
criteria
<24m 24-59m
>5 yrs
stage 4
disease
<350 cells
stage 3
disease
CD4 percent
All
<25%
CD4
count/mm3
All
<750 cells
36 to 59 m
≥5 yrs
Clinical criteria
Stage 4 disease
Stage 3 disease (for
children aged over 12
months with TB, LIP,
OHL or low plts, ART
initiation may be
delayed
What is the age
of the child?
< 2yrs
Assessing HIV +ve children
for ART eligibility
2yrs
&
above
WHO clinical
Stage 3 or 4?
NO
What is the
age & CD4
count?
2 to
<5yrs
Yes
CD4% <25%
or count <750
START ARV’S
5yrs &
above
CD4 count
<350 cells
2 to <5yrs
CD4% >25% or count >750
5yrs and above
CD4 count >350
Continue
Monitoring
Starting ART in children under 18 months without
confirmed HIV status(presumptive diagnosis of HIV)
HIV +
Rapid
test
HIV +
Rapid
test
OR
Any 2 of the following
•Oral thrush
•Severe pneumonia
•Severe sepsis
HIV stage 4
conditions
Recent HIV related maternal death
or
CD4 % <20%
START ARV’S
but take DBS to confirm HIV status
Choosing a Regimen
• The first line regimen is the best chance
to achieve maximum and sustained viral
suppression
Examples of Combinations to be avoided
• TDF+DDI
– Low potency
– Interactions
• TDF+ABC
– Early treatment failure
• d4T+ddI
– Mitochondrial Toxicity
• D4T +AZT
– Competition for same site
Monitoring children on ART
Rationale of monitoring
Assess effectiveness:
Improvement or Treatment failure
Assess safety:
Toxicity, Tolerability, Drug interactions
Assess adherence to the drugs
Taking the correct regimen, correct dose, at the right time
How do we monitor children on ART?
• Clinical
• Laboratory
• Psychosocial
Clinical monitoring
1st Visit after ART initiation
• Review understanding of
HIV: disease process and
adherence strategies
• Observe accurate dosing
and administration of drugs
by caregiver
• Full clinical assessment
• Return visit in 2 weeks
Monthly clinical monitoring
• Interval medical history,
symptom check
– Wt,Ht, physical exam,
nutritional assessment
– Side effects/toxicity, IRIS
– Assess adherence
• Ask for demonstration of dose
and administration of
medication at each visit
• Recalculate dose
• Dispense more doses
Laboratory monitoring
Immunological testing
– CD4 counts: done every 6 months or if there are
other features suggesting treatment failure
Virological testing
- Done every 6 – 12 months if available
Lab monitoring
Lab test for diagnosis
and monitoring
Baseline
( entry into care)
Initiation of
1st or 2nd
regimen
HIV diagnostic testing
.
Hb
.
.
.
.
Every six
months
.
.
WBC and differential
CD4% or absolute
CD4 count
As required or
symptom
directed
.
.
Preg. Test in adols
.
Chemistry
.
VL
.
.
OI screening
.
Psychosocial Monitoring
•
•
•
•
•
Progress at school
Relationships with family members, friends
Attitude to daily drug taking, adherence
Progress of disclosure
Development into adolescence – sexual
awareness, behavioural issues
34
What is substitution?
Substitution is the process of replacing one drug
with another.
When or why do we substitute drugs in the 1st line
regimen?
Main reasons for substitution of an ARV drug:
– Toxicity
– Pregnancy
– Development of OI like TB, Hep B., etc
– Change in treatment guidelines
Examples of substitution
Drugs
What to
substitute with
ABC or D4T
EFV
Reason to
change the drug
Anaemia
(toxicity)
pregnancy
NVP
TB treatment
EFV
AZT
Steven Johnsons
syndrome
(toxicity)
NVP
When do we switch from 1st line to a 2nd line
regimen?
Switch from one ARV regimen to another when there is
Treatment Failure
Parameters used to assess ARV Treatment Failure include:
•Clinical
•Immunological
•Virological
Remember:
Always consult and discuss the case with a colleague
before you substitute a drug or switch a regimen!
Immunological failure or not?
• Patient takes D4T+3TC+NVP for 1 year and 6
months.
• CD4 was measured at baseline (50 cells/ml),
month 6 (143) , month 12 (247) , month 18
(220).
