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Initiation and Monitoring of
Therapy
Unit 8
HIV Care and ART:
A Course for Physicians
Learning Objectives
 Define HAART and identify goals of Antiretroviral
Therapy (ART)
 Describe the preparation and indications for
initiation of ART
 Describe the first line ART regimens in Ethiopia
 Identify the goals and ways of monitoring ART
 Explain IRIS and its implications during
monitoring
2
History of ART
 In 1986 AZT was discovered as the first ARV
drug
 Reduced viral replication
 Effect short lived due to the rapid development of
resistance
 Dual therapy showed better results than
monotherapy
 Effect still limited by resistance
 In 1996, HAART was introduced
 Sustained clinical and virological response seen
3
What is HAART?
 HAART stands for Highly Active Anti Retroviral
Therapy
 Similar to ART (can be used interchangeably)
 A combination of at least three effective ARV
drugs
 Controls HIV replication with reduced risk of
resistance development
 However, it does not eliminate the virus from the
body. It is not a cure
4
Goals of HAART- Primary
 Reduce HIV RNA (viral load) to undetectable
levels within 4-6 months of ART initiation with
durable suppression
 Increase CD4 cell count, allowing preservation
or improvement of immune function
 Reduce HIV related morbidity thereby improving
quality of life of the patient
 Reduce HIV related mortality
5
Goals of HAART- Secondary
 Reduction of the incidence of HIV by:
 Increasing uptake of HCT
 Prevention of mother to child transmission
 Reducing stigma and discrimination through raising
community’s hope
 Reducing transmission of HIV at the community level
6
What Factors Determine the
Success of HAART?
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ADHERENCE!
Appropriate preparation for initiation
Use of effective first line regimen
Proper monitoring for side effects and disease
progression
7
Introductory Case: Meseret
 Meseret, a 25-year-old female, came to the ART
clinic after she was referred from the VCT center
 She decided to be tested for HIV because she
observed significant but unintentional weight loss in
the last 2 months
 Her boyfriend recently died from chronic couch and
marked weight loss and she believes he had
underlying HIV infection
 She was told that she is HIV positive 3 days ago
 What should be done to prepare Meseret for
HAART initiation?
8
Preparation for HAART Initiation
 Baseline clinical and lab evaluation
 Identify and treat OIs
 Assess for the presence of indications for ART
 Clinical staging
 CD4 values
 Assess patient readiness
 Acceptance of HIV status and benefits of ART
 Psychological, financial, socio-cultural issues
 Strong adherence counseling
 Prepare patient follow-up for after initiation of ART
9
Initial Evaluation for Initiation
of ART
Introductory Case: Meseret (2)
 What should be done in the baseline
assessment to evaluate Meseret?
11
The Baseline Assessment
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Baseline health history
Physical examination
Clinical staging
Laboratory testing
12
Baseline Health History
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Current symptoms
Usual source and pattern of seeking care
Psychiatric or emotional disorders
Surgical history
 Date
 Recovery status
 Review of systems
 Past medical illness
13
Baseline Health History (2)
 Childhood Illnesses
 Varicella
 Immunizations
 Family Medical History
 Medical conditions
 Mental health
 Sexually Transmitted Infections (STI)
 Treatment and follow-up
14
Baseline Health History (3)
 Gynecologic and Obstetrical History
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Menstrual history
Pregnancy history
Methods of birth control
PMTCT history
 Children’s HIV Status
15
Baseline Health History (4)
 Medication History
 Previous/current medications including HAART
 Drug allergy
 Adherence history
• Assess adherence to care and medications
• Assess family/household support
 Nutritional History
 Access to food
 Social history
 Patient beliefs and misconceptions
16
Baseline Physical Exam
 Do complete physical examination
 Special attention to:
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Weight
Height (head circumference in children)
Oral cavity
Lymph nodes
Lungs and CVS
Skin: full exam including rectogenital region
Liver and spleen size
For women, pelvic exam and pregnancy status
Funduscopic and neurological evaluation
17
Introductory Case: Meseret (3)
 When asked her health history, Meseret reports:
 No complaints other than weight loss
 Treated for pulmonary TB one year ago
 No history of STI
 On examination, Meseret looks thin with silky
hair.
 Weight 42 kg (50 kg 6 months back)
 No oral thrush
 No other remarkable finding
18
Introductory Case: Meseret (4)
 Is Meseret eligible for ART?
 What baseline lab tests would you request for
Meseret?
19
Baseline Laboratory Testing
 HIV antibody test
 Hemoglobin or hematocrit and WBC with
differential count
 Serum ALT or AST, bilirubin
 Serum creatinine & BUN
 CD4 lymphocyte count
 Pregnancy test (women)
 Other tests are indicated when appropriate
based on patient current and past medical
history e.g. CXR, sonography etc
20
Baseline Laboratory Testing (2)
 Other tests:
 Serum glucose
 Amylase
 Serum lipids
 Viral load testing
21
When to Start ART
 Starting Antiretroviral Drugs is NOT AN
EMERGENCY!
