Overview of Antiretroviral Therapy: Options and Preferred Regimens

1. Hyman M. Scott, MD, MPH University of California, San Francisco Division of Infectious Diseases & Center for AIDS Prevention Studies Overview of Antiretroviral Therapy: Options and Preferred Regimens

2. Disclosures • I have no financial disclosures or conflicts of interest.

3. Goals • Learn the differences between ARV classes. • Learn the “class effects”. • Learn one or two drugs with important side-effects within each class. • Activity: Construct a regimen for your “partner”.

4. Multiple Hit Gameplan

5. Multiple Hit Gameplan Nucleoside Reverse Transcriptase Inhibitors Intergrase Inhibitors Fusion & CCR5 Inhib.

6. FDA Approved Antiretrovirals

7. How to decide on a regimen • Key principle: 3 activedrugs • 2 NRTI + NNRTI or PI • “Nuc” backbone + either PI or NNRTI • Choosing a regimen • Step 1: Decide: NNRTI or PI • Step 2: Pick a NRTI ”backbone” • Choose components based on toxicity • Take into account side effect, pill burden, patient preference, and cost

8. Nucleoside Reverse Transcriptase Inhibitors Multiple Hit GamePlan Nucleoside Reverse Transcriptase Innibitors Fusion & CCR5 Inhib.

9. Nucleoside Reverse Transcriptase Inhibitors Class Effects: NRTIs • NRTI = “Backbone” of ART • Foundation of most ART combinations

10. Nucleoside Reverse Transcriptase Inhibitors Class Effects: NRTIs Advantages Disadvantages Individual drugs with unique side effects/toxicities. AZT Abacavir Class effect: Lactic acidosis Mitochondrial toxicity Peripheral neuropathy Lipodystrophy Hepatotoxicity • Essential part of most ART combination • Fewer drug-drug interactions • Newer NRTIs are well tolerated.

11. Truvada • Combination of Tenofovir and Emtricitabine. • “Backbone” of most ARV Regimens • Adult Dosage • 1 tablet once Daily • Counseling Points • Can cause kidney problems and bone loss. • Headache, nausea, diarrhea are possible side effects. • Otherwise usually well tolerated. • Also treats Hepatitis B virus infection.

12. Non-Nucleoside Reverse Transcriptase Inhibitors Multiple Hit GamePlan Nucleoside Reverse Transcriptase Innibitors Intergrase Inhibitors Fusion & CCR5 Inhib.

13. Non-Nucleoside Reverse Transcriptase Inhibitors Class Effects: NNRTIs • Generally well tolerated but: • All can cause • Rash • Liver injury

14. Non-Nucleoside Reverse Transcriptase Inhibitors Class Effects: NNRTIs Advantages Disadvantages Prone to resistance single mutation Cross resistance among NNRTIs Rash; hepatotoxicity Potential drug interactions • Ease (low pill burden) • Tolerability • Fewer metabolic effects • lipodystrophy, dyslipidemia

15. Efavirenz • Once of the most commonly prescribed ARVs. • Adult Doses • 6oomg once Daily • Available as 1 pill daily AtriplaTM • Counseling Points • Side effects including vivid (sometimes disturbing) dreams, insomnia, somnolence, difficulty concentrating, dizziness, amnesia, confusion or agitation. • Should be take before bedtime to avoid daytime difficulties. • Can cause a rash.

16. Protease Inhibitors Multiple Hit GamePlan Nucleoside Reverse Transcriptase Innibitors Intergrase Inhibitors Fusion & CCR5 Inhib.

17. Protease Inhibitors Class Effects: PIs • Ushered in the HAART era in late 1990s • Potent inhibitor of HIV replication • Most common side effects: • Hyperlipidemia • Hyperglycemia • Fat redistribution • multiple drug-drug interactions

18. Protease Inhibitors Class Effects: PIs Advantages Disadvantages Metabolic complications fat maldistribution, dyslipidemia, insulin resistance Side Effects Nausea/vomiting, diarrhea, bloating. Drug interactions High cost • High potency • Longest prospective data (durability) • Esp. in advanced AIDS • Less susceptible to resistance • Used to be “Salvage” therapy when NNRTI fails, but now “First Line” options

19. Atazanavir • Once of the most commonly prescribed ARVs. • Adult Doses • 3oomg once Daily WITHritonavir 100 mg po • Counseling Points • Side effects include nausea, diarrhea, bloating. • Will cause jaundice, not dangerous but can cause reversible yellowing of eyes • Can cause a rash. +

20. Darunavir • Adult Dose • 800mg Once Daily OR 600 mg twice Daily WITHritonavir 100 mg • Counseling Points • Take with food • AEs: Rash (7%), abdominal pain, constipation, headache • Caution with sulfa allergy +

21. CCR5 co-receptor antagonist Multiple Hit GamePlan Nucleoside Reverse Transcriptase Innibitors Intergrase Inhibitors Fusion & CCR5 Inhib.

22. CCR5 co-receptor antagonist Class Effects: CCR5 antagonists Advantages Disadvantages Extra ($$) testing needed prior to use Side Effects Cough, rash, muscle and joint pain, abd pain, dizziness More heart complications seen in clinical trials. • Potential for use in people who have failed many other regimens. • Can cause a higher CD4 response compared to some other ARVs

23. Intergrase Inhibitor Multiple Hit GamePlan Nucleoside Reverse Transcriptase Innibitors Intergrase Inhibitors Fusion & CCR5 Inhib.

24. Intergrase Inhibitor Class Effects: Intergrase Inhibitors • Favorable side-effect profile and can be used by those with existing mutations. • Can cause a rapid decrease in HIV viral load.

25. Intergrase Inhibitor Class Effects: Intergrase Inhibitors Advantages Disadvantages Twice daily dosing Lower “barrier” to developing resistance. Side Effects Nausea/vomiting Muscle damage • Favorable side effect profile. • Few drug-drug interactions.

26. Raltegravir • Very well tolerated and can cause rapid decline in HIV VL. • Adult Dose • 300mg twice Daily • Counseling Points • Take with food • AEs: Rash (7%), abdominal pain, constipation, headache • Caution with sulfa allergy

27. Preferred Regimens EFV ATV/r TDF/FTC DRV/r RAL

28. Fixed Dose Combinations

29. Multiple Hit Gameplan

30. Choosing a regimen… • You and partner will have to decide on a regimen to start. • Instructions • You will be starting a regimen and your partner will discuss the options with you. • Choose a regimen that has three drugs from at least two classes. • Discuss and be OK with # of pills and side effects. • Find one potential difficulty with taking the regimen and one potential solution

31. Thank you!

32. Additional slides

33. FDA Approved Antiretrovirals

34. FDA Approved Antiretrovirals

35. FDA Approved Antiretrovirals

36. FDA Approved Antiretrovirals

37. FDA Approved Antiretrovirals