DHHS Revised Adult and Adolescent Guidelines 1/29/2008

1. DHHS Revised Adult and Adolescent Guidelines 1/29/2008 Swati Modi, M.D. Faculty, Florida/Caribbean AETCAssistant Professor, University of Florida Center for HIV/AIDS Research, Education and Service (UF CARES), Pediatric Infectious Disease and Immunology, University of Florida College of Medicine, Jacksonville, Florida.

2. Disclosure of Financial Relationships This speaker has no significant financial relationships with commercial entities to disclose. This slide set has been peer-reviewed to ensure that there areno conflicts of interest represented in the presentation.

3. Course Objectives As a result of attending this 1 hour course on HIV/AIDS, the participant will be able to: Recognize current recommendation of when to start HIV therapy Recognize current DHHS guidelines regarding preferred and alternative Anti-retroviral therapy and be familiar with antiretrovirals which are not recommended Recognize when an HIV regimen is failing Identify indications for drug resistance testing Be familiar with implications of treatment interruption in HIV therapy and identify acute HIV syndrome Identify and locate the latest Department of Health and Human Service adult and adolescent guidelines to treat HIV

4. When to Start.. • Current recommendation: ART for all patients with CD4 <350 cells/mm³, certain others regardless of CD4 depending on presence of co-morbid conditions. • Current recommendations no longer define a group of people who should not be treated • Other major determinant for timing of initiation of therapy: • Concern about adherence to therapy • Depression • Substance abuse

5. Special considerations in patients presenting with an opportunistic disease • Early initiation of ART near time of initiation of OI treatment (within 1st 2 weeks) should be considered for most patients with an acute OI, excluding TB. • For TB disease, awaiting a response to OI therapy may be warranted before initiation of ART. Experts recommend making the decision based upon the immunological status of the patient: • CD4+ count <100 cells/μL: ART should be started after ≥2 weeks of TB treatment to reduce confusion about overlapping toxicities, drug interactions, and the occurrence of paradoxical reactions or IRIS • CD4+ count of 100–200 cells/μL: ART may be delayed until the end of the 2-month intensive phase of anti-TB treatment • CD4+ count >200 cells/μL: ART could be started during the anti-TB maintenance phase • CD4+ count >350 cells/μL: ART could be started after finishing anti-TB treatment

6. Maintain higher CD4 count; 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)

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

8. HAART at higher CD4 T-cells Treat all (regardless of CD4 count): • Pregnant women • HIV associated Nephropathy (HIVAN) • Co-Infection with hepatitis B, requiring treatment for HBV

9. HIVAN (HIV Associated Nephropathy) • HIVAN: Most common cause of Chronic Renal Failure in persons living with HIV infection. • More common in black than in white patients. • Not related to CD4 T-cell depletion, ongoing viral replication appears to be directly involved in renal injury. • Antiretroviral therapy in patients with HIVAN has been associated with preserved renal function and prolonged survival, and therefore should be initiated in individuals with diagnosis of HIVAN regardless of CD4 cell counts. • Keep in mind that NRTIs except Abacavir are renally excreted and so may require dose adjustment depending on creatinine clearance.

10. HIV/HBV Co-Infection: • Treat BOTH infections to prevent development of HBV resistant mutants • HBV resistance to lamivudine monoterapy: 40% at 2 years, 90% at 4 years • Elevation in transaminases: Think of IRIS vs. Antiretroviral therapy as a cause. However keep HBeAg seroconversion in mind. • Discontinuation of emtricitabine, lamivudine, and tenofovir may potentially cause serious hepatocellular damage resulting from reactivation of HBV

11. Antiretroviral therapy

12. Sites of Action of ART

13. Current Antiretroviral Medications

14. Considerations in Choosing Regimen • Comorbidities • Adherence potential • Dosing convenience • Potential adverse effects • Potential drug interactions • Pregnancy potential • Results of drug resistance test • Gender and CD4 count, if considering nevirapine • HLA B*5701 testing, if considering abacavir www.aidsetc.org

15. Tests Prior to Initiating Therapy • 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 • Consider in patients with virologic failure on aCCR5 antagonist

