Comprehensive Guideline Summary

1. Comprehensive Guideline Summary Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents December 2009 AETC NRC Slide Set

2. About This Presentation These slides were developed using the December 2009 Treatment Guidelines. The intended audience is clinicians involved in the care of patients with HIV. Because the field of HIV care is rapidly changing, users are cautioned that the information in this presentation may become out of date quickly. It is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. -AETC NRC http://www.aidsetc.org www.aidsetc.org

3. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Developed by the Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of the Office of AIDS Research Advisory Council (OARAC) www.aidsetc.org

4. Guidelines Outline • Overview • Initiation of Therapy • Management of the Treatment-Experienced Patient • Special Issues www.aidsetc.org

5. What the Guidelines Address • Baseline evaluation • Laboratory testing (HIV RNA, CD4 cell count, resistance) • When to initiate therapy • When to change therapy • Therapeutic options • Adherence • ART-associated adverse effects www.aidsetc.org

6. What the Guidelines Address (2) • Treatment of acute HIV infection • Special considerations in adolescents, pregnant women, injection drug users, HIV-2 infection, and patients coinfected with HIV and HBV, HCV, or TB • Preventing secondary transmission www.aidsetc.org

7. Websites to Access the Guidelines • http://aidsinfo.nih.gov • http://www.aidsetc.org www.aidsetc.org

8. Improve quality of life Reduce HIV-related morbidity and mortality Restore and/or preserve immunologic function Maximally and durably suppress HIV viral load Prevent HIV transmission Goals of Treatment www.aidsetc.org

9. Selection of ARV regimen Maximizing adherence Pretreatment resistance testing Tools to Achieve Treatment Goals www.aidsetc.org

10. Improving Adherence • Support and reinforcement • Simplified dosing strategies • Reminders, alarms, timers, and pillboxes • Ongoing patient education • Trust in primary care provider www.aidsetc.org

11. Use of CD4 Cell Levels to Guide Therapy Decisions • CD4 count • The major indicator of immune function • Most recent CD4 count is best predictor ofdisease progression • A key factor in decision to start ART or OI prophylaxis • Important in determining response to ART • Adequate response: CD4 increase 50-150 cells/µL per year • CD4 monitoring • Check at baseline (x2) and at least every3-6 months www.aidsetc.org

12. Use of HIV RNA Levels to Guide Therapy Decisions • HIV RNA • May influence decision to start ART and help determine frequency of CD4 monitoring • Critical in determining response to ART • Goal of ART: HIV RNA below limit of detection (ie, <40-75 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 3-6 months with stable patients www.aidsetc.org

13. Testing for Drug Resistance • Before initiation of ART: • Transmitted resistance in 6-16% of HIV-infected patients • In absence of therapy, resistance mutations may decline over time and become undetectable by current assays, but may persist and cause treatment failure when ART is started • Identification of resistance mutations may optimize treatment outcomes • Resistance testing (genotype) recommended for all at entry to care • Recommended for all pregnant women • Patients with virologic failure: • Perform while patient is taking ART, or ≤4 weeks afterdiscontinuing therapy • Interpret in combination with history of ARV exposureand ARV adherence www.aidsetc.org

14. Drug Resistance Testing: Recommendations www.aidsetc.org

15. Drug Resistance Testing: Recommendations (2) www.aidsetc.org

16. Drug Resistance Testing: Recommendations (3) www.aidsetc.org

17. Drug Resistance Testing: Recommendations (4) www.aidsetc.org

18. Other Assessment andMonitoring Studies • HLA-B*5701 screening • Recommended before starting abacavir, to reduce riskof hypersensitivity reaction (HSR) • HLA-B*5701-positive patients should not receive ABC • Positive status should be recorded as an ABC allergy • If HLA-B*5701 testing is not available, ABC may be initiatedafter counseling and with appropriate monitoring for HSR • Coreceptor tropism assay • Should be performed when a CCR5 antagonistis being considered • Requires plasma HIV RNA ≥1,000 copies/mL • Consider in patients with virologic failure on aCCR5 antagonist www.aidsetc.org

