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HIV Treatment Guidelines: Reviewing Essentials for Optimal Care

Sponsored for CME credit by Rush University Medical Center. Supported by an independent educational grant from Gilead Sciences Medical Affairs. HIV Treatment Guidelines: Reviewing Essentials for Optimal Care. Educator. The Very Rev. Father Drew A. Kovach, MD, MDiv. Director of HIV Services

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HIV Treatment Guidelines: Reviewing Essentials for Optimal Care

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  1. Sponsored for CME credit by Rush University Medical Center Supported by an independent educational grant from Gilead Sciences Medical Affairs HIV Treatment Guidelines:Reviewing Essentials for Optimal Care

  2. Educator The Very Rev. Father Drew A. Kovach, MD, MDiv. Director of HIV Services Kaiser Permanente Hawaii

  3. Rush University Medical Center is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Rush University Medical Center designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. The Association of Nurses in AIDS Care (ANAC) is an approved provider of continuing education in nursing by the Virginia Nurses Association Continuing Education Approval Committee, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education (UPN #012-999-07-206-L02-P). This slide kit is accredited for one hour of continuing education credit. The University of Florida College of Pharmacy will mail Statements of Continuing Education Credit within 30 working days after receiving evidence of successful completion of the course. Successful completion means that you must attend the entire program and complete an evaluation form. This program is accredited for case managers through the Commission for Case Manager Certification (CCMC). To have clock hours added to your certification file, please submit the verification of completion form provided by your host directly to CCMC. Supported by an independent educational grant from Gilead Sciences Medical Affairs. Accreditation and Designation

  4. Faculty:CME Course Director Harold A. Kessler, MD Professor of Medicine and Immunology/Microbiology Associate Director, Section of Infectious Diseases Rush University Medical Center Chicago, Illinois

  5. Faculty:Content Development and Training Renslow D. Sherer, MD Clinical Associate Section of Infectious DiseaseThe University of Chicago Director, Infectious Disease Unit Project HOPE Chicago, Illinois

  6. Disclosure Information • It is the policy of the Rush University Medical Center Office of Continuing Medical Education to ensure that its CME activities are independent, free of commercial bias and beyond the control of persons or organizations with an economic interest in influencing the content of CME • Everyone who is in a position to control the content of an educational activity must disclose all relevant financial relationships with any commercial interest (including but not limited to pharmaceutical companies, biomedical device manufacturers, or other corporations whose products or services are related to the subject matter of the presentation topic) within the preceding 12 months • If there are relationships that create a conflict of interest, these must be resolved by the CME Course Director in consultation with the Office of Continuing Medical Education prior to the participation of the faculty member in the development or presentation of course content

  7. Disclosure Information:CME Course Director • Harold A. Kessler, MD • Grants/Research Support • Boehringer Ingelheim, Gilead Sciences, Merck, Tibotec, Theratechnologies • Consultant • Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Tibotec, Virco • Speakers’ Bureau • Bristol-Myers Squibb, GlaxoSmithKline, Merck, Tibotec, Virco • Stock Shareholder • Abbott Laboratories, GlaxoSmithKline, Merck • Other Financial or Material Support: none

  8. Disclosure Information:Content Faculty • Renslow D. Sherer, MD • Grants/Research Support • Abbott Laboratories, Johnson & Johnson, Pfizer • Consultant • Abbott Laboratories, GlaxoSmithKline, Tibotec • Speakers’ Bureau • Abbott Laboratories • Stock Shareholder • None • Other Financial or Material Support • None

  9. Disclosure Information:Medical Writer • Peter Pinkowish • Grants/Research Support • None • Consultant • None • Speakers’ Bureau • None • Stock Shareholder • None • Other Financial or Material Support • None

  10. Disclosure Information:Educator • Drew A. Kovach, MD, MDiv. • Grants/Research Support • None • Consultant • Gilead • Speakers’ Bureau • Gilead, BMS, Merck, Monogram Biosciences • Stock Shareholder • None • Other Financial or Material Support • None

  11. Opinions and Off-Label Discussions The opinions or views expressed in this educational program are those of the participants and do not necessarily reflect the opinions or recommendations of Gilead Sciences Medical Affairs, Rush University Medical Center, University of Florida College of Pharmacy, Association of Nurses in AIDS Care, or Commission for Case Manager Certification The faculty may have included discussion on unlabeled uses of a commercial product or an investigational use of a product not yet approved for this purpose Please consult the full prescribing information before using any medication mentioned in this program