• Is this failure or not?
• Not enough indications to say it’s failure.
• CD4 physiological variation more probable.
• Look also at CD4%; less variable.
• In case of doubt, and before deciding on treatment switch, do another CD4 test
(same machine, same lab) +/- 1 or 2 months later
What 2nd line to Use
National ART Paediatric Guidelines
help us to:
• Decide when to start ARVs
• Decide on the 1st line regimen to use
• Decide the ARV regimen to use in special
clinical conditions
• Identify a failing regimen
• Decide a 2nd line regimen to switch to
IRIS (Immune reconstitution Inflammatory
Syndrome)
Definitions
• Previously quiescent diseases which become
symptomatic or worse after the introduction of
HAART (unmasking type)
OR
• Worsening of symptoms of OI’s that were already
under effective treatment (TB, AC,CMV), shortly
after starting HAART (paradoxical worsening)
How does IRIS come about?
• There is a quiescent disease like TB, MAC and a
failed immune system.
• On starting ART, the immune system begins to
recover and mount an attack on these quiescent
diseases.
• This makes the symptoms of the quiescent disease
appear or re-appear if it was previously there
Comparison between IRIS and
Treatment failure
Parameter
IRIS
Treatment
Failure
Opportunistic
infections
CD4+ counts
Worsen
Worsen
Increase
Decrease
Viral load
Decrease
Increase
Treatment of IRIS
• Continue ART (sometimes stop needed due to
interactions or patient’s condition too bad)
• Treat the IRIS according to the presenting OI with the
standard treatment for that condition e.g. TB (if already
on Rx , intensification may be required)
• Add corticosteroids in case of severe inflammatory
response e.g. dyspnoea due to large thoracic LN, or
severe CNS (e.g. prednisolone 20-40 mg/day, 2 weeks-1
month)
• Use mechanical measures (drainage)
• Use of NSAID (ASA)
Activity: Case # 1
• John is a one year old, HIV +ve child who was started on
AZT+3TC and NVP at 2 months of age. The child has been
adherent to his treatment. His CD4+ has fallen from 500 to
150 cells over 6 months. He was well until 2 weeks ago when
he developed oral thrush. He has been treated with
Ketoconazole with no improvement.
Qn1: What is the Treatment stage?
Stage 3
Qn2: Would you switch therapy in the child and why?
Length on treatment >24 weeks, Adherent to treatment yes
Then switch because there is clinical and immunological failure.
Qn3: what ARV regimen would you give?
ABC +3TC+LPV/r
Activity: Case # 2
Na-gundi is a 4 year old girl who has been on AZT+3TC+ NVP for
the past 3 months, and she has not missed her drugs. Her
mother reports that she has developed symptoms of cough and
difficulty in breathing. Her mother also reports that she thinks
that Na-gundi gets a bit hot especially in the afternoon and
sweats a lot at night. Na-gundi was treated with IV ceftriaxone
for 5 days with no improvement.
•IRIS – TB
• Pneumonia
Qn1: What could be the diagnosis in Na-gundi?
Sputum ZN
Qn2: What other investigations would you do ? CXR
Mantoux test
Early CD4+ counts
Qn 3: Would you switch treatment in this child and why?
•No
•Duration on treatment= 12 weeks
•Adherence good
•If she has confirmed TB – IRIS, substitute NVP for Efavirez
Practical 3
Mukonogum is an 8 year old boy. He has been on AZT+
3TC +•Yes
NVP
for 3onyears
He has been
- Duration
ART >24now.
weeks, Adherent-Yes,
Clinicaladherent
failure- yes , and
doingImmunological
very wellfailure-Yes
until 1 month ago when he developed
•ABC+ 3TC + LPV/Rtr
skin •Factors
rashesforand
pneumonia. His CD4 count when he
clarification:
started Adherence
treatment was 200. His CD4 as per last month
Tolerability (e.g. side effects)
was 300.Pharmacokinetic
It was repeated
2 daysrequirements
ago and it was 90
issues (food/fasting
Drug-drug
interactions
cells/mm
.
1.
Potency of current ARTs
FromPrior
thisART
information
experience do you think Mukonogum is
•Potential
for or known resistance
his first
line regimen?
failing on
2. If yes, which regimen are you likely to switch him to?
3. What factors do you need to clarify on before you initiate
him on the second line?