19. When to Start ART • Potent ART may improve and preserve immunefunction in most patients with virologic suppression, regardless of baseline CD4 count • ART indicated for all with low CD4 count or symptoms • Earlier ART may result in better immunologic responsesand better clinical outcomes • Reduction in AIDS- and non-AIDS-associated morbidity and mortality • Reduction in HIV-associated inflammation and associated complications • Reduction in HIV transmission • Recommended ARV combinations are considered to bedurable and tolerable www.aidsetc.org

20. When to Start ART • 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 <500 cells/µL • For patients with CD4 >500 cells/µL, 50% of the panel recommend ART, 50% consider ART to be optional • Randomized control trial (RTC) data support benefit of ART if CD4 350 • No RTC data on benefit of ART at CD4 >350, but observational cohort data • Currently available ARVs are effective and well tolerated www.aidsetc.org

21. Cohort study data show survival benefit if ART initiated at CD4 count >500 cells/µL Earlier ART may prevent HIV-related end organ damage; deferred ART may not reliably repair damage acquired earlier Increasing evidence of direct HIV effects on various end organs and indirect effects via HIV-associated inflammation End organ damage occurs at all stages of infection Potential Benefits of Early Therapy (CD4 count >500 cells/µL) www.aidsetc.org

22. Potential decrease in risk of many complications, including: HIV-associated nephropathy Liver disease progression from hepatitis B or hepatitis C Cardiovascular disease Malignancies (AIDS defining and non-AIDS defining) Neurocognitive decline Blunted immunological response due to ART initiation at older age Persistent T-cell activation and inflammation Potential Benefits of Early Therapy (CD4 count >500 cells/µL) (2) www.aidsetc.org

23. Prevention of sexual and bloodborne transmission of HIV Prevention of mother-to-child transmission of HIV Potential Benefits of Early Therapy (CD4 count >500 cells/µL) (3) www.aidsetc.org

24. ARV-related toxicities Drug resistance Nonadherence to ART Cost Potential Limitations of Early Therapy (CD4 count >500 cells/µL) www.aidsetc.org

25. Recommendations for Initiating ART * Treatment with fully suppressive drugs active against both HIV and HBV is recommended. www.aidsetc.org

26. Recommendations for Initiating ART (2) www.aidsetc.org

27. Recommendations for Initiating ART (3) • “Patients initiating ART should be willing and able to commit to lifelong treatment and should understand the benefits and risks of therapy and the importance of adherence.” • Patients may choose to postpone ART • Providers may elect to defer ART, based on patients’ clinical and/or psychosocial factors www.aidsetc.org

28. Consider More Rapid Initiation of ART • Pregnancy • AIDS-defining condition • Acute opportunistic infection • Lower CD4 count (eg, <200 cells/µL) • Rapid decline in CD4 • Higher viral load • HIVAN • HBV coinfection when HBV treatment is indicated www.aidsetc.org

29. Consider Deferral of ART • Clinical or personal factors may support deferral of ART • If CD4 is low, deferral should be considered only in unusual situations, and with close follow-up • When there are significant barriers to adherence • If comorbidities complicate or prohibit ART • “Elite controllers” and long-term nonprogressors www.aidsetc.org

30. Current ARV Medications www.aidsetc.org

31. Initial ART Regimens: DHHS Categories • Preferred • Randomized controlled trials show optimal efficacy and durability • Favorable tolerability and toxicity profiles • Alternative • Effective but have potential disadvantages • May be the preferred regimen in individual patients • Acceptable • Less virologic efficacy, lack of efficacy data, or greater toxicities • May be acceptable but more definitive data are needed www.aidsetc.org

32. Initial Treatment: Choosing Regimens • 3 main categories: • 1 NNRTI + 2 NRTIs • 1 PI + 2 NRTIs • 3 NRTIs • Combination of NNRTI or PI + 2 NRTIs preferred for most patients • Fusion inhibitor, CCR5 antagonist, integrase inhibitor not recommended in initial ART • Few clinical end points to guide choices • Advantages and disadvantages to eachtype of regimen • Individualize regimen choice www.aidsetc.org

33. Initial Treatment: Preferred 1. EFV should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception. 2.3TC can be used in place of FTC and vice versa. www.aidsetc.org

34. Initial Treatment: Alternatives 1. EFV should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception. 2. 3TC can be used in place of FTC and vice versa. 3. ABC should not be used in patients who test positive for HLA B*5701; caution if HIV RNA >100,000 copies/mL, or if high risk of cardiovascular disease. 4. NVP should not be started if pre-ARV CD4 >250 in women or >400 in men. www.aidsetc.org

