HIV Treatment Update Awewura Kwara, MD, MPH&TM Associate Professor of Medicine and Infectious Diseases Brown University
Outline Rationale for highly active antiretroviral therapy (HAART) When to start HAART What to use in first-line HAART What to use in second-line HAART Clinical and laboratory monitoring Summary
Redefining the pathogenesis of progressive lymphopenia in HIV infection Perelson AS et al. Science 1996;271:1582-6
Immune response to ARV Rx
Deaths per 100,000 Population Trends in Annual Rates of Death from HIV/AIDS Among Men 25-44 Years Old, USA, 1982-1998 70 60 50 40 30 20 10 0 82 84 86 88 90 92 94 96 98* National Center for Health Statistics National Vital Statistics System Year *Preliminary 1998 data Source: CDC - Center for Infectious Diseases
Adults and children estimated to be living with HIV, by WHO Region, 2010 Americas 3.0 million [2.6 million 3.5 million] Europe 2.3 million [2.1 million 2.5 million] Eastern Mediterranean 560 000 [410 000 790 000] Africa 22.9 million [21.7 million 24.2 million] South-East Asia 3.5 million [3.0 million 3.9 million] Western Pacific 1.3 million [1.1 million 1.5 million] Total: 34.0 million [31.6 million 35.2 million]
Estimated adult and child deaths from AIDS, by WHO Region, 2010 Americas 96 000 [71 000 120 000] Europe 99 000 [84 000 120 000] Eastern Mediterranean 38 000 [27 000 53 000] Africa 1.2 million [1.1 million 1.4 million] South-East Asia 230 000 [190 000 260 000] Western Pacific 80 000 [64 000 99 000] Total: 1.8 million [1.6 million 1.9 million]
Deaths per 100 Person-Years 11 Effect of ART on Mortality Over Time % of Patients on ART Deaths per 100 Person-Years 8 90 7 80 6 5 4 3 2 1 a 70 60 50 40 30 20 10 Patients on ART, % 0 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 a P =.008 for trend. Palella FJ et al. J Acquir Immune Defic Syndr. 2006;43(1):27-34.
Number of people (all age groups) receiving and needing antiretroviral therapy, and percentage coverage in low- and middleincome countries by region, 2009 to 2010
Available at: http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf
Background WHO guidelines for were first published in 2002 Revisions in 2003 and 2006 Emphasis on public health approach New evidence on the following led to 2010 guidelines: When to initiate ART Optimal ART regimens Management of HIV/TB coinfection Management of HIV/HBV coinfection Management of ART failure
Guiding principles Do no harm Accessibility Quality of care Equity of access Efficiency in resource use Sustainability
Summary of changes Earlier initiation of ART Simplified, less toxic ARVs for use in first and second-line therapies Promoting initiation of ART for all patients with HIV/TB co-infection Promoting improved HBV diagnosis and more effective treatment HIV/HBV coinfection More strategic monitoring for efficacy and toxicity
The Move Toward Simpler Regimens Regimen Dosing Daily pill burden Issues 1996 d4t/3tc/ indinavir 10 pills, Q8H Food restrictions, liquids frequently Poor tolerability Short- and long-term toxicities 1998 ZDV/3TC/ efavirenz 2002 ZDV/3TC/EFV 5 pills, BID 3 pills, BID Gastrointestinal (GI) effects, anemia, neutropenia Central nervous system (CNS) toxicities Mitochondrial-related toxicities Gastrointestinal (GI) effects, anemia, neutropenia Central nervous system (CNS) toxicities Mitochondrial-related toxicities
The Move Toward Simpler Regimens Regimen Dosing Daily pill burden Issues 2003 TDF/ [FTC or 3TC] / EFV 3 pills, QD Generally well tolerated; GI effects, CNS effects (EFV) 2004 TDF/FTC or ZDV/3TC with EFV Now 2 pills QD 1 pill QD Minimal side effects, good PK, and no food restrictions without compromising efficacy Minimal to no side effects, good PK, and no food restrictions without compromising efficacy
WHEN TO START
SMART: Study Design and Findings CD4 cell count >350 cells/mm³ N=5472 Virologic Suppression (VS) Strategy Continuous use of ART to maintain viral load as low as possible (n=2752) Drug Conservation (DC) Strategy Defer ART until CD4 count is <250; then episodic ART based on CD4 count to increase counts to >350 (n=2720) Study was stopped January 2006 due to increased risk of progression of disease during the first 2 years of the trial for the DC versus the VS group Increased risk included progression of disease (the primary endpoint), and progression of major non-hiv/aids-related diseases El-Sadr et al. New Engl J Med. 355(22): 2283-2296. 20
SMART: Non-AIDS Event Rates With Continuous vs Deferred/Intermittent ART 21 Significantly more individuals in DC arm developed major CV, renal, or hepatic disease than those in VS arm Significantly more individuals in DC arm experienced grade 4 event or death from any cause than individuals in VS arm Endpoint VS (n=2752) DC (n=2720) HR (95% CI) P Value Grade 4 event or death from any cause 164 205 1.3 (1.0-1.6).03 Death by any cause 30 55 1.8 (1.2-2.9).007 Major CV, renal, or hepatic disease 39 65 1.7 (1.1-2.5).009 Fatal/nonfatal CV disease 31 48 1.6 (1.0-2.5).05 Fatal/nonfatal renal disease 2 9 4.5 (1.0-20.9).05 Fatal/nonfatal liver disease 7 10 1.4 (0.6-3.8).46 El-Sadr WM et al. N Engl J Med. 2006;355:2283-2296.