 Criteria for initiation must be met
 At least two visits are necessary before initiation
to ensure patient readiness
22
Indications for ART
 Based on ‘Guidelines for Use of Antiretroviral
Drugs in Ethiopia,’ January 2005.
 Adapted from the revised WHO guidelines
 Can be used in the presence or absence of CD4
values
 Uses WHO clinical staging, CD4 count and TLC as
appropriate
 Designed for:
 Physicians and other health-care providers
 HIV/AIDS program managers, health planners, and
experts working on drug selection and procurement
23
Objectives of the Guidelines
 Ensure evidence-based, safe, and rational use
of antiretroviral drugs
 Provide standardized approach to the use of
ARV drugs in the comprehensive HIV/AIDS care
in Ethiopia
 Serve as a reference resource to health care
providers and people living with HIV/AIDS
24
Clinical Criteria for ART
Initiation for Adults
 If CD4 count available:
 WHO stage IV irrespective of CD4
 WHO stage III with CD4 ≤ 350/mm3
 CD4 < 200/mm3 irrespective of the clinical stage
 If CD4 count not available:
 WHO stage IV irrespective of TLC
 WHO stage III irrespective of TLC
 WHO stage II with TLC < 1200/ mm3
25
Introductory Case: Meseret (5)
 The following lab tests were obtained for
Meseret:
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Hct: 36%
WBC: 4000/mm3 ; L- 20%
BUN, creatinine and ALT – within normal limits
Urine pregnancy test—negative
CD4- specimen to be sent to regional lab (result
expected in 2 weeks)
 Is she eligible for ART?
26
Introductory Case: Meseret (6)
 Meseret was counseled by the ART nurse about:
 Living positively with the virus
 Availability of treatment free of charge
 Need for 100% adherence
 Started with cotrimoxazole 960mg daily
 Made appointment to return in two weeks
27
Ethiopian First-Line Regimens
Usage in Women
Usage in TB coinfection
ARV Regimen
(of childbearing age or
pregnant)
d4T/3TC/NVP
Yes
Not with RIF
containing regimen
ZDV/3TC/NVP
Yes
Not with RIF
containing regimen
d4T/3TC/EFV
No
Yes; increase dose of
EFV to 800mg
No
Yes; increase dose of
EFV to 800mg
ZDV/3TC/EFV
28
Special Considerations in
Selecting Regimens
 If there is potential for pregnancy, avoid EFV due
to teratogenicity
 If patient is taking Rifampicin, use EFV instead
of NVP
 If patient has anemia, use d4T instead of ZDV
 Avoid the following in HAART combinations:
 d4T+ ZDV due to pharmacodynamic antagonism
 d4T+ ddI in pregnancy due to greatly increased risk of
lactic acidosis
29
Introductory Case: Meseret (7)
 Meseret returned in 2 weeks with enthusiasm to
start ART
 CD4 = 150/mm3
 What drugs would you start her with?
30
Key Points on Starting ART
 Not an emergency
 Has to be individualized
 Ensure fulfillment of eligibility criteria before
initiating
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Medical
Emotional
Social
Follow-up
Access to ARVs ensured
31
Monitoring Therapy
Goals of Monitoring ART
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Detect drug toxicity, interactions and side effects
Evaluate initial response to therapy
Assess adherence
Recognize treatment failure as early as possible
33
Types of Monitoring
 Clinical assessment
 Laboratory monitoring
34
Clinical Assessment
 Conduct physical examination and symptom
review at each visit
 Compare current status to baseline
35
Clinical Assessment (2)
 History
 Drug side effects: nausea, vomiting, jaundice, RUQ
pain, bad dreams, etc
 Symptoms of OIs such as cough, fever, severe
headache, etc
 Adherence to medications
 Physical exam
 Take weight at each visit
 Look for signs of drug side effects and OIs
36
Laboratory Monitoring
 Should be done on regular basis according to
Ethiopian Guidelines, and as needed for specific
clinical conditions
 Detects side effects (toxicity) of drugs before
clinical symptoms and signs appear
 Used for early detection of response to therapy
37
Laboratory Tests for Toxicity Monitoring
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Hgb/Hct
WBC and differential, platelet count
ALT, AST
Other tests
 Lipid profile for PI or EFV containing regimens
 Blood sugar for PI containing regimens
 Creatinine for IDV containing regimens
38
Laboratory Tests for Monitoring
Response to Therapy
 CD4 testing
 Used to monitor immunological response
 With successful therapy, it is expected to rise about
50-100/mm3 per year
 Viral load testing
 Should be done at baseline, three months after
initiation to detect early treatment success, and at 6
months to see if viral load is detectable
 Successful treatment decreases viral load by at least
1 log at 6-8 weeks and to undetectable levels by 24
weeks
39
Recovery of CD4 Cells Continues for
Years after Starting HAART
40
Source: Binquet C, et al. Am J Epidem, 2000.