35. Initial Treatment: Acceptable 1. EFV should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception. 2. 3TC can be used in place of FTC and vice versa. 3. ABC should not be used in patients who test positive for HLA-B*5701; caution if HIV RNA >100,000 copies/mL, or if high risk of cardiovascular disease . www.aidsetc.org

36. Initial Treatment: May Be Acceptable but More Definitive Data Needed 1. 3TC can be used in place of FTC and vice versa. 2. ABC should not be used in patients who test positive for HLA-B*5701; caution if HIV RNA >100,000 copies/mL, or if high risk of cardiovascular disease. 3. Tropism testing required before treatment with MVC; use only if only CCR5-tropic virus is present. www.aidsetc.org

37. Initial Treatment: Use with Caution 1.3TC can be used in place of FTC and vice versa. 2.ABC should not be used in patients who test positive for HLA-B*5701; caution if HIV RNA >100,000 copies/mL, or if high risk of cardiovascular disease. 3. NVP and ABC both can cause hypersensitivity reaction in first few weeks of treatment. 4. NVP should not be started if pre-ARV CD4 >250 in women or >400 in men. 5. Early virologic failure in some patients; larger studies under way. 6. Virologic failure may select mutations that confer cross-resistance to DRV. www.aidsetc.org

38. ARVs Not Recommended inInitial Treatment www.aidsetc.org

39. ARVs Not Recommended inInitial Treatment (2) www.aidsetc.org

40. ARV Medications: Should Not Be Offered at Any Time • ARV regimens not recommended: • Monotherapy with NRTI* • Dual-NRTI therapy • 3-NRTI regimen (except ABC + 3TC + ZDV or possibly TDF + 3TC + ZDV, when other regimens are not desirable) * If ZDV monotherapy is being considered for prevention of mother-to-child transmission, see Public Health Service Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-Infected Women for Maternal Health and Interventions toReduce Perinatal HIV Transmission in the United States. www.aidsetc.org

41. ARV Medications: Should Not Be Offered at Any Time (2) • ARV components not recommended: • ddI + d4T • FTC + 3TC • d4T + ZDV • DRV, SQV, or TPV as single PIs (unboosted) www.aidsetc.org

42. ARV Medications: Should Not Be Offered at Any Time (3) • ARV components not recommended: • EFV during pregnancy and in women with significant potential for pregnancy • NVP initiation in women with CD4 counts of >250 cells/µL or in men with CD4 counts of >400 cells/µL • ETR + unboosted PI • ETR + RTV-boosted ATV, FPV, or TPV • 2-NNRTI combination www.aidsetc.org

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

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

45. ADVANTAGES Virologic response noninferior to EFV Fewer adverse events than with EFV Fewer drug-drug interactions than with PIs or NNRTIs NNRTIs and PIs preserved for future use DISADVANTAGES Less experience with IIs, limited data Twice-daily dosing Lower genetic barrier to resistance than PIs No data with NRTIs other than TDF/FTC in initial therapy ARV Components in Initial Therapy: II (Raltegravir) www.aidsetc.org

46. 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 www.aidsetc.org

47. All NNRTIs: Rash, including Stevens-Johnson syndrome Drug-drug interactions EFV Neuropsychiatric Teratogenic in nonhuman primates + cases of neural tube defects in human infants after first trimester exposure NVP Higher rate of rash Hepatotoxicity (may be severe and life-threatening;risk higher in patients with higher CD4 counts at the time they start NVP) Adverse Effects: NNRTIs www.aidsetc.org

48. All PIs: Hyperlipidemia Insulin resistance and diabetes Lipodystrophy Elevated LFTs Possibility of increased bleeding riskfor hemophiliacs Drug-drug interactions Adverse Effects: PIs www.aidsetc.org

49. ATV Hyperbilirubinemia PR prolongation Nephrolithiasis DRV Rash Liver toxicity FPV GI intolerance Rash Possible increased risk of MI Adverse Effects: PIs (2) www.aidsetc.org

50. IDV Nephrolithiasis GI intolerance LPV/r GI intolerance Possible increased risk of MI PR and QT prolongation NFV Diarrhea Adverse Effects: PIs (3) www.aidsetc.org