Principles of Antiretroviral Therapy

Principles of Antiretroviral Therapy Ten Principles of Antiretroviral Therapy Skills Building Workshop: Clinical Management of HIV Infection and Antiretroviral Therapy, 11 th ICAAP, November 21st, 2011, Bangkok, Thailand Steven C. Johnson MD, Professor of Medicine, Division of Infectious Diseases; Director, University of Colorado HIV/AIDS Clinical Program; University of Colorado School of Medicine, Aurora, Colorado; Email: Steven.Johnson@ucdenver.edu Source: CDC/Public Health Image Library 1. Antiretroviral drugs work by blocking one or more steps in HIV replication Entry Inhibitors: Target Fusion or CCR5 HIV RNA Nucleus DNA Reverse Transcriptase Integrase Protease Integrase Inhibitors CD4+ T-Cell Reverse Transcriptase Inhibitors: NRTIs (Nucleosides, Nucleotides) and NNRTIs Protease Inhibitors

To enter a cell, HIV uses the CD4 receptor and a co-receptor, either CCR5 or CXCR4. The drug maraviroc blocks CCR5. CD4 2. Combinations of at least 3 drugs are typically required for full effect Drug Regimen Single NRTI Dual NRTI 2 NRTIs + NNRTI or PI or INSTI Reduction in Viral Load 0.5-1.5 log 1-2 log Up to 6 log CCR5 CXCR4 T-cell surface Berger EA, et al. Nature. 1998;391:240. Combination ARV regimens are much more potent than monotherapy or 2-drug therapy Effects of Potent Combination ART Virologic and immunologic effect: Potent inhibition of viral replication Early HIV infection: prevents CD4 decline Advanced HIV infection: allows CD4 recovery Clinical effect Prevention or improvement of AIDS-related diseases and other HIV-related complications Reduced morbidity, hospitalization, and mortality The potential for a normal life span Common 3-drug regimens in Antiretroviral Treatment Guidelines 2 NRTIs + a non-nucleoside reverse transcriptase inhibitor (NNRTI) 2 NRTIs + a boosted protease inhibitor 2 NRTIs + an integrase strand transfer inhibitor (INSTI)

Effect of ART on Mortality Over Time 3. Baseline laboratory tests are necessary to safely initiate therapy Deaths per 100 Per rson-years % of Patients on ART Deaths per 100 Person-Years 8 90 7 80 70 6 60 5 50 4 40 3 30 2 20 1 10 0 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 Palella FJ et al. J Acquir Immune Defic Syndr. 2006;43(1):27-34. Patien nts on ART, % General Lab Testing CBC with differential Chemistry panel with liver enzymes, serum creatinine, and glucose Urinalysis Fasting lipid panel HIV Lab Testing CD4 lymphocyte count HIV RNA level HIV genotyping Other (Tropism, HLA B*5701) Screens for Co-Infections Total Hepatitis A antibody Hepatitis B core antibody Hepatitis B surface antibody Hepatitis B surface antigen Hepatitis C antibody Treponema AB Toxoplasma IgG PPD or interferon gamma release assay 4. Adherence to therapy is critical to success and must be supported Virologic response falls sharply with diminished adherence to therapy Most regimens require adherence of greater than 90% to be fully effective 100 Nonadherence may lead to lack of clinical effect and the development of drug resistance Adherence should be assessed at each visit and can be monitored through patient interview, pill counts, and refill history from a dispensing pharmacy The use of fixed-dose combinations, when available, can help with adherence Patients with HIV RNA <400 copies/ /ml, % 80 60 40 20 0 >95 90-95 80 90 70-80 <70 PI adherence, % (electronic bottle caps) Paterson, et al. Annals of Internal Medicine, 2000;136:253

5. Patients on ART should be monitored for drug interactions Drug Interactions With Atazanavir: Effect on Trough Concentrations Protease inhibitors, through inhibition of cytochrome p450 enzymes, may lead to higher levels of co-administered drugs Nevirapine and efavirenz, through induction of cytochrome p450 enzymes, may reduce levels of co-administered drugs ATV Trou ugh (ng/ml) 900 800 700 600 500 400 300 200 100 A number of other drug-drug interactions are important; many are reviewed in the antiretroviral treatment guidelines 0 Atazanavir 400 mg daily Atazanavir 300 mg + Ritonavir Atazanavir Dose and Combination Atazanavir/ritonavir + Rifampin 6. Patients on ART should be monitored for side effects of therapy Drug Usual Dose Side Effects Zidovudine (AZT) Emtricitabine (FTC) Lamivudine (3TC) Tenofovir (TDF) Efavirenz (EFV) Nevirapine (NVP) 300 mg twice daily Nausea, anemia, leukopenia 200 mg once daily Well tolerated 150 mg twice daily or 300 mg once daily Well tolerated 300 mg once daily Bone and renal toxicity 600 mg at bedtime CNS toxicity, skin rash 200 mg daily x 2 weeks then 200 mg twice daily Skin rash, hepatotoxicity Potentially Serious and/or Life-Threatening Toxicities with Antiretroviral Agents Nucleoside analogue RTIs: syndrome of lactic acidosis and hepatic steatosis Zidovudine: anemia, leukopenia Didanosine: pancreatitis Stavudine: peripheral neuropathy Abacavir: hypersensitivity reaction Nevirapine: hepatotoxicity NNRTIs: skin rash/erythema multiforme Protease inhibitors: diabetes mellitus, hyperlipidemia