  12. Program Evaluation Your feedback is essential for measuring the success of this CME/CE program Completion of the program evaluation, included within your materials, and submission to the onsite program Host is required CME/CE credits for this program cannot be provided without a completed evaluation A post-activity brief online survey will be e-mailed to you in 4 to 8 weeks to assess how your participation in this educational activity has affected your practice of medicine

  13. Slide Handouts • The enclosed slide handouts are provided for reference purposes only • The faculty presenter may have customized the slides through reordering or deleting and thus the handouts may not exactly match the presentation

  14. Learning Objectives (CME, CE, CPE) • At the completion of this educational activity, participants should be able to: • Explain the current recommendations on when to initiate antiretroviral therapy defined by the Department of Health and Human Services (DHHS) guidelines • Describe the efficacy and safety data from key clinical trials on preferred initial antiretroviral regimens recommended by the DHHS guidelines • Explain what constitutes treatment failure and review treatment considerations when a change in therapy is warranted

  15. A Brief History of Antiretroviral Therapy • Early 80’s • No antiretroviral therapy • Late 80’s • Zidovudine monotherapy • Early 90’s • Sequential NRTI monotherapy and dual-NRTI therapy • Late 90’s • The early HAART era • Early 00’s • Trials of treatment interruption • Late 00’s • Earlier initiation of therapy • More potent, durable regimen combinations • New classes of therapy

  16. What’s New With the DHHS Guidelines • What to start with • Abacavir/lamivudine now a preferred NRTI (if negative for HLA-B*5701) • Zidovudine/lamivudine changed to alternative NRTI • Ritonavir-boosted saquinavir acceptable for initial therapy, but inferior to preferred or alternative PIs • Options no longer recommended • Nelfinavir • Stavudine + lamivudine • Abacavir/zidovudine/lamivudine • Treatment interruption • Long-term treatment interruption not recommended January 29, 2008 November 3, 2008 • What to start with • Abacavir/lamivudine now an alternate NRTI due to concerns about increased risk of myocardial infarction and virologic potency in patients with baseline HIV RNA >100,000 copiers/mL • Ritonavir-boosted darunavir and once-daily lopinavir/r are now preferred PIs • Use with caution • Nevirapine + tenofovir DF + emtricitabine (or lamivudine) • Options no longer recommended • Unboosted atazanavir + didanosine + emtricitabine (or lamivudine) • Resistance testing recommended for baseline HIV RNA 500-1000 copies/mL Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.

  17. Program Overview • When to start treatment • Treatment goals • What to start with • Assessing treatment failure and when to change

  18. When to Start Treatment Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008; Hammer SM, et al. JAMA. 2008;300:555-570.

  19. Maintain higher CD4 count and prevent potentially irreversible damage to the immune system Decreased risk for HIV-associated complications Tuberculosis, non-Hodgkin’s lymphoma, Kaposi’s sarcoma, peripheral neuropathy, HPV-associated malignancies, and HIV-associated cognitive impairment Decreased risk of nonopportunistic conditions Cardiovascular disease, renal disease, liver disease, and non–AIDS-associated malignancies and infections Decreased risk of HIV transmission Treatment-related side effects and toxicities Development of drug resistance due to incomplete viral suppression Loss of future treatment options Less time for patient adjustment to disease and treatment requirements Increased total time on medication Premature use of therapy before potentially better/safer future options are available Transmission of drug-resistant virus in patients who do not maintain full virologic suppression Potential Benefits and Risksof Early Therapy Benefits Risks Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.

  20. NA-ACCORD:The Case for Earlier Initiation • North American AIDS Cohort Collaboration on Research and Design • 22 HIV research cohorts from United States and Canada • Determine all-cause mortality in patients with CD4 between 351 to 500 cells/mm3 • Treatment arms • Initiate treatment with CD4 between 351 to 500 cells/mm3 • Deferred treatment with CD4 between 351 to 500 cells/mm3 Kitahata M, et al. 48th ICAAC. Washington, DC, 2008. Abstract H-869b.

  21. NA-ACCORD:Relative Hazard of All-Cause Mortality Rate of virologic suppression was similar between groups. HIV RNA was not an independent predictor of mortality. Kitahata M, et al. 48th ICAAC. Washington, DC, 2008. Abstract H-869b.

