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Antiretroviral drug: when

is the best time to initiate


ARV in nave patient?
Endah Citraresmi
HIV Task Force, Indonesia Pediatric Society
Harapan Kita Women & Children Hospital

Start ARV

Diagno
sis

Improve
survival &
quality of
life

Mortality and Frequency of Use of Combination Antiretroviral


Therapy Including a Protease Inhibitor among HIV-Infected
Patients with Fewer than 100 CD4+ Cells/mL

Palella et al. N Engl J Med 1998; 338:853-860

Goal of therapy

Cure the
patient of
infection
Not yet achievable

Control the
infection for a
long period of
time

Starting ARV

Restoratio
n of cell
mediated
immunity

11.5-21%:
IRIS
clinical
ARV
deteriorati
toxicities
on
Failure

Antiretrovi
ral therapy
(ART)
Significant
survival's
improvem
ent

Reduction
opportunis
tic
infections

Eligibility of ARV:
- CD4?
- IO? = WHO
category?
Treat IO how
long?
Prepare and
assess adherence
Diagnosis:
- Definitive
- Presumpt
ive

Start ARV:
- Monitor
adverse
reactions
- Monitor IRIS
Monitor:
Growth
Development
Psychosocial
Improve
survival &
quality of
life

Factors to consider in decisions regarding


initiation of antiretroviral therapy in HIV-infected
infants, children, and adolescents

The severity of HIV disease and risk of progression as determined by


presence or history of HIV-related serious or AIDS-defining illnesses, and the
childs CD4 cell count and plasma HIV RNA level
Availability of appropriate and palatable drug formulations for the child
and pharmacokinetic information on appropriate dosing in the childs age group
Potency, complexity (eg dosing frequency, food and fluid requirements), and
potential short- and long-term adverse effects of the antiretroviral regimen
Effect of initial regimen choice on later therapeutic options
Presence of co-morbidity that could affect drug choice, such as tuberculosis,
hepatitis B or C infection, or chronic renal or liver disease
Potential antiretroviral drug interaction with other medications required by
the child
The ability of the caregiver and child to adhere to the regimen

Probability of Death or a First


Event, According to Treatment
Group
CHER (Children with HIV Early
Antiretroviral
Trial
377
HIV-infected infantsTherapy)
6 to 12 weeks
of age
with a CD4 of 25% or more
Randomly assigned to:
receive ART when the CD4 decreased to
<20% (or 25% if the child <1 year) or
clinical criteria were met (the deferred
antiretroviral-therapy group)
immediate initiation of limited antiretroviral
therapy (the early antiretroviral-therapy
groups)
Death: 16% (deferred-therapy group) versus
4% (early-therapy groups) (hazard ratio for
death, 0.24; 95% CI,0.11 to 0.51; P<0.001.
Disease progressed: 26% (deferredtherapy group) versus 6% (early-therapy
groups) (hazard ratio for disease progression,
0.25; 95% CI, 0.15 to 0.41; P<0.001).
Violari, N Engl J Med 2008;359:2233-44.

Early HIV diagnosis and early


antiretroviral therapy reduced early
infant mortality by 76% and HIV
progression by 75%.

Pediatric Randomized Early


versus Deferred Initiation in
Cambodia and Thailand (PREDICT)
trial
300 Thai and Cambodian children infected
with HIV, with a median age of 6.4 years, CD4
percentages of 1524%, randomly allocated
to early treatment (CD4 % 1524%) or
deferred treatment (started after a decline in
CD4 percentage to <15% or development of
CDC category C events)
AIDS-free survival at week 144 in the deferred
treatment group was 98.7% (95% CI 94.7
99.7; 148 of 150 patients) compared with
97.9% (93.799.3; 146 of 149 patients) in the
early treatment group (p=0.6).

Differences in mean height-for-age Z score


between treatment groups at each study
visit

Puthanakit et al, Lancet Infect Dis.2012;12:933

WHO guideline 2010 10,11


Adults & adolescents
CD4 350 cells/mm3
WHO clinical stage 3 or 4
regardless of CD4 count
WHO stage 1 or 2 should
get access to CD4 to
decide when to start
treatment
Children
Start ART to all HIV infected
children:
12-24 mo: all
24-59 mo : CD4 750
cells/mm3 or 25%
>5 yo: 350 cells/mm3
WHO clinical stage 3 or
4 : all

WHO guideline 2013

12

Adults & adolescents (10


yo)
CD4 500 cells/mm3
Priority:
WHO clinical stage 3 or 4, or
CD4 350 cells/mm3
Children 5 yo: CD4 500
cells/mm3
Priority:
WHO clinical stage 3 or 4
CD4 count 350 cells/mm3
Initiate ART regardless of
CD4 cell count
WHO clinical stage 3 or 4
Active TB disease
Children 1-5 yo : all
Priority:
Children 12 yo, or
WHO clinical stage 3 or 4, or
CD4 750 cells/mm3 or
<25%, whichever is lower