7. Patients should be monitored for IRIS (Immune Reconstitution Inflammatory Syndrome) Initiation of antiretroviral therapy may lead to worsening or altered clinical manifestations of opportunistic infections Respiratory failure with PCP Acute MAC lymphadenitis Flares of Hepatitis B and C Life-threatening deterioration with cryptococcal meningitis Clinical worsening of tuberculosis 8. When feasible, patients should be evaluated for drug resistance Primary or transmitted drug resistance Present prior to the initiation of therapy Acquired drug resistance Develops in a patient while on therapy Patient nonadherence can lead to resistance Prescribing errors can lead to resistance Assessed by HIV resistance testing (genotype or phenotype) Mutations Selected by NRTIs 9. Once on ART, monitoring the response to therapy is critical Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine Effective antiretroviral therapy will have 3 effects: The HIV viral load will be rapidly reduced The CD4 lymphocyte count will increase over time, the rate varying from patient to patient Clinical improvement will occur: Existing opportunistic infections will improve Other symptoms such as fever, malaise, anorexia, weight loss, etc. will improve The risk of future opportunistic infections and other HIV-related complications will be reduced www.iasusa.org

Laboratory monitoring in patients on antiretroviral therapy Ideally, laboratory tests (CBC, chemistries, CD4, and HIV viral load) should be drawn 1 month into therapy Effective regimens typically reduce the HIV viral load by at least 2-3 log after 1 month of therapy Effective regimens should lead to an undetectable HIV viral load in 3-6 months Once undetectable, laboratory tests for toxicity (CBC, chemistries) and efficacy (CD4, HIV viral load) should be done every 3-6 months. 10. Antiretroviral therapy can also prevent HIV transmission: Clinical Trial HPTN 052 1763 Couples Where One is HIV+ and One is HIV- Immediate ART (N = 886 couples) Delayed ART (N = 877 couples) Cohen M, et al. NEJM 2011;365:493-505 Results: 96% Reduction in HIV Transmission Challenges of Antiretroviral Therapy Immediate Therapy Delayed Therapy Clinician experience Communication skills Number of Couples 886 877 Number of HIV 4 35 transmissions HIV transmissions genetically linked Rate of HIV transmission per 100 patient-years 1 27 0.1 1.7 Cohen M, et al. NEJM 2011;365:493-505 Viral Load Resistance Latent reservoirs Viral fitness Virus Clinician Patient Drug Access to care Disease stage Co-morbidities Pregnancy potential Adherence Potency Pharmacokinetics Tolerability Toxicity Convenience Drug interactions Cost

Summary of Clinical Program Outcomes, University of Colorado HIV Program, 1995-2012 14 Era of Combination ART WHO Guidelines 2013 12 10 8 6 4 2 0 Mortality (%) PCP (%) Inpatient Days 1600 HIV+ Patients in Care in 2012 Skills Building Workshop: Clinical Management of HIV Infection and Antiretroviral Therapy, 11 th ICAAP, November 21st, 2011, Bangkok, Thailand Steven C. Johnson MD, Professor of Medicine, Division of Infectious Diseases; Director, University of Colorado HIV/AIDS Clinical Program; University of Colorado School of Medicine, Aurora, Colorado; Email: Steven.Johnson@ucdenver.edu Consolidated Guidelines on the use of Antiretroviral Drugs for Treating and Preventing HIV Infection Released in June 2013 Available at the WHO website: Case Study A 36 year old male is diagnosed with HIV infection His initial CD4 count is 420 cells/mm 3 with an HIV viral load of 42,000 copies/ml He has a history of a + PPD treated with INH but no evidence of active TB He has a positive Hepatitis B surface antigen with elevated liver enzymes His partner is HIV-negative

Case Study When should antiretroviral therapy be started in this patient? A 36 year old male is diagnosed with HIV infection His initial CD4 count is 420 cells/mm 3 with an HIV viral load of 42,000 copies/ml He has a history of a + PPD treated with INH but no evidence of active TB He has a positive Hepatitis B surface antigen with elevated liver enzymes His partner is HIV-negative When should ART be started? Case Study As a priority, ART should be initiated in all individuals with severe or advanced HIV clinical disease (WHO clinical stage 3 or 4) and individuals with CD4 count 350 cells/mm 3 strong recommendation, moderate-quality evidence ART should be initiated in all individuals with HIV with CD4 count >350 cells/mm³ and 500 cells/mm 3 regardless of WHO clinical stage strong recommendation, moderate-quality evidence A 36 year old male is diagnosed with HIV infection His initial CD4 count is 420 cells/mm 3 with an HIV viral load of 42,000 copies/ml He has a history of a + PPD treated with INH but no evidence of active TB He has a positive Hepatitis B surface antigen with elevated liver enzymes His partner is HIV-negative