  22. NA-ACCORD: Survival Benefit When Initiating HAART With CD4 >500 Cells/mm3 • Determine impact of initiating HAART at CD4 >500 cells/mm3 on predicted survival • Treatment arms • Initiate treatment with CD4 >500 cells/mm3 • Deferred treatment when CD4 decreases to <500 cells/mm3 Kitahata M, et al. 16th CROI. Montreal, 2009. Abstract 71.

  23. NA-ACCORD: Improved Survival AssociatedWith Initiating HAART With CD4 >500 Cells/mm3 As expected, both IDU and HCV coinfection were independent predictors of mortaility. HIV RNA was not an independent predictor of mortality. Kitahata M, et al. 16th CROI. Montreal, 2009. Abstract 71.

  24. SMART Study: Benefits of Continuous Treatment of HIV Disease • Open-label study • CD4-guided intermittent therapy • Stop: CD4 >350 cells/mm3 • Resume: CD4 <250 cells/mm3 • Continuous therapy • Prematurely stopped January 2006 • 5.7% reduction in absolute risk of opportunistic disease and serious non-AIDS events (CVD, hepatic and renal diseases, non-AIDS cancers and death) with continuous versus intermittent therapy Rate of OD/Death Intermittent therapy (n=2720) Continuous therapy (n=2752) 9.8 9.7 Rate (per 100 person-years) 4.1 3.4 2.9 2.5 2.2 1.3 1.1 0.8 Overall <250 250-349 350-499 >500 Latest CD4 (cells/mm3) SMART Study Group. J Infect Dis. 2008;197:1145-1155.

  25. SMART Study: Retrospective ExploratoryAnalysis of Cardiovascular Disease Events *P=0.05; †P=0.03; ‡P=0.009. Phillips A, et al. 14th CROI. Los Angeles, 2007. Abstract 41.

  26. Recent exposure (yes/no) Cumulative exposure (per year) D:A:D Study: Risk of MI Per Exposureto Individual NRTIs, PIs, and NNRTIs PIs and NNRTIs (Cumulative Exposure) NRTIs (Recent and Cumulative Exposure) Relative Risk (95% CI) Relative Risk (95% CI) ZDV ddI d4T ABC IDV 3TC TDF NFV LPV/r NVP SQV EFV Number of P-Y FU: No. of MIs: Number of P-Y FU: No. of MIs: 74,407 331 95,320 405 138,109 523 152,009 554 53,300 221 39,157 139 56,529 197 37,136 150 68,469 298 44,657 221 61,655 228 58,946 221 Adjusted for baseline demographics and cardiovascular risk factors and for latest measures of lipids, metabolic parameters, CD4 count, and HIV RNA level. P-Y FU: patient-years follow-up. Recent use: current or within the last 6 months. Lundgren J, et al. 16th CROI. Montreal, 2009. Abstract 44LB.

  27. D:A:D Study:Conclusions • Abacavir, didanosine, indinavir, and lopinavir/ritonavir were associated with an increased risk of MI • For indinavir and lopinavir/r • Risk increased with cumulative exposure • No significant associations between exposure to other NRTIs including tenofovir DF, NRTIs, or the other PIs and the risk of MI • Concomitant use of ritonavir did not appear to modify the effects of saquinavir or indinavir Lundgren J, et al. 16th CROI. Montreal, 2009. Abstract 44LB.

  28. Liver Disease is the Second Leading Cause of Death in HIV-Infected Patients (1999-2004) • D:A:D study (n=23,441) • Median follow-up: 3.5 years • Baseline characteristics • Nadir CD4: 200 cells/µL • Previous AIDS: 26.5% • HCV positive: 22.5% • Active HBV infection: 6.8% • Inactive HBV infection: 21.4% • Receiving combination antiretroviral therapy: 88.7% • Mortality • Total: 5.3% • Incidence: 1.62 per 100 person-years • Median age: 44 years Cause of Death (n=1246) 31.1% Patients (%) 14.5% 11.0% AIDS Liver-Related Diseases CVD Weber R, et al. Arch Intern Med. 2006;166:1632-1641.