16. 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, neuropsychiatric side effects Potential drug interactions (CYP450) Antiretroviral Components in Initial Therapy: NNRTIs www.aidsetc.org

17. 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 ritonavir Antiretroviral Components in Initial Therapy: PIs www.aidsetc.org

18. 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) Triple NRTI regimens show inferior virologic response compared with efavirenz- and indinavir-based regimens* ARV Components in Initial Therapy: NRTIs * Triple NRTI regimen of abacavir + lamivudine + zidovudine to be used only when a preferred or alternative NNRTI- or PI-based regimen cannot or should not be used as first-line therapy. www.aidsetc.org

19. Antiretroviral Components Recommended for Treatment of HIV-1 Infection in Treatment Naïve Patients (http://AIDSinfo.nih.gov)

20. Cardiovascular Safety of Abacavir (ABC) • D:A:D study group reported their analysis of association of NRTI use and risk of myocardial infarction (MI) • A separate analysis conducted by GlaxoSmithKline using their internal database containing data from 54 clinical trials and post-marketing reports: GlaxoSmithKline did not find any evidence of an increase in cardiovascular disease in their clinical trials among patients who received ABC. • HEAT study: Abacavir/lamivudine noninferior to tenofovir/emtricitabine in combination with once-daily Kaletra • At this point, preliminary information available from these studies does not warrant a change in its current recommendations regarding the use of antiretroviral drugs in adults and adolescents • Clinicians should consider all available information so that the optimal therapeutic choice for each patient is based on individual patient characteristics and the potential risks and benefits of each treatment component http://aidsinfo.nih.gov/contentfiles/ABCComm.pdf

21. ARVs Not Recommended in Initial Treatment (1) *Should not be given to pregnant women www.aidsetc.org

22. ARVs Not Recommended in Initial Treatment (2) www.aidsetc.org

23. ARVs Not Recommended as Part of Antiretroviral Regimen www.aidsetc.org

24. Antiretroviral Regimens or Components That ShouldNot Be Offered At Any Time When constructing an antiretroviral regimen for an HIV-infected pregnant woman, please consult “Public Health Service Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States” in http://www.aidsinfo.nih.gov/guidelines/. When considering an antiretroviral regimen to use in post-exposure prophylaxis, please consult “Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis” in CDC MMWR Recommendations and Reports. September 30, 2005/54 (RR 09); 1–17 and “Management of Possible Sexual, Injection-Drug-Use, or Other Non-occupational Exposure to HIV, Including Considerations Related to Antiretroviral Therapy” in CDC MMWR Recommendations and Reports. January 21, 2005/54 (RR 02); 1–19.

25. Should Not Be Offered at Any Time • Efavirenz in pregnancy and in women with significant potential for pregnancy: associated with significant teratogenic effects • Nevirapine initiation in treatment-naïvewomen with CD4 >250 cells/mm³ or men with CD4 >400 cells/mm³: Greater risk of symptomatic, including serious and life-threatening, hepatic events have been observed in these patient groups. Nevirapine should be initiated only if the benefit clearly outweighs the risk • Atazanavir + indinavir: Both can cause grade 3 to 4 hyperbilirubinemia and jaundice. Additive/Worsening effect? www.aidsetc.org

26. Comparison of Different Classes: The Trials

27. NNRTI Vs PI based Regimen as First Line Therapy • A1424-034 study demonstrated comparable virologic and immunologic responses with atazanavir and efavirenz based regimens • ACTG A5142- better virologic responses with efavirenz based regimen compared with lopinavir/ritonavir based regimen, but better CD4 responses and less resistance following virologic failure with lopinavir/ritonavir plus two NRTIs.

28. NNRTI Vs PI based Regimen as First Line Therapy • Drug resistance to most PIs requires multiple mutations in the HIV protease, and it seldom develops following early virologic failure, especially when ritonavir boosting is used. • Resistance to efavirenz or nevirapine, however, is conferred by a single mutation in reverse transcriptase, and develops rapidly following virologic failure • In terms of convenience, NNRTI-based regimens are among the simplest to take, particularly with the coformulated tablet containing tenofovir, emtricitabine, and efavirenz, which allows for once daily dosing with a single pill. • PI-based Currently preferred regimens are usually used with ritonavir (Boosting), may be dosed once- or twice daily, and generally require more pills in the regimen.

