KITSO AIDS Training Program
Lecture 4:
Principles of ARV Therapy
in the
Botswana National ARV Program
delivered by
Dr. Ndwapi Ndwapi, BHP
1
Learning Objectives
• To know the goals of ARV therapy.
• To know when to start ARV therapy in
Botswana.
• To know which regimens to use in Botswana.
• To know how to monitor ARV therapy in
Botswana.
2
What is Antiretroviral Therapy?
• ART
Antiretroviral Therapy
• ARV
Antiretroviral
• HAART
Highly Active Antiretroviral
Therapy
3
Goals of ARV Therapy
• Clinical: Prolong life, improve quality of life, and
sustain productivity.
• Virologic: Achieve maximal suppression of HIV
- Viral load should fall by at least 1.0 log (to at
least 1/10th of baseline viral load) by 3 months.
- By 6 months viral load should be less than 400.
• Immunologic: Reverse immune system damage.
4
Principle 1
The most effective way to suppress HIV
replication is the simultaneous initiation of
combinations of at least three effective ARV
drugs (HAART).
The use of at least three ARV drugs for ARV
treatment is mandatory under the Botswana
National ARV Program.
5
Principle 2
Drugs used in ARV therapy regimens
should be used according to the Botswana
National ARV Guidelines in the most
effective and tolerable pattern that a
patient can manage.
However, the Guidelines are not a
substitute for good clinical decision
making.
6
Principle 3
Disease progression differs among HIV-infected
persons. The decision to begin treatment
should be individualized and based upon three
major factors:
1. The degree of HIV-related disease.
2. The degree of HIV-related immunosuppression.
3. A solid adherence plan and a working
relationship with the health care system.
7
When to Initiate ARV Therapy
Eligibility Criteria:
• The presence of an AIDS-defining illness and/or
AIDS-defining symptoms, regardless of CD4 count.
• A CD4 count less than 200 cells/uL.
• Any HIV+ child less than 12 months of age.
• HIV+ children over 1 year old who are symptomatic
or immunosuppressed.
• TRY TO AVOID starting a patient on ARV drugs until
acute opportunistic infections are stabilized and
patient is discharged from the hospital.
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e.g., cryptococcal meningitis
When to Initiate ARV Therapy (2)
• AIDS-defining symptoms and/or illnesses merit ARV
therapy, regardless of CD4 count:
- KS
- TB
- Recurrent pneumonia
- Recurrent severe bacterial infections
- Wasting Syndrome/Chronic fevers
- Chronic diarrhea
- VZV involving at least 2 distinct episodes or more than one
dermatome
- Peripheral neuropathy
- CA of cervix
- Lymphoma
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- Thrush
Before Therapy is Initiated
All Patients:
• Complete History and Physical, including IPT/TB
history
• Comprehensive Laboratories
ARV-Experienced Patients:
• Obtain full treatment history.
- What prior regimen/s has the patient taken?
- What was the duration of the therapy?
- If switched, why?
- How was adherence?
- Obtain all possible old CD4 and VL results.
10
Longitudinal Monitoring
• Monitoring Adherence
– Discuss at each visit
• Monitoring tolerability of ART
– Direct questioning
– Clinical assessment and laboratory tests
• Monitoring efficacy of ART
– Clinical indicators (weight)
– CD4 and Viral load measurements
11
Testing Schedule
Baseline
(before
Initiation)
FBC
Chem
(CD4)
VL
RPR
Therapy
Initiation
(2 wks after
baseline)
2/52
4/52
3/12
6/12
9/12
(FBC)
(LFT)
CD4
VL
(FBC)
(LFT)
CD4
VL
(following
Initiation)
LFT*
(chest X-ray only if indicated)
* SGOT and SGPT if on NVP
FBC
LFT
FBC
LFT
CD4
VL
12
Full Chemistry
•
•
•
•
•
•
SGOT/AST
SGPT/ALT
Alk Phos
Creatinine
+/-T. Bili
+/- Electrolytes
13
Principle 4
ARV Therapy is a
life-long
commitment.
14
Clinicians must assess a
patient’s understanding and
readiness to make a life-long
commitment to taking ARV
medications before beginning
treatment.
15
Principle 5
The more treatment-experienced a
patient is, the less likely that
subsequent ARV regimens will be
effective.
The best chance of success with ARV
therapy is with the first regimen.
