PRINCIPLES OF ART IN TANZANIA

1. PRINCIPLES OF ART IN TANZANIA Humphrey Shao MD, MHS

2. Goals of ART • Eradication of HIV? Not possible with currently available ARV medications

3. Improved quality of life Reduction of HIV-related morbidity and mortality Restoration and/or preservation of immunologic function Maximal and durable suppression of viral load Prevention of vertical transmission Prevention of transmission to sexual partners Selection of ARV regimen Preservation of future treatment options Rational sequencing of therapy Maximizing adherence Use of resistance testing in selected clinical settings ART Goals & Tools to Achieve Them

4. Baseline Evaluation • Complete History & Physical exam. • Laboratory testing: • HIV antibody • CD4 cell count • Plasma HIV RNA • Resistance test (genotype) • CBC, chemistry profile, BUN, Cr, transaminase • Fasting glucose and lipids • RPR or VDRL • Hepatitis A, B, C serology • Toxoplasma IgG

5. Tuberculin skin test (TST) or IFN-γ release assay Chest X ray (if symptoms, or positive TST or IFN-γ release assay) Gynecologic exam with Pap smear Testing for chlamydia and gonorrhea Ophthalmology exam (CD4 count <100 cells/µL) Before Initiating ART: Additional Tests

6. Considerations in Initiating ART • Willingness of patient to begin and the likelihood of adherence • Degree of immunodeficiency(CD4 cell count) • Plasma HIV RNA • Risk of disease progression • Potential benefits and risks of therapy

7. Considerations in Initiating ART(2) • ART should be considered lifelong therapy • Interruption of ART is not recommended, except for serious toxicities or inability to take oral medications • Usually causes immediate virologic rebound, with CD4 decline

8. Use of CD4 Cell Levels to Guide Therapy Decisions • CD4 count • The major indicator of immune function • Most recent CD4 count is best predictor of disease progression • CD4 count usually is the most important consideration in decision to start ART • Important in determining response to ART • Adequate response: CD4 increase 100-150 cells/µL per year • CD4 monitoring • Check at baseline (x2) and at least every 3-6 months

9. Use of HIV RNA Levels to Guide Therapy Decisions • HIV RNA: • Less important than CD4 count, but may influence decision to start ART and determine frequency of CD4 monitoring • Critical in determining response to ART • Goal of ART: HIV RNA below limit of detection (ie, <40 to <80 copies/mL, depending on assay) • RNA monitoring: • Check at baseline (x2) • Immediately before initiating ART • 2-8 weeks after start or change of ART • Every 3-4 months with stable patients

10. When to Start ART • Potent ART may improve and/or preserve of immune function in most patients with virologic suppression, regardless of baseline CD4 count • ART indicated for all with low CD4 count or symptoms • Earlier initiation of ART may result in better immunologic responses and better clinical outcomes • Recommended ARV combinations are considered to be durable and tolerable • Exact CD4 count at which to initiate therapy not known, but evidence points to starting at higher counts • Current recommendation: ART for all patients with CD4 counts of <350 cells/µL, certain others regardless of count

11. Indications for ART Treat all: • History of AIDS-defining illness • CD4 count of <200 cells/µL Strong evidence of decreased mortality and morbidity if ART is given to patients with symptoms of AIDS or CD4 counts of <200 cells/µL

12. Indications for ART (2) Treat all: • CD4 counts of 200-350 cells/µL Data suggest risk of AIDS-related events and non- AIDS-defining conditions is higher in this range than at >350 cells/µL

13. Indications for ART (3) Treat all (regardless of CD4 count): • Pregnant women • To treat maternal infection and reduce risk of perinatal transmission • HIV-associated nephropathy (HIVAN) • Not clearly related to CD4 decline; ART may preserve renal function • HBV coinfection, if HBV treatment is needed • TNF + 3TC or FTC is recommended • If ART is not started, HBV therapy should not include agents that may select for resistance to ARVs

14. Indications for Initiating ART: Chronic Infection * Treatment with fully suppressive drugs active against both HIV and HBV is recommended.

