Side effects of ARV Treatment

1. Ardis Ann Moe, M.D. UCLA CARE Clinic/NEVHC HIV Clinic Van Nuys. 19 August 2013 Side effects of ARV Treatment

2. Objectives • To describe the major side effects of HIV treatment • To know useful lab tests for HIV side effect monitoring • To be able to change from one set of HIV medications to another to prevent side effects • To review case studies of how to choose initial HIV regimen, and what regimen to switch to in the event of side effects

3. Quick-and-dirty: Plans A,B,C and D • Plan A: “A pill A day for type A personalities” Atripla, complera, stribild • Low barrier to resistance

4. Plan B: “Boosted protease inhibitor for batty buddies on the brink” • Most useful when you have desperately ill patients with OI or AIDS cancers OR mentally ill patients OR patients with other adherence risks • Reyataz/norvir/truvada • Lexiva/norvir/truvada • Prezista/norvir/truvada • High barriers to resistance.

5. Plan C: “Curses, I forgot the Contraception” • Kaletra and Combivir • First choice for pregnant women with HIV

6. Plan D: for Drug-drug interactions OR DARN I stuck myself • Isentress +truvada • Has fewest drug interactions • Preferred drug for needlestick injuries

8. Nucleoside Analogs • As a class they are associated with lactic acidosis • Pancreatitis—rare in most of the common nucleoside analogs, common in didanosine (Videx) • Most side effects linked to some form of mitochondrial poisoning; often organ specific.

9. Tenofovir/emtricitabine: truvada • Most common nucleoside/tide backbone for most HIV cocktails • Tenofovir: nucleotide analog: • Causes Fanconi’s syndrome and renal insufficiency • May lead to irreversible kidney failure if not discontinued in time. • Also treats hepatitis B effectively • May also cause GI upset

10. Emtricitabine • Rash—most likely to case rash of all the nucleosides • Also treats hepatitis B

11. Abacavir/lamivudine: Epzicom • Abacavir: associated with hypersensitivity reaction; flu-like illness with high fevers, diarrhea, cough, rash that can progress to anaphylaxis. Occassional headaches • Lamivudine. Probably can be put in the drinking water. • Sometimes patients tolerate the separate ingredients better than the combo drug

12. Zidovudine/lamivudine: Combivir • Zidovudine: Anemia, leucopenia, fatigue, headache, nausea. Myositis “AZT Butt” • Approved in 1987; first HIV medication • Also causes some facial wasting • BID drug

14. Less commonly used nucleosides • Didanosine: Videx • High risk of pancreatitis, especially when combined with stavudine (zerit),peripheral neuropathy, lactic acidosis. • Single most dangerous drug in the whole HIV armamentarium

15. Stavudine (Zerit) • Peripheral neuropathy, facial wasting, lactic acidosis, pancreatitis. • Used as a “bridge” drug when more commonly used nucleosides are not able to be taken.

18. Stocking-glove pattern of neuropathy

19. Protease inhibitors • 1st generation PI’s approved 1996; 2nd generation 2003 • As a class they all cause insulin resistance and risk of diabetes. • Diabetes may only be partially reversible once it has occurred and the protease inhibitors are stopped • They all cause diarrhea, nausea and GI upset. • They all have significant drug interactions: cytochrome p450 inhibitors

20. Protease inhibitors have best data for patient survival after diagnosis of AIDS related cancers or opportunistic infections

21. 1st generation protease inhibitors: • Lopinavir/ritonavir: Kaletra (BID) • Saquinavir: Invirase (BID) • Indinavir: Crixivan (BID) • Nelfinavir: Viracept (TID)

22. Except for kaletra, most 1st generation PI’s not used. • All 1st generation PI’s have elevated cholesterol, triglycerides, and fat accumulation problems.

23. Buffalo hump

24. “Crix Belly”

25. Lipodystrophy is one of patient’s major concerns; some patients would rather die of HIV complications than have body-shape changes. • Similar issue to women with breast cancer and mastectomy • For 1st gen PI’s, risk 75% after 2 years of treatment

26. Second generation protease inhibitors • Atazanavir: Reyataz • Fos-Amprenavir: Lexiva • Darunavir: Prezista • Much less likely to cause lipodystrophy or cause elevated lipids • Overall much better tolerated than 1st gen PI’s.

27. Atazanavir: • Can also cause unconjugated bilirubin elevation and scleral icterus. Usual bilirubin levels 2-3.0 • Need to change meds when scleral icterus evident or bilirubin levels >3.5 • Has drug interaction with proton pump inhibitors; Needs to be taken 12 hours away from dosing of PPI. • Best GI tolerance of all PI’s.