When should ART be started? ART should be initiated in all individuals with HIV regardless of WHO clinical stage or CD4 cell count in the following situations: Individuals with HIV and active TB disease strong recommendation, low-quality evidence Which antiretroviral combination should be used? Individuals co-infected with HIV and HBV with evidence of severe chronic liver disease strong recommendation, low-quality evidence Serodiscordant couples should be offered ART to reduce HIV transmission to uninfected partners strong recommendation, high-quality evidence Case Study 2013 Treatment Guidelines: What to Start A 36 year old male is diagnosed with HIV infection His initial CD4 count is 420 cells/mm 3 with an HIV viral load of 42,000 copies/ml He has a history of a + PPD treated with INH but no evidence of active TB He has a positive Hepatitis B surface antigen with elevated liver enzymes First-line ART should consist of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a non-nucleoside reverse-transcriptase inhibitor (NNRTI). TDF + 3TC (or FTC) + EFV as a fixed-dose combination is recommended as the preferred option to initiate ART (strong recommendation, moderate-quality evidence). His partner is HIV-negative

2013 Treatment Guidelines: What to Start If TDF + 3TC (or FTC) + EFV is contraindicated or not available, one of the following options is recommended: AZT + 3TC + EFV AZT + 3TC + NVP TDF + 3TC (or FTC) + NVP - strong recommendation, moderate-quality evidence Countries should discontinue d4t use in first-line regimens because of its metabolic toxicities strong recommendation, moderate-quality evidence WHO Guidelines: First-line Antiretroviral Agents (NRTIs and NNRTIs) Drug Usual Dose Potential Toxicities Zidovudine (AZT) Emtricitabine (FTC) Lamivudine (3TC) Tenofovir (TDF) Efavirenz (EFV) Nevirapine (NVP) 300 mg twice daily Nausea, anemia, leukopenia 200 mg once daily Well tolerated 150 mg twice daily or 300 mg once daily Well tolerated 300 mg once daily Bone and renal toxicity 600 mg at bedtime CNS toxicity, skin rash 200 mg daily x 2 weeks then 200 mg twice daily Skin rash, hepatotoxicity Case Study Therapy is initiated with a fixed dose combination of tenofovir, lamivudine, and nevirapine Two months into therapy, the CD4 count is 210 cells/mm 3 with an HIV viral load of 37,500 copies/ml The patient reports some nonadherence to therapy Oral thrush is noted on exam HIV resistance testing is not available Which antiretroviral combination should the patient be switched to?

Target Population Adults and Adolescents (> 10 years) HIV and HBV Co- Infection Second-Line ART for Adults and Adolescents Preferred Second Line Regimen If D4T or AZT was used in first- line ART If TDF was used in first-line ART TDF + 3TC (or FTC) + ATZ/r or LPV/r AZT + 3TC (or FTC) + ATZ/r or LPV/r AZT + TDF + 3TC (or FTC) + ATZ/r or LPV/r Case Study His therapy is changed to a combination of zidovudine, tenofovir, lamivudine, and atazanavir boosted by ritonavir Trimethoprim-sulfamethoxazole is initiated for PCP prophylaxis Two months into this therapy, the CD4 count is 350 cells/mm 3 with an HIV viral load of 420 copies/ml Three months into therapy, the HIV viral load is less than 50 copies/ml Switch to 2013 guidelines will increase eligibility from 16.7 to 25.9 million people globally 9.7 million people on ART by end of 2012 Actual and projected numbers of people receiving antiretroviral therapy in low-and middle-income countries, and by WHO Region, 2003 2015 2010 2013 9.7 million 5.8 million 1.2 16.7 million on ART CD4 <350* 9.7 million 9.7 million 2.6 0. 7 3.2 on ART CD4 <500* <5 yo 25.9 million +/- with CD4 > 500 Number of people eligible for ART in low- and middle-income countries in million per WHO 2010 and 2013 ARV guidelines. Presented by G Weiler at IAS 2013. Source: 2013 Global AIDS Response Progress Reporting (WHO/UNICEF/UNAIDS). Presented by G Weiler at IAS 2013.

Impact: ART averted 4.2 million deaths Annual number of people dying from AIDS-related causes in low- and middle-income countries globally compared with a scenario of no antiretroviral therapy, 1996 2012 a The data points for 2012 are projected based on the scaling up of programmes in 2009 2011 and do not represent official estimates of the number of annual AIDSrelated deaths. Presented by G Weiler at IAS 2013. Summary of WHO 2013 ART Guidelines In 2013, the new WHO guidelines raised the threshold for ART to CD4 < 500 cells/mm 3 The guidelines also recommend ART, regardless of CD4 count for: Serodiscordant couples (one HIV+, one HIV-) Pregnant women Persons with active Hepatitis B Persons with active TB Children under 5 years of age TDF + 3TC (or FTC) + EFV as a fixed-dose combination is recommended as the preferred option to initiate ART in adults and adolescents