15. Indications for Initiating ART: Chronic Infection (2)

16. Maintain higher CD4; prevent irreversible immune system damage Decrease risk of HIV-associated complications eg, TB, NHL, KS, peripheral neuropathy, HPV-associated malignancies, HIV-associated cognitive impairment Decrease risk of nonopportunistic conditions and non-AIDS-associated conditions eg, CV, renal, and liver disease; malignancies; infections Decrease risk of HIV transmission Potential Benefits of Early Therapy (CD4 count >350 cells/µL)

17. ARV-related side effects and toxicities Drug resistance (caused by ART failure) Inadequate time to learn about HIV, treatment, and adherence Increase in total time on ART; greater chance of treatment fatigue Current ART may be less effective or more toxic than future therapies Transmission of ARV-resistant virus, if incomplete virologic suppression Potential Risks of Early Therapy (2)(CD4 count >350 cells/µL)

18. Current ARV Medications

19. Initial Treatment: Choosing Regimens (2) • Considerations: • Comorbidities (eg, liver, psychiatric, or cardiovascular disease; tuberculosis; pregnancy) • Adherence potential • Dosing convenience (eg, pill burden, dosing frequency) • Potential adverse effects • Potential drug interactions • Pregnancy potential • Results of drug resistance test • Gender and CD4 count, if considering NVP • HLA B*5701 testing, if considering ABC

20. ADVANTAGES Long half-lives Less metabolic toxicity (dyslipidemia, insulin resistance) than with some PIs PI options preserved for future use DISADVANTAGES Low genetic barrier to resistance – single mutation Cross-resistance among most NNRTIs Rash; hepatotoxicity Potential drug interactions (CYP450) ARV Components in Initial Therapy: NNRTIs

21. ADVANTAGES Higher genetic barrier to resistance PI resistance uncommon with failure (boosted PI) NNRTI options preserved for future use DISADVANTAGES Metabolic complications (fat maldistribution, dyslipidemia, insulin resistance) GI intolerance Potential for drug interactions (CYP450), especially with RTV ARV Components in Initial Therapy: PIs

22. ADVANTAGES Established backbone of combination therapy Minimal drug interactions DISADVANTAGES Lactic acidosis and hepatic steatosis reported with most NRTIs (rare) ARV Components in Initial Therapy: Dual-NRTI Pairs

23. ADVANTAGES Established backbone of combination therapy Minimal drug interactions PI and NNRTI preserved for future use DISADVANTAGES Lactic acidosis and hepatic steatosis reported with most NRTIs (rare) 3-NRTI regimens show inferior virologic response compared with EFV- and IDV-based regimens* ARV Components in Initial Therapy: NRTIs * 3-NRTI regimen of ABC + 3TC + ZDV to be used only when a preferred or alternative NNRTI- or PI-based regimen cannot or should not be used as first-line therapy.

24. The Patient’s First HAART • Start when the patient (not the provider) is emotionally, psychologically and intellectually ready to start. • Explain the natural progression of HIV infection. • Explain the way the ARV’s work against the HIV. • Know the preferences and concerns of the patient. • Introduce the adequate ARV regimens according to her/his needs. HAART IS NOT AN EMERGENCY

25. The Doctor’s First HAAART Start with the best regimen for the patient: • Most tolerable. • Best chance for adherence. • Most adequate for the patient’s lifestyle and habits. • The most salvageable. HAART IS NOT AN EMERGENCY

26. THE COMBO’S:WHAT TO START WITH?

27. The Combo’s • The MoHSW recommends the following drugs for first line treatment: • • Zidovudine (AZT) • • Stavudine (d4T) • • Lamivudine (3TC) • • Emtricitabine (FTC) • • Tenofovir (TDF) • • Nevirapine (NVP) • • Efavirenz (EFV)

28. The Combo’s • The following drug combinations can be made out of these drugs • AZT+3TC+NVP • • AZT+ 3TC+EFV • • d4T+3TC+NVP • • d4T+3TC+EFV • • TDF+FTC+EFV • • TDF+FTC +NVP • • TDF+3TC+EFV • • TDF+3TC+NVP