WHO guideline 2015 13


Adolescents (10-19 yo): all
Priority:
WHO clinical stage 3 or 4
CD4 350 cells/mm3

Infant & children <10 yo: all


Priority:
2 yo: all
<5 yo: WHO clinical stage 3
or 4 or CD4 750 cells/mm3
or CD4 <25%
5 yo: WHO clinical stage 3
or 4 or CD4 350 cells/mm3

Summary: Initiating ART in


children
WHO
guideline
2010

WHO
guideline
2013

WHO
guideline
2015

WHO clinical stage


3 or 4

ALL

ALL

ALL

0 12 mo

ALL

ALL

ALL

12 24 mo

ALL

ALL

ALL

24 59 mo

CD4 750
cells/mm3 or
25%

ALL
Priority: CD4 750
cells/mm3 or <25%

ALL
Priority: : CD4 750
cells/mm3 or <25%

5 10 yo

CD4 350
cells/mm3

CD4 500
cells/mm3
Priority: CD4 350
cells/mm3

ALL
Priority: CD4 350
cells/mm3

10 19 yo
(adolescents)

CD4 350
cells/mm3

CD4 500
cells/mm3
Priority:CD4 350

ALL
Priority: CD4 350
cells/mm3

ARV Indication Indonesia MOH 2014


Age

Clinical Immunological
Criteria
Criteria

<24 mo

Therapy

Treat all

>24 mo Stage 3 & 4a

Treatb

Stage 2

Stage 1

<25% in children
age 24-59 mo
<350 cells/mm3 in
children >5 yo

Dont treat if no
CD4 value
Treat if CD4 < ageadjusted value

a. Opportunistic infection treatment should take precedence


b. If possible, check CD4 to monitor the treatment

What to prepare?
Starting ART is not an emergency

Asses and
address possible
problems in
adherence
Screen for opportunistic
infection
and treat
to reduce risk of immune reconstitution
inflammatory syndrome (IRIS)

Potential advantages and disadvantages of


starting antiretroviral therapy (ART) early in
the course of treatment for serious
opportunistic infections (OIs)
Potential advantages of
early initiation of ART
Prevent progressive
immunodeficiency
More rapid immune recovery
More rapid resolution of OI
Rapid reduction in mortality risk
Prevention of further OIs and
other morbidity

Potential disadvantages of
early initiation of ART
(overlapping treatment)
High pill burden
Co-toxicity
Pharmacokinetic drug interactions
Immune reconstitution disease
More difficult to identify drug
causing toxicity
Current opinion in infectious diseases. 2011;24:34-42

Timing of Initiation of Antiretroviral Drugs during Tuberculosis


Therapy
Kaplan-Meier survival curves

NEJM. 2010;362:697-706

Early versus Delayed Initiation of Antiretroviral Therapy for


Concurrent HIV Infection and Cryptococcal Meningitis in SubSaharan Africa
Kaplan-Meier survival estimates by treatment group

Clin Infect Dis.2010;50:1532-8.

Early Antiretroviral Therapy Reduces AIDS


Progression/ Death in Individuals with Acute
Opportunistic Infections: A Multicenter Randomized
Strategy Trial (ACTG A5164 study)

Time to ART initiation from the start of


OI/BI treatment. Early arm median 12
days [IQR 913 days]; Deferred arm
median 45 days [IQR 4155 days].

Time to AIDS progression or death. HR


= 0.53 Early versus Deferred ART
[95%CI 0.300.92 p = 0.023].
Zolopa et al. PLoS ONE; 2009; 4: e5575.

When to start?
US CDC
guidelines

Urgent treatment (ie within 1-2 weeks)


for all such children with severe HIV disease
(stage-3-defining opportunistic illnesses in
HIV infection), regardless of immunologic or
virologic status

WHO
Consolidated
guidelines
2013

ART should be started in any child with


active TB disease as soon as possible
and within 8 weeks following the
initiation of antituberculosis treatment,
regardless of the CD4 cell count and clinical
stage

Screen for Opportunistic


Infections
Opportunistic infections: infection by a microorganism that normally does
not cause disease but becomes pathogenic when the bodys immune
system is impaired
Children acquired OI vertically from the mother of horizontally from the
environment
Screen for:
TB: Mantoux test (consider IGRA if available), chest x-ray, gastric washings for
AFB
Hepatitis A IgG, HBsAg, anti-HBsAg, HCV IgG, Syphilis serology
IgG for EBV, CMV, HSV, VZV, Toxoplasmosis
Plasma CMV PCR in advanced disease
Stools / urine / throat swabs / blood cultures / malaria films / sexual health screen
if appropriate

Social & pharmacological


aspects before starting ART
Social aspects
Motivation to begin therapy
Ability for the patient to adhere
to the long-term therapy
Lifestyle pattern of the patient
Economic stability of the family
Existence of family support
Knowledge of the pros and cons
of starting the therapy

Pharmacological
aspects
Dosing and frequency of the
drugs
Tolerability of the regimen
Access and availability of drugs

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