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ARVs in the Botswana National Program
NRTIs
Nucleoside Reverse
Transcriptase Inhibitors
AZT (Zidovudine)
3TC (Lamivudine)
d4T (Stavudine)
ddI (Didanosine)
NNRTIs
PIs
Non-Nucleoside Reverse
Transcriptase Inhibitors
Protease Inhibitors
EFV (Efavirenz)
NVP (Nevirapine)
LPV/r (Kaletra)
NFV (Nelfinavir)
SQV (Saquinavir)
RTV (Ritonavir)
(AZT+3TC) (Combivir)
Special Order:
ABC (Abacavir)
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Mechanism of Action of ARVs
• NRTIs and NNRTIs block HIV replication early
in its life-cycle by inhibiting reverse
transcription.
• PIs block HIV replication late in its life-cycle
by inhibiting protease-catalyzed assembly of
the virus.
18
Mechanisms of Action
NRTIs & NNRTIs
• NRTIs and NNRTIs inhibit reverse
transcriptase by different mechanisms:
• NRTIs are false nucleosides and--once
incorporated into the DNA chain--terminate
further elongation of the DNA chain.
• NNRTIs directly inhibit the enzymatic
function of reverse transcriptase by binding at
the catalytic site.
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NRTIs
(Nucleoside Reverse Transcriptase Inhibitors)
AZT (Zidovudine)
ddI (Didanosine)
d4T (Stavudine)
3TC (Lamivudine)
(AZT+3TC)
Reverse Transcriptase
Protease
(Combivir)
RNA
ABC (Abacavir)
RNA
DNA
CD4 T -Lymphocyte
RNA
20
NNRTIs
(Non-Nucleoside Reverse Transcriptase Inhibitors)
EFV (Efavirenz)
NVP (Nevirapine)
Reverse Transcriptase
Protease
RNA
RNA
RNA
DNA
CD4 T -Lymphocyte
RNA
21
Mechanism of Action: PIs
• PIs inhibit protease by binding at the catalytic
site.
22
PI’s
(Protease Inhibitors)
LPV/r (Kaletra)
NFV (Nelfinavir)
SQV (Saquinavir)
RTV (Ritonavir)
Protease
Reverse
Transcriptase
RNA
RNA
RNA
DNA
CD4 T -Lymphocyte
RNA
23
Botswana Guidelines
NRTI’s
1st Line
2nd Line
AZT+3TC
NNRTI’s
PI’s
EFV or NVP
ddI + d4T
NFV / LPV/r
2 recycled NRTIs*
SQV/RTV
3rd Line
* Depending on resistance assay and specialist
consultation.
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Standard 1st line ARV Therapy
•
•
2 NRTIs
(AZT+3TC)
+
+
Combivir
+
(AZT+ 3TC)
+
Combivir
+
1 NNRTI
EFV
Efavirenz
NVP
Nevirapine
- Give NVP to women with reproductive potential
and to children less than 3 years of age.
25
Standard Dosages - First Line Therapy
(1)
• (AZT + 3TC) -- Combivir
- 1 tablet BD
• EFV -- Efavirenz
- 600 mg HS
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Standard Dosages - First Line Therapy
(2)
• (AZT+3TC) -- Combivir
1 tablet BD
• NVP -- Nevirapine
200 mg BD
• Begin NVP, 200 mg OD for two weeks.
• After two weeks, increase NVP to 200 mg BD and
check LFT’s.
• Dose escalation of NVP will reduce the incidence of
side effects.
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Clinical Issues with 1st Line Therapy
• Selection of 1st line therapy is simple within national
guidelines.
(AZT+3TC) + EFV or (AZT+3TC) + NVP
• Due to side-effects--for example, anemia--different
NRTIs may need to be used for first line therapy.
• d4T + 3TC is the alternative NRTI combination for
first line therapy when the baseline hemoglobin is
<7.5g/dL, or when AZT-associated anemia
develops.
• 1st line therapy will hopefully work for several years.
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Changing Regimens
In the course of therapy there are two reasons to
change regimens:
1. Toxicity
- Adverse reaction to a particular ARV drug in the
regimen.
CHANGE ONLY THE OFFENDING DRUG, RETAINING
ACCOMPANYING ARV DRUGS.
Or
2. Therapy Failure
- Inability of the drug regimen to suppress the replication
of the HIV virus.
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CHANGE ENTIRE REGIMEN
Principle 6
Therapy failure MUST be addressed
promptly, and the patient must not be
kept on a failing regimen for a long period
of time.
