1. HIV opportunistic infections and HIV treatment Sabrina Assoumou, MD Section of Infectious Diseases

2. Outline Case 1 Case 1 HIV opportunistic infections HIV opportunistic infections HIV treatment principles HIV treatment principles HIV treatment options HIV treatment options Case 2 Case 2

3. Case 1 40 y/o F admitted with 40 y/o F admitted with –Fever, HA, and sweats for 3 weeks –Diplopia and increased somnolence for 1d Diagnosed with HIV two months ago ( CD4 166, vl 66,923). ARVs were started immediately. Diagnosed with HIV two months ago ( CD4 166, vl 66,923). ARVs were started immediately. Current regimen: tenofovir, emtricitabine and efavirenz Current regimen: tenofovir, emtricitabine and efavirenz

4. Case 1 (con’t) PE: 100.8 F PE: 100.8 F –Awake but drowsy and oriented to person, but not time –L eye cannot move laterally with leftward gaze CT scan: mildly increased ventricle size CT scan: mildly increased ventricle size LP: Cell count 122, gluc 62, Protein 433 LP: Cell count 122, gluc 62, Protein 433

5. Case 1 (con’t) Infection with which of the following is the most likely cause of this patient’s clinical presentation? a) Cryptococcus neoformans b) CMV c) Histoplasma capsulatum d) Toxoplasma gondii

6. HIV Opportunistic Infections

7. Primary OI prophylaxis CD4 <200 CD4 <200 CD4 <100 CD4 <100 CD4 <50 CD4 <50

8. Primary OI prophylaxis CD4 <200: PCP CD4 <200: PCP CD4 <100: Toxoplasmosis if positive serology CD4 <100: Toxoplasmosis if positive serology CD4 <50: MAI CD4 <50: MAI

9. Severe PCP

10. Toxoplasmosis

11. PML

12. MAI-filled macrophages in spleen

13. Thrush

14. Herpes Zoster (Shingles)

15. Cytomegalovirus Retinitis

16. HIV therapy

17. Goals of therapy Improve quality of life Improve quality of life Reduce HIV-related morbidity and mortality Reduce HIV-related morbidity and mortality Restore and/or preserve immunologic function Restore and/or preserve immunologic function Maximally and durably suppress HIV viral load Maximally and durably suppress HIV viral load Prevent HIV transmission Prevent HIV transmission

18. HIV therapy Who? Who? What? What? When? When? Check genotype prior to initiation Check genotype prior to initiation

19. Initial ART Regimens: DHHS Categories Preferred Preferred –Randomized controlled trials show optimal efficacy and durability –Favorable tolerability and toxicity profiles Alternative Alternative –Effective but have potential disadvantages –May be the preferred regimen in individual patients Acceptable Acceptable –Less virologic efficacy, lack of efficacy data, or greater toxicities

20. Preferred regimen 3 main categories: 3 main categories: –1 NNRTI + 2 NRTIs –1 PI + 2 NRTIs –1 II + 2 NRTIs

21. Initial Treatment: Preferred NNRTI based Efavirenz/Tenofovir/Emtricitabine Efavirenz/Tenofovir/Emtricitabine PI based Atazanavir/ritonavir + Tenofovir/Emtricitabine Atazanavir/ritonavir + Tenofovir/Emtricitabine Darunavir/ritonavir + Tenofovir/Emtricitabine Darunavir/ritonavir + Tenofovir/Emtricitabine II based Raltegravir + Tenofovir/Emtricitabine Raltegravir + Tenofovir/Emtricitabine

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

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

24. ARV Components in Initial Therapy: Raltegravir ADVANTAGES Virologic response noninferior to EFV Virologic response noninferior to EFV Fewer adverse events than with EFV Fewer adverse events than with EFV Fewer drug-drug interactions than with PIs or NNRTIs Fewer drug-drug interactions than with PIs or NNRTIs NNRTIs and PIs preserved for future use NNRTIs and PIs preserved for future useDISADVANTAGES Twice-daily dosing Twice-daily dosing Lower genetic barrier to resistance than PIs Lower genetic barrier to resistance than PIs

