1. KITSO AIDS Training Program
Lecture 4:
Principles of ARV Therapy
in the
Botswana National ARV Program
delivered by
Dr. Ndwapi Ndwapi, BHP
Principles of ARV Therapy in the Botswana National Program

2. 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.

3. What is Antiretroviral Therapy?
ART Antiretroviral Therapy
ARV Antiretroviral
HAART Highly Active Antiretroviral
Therapy

4. KITSO AIDS Training Program
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.
Principles of ARV Therapy in the Botswana National Program

5. KITSO AIDS Training Program
Principle 1
KITSO AIDS Training Program
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.
Principles of ARV Therapy in the Botswana National Program

6. KITSO AIDS Training Program
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.
Principles of ARV Therapy in the Botswana National Program

7. Principle 3 2. The degree of HIV-related immunosuppression.
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.

8. When to Initiate ARV Therapy
KITSO AIDS Training Program
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.
e.g., cryptococcal meningitis
Principles of ARV Therapy in the Botswana National Program

9. When to Initiate ARV Therapy (2)
KITSO AIDS Training Program
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
- Thrush
Principles of ARV Therapy in the Botswana National Program

10. Before Therapy is Initiated
KITSO AIDS Training Program
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.
Principles of ARV Therapy in the Botswana National Program

11. 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

12. KITSO AIDS Training Program
Testing Schedule
Baseline
(before
Initiation)
Therapy Initiation
(2 wks after baseline)
2/52
(following
4/52
3/12
6/12
9/12
FBC
Chem
(CD4) VL
RPR
LFT*
LFT
CD4
(FBC)
(LFT)
(chest X-ray only if indicated)
* SGOT and SGPT if on NVP
Principles of ARV Therapy in the Botswana National Program

13. KITSO AIDS Training Program
Full Chemistry
SGOT/AST
SGPT/ALT
Alk Phos
Creatinine
+/-T. Bili
+/- Electrolytes
Principles of ARV Therapy in the Botswana National Program

14. ARV Therapy is a life-long commitment.
Principle 4
ARV Therapy is a
life-long commitment.

15. Clinicians must assess a patient’s understanding and readiness to make a life-long commitment to taking ARV medications before beginning treatment.

16. 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.

17. ARVs in the Botswana National Program
NRTIs NNRTIs PIs
Nucleoside Reverse Non-Nucleoside Reverse Protease Inhibitors
Transcriptase Inhibitors Transcriptase Inhibitors
AZT (Zidovudine) EFV (Efavirenz) LPV/r (Kaletra)
3TC (Lamivudine) NVP (Nevirapine) NFV (Nelfinavir)
d4T (Stavudine) SQV (Saquinavir)
ddI (Didanosine) RTV (Ritonavir)
(AZT+3TC) (Combivir)
Special Order:
ABC (Abacavir)

18. 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.

19. 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.

20. NRTIs (Nucleoside Reverse Transcriptase Inhibitors)
KITSO AIDS Training Program
NRTIs (Nucleoside Reverse Transcriptase Inhibitors)
AZT (Zidovudine)
ddI (Didanosine)
d4T (Stavudine)
3TC (Lamivudine)
(AZT+3TC)
(Combivir)
ABC (Abacavir)
Reverse Transcriptase
Protease
RNA
RNA
RNA
CD4
DNA
RNA
CD4 T -Lymphocyte
Principles of ARV Therapy in the Botswana National Program

21. NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors)
KITSO AIDS Training Program
NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors)
EFV (Efavirenz)
NVP (Nevirapine)
Reverse Transcriptase
Protease
RNA
RNA
CD4
RNA
DNA
RNA
CD4 T -Lymphocyte
Principles of ARV Therapy in the Botswana National Program

22. Mechanism of Action: PIs
PIs inhibit protease by binding at the catalytic site.

23. PI’s (Protease Inhibitors)
KITSO AIDS Training Program
PI’s (Protease Inhibitors)
LPV/r (Kaletra)
NFV (Nelfinavir)
SQV (Saquinavir)
RTV (Ritonavir)
Protease
Reverse Transcriptase
RNA
RNA
RNA
CD4
DNA
RNA
CD4 T -Lymphocyte
Principles of ARV Therapy in the Botswana National Program