  29. Independent Predictorsof Liver-Related Death Latest CD4 Cell Count (cells/µL) <50 50-99 100-199 200-349 350-499 >500 16.06 11.54 7.14 3.95 1.67 2.01 HIV Acquisition via IDU Hepatitis C Status Negative Positive 6.66 Hepatitis B Status Negative Positive 3.73 0.2 1.0 10 100 Multivariate analysis. Not shown: Age per 5 years (1.32). Relative Rate of Death Weber R, et al. Arch Intern Med. 2006;166:1632-1641.

  30. HOPS Cohort: Early Initiation of HAART Decreases Risk of Toxicities • Prospective, dynamic cohort (>8000 patients) • 8-year follow-up • Incidence of nucleoside analogue-associated toxicities was significantly reduced when HAART was initiated at progressively higher CD4 cell counts • These data suggest that a delay in initiating HAART increases the risk of toxicities Multivariate analysis. *Referent to CD4 cell count 200 to 349 cells/mm3. †P=0.022. ‡P=0.009. Lichtenstein KA, et al. JAIDS. 2008;47:27-35.

  31. Program Overview • When to start treatment • Treatment goals • What to start with • Assessing treatment failure and when to change

  32. Treatment Goals • Primary goals • Reduce HIV-related morbidity and prolong survival • Improve quality of life • Restore and preserve immunologic function • Maximally and durably suppress viral load • Prevent vertical HIV transmission Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.

  33. Maximal Viral Suppressionin Initial Therapy • Use two, preferably three, active drugs from multiple drug classes • HIV RNA <50 copies/mL usually occurs within the first 12 to 24 weeks of therapy • Predictors of virologic success • High potency of antiretroviral regimen • Excellent adherence to treatment regimen • Low baseline HIV RNA level • Higher baseline CD4 cell count • Rapid reduction in HIV RNA level in response to treatment • >1 log10 copies/mL in 1 to 4 months Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.

  34. Strategies to Achieve Treatment Goals • Selection of initial combination regimen tailored to the patient • Efficacy, pill burden, potential side effects • Pretreatment drug resistance testing • Improve potential for adherence • Simplify medication regimens • Address patient factors (eg, active substance abuse, depression) • Discuss health system issues (eg, interruptions in medication access • Inadequate treatment education and support Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.

  35. Prevalence ofTransmitted Drug Resistance Europe 2002/2003 (n=1083) USA 2005 (n=240) USA adolescents 2005 (n=55) 18% 17% 15% 11% Resistance (%) 9% 7% 5% 5% 4% 4% 3% 2% Any Class NRTI NNRTI PI Wensing AM, et al. J Infect Dis. 2005;192:958-966. Wensing AM, et al. 16th IAC, 2006. Abstract TuAB0101. Ross L, et al. 46th ICAAC, 2006. Abstract H-993. Viani R, et al. J Infect Dis. 2006;194:1505-1509.

  36. Drug Resistance Testing • Recommended for all HIV-infected individuals entering care, regardless of whether therapy will be initiated • If therapy is deferred, consider repeating testing at the time of antiretroviral therapy initiation • Genotypic assay is preferred for treatment-naïve patients • Recommend genotypic testing • All pregnant women prior to initiation of therapy • Those entering pregnancy with detectable HIV RNA levels while on therapy • Recommended when HIV RNA 500 to 1000 copies/mL • Amplification of the virus may not be reliable Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.

  37. HLA-B*5701 Screening • Recommended before starting abacavir-containing regimen • Reduce the risk of hypersensitivity reaction • HLA-B*5701 positive • Avoid abacavir • Record as abacavir allergy in patient’s medical record • If HLA-B*5701 screening is not readily available • Reasonable to initiate abacavir with appropriate clinical counseling and monitoring for any signs of hypersensitivity reaction Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008. Hammer SM, et al. JAMA. 2008;300:555-570.

  38. Program Overview • When to start treatment • Treatment goals • What to start with • Assessing treatment failure and when to change

  39. DHHS Guidelines Recommendations for Treatment-Naïve Patients Select 1 NNRTI or 1 PI Plus a Dual NRTI 1Do not use during 1st trimester of pregnancy or in those with high pregnancy potential. Use with caution in patients with unstable psychiatric disease. 2Do not use in patients who require high-dose (>20 mg omeprazole equivalent/day) proton-pump inhibitors (PPIs). Use with caution in patients on PIIs on any dose, H2 blockers, or antacids. 3Do not use lopinavir/r once-daily in pregnant women. 4Do not use in patients with severe hepatic impairment (Child-Pugh score B or C) and in women with CD4 cell count >250 cells/mm3 or in men with CD4 cell count >400 cells/mm3. 5Do not use in combination with tenofovir DF or didanosine/lamivudine. 6Do not use in patients who test positive for HLA-B*5701. Use with caution in patients with baseline HIV RNA >100K copies/mL and in patients at high risk for cardiovascular disease. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.