29. Measurement of Success of ART Regimen • HIV RNA less than 400 copies/mL after 24 weeks • HIV RNA less than 50 copies after 48 weeks • Achieve and maintain adequate CD4 increase with virologic suppression • Avoidance of HIV-related events • After 3 months of therapy • Does not include immune reconstitution syndromes www.aidsetc.org

30. Indicators of Antiretroviral Treatment Failure • HIV RNA greater than 400 copies/mL after 24 weeks • HIV RNA greater than 50 copies/mL after 48 weeks • Rebound in viral load after suppression • Failure to achieve and maintain adequate CD4 increase despite virologic suppression • Clinical progression of HIV despite treatment www.aidsetc.org

31. Drug Resistance Testing: Recommendations

32. Drug Resistance Testing: Recommendations (2)

33. Clinical Progression • Occurrence or recurrence of HIV-related events (after at least 3 months on an antiretroviral regimen), excluding immune reconstitution syndromes • Management: • Rule out immune reconstitution syndrome which may respond toanti-inflammatory treatment • may not warrant a change in therapy in the setting of suppressed viremia and adequate immunologic response

34. Special Issues • Treatment Interruptions • Acute HIV infection

35. Treatment Interruption • No treatment interruption except if the patient is too sick or needs a surgery or part of a clinical trial • May cause viral rebound, immune decompensation and clinical progression, development of drug resistance, increases risk of HIV transmission • Increases risk of HIV and non-HIV related complications

36. Short Term Interruption in ART • In case of life threatening toxicity: Stop all drugs simultaneously • If it is planned short term interruption • When all ARVs have similar half-lives: Stop all drugs simultaneously • When ARVs have different half-lives: stopping all drugs at same time may result in functional monotherapy. Consider staggered discontinuation

37. ART Interruptions: ARV Specific Issues • Discontinuation of Efavirenz, Etravirine or Nevirapine: All have long half lives. Consider stopping them before the NRTI component to avoid potential mono therapy. Or Consider substitution of a NNRTI with a PI for a period of time before stopping all ARVs • If the Nevirapine has been discontinued for more than 2 weeks, it should be restarted with the usual dose escalation period

38. Interruption of ART: ARV-Specific Issues Discontinuation of emtricitabine, lamivudine, or tenofovir in patients with hepatitis B: • Flare of hepatitis may occur on discontinuation of any of these ARVs • Monitor closely • Consider initiating adefovir for HBV treatment • Entecavir should not be used in patients not on suppressive ART

39. Fever Lymphadenopathy Pharyngitis Rash Myalgia or arthralgia Diarrhea Headache Nausea and vomiting Hepatosplenomegaly Weight loss Thrush Neurological symptoms Acute Retroviral Syndrome: Common Signs and Symptoms

40. Acute HIV Infection: Diagnosis • Maintain high level of suspicion in patients with compatible clinical syndrome + risks • Plasma HIV RNA + HIV antibody test • Often, detectable HIV RNA with negative or indeterminate HIV antibody test • Low-positive HIV RNA (<10,000 copies/mL) may be false positive • Qualitative HIV RNA test can be used • If diagnosis is made by HIV RNA testing, confirmatory serologic testing should be performed subsequently

41. Possible Benefits: Decrease the severity of acute disease Alter the viral “set point” Reduce the rate of mutation by suppressing viral replication Preserve immune function Reduce risk of viral transmission Possible Risks: Drug-related toxicity Earlier emergence of drug resistance Limitation of future treatment options Potential need for indefinite treatment Adverse effects on quality of life Acute HIV Infection: Treatment

42. Acute HIV: Treatment Regimen • ARV regimen selection and monitoring are same as for chronic infection • Resistance testing (genotype) is recommended before ART selection • Resistance to NNRTIs is more common than resistance to PIs; consider using PI-based regimen if ART is initiated before resistance test results are available www.aidsetc.org

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

44. Thank you!!