24. Botswana Guidelines NRTI’s NNRTI’s PI’s AZT+3TC EFV or NVP
ddI + d4T NFV / LPV/r
2 recycled NRTIs* SQV/RTV
* Depending on resistance assay and specialist consultation.
1st Line
2nd Line
3rd Line

25. Standard 1st line ARV Therapy
KITSO AIDS Training Program
Standard 1st line ARV Therapy
2 NRTIs NNRTI
(AZT+3TC) EFV
Combivir Efavirenz
(AZT+ 3TC) NVP
Combivir Nevirapine
- Give NVP to women with reproductive potential and to children less than 3 years of age.
Principles of ARV Therapy in the Botswana National Program

26. Standard Dosages - First Line Therapy (1)
(AZT + 3TC) -- Combivir
- 1 tablet BD
EFV -- Efavirenz
- 600 mg HS

27. 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.

28. Clinical Issues with 1st Line Therapy
KITSO AIDS Training Program
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.
Principles of ARV Therapy in the Botswana National Program

29. KITSO AIDS Training Program
Changing Regimens
KITSO AIDS Training Program
In the course of therapy there are two reasons to change regimens:
Toxicity
- Adverse reaction to a particular ARV drug in the regimen.
CHANGE ONLY THE OFFENDING DRUG, RETAINING ACCOMPANYING ARV DRUGS. Or
Therapy Failure
- Inability of the drug regimen to suppress the replication of the HIV virus.
CHANGE ENTIRE REGIMEN
Principles of ARV Therapy in the Botswana National Program

30. KITSO AIDS Training Program
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.
Principles of ARV Therapy in the Botswana National Program

31. KITSO AIDS Training Program
Principle 7
Decisions about changing a patient to second or third line regimens should be reviewed with an HIV specialist as soon as possible.
Principles of ARV Therapy in the Botswana National Program

32. 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 AIDS-defining event.

33. 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).

34. 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.

35. 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.

36. Standard 2nd Line ARV Therapy
KITSO AIDS Training Program
Standard 2nd 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 specialist about NRTI backbone.
Principles of ARV Therapy in the Botswana National Program

37. Standard Dosages - Second Line Therapy
KITSO AIDS Training Program
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 c
Principles of ARV Therapy in the Botswana National Program

38. 3rd Line or Salvage Therapy
KITSO AIDS Training Program
3rd Line or Salvage Therapy
2 Recycled NRTIs PIs
2 NRTI’s 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.
Principles of ARV Therapy in the Botswana National Program

39. 3rd Line or Salvage Therapy (2)
KITSO AIDS Training Program
3rd Line or Salvage Therapy (2)
Genotypic resistance testing should be done to guide choice of drugs for the third line regimen.
Principles of ARV Therapy in the Botswana National Program

40. TB/HIV Co-infection and HAART
KITSO AIDS Training Program
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 is initiated.
Principles of ARV Therapy in the Botswana National Program

41. TB/HIV Co-infection and HAART (2)
KITSO AIDS Training Program
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 HS if weight > 60 kg.
Principles of ARV Therapy in the Botswana National Program

42. TB/HIV Coinfection and HAART (3)
KITSO AIDS Training Program
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.
Principles of ARV Therapy in the Botswana National Program

43. KITSO AIDS Training Program
Principle 8
Being “naïve” to a class of drugs is the single most important factor in predicting response to future salvage therapy.
Principles of ARV Therapy in the Botswana National Program

44. KITSO AIDS Training Program
Principle 9
Adherence strategies between patient and clinician are as important or
more important
than any choice of ARV drugs.
Principles of ARV Therapy in the Botswana National Program

45. KITSO AIDS Training Program
Principle 10
All HIV-infected persons, even those taking ARV medications with viral loads below detectable limits, remain infectious.
Principles of ARV Therapy in the Botswana National Program

46. KITSO AIDS Training Program
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.
Principles of ARV Therapy in the Botswana National Program