  40. IAS-USA Guidelines Recommendations for Treatment-Naïve Patients Select 1 NNRTI or 1 PI Plus a Dual NRTI 1A baseline urinalysis and estimation of creatinine clearance or glomerular filtration rate for assessment of renal function are recommended. All patients receiving tenofovir should be observed for development of renal dysfunction. Lamivudine can be substituted for emtricitabine. 2Emtricitabine can be substituted for lamivudine. Hammer SM, et al. JAMA. 2008;300:555-570.

  41. Factors to ConsiderWhen Selecting an Initial Regimen • Comorbidity or conditions • Adherence potential • Dosing convenience and frequency, food and fluid considerations • Potential adverse events • Potential drug interactions • Pregnancy potential • Results of genotypic drug testing • Gender and pretreatment CD4 cell count if considering nevirapine Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.

  42. DHHS Guidelines Recommendations:Dual NRTI Components • Preferred • Emtricitabine/tenofovir DF* • Alternative • Abacavir/lamivudine* (if negative for HLA-B*5701) • Zidovudine/lamivudine* • Didanosine + lamivudine or emtricitabine *Emtricitabine may be used in place of lamivudine or visa versa. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.

  43. Recent exposure (yes/no) Cumulative exposure (per year) D:A:D Study: Risk of MI Per Exposureto Individual NRTIs, PIs, and NNRTIs PIs and NNRTIs (Cumulative Exposure) NRTIs (Recent and Cumulative Exposure) Relative Risk (95% CI) Relative Risk (95% CI) ZDV ddI d4T ABC IDV 3TC TDF NFV LPV/r NVP SQV EFV Number of P-Y FU: No. of MIs: Number of P-Y FU: No. of MIs: 74,407 331 95,320 405 138,109 523 152,009 554 53,300 221 39,157 139 56,529 197 37,136 150 68,469 298 44,657 221 61,655 228 58,946 221 Adjusted for baseline demographics and cardiovascular risk factors and for latest measures of lipids, metabolic parameters, CD4 count, and HIV RNA level. P-Y FU: patient-years follow-up. Recent use: current or within the last 6 months. Lundgren J, et al. 16th CROI. Montreal, 2009. Abstract 44LB.

  44. D:A:D Study:Conclusions • Abacavir, didanosine, indinavir, and lopinavir/ritonavir were associated with an increased risk of MI • For indinavir and lopinavir/r • Risk increased with cumulative exposure • No significant associations between exposure to other NRTIs including tenofovir DF, NRTIs, or the other PIs and the risk of MI • Concomitant use of ritonavir did not appear to modify the effects of saquinavir or indinavir Lundgren J, et al. 16th CROI. Montreal, 2009. Abstract 44LB.

  45. Abacavir and CVD Risk:Summary of Key Studies/Analyses Reiss P. 16th CROI. Montreal, 2009. Abstract 152.

  46. DHHS Guidelines Recommendations:NNRTI or PI Components • Preferred • Efavirenz* • Atazanavir + ritonavir • Darunavir + ritonavir • Fosamprenavir + ritonavir bid • Lopinavir/ritonavir qd or bid • Alternative • Nevirapine (females and males with CD4 <250 and <400 cells/mm3, respectively) • Atazanavir (add ritonavir 100 mg/day if used with tenofovir DF) • Fosamprenavir, fosamprenavir + ritonavir qd • Saquinavir + ritonavir *Except during 1st trimester of pregnancy or in women with high pregnancy potential. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.

  47. Antiretroviral Agents Not Recommended as Initial Therapy Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.

  48. Antiretroviral Regimens That Should Not Be Offered At Any Time Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.

  49. Antiretroviral Components That Should Not Be Offered At Any Time Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.

  50. Program Overview • When to start treatment • Treatment goals • What to start with • Assessing treatment failure and when to change

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