25. ARV-Associated Adverse Effects: Rash Most common with NNRTIs, especially Nevirapine Most common with NNRTIs, especially Nevirapine –Most cases mild to moderate, occurring in first 6 weeks of therapy; occasionally serious (eg, Stevens-Johnson syndrome) PIs: especially Darunavir PIs: especially Darunavir NRTIs: especially abacavir (hypersensitivity syndrome) NRTIs: especially abacavir (hypersensitivity syndrome) CCR5 antagonist: Maraviroc CCR5 antagonist: Maraviroc

26. ARV-Associated Adverse Effects: Nephrotoxicity Renal insufficiency associated with Tenofovir, Indinavir Renal insufficiency associated with Tenofovir, Indinavir TDF: TDF: –Cr, proteinuria, glycosuria, hypophosphatemia, hypokalemia Indinavir: Cr, pyuria, hydronephrosis or renal atrophy Indinavir: Cr, pyuria, hydronephrosis or renal atrophy Nephrolithiasis: Indinavir, Atazanavir Nephrolithiasis: Indinavir, Atazanavir

27. ARV-Associated Adverse Effects: Hepatotoxicity Severity variable: usually asymptomatic, may resolve without treatment interruption Severity variable: usually asymptomatic, may resolve without treatment interruption May occur with any NNRTI or PI, most NRTIs May occur with any NNRTI or PI, most NRTIs –Nevirapine: risk of severe hepatitis in first 18 weeks of use (monitor LFTs closely) risk of severe hepatitis in first 18 weeks of use (monitor LFTs closely) increased risk in chronic hepatitis B and C increased risk in chronic hepatitis B and C women, and high CD4 count at initiation (>250 cells/µL in women, >400 cells/µL in men) women, and high CD4 count at initiation (>250 cells/µL in women, >400 cells/µL in men)

28. ARV-Associated Adverse Effects: Insulin Resistance, Diabetes Insulin resistance, hyperglycemia, and diabetes associated with AZT, some PIs (LPV/r), especially with chronic use Insulin resistance, hyperglycemia, and diabetes associated with AZT, some PIs (LPV/r), especially with chronic use Mechanism not well understood Mechanism not well understood –Insulin resistance, relative insulin deficiency Screen regularly: fasting glucose Screen regularly: fasting glucose

29. ARV-Associated Adverse Effects: Hyperlipidemia  Total cholesterol, LDL, and triglycerides  Total cholesterol, LDL, and triglycerides –Associated with all RTV-boosted PIs, efavirenz, AZT, abacavir  HDL seen with efavirenz, ritonavir-boosted PIs  HDL seen with efavirenz, ritonavir-boosted PIs Concern for cardiovascular events, pancreatitis Concern for cardiovascular events, pancreatitis Monitor regularly Monitor regularly Treatment: consider ARV switch; lipid-lowering agents (caution with PI + certain statins) Treatment: consider ARV switch; lipid-lowering agents (caution with PI + certain statins)

30. Case 2 25 yo F who is 12 weeks pregnant 25 yo F who is 12 weeks pregnant –Found to be HIV-infected during routine pregnancy evaluation –She is asymptomatic PE: normal. No oral thrush, LAD PE: normal. No oral thrush, LAD CD4 865, vl 510 CD4 865, vl 510 Hepatitis B negative, Genotype: no resistance Hepatitis B negative, Genotype: no resistance

31. Case 2 ( con’t) Which of the following is the most appropriate management? Which of the following is the most appropriate management? a) Begin ARVs at the onset of labor b) Begin tenofovir, emtricitabine, and efavirenz, now c) Begin AZT, lamivudine, lopinavir- ritonavir d) Repeat CD4 and treat if the CD4 is <500

32. Conclusions Remember CD4 cut offs for primary OI prophylaxis ( 200, 100, 50) Remember CD4 cut offs for primary OI prophylaxis ( 200, 100, 50) ALL HIV-infected patients should be on ARVs ALL HIV-infected patients should be on ARVs Basic regimen 2NNRTI + PI or NNRTI or II Basic regimen 2NNRTI + PI or NNRTI or II