28. Fosamprenavir: • Can be taken with PPI’s • Some risk of rash

29. Darunavir: • Has sulfa moiety ;some risk of rash, esp in sulfa allergic patients (not a contraindication) • Has worst GI tolerance of second generation PI’s • Can be used for salvage treatment, but if patient is resistant to this PI, cannot salvage with any other PI

30. Non nucleoside analogs • As a class they all cause rash and have significant drug interactions (cytochrome p450)

31. Efavirenz: Sustiva • Best known of all the nucleoside analogs • Causes severe depression, panic attacks, insomnia (interfere with REM sleep), vivid dreams. • May also increase cholesterol • Neural tube defects in newborns • Used with truvada to make Atripla. • Has to be taken on an empty stomach at bedtime

32. Neviripine: Viramune • Most likely to cause Stevens-Johnson syndrome

33. Etravirine: Intelence • Twice daily dosing • Vivid dreams • Gritty taste; dissolves in mouth

34. Rilpivirine: Edurant. Used with truvada to make Complera • “Atripla Junior” can cause some depression and vivid dreams; usually less than efavirenz • Has to be taken with a substantial meal. • Cannot be taken on the same day as PPI’s or H2 blockers.

35. Delavirine: Rescriptor • Rarely used • Twice daily • Rash, birth defects

36. Integrase inhibitors • Raltegravir: Isentress • Dolutegravir: Tivicay • Elvitegravir (used with cobisistat) • As a class, they all cause diarrhea and occasional vivid dreams.

37. Raltegravir: • BID drug; can be given safely with most cytochrome p450 active meds • Needs to be taken 2 hours away from PPI’s

38. Stribild: truvada + elvitegravir +cobisistat • Boosting agent: cobisistat: cytochrome p450 active agent. • Also needs to be taken 2 hours away from PPI’s • Has all the side effects of truvada as well.

39. Dolutegravir: • Common: headache and insomnia. • Can worsen liver function when patient has hep C or hep B

40. Entry inhibitors • Enfuviritide. • Twice daily injectable drug. • GP41 inhibitor “condom for HIV virus” • Painful lumps on skin from local reaction to medication • No drug interactions. • $2,000 for this medication alone • Generally used for deep salvage treatment of HIV

41. Maraviroc: Selzentry • Twice daily drug • Risk of orthostatic hypotension • Risk of rash (small) Only effective in CCKR5 trophic HIV virus. “condom for CD4 cell” Can be used in initial therapy, or as salvage.

42. Blood tests necessary for monitoring • Abacavir: use HLA B5701 allele testing PRIOR to dosing. • If POSITIVE, then patient has high likelihood of developing abacavir hypersensitivity reaction

43. Creatinine; urinalysis. • Use this prior to dosing and every 3-6 months for patient on tenofovir containing regimens. Elevated urine protein, elevated creatinine are indications to considers switching tenofovir to another medication

44. Bilirubin, ALT, AST • Bilirubins can be used as a marker for compliance for atazanavir • Bilirubin >3.5 or symptomatic scleral icterus may be indication for changing atazanavir • All HIV meds (except for fuzeon) have some liver toxicity so ALT, Ast should be monitored as well. • Hep C can get better with HIV treatment (avoid atazanavir, dolutegravir) • Hep B treatment gets better with truvada

45. CBC with plts and diff • Thromboctopenia can improve within a few days of starting HIV meds • AZT may initially worsen, and then improve anemia

46. Hemogloblin A1C, glucose • PI’s make diabetes more likely • Insulin resistance presents as elevated HBA1c first.

47. Amylase, lipase • Perform when clinical suspicion of pancreatitis • Not helpful for routine monitoring if patient does not have symptoms of pancreatitis.

48. Clinical cases: • 32 yo homeless man, HIV+ new diagnosis. • Alcoholic, depressed,Cr 2.3. Hepatitis C. • What drug regimen would you try to AVOID. • What initial labs do you need to make a drug choice decision?

49. 65 yo male new dx of HIV infection. • Hx of afib and cardiac arrythmia. On amiroidarone and warfarin. Cr. 1.0 • What HIV medications do you need to AVOID? • What drug cocktails can be used in him?

50. 31 yo pregnant woman with HIV. • Chronic active hepatitis B • What HIV medications should she AVOID • What are her best choices of HIV meds?