Ethiopian Guidelines for Lab Monitoring
Regimen
ART
Lab Test
Frequency
1
d4T/3TC/NVP
ALT
TLC or CD4
Baseline, 2, 4, & 8 wks, & q6 mos
Baseline & q6 months
Other
D4t/3TC/EFV*
ALT
TLC or CD4
Baseline & Symptom directed
Baseline & q6 months
AZT/3TC/EFV*
ALT
TLC or CD4
Hgb
Baseline & Symptom directed
Baseline & q6 months
Baseline, 4, and 12 weeks,
thereafter symptom directed
AZT/3TC/NVP
ALT
TLC or CD4
Hgb
Baseline, 2, 4, & 8 wks, & q6mos
Baseline & q6 months
Baseline, 4, and 12 weeks,
thereafter symptom directed
41
Introductory Case: Meseret (8)
 Meseret was started on ART after intensive
adherence counseling:
 Stavudine 30mg BID
 Lamivudine 150mg BID
 Nevirapine 200mg daily
 When should her next appointment be?
 What would you do at the time of her next visit?
42
Introductory Case: Meseret (9)
 Next visit after 2 weeks
 Her evaluation includes:
 Symptoms of drug side effects like skin rash and
itching, jaundice
 Assessment of adherence
 Any other new symptom
 Look for icterus, skin rash; measure her weight
 Do ALT
43
Introductory Case: Meseret (10)
 At her two week visit you find:
 No complaints except mild itching over the trunk
without rash
 No jaundice
 Good adherence
 The dose of NVP increased to 200mg BID
44
Introductory Case: Meseret (11)
 At her third post-ART visit (2 months after
initiation of ART), she reported a cough of 2
weeks duration
 Has associated scanty sputum and low grade
fever
 Chest is clear
 List the differential diagnosis for her current
symptoms
45
Introductory Case: Meseret (12)
 Differential diagnosis
 Pulmonary TB
 Upper respiratory tract infection
 Pneumonia (PCP, bacterial, fungal)
46
Introductory Case: Meseret (13)
 Investigations revealed:
 WBC= 5000/mm3; L= 25%
 Sputum for AFB negative
 CXR showed bilateral lower lung nodular infiltrates
with left sided pleural effusion
 Pleural fluid analysis revealed lymphocytic &
exudative fluid
47
Introductory Case: Meseret (14)
 Presumptive diagnosis of Tuberculosis was
made.
 What went wrong with Meseret?
48
Immune Reconstitution
Inflammatory Syndrome (IRIS)
 IRIS is the occurrence of an inflammatory
condition (OI) a few weeks to 6 months after the
initiation of ART due to restoration of immune
status
 It may manifest as:
 A new OI occurring for the first time
 Reappearance of a previously treated OI
 Flare up of an existing viral infection like viral hepatitis
or herpes simplex
49
IRIS (2)
 Mechanism:
 When effective ART regimen is given, the CD4 cells
increase in number rapidly
 A previously sub-clinical infection would trigger an
inflammatory response and tissue damage
 The quiescent infection will become a clinically
apparent disease
50
IRIS (3)
 Timing:
 Usually occurs in patients with very low CD4 count
(<50/mm3)
 IRIS usually occurs within 6 months after initiation of
effective ART
 However, some episodes of IRIS have been
documented up to 18 months after initiation of ART
51
IRIS (4)
 Clinical manifestations
 Fever is a prominent feature
 Usually the infections have atypical presentation
• (Mediastinal lymphadenopathy and pleural/pericardial
effusion in TB)
 Common infections that manifest with IRS include:
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Tuberculosis
Cryptococcal meningitis
Herpes simplex and herpes zoster
CMV retinitis
Viral hepatitis
MAC infection
52
IRIS (5)
 Approach to treatment:
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Recognize the situation is IRIS, not treatment failure
Continue ART
Start treatment of the specific OI
Steroids may be helpful in particularly severe cases of
IRIS e.g. severe dyspnea or TBC meningitis
53
IRIS (6)
 Implications of IRIS on patient monitoring:
 IRIS may be easily confused with treatment failure
 Some features of IRIS may mimic drug side effect and
the distinction may be difficult
• Viral hepatitis presenting as IRIS may be difficult to
distinguish from hepatotoxicity due to ARV drugs
 Patients may feel that they are getting worse with
ART
 Negative effect on adherence
54
IRIS (7)
 IRIS versus treatment failure
 IRIS usually occurs within 3-6 months
 IRIS occurs in the face of increasing CD4 count
 Viral load determination is the most reliable way of
differentiating the 2 conditions
55
Introductory Case: Meseret (15)
 Meseret has TB presenting as IRIS
 Started on RHZE and pyridoxine
 She was continued on d4T and 3TC
 NVP was switched to EFV (800mg)
 Showed significant improvement after 1 month
of anti-TB treatment
56
Case Studies
Handouts 8.2 and 8.3
Key Points
 The primary goal of ART is to reduce morbidity
and mortality by controlling viral replication and
improving the immune function
 ART may be started after adequate preparation
of the patient for ART and based on the
presence of indications for treatment
 Decision on when to start ART and what to start
with is based on the Ethiopian guidelines
58
Key Points (2)
 The most important factor that determines the
outcome of ART is adherence
 Proper and scheduled monitoring is important to
detect drug toxicity and treatment failure early
 Monitoring involves clinical assessment and
laboratory tests
 IRIS may be easily confused with treatment
failure and drug toxicity
59