30
Principle 7
Decisions about changing a patient to
second or third line regimens should be
reviewed with an HIV specialist as soon
as possible.
31
Therapy Failure
• Virologic: failure to suppress HIV
replication, i.e., viral load.
• Immunologic: failure to increase CD4
count.
• Clinical: occurrence of an OI or other AIDSdefining event.
32
Therapy Failure (2)
• For the patient not yet on HAART, decisions
about when to initiate ARVs focus on
immunologic (i.e., CD4 count) and clinical
factors (AIDS-defining illnesses/symptoms).
• Once the patient starts HAART, decisions
about therapy success or therapy failure focus
primarily on the virologic response (i.e., viral
load).
33
Therapy Failure (3)
• Only rarely will a patient have immunological
or clinical failure with an undetectable viral
load. Such patients must be reviewed with an
HIV specialist before changing regimens.
• In general, “therapy failure” means virologic
failure, and the two terms are usually used
interchangeably.
34
Definition of Therapy (i.e. virologic)
Failure
• The ARV regimen initially fails to suppress
replication—ie., the viral load does not fall by
at least 1.0 log by 3 months, and is not less
than 400 by 6 months.
or
• The regimen initially suppressed replication
(viral load <400 copies/ml), but at a later date
the viral load becomes detectable.
35
Standard
nd
2
Line ARV Therapy
2 NEW NRTIs
+
NFV or LPV/r
d4T + ddI
+
NFV or LPV/r
(stavudine)
+ (didanosine)
+
(nelfinavir) or (kaletra)
• 2nd Line therapy should be used if a patient’s viral
load fails to be < 400 copies/ml after 6 months of
therapy, or if viral load initially suppresses but later
increases.
• If d4T had been part of the first-line regimen
because of anemia, and if the patient’s hemoglobin
has increased, then AZT/ddI should be the NRTI
backbone. If anemia has persisted, consult with HIV
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specialist about NRTI backbone.
Standard Dosages - Second Line
Therapy
• d4T:
If < 60kg, 30mg BD
If ≥ 60kg, 40mg BD
• ddI:
If < 60kg, 300mg OD
If ≥ 60kg, 400mg OD
• NFV:
1250mg BD (five 250mg capsules/dose)
• LPV/r:
400mg/100mg (3 Kaletra capsules) BD
37
rd
3
Line or Salvage Therapy
2 Recycled NRTIs
2 NRTI’s
+
+
2 PIs
RTV/SQV
• A patient who has failed two regimens will need
therapy that takes into account the previous drug
history.
• Adherence assessment is crucial.
• Two new PI’s plus recycled NRTIs.
• Always discuss with experienced ARV specialist.
• Successful salvage therapy can be difficult to
achieve.
38
rd
3
Line or Salvage Therapy (2)
Genotypic resistance testing
should be done to guide choice
of drugs for the third line
regimen.
39
TB/HIV Co-infection and HAART
• Patients with newly diagnosed TB and not on
HAART should be treated for TB first, and
HAART should be delayed.
• Timing of HAART initiation in active TB
depends upon CD4 count and clinical
condition of the patient.
• Patients already on HAART and who develop
active TB should continue HAART while ATT
40
is initiated.
TB/HIV Co-infection and HAART (2)
• Patients on ATT and NVP-containing HAART
do not require dose adjustment of NVP.
• Patients on ATT and EFV-containing HAART
may require dose adjustment of EFV:
– If weight > 60 kg, some authorities would not
change EFV dose.
– Guidelines advise increasing EFV dose to 800mg
41
HS if weight > 60 kg.
TB/HIV Coinfection and HAART (3)
Because of serious drug-drug interactions
between rifampicin and protease
inhibitors, patients who develop TB
while on second-line regimen must be
referred to a specialist for evaluation.
42
Principle 8
Being “naïve” to a class of drugs
is the single most important
factor in predicting response to
future salvage therapy.
43
Principle 9
Adherence strategies between patient
and clinician are as important
or
more important
than any choice of ARV drugs.
44
Principle 10
All HIV-infected persons, even those
taking ARV medications with viral
loads below detectable limits, remain
infectious.
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Final Summary
• ARV choices are limited, protect them by
– using 3 drugs simultaneously.
– promoting adherence.
• For any drug change make sure the reasons
are clearly documented.
• If in doubt, ask the most experienced HIV
physician.
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