29. The Combo’s • Note: The following drugs may appear in fixed drug combinations (FDC): • • AZT+3TC, e.g. Combivir or Duovir • • AZT+3TC+NVP, e.g. Duovir N • • d4T+3TC+NVP, e.g. Triomune • • TDF+FTC+EFV, e.g. Atripla • • TDF+3TC • • TDF+FTC, e.g. Truvada

30. Measurement of Adherence • No gold standard • Patient self-report overestimates adherence, but is associated with viral load responses and is most useful method in the clinic setting • Self-report of suboptimal adherence is strong indicator of nonadherence

31. Predictors of Good Adherence • Emotional and practical supports • Convenience of regimen • Understanding of the importance of adherence • Belief in efficacy of medications • Feeling comfortable taking medicationsin front of others • Keeping clinic appointments • Severity of symptoms or illness

32. All NRTIs: Lactic acidosis and hepatic steatosis Higher incidence with d4T(d4T > ddI = ZDV > TDF = ABC = 3TC = FTC) Lipodystrophy(higher incidence with d4T) Adverse Effects: NRTIs

33. All NNRTIs: Rash Drug-drug interactions NVP: hepatotoxicity (may be severe and life-threatening); rash including Stevens-Johnson syndrome EFV: neuropsychiatric, teratogenic in primates (FDA pregnancy class D) Adverse Effects: NNRTIs

34. All PIs: Hyperlipidemia Insulin resistance and diabetes Lipodystrophy Elevated LFTs Possible increased bleeding risk in hemophiliacs Drug-drug interactions Adverse Effects: PIs

35. First Line Regimen- d4T/ 3TC/ NVP Minor side effects: • Headaches, nausea, gastro-intetestinal disorder insomnia Manage symptomatically Major side effects: • Immediate: peripheral neuropathy, hepatitis, pancreatitis, skin reactions • Long term: lactic acidosis, lipodystrophy syndrome

36. Example: peripheral neuropathy[due to d4T] Step-wise series of actions: • Minimise possible risk factors • Symptomatic: amitryptiline; NSAIDS • Reduce dose d4T/3TC/NVP [40mg-30mg] • If no better then may have to stop or consider referral to a centre for alternative first line regimen

37. Example: drug-induced hepatitis[due to NVP] • Stop ARV therapy if clinical evidence of hepatitis or if AST > 5 times upper limit • If evidence of hepatitis (ie jaundice) then safest thing is to STOP ARV therapy • DO NOT give d4T/3TC/NVP again • When better consider referral and substitute with alternative first line regimen

38. Example: drug-induced pancreatitis[due to stavudine or rarely lamivudine] • Suspect if patient develops severe abdominal pain, nausea and vomiting • Diagnosis is difficult in district hospitals: amylase / US/ CT scan • Either refer patient or stop therapy: if referral takes time then STOP

39. Example: drug-induced skin rash[due to Nevirapine] • In first two weeks of ART: • observe either in or out of hospital • dose of nevirapine stays at 200 mg daily • try anti-histamines • if rash improves or stays stable increase NVP dose to 200 mg twice a day • if rash deteriorates or mucous membranes are involved then STOP nevirapine

40. Example: drug-induced skin rash[due to Nevirapine] • After the first two weeks of ART: • any skin problem needs hospital assessment • if just itching then add anti-histamine and continue ARV therapy • if rash occurs carefully assess and rule out other causes • if rash worsens and if mucosal membranes involved STOP ART

41. Changing Antiretroviral Therapy • Drug adverse events – Toxicities, including: • • Intolerable side effects • • Drug interactions • • During pregnancy if the patient is on EFV • Treatment failure including: • • Clinical failure – occurrence or persistence of HIV related OIs • • Immunological failure • • Virological failure

42. Thank you!!!

43. Types of Antiretroviral Drugs • The currently existing and commercially available antiretroviral drugs fall into the following five main categories: • Binding and Fusion Inhibitors • Nucleoside reverse transcriptase inhibitors (NRTIs) • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) • Nucleotide reverse transcriptase inhibitors (Nucleotide analogues) • Protease inhibitors (Pls)