Cumulative Probability of Opportunistic Disease or Death* SMART: Cumulative Probability of OI/Death With Continuous vs Deferred/Intermittent ART 22 In January 2006, the study was modified to restart ART in DS group following the recommendations by the DSMB, and follow-up continued through July 2007 Cumulative Probability of OI/death From Any Cause Before Study Modification 0.06 Overall HR, 2.9 (Cl, 1.9-4.5); P <.001 Change in HRs (log-time term); P =.23 DC Group VS Group Cumulative Probability of OI/death From Any Cause Following Study Modification 0.06 Overall HR, 1.4 (Cl, 1.0-2.0); P =.04 Change in HRs (log-time term); P =.29 0.04 0.02 HR, 2.1 (Cl, 1.1-4.2); P=.04 HR, 3.9 (Cl, 1.8-8.5); P<.001 HR, 3.7 (Cl, 1.6-8.4); P=.003 0.04 0.02 HR, 2.2 (Cl, 1.1-4.3); P=.034 HR, 1.3 (Cl, 0.8-2.3); P=.32 HR, 1.2 (Cl, 0.7-2.2); P=.55 0 0 6 12 18 Time from Randomization (mo) 0 0 6 12 18 Time from Study Modification (mo) Participants in the risk set, n DC group 1892 1297 957 VS group 1914 1305 978 Participants in the risk set, n DC group 2508 2446 2414 VS group 2617 2567 2528 SMART Study Group. Ann Intern Med. 2008;149(5):289-299.
Likelihood of Achieving a Normal CD4 Cell Count Depends on When You Start Mean CD4 Cell Count (cells/mm 3 ) 23 1000 Johns Hopkins HIV Clinical Cohort 1 1000 ATHENA National Cohort 2 800 800 600 600 400 200 0 >350 201-350 <200 0 1 2 3 4 5 Years on ART 400 200 0 500 350-500 200-350 50-200 <50 0 48 96 144 192 240 288 336 Weeks From Starting ART Magnitude of increase in CD4 cell count greatest if therapy started at low CD4 cell counts, but greater likelihood of CD4 cell count normalization with earlier therapy 1 Moore R, et al. Clin Infect Dis. 2007;44(3):441-446. 2 Gras L, et al. J Acquir Immune Defic Syndr. 2007;45(2):183-192.
Summary of Benefits and Potential Limitations of Initiating ART in Treatment-Naïve Patients Reduction in mortality Benefits Reduction in HIV-related morbidity, including: HIV-associated nephropathy Cardiovascular disease AIDS-defining and non-aids defining malignancies Neurocognitive complications More robust immunologic response when treatment is initiated at a younger age Potential Limitations May be unknown complications related to cumulative use of HAART Earlier resistance in nonadherent patients Nonadherence to HAART Adds to annual cost, but several studies showed that initiating HAART at higher CD4 cell counts may be cost effective Reduced risk of liver disease progression in patients coinfected with HBV and/or HCV Prevention of HIV transmission Adapted from the Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. US Dept of Health and Human Services; 2009. http://www.aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf. Accessed December 1, 2009. 24
When to start ART 2010 WHO guidelines Target population HIV+ asymptomatic ARV-naive HIV+ symptomatic ARV-naive HIV+ pregnant women 2010 guidelines CD4 350 cells/mm3 WHO stage 2 if CD4 350 cells/mm3 WHO stage 3 or 4 irrespective of CD4 count CD4 350 cells/mm3 irrespective of symptoms WHO stage 3 or 4 irrespective of CD4 count HIV/TB coinfection ARV-naive HIV/HBV coinfection ARV-naive Presence of active TB irrespective of CD4 count Need for HBV treatment, irrespective of CD4 count
When to start 2012 International AIDS Society guidelines ART is recommended and should be offered regardless of CD4 count IAS, JAMA July 25, 2012
WHAT TO START?
Retrovirus life cycle Fusion inhibitors Maturation inhibitor Coreceptor inhibitors Reverse transcriptase inhibitors Protease inhibitors Integrase inhibitors
Available ARVs for global HIV treatment programs Nucleoside reverse transcriptase inhibitors (NRTIs) Zidovudine (AZT), lamivudine (3TC), tenofovir (TDF), emtricitabine (FTC), abacavir (ABC) Nonnucleoside reverse transcriptase inhibitors (NNRTIs) Efavirenz (EFV), Nevirapine (NVP) Protease inhibitors (PIs) Lopinavir/ritonavir (LPV/r), atazanavir/ritonavir (ATV/r), saquinavir (SQV), ritonavir (RTV)
WHO recommended first-line regimens Target population HIV+ ARV-naïve HIV+ pregnant women HIV/TB coinfection HIV/HBV coinfection 2010 ART guideline AZT or TDF + 3TC (or FTC) + EFV or NVP AZT + 3TC + NVP AZT is preferred but TDF is acceptable EFV can be used but not during first trimester AZT or TDF + 3TC (or FTC) + EFV NNRTI + TDF + 3TC (or FTC)
From: Antiretroviral Treatment of Adult HIV Infection: 2012 Recommendations of the International Antiviral Society USA Panel JAMA. 2012;308(4):387-402. doi:10.1001/jama.2012.7961 Date of download: 8/8/2012 Copyright 2012 American Medical Association. All rights reserved.
From: Antiretroviral Treatment of Adult HIV Infection: 2012 Recommendations of the International Antiviral Society USA Panel JAMA. 2012;308(4):387-402. doi:10.1001/jama.2012.7961 Date of download: 8/8/2012 Copyright 2012 American Medical Association. All rights reserved.
WHO recommended second-line ART If AZT or D4T used in first-line TDF + 3TC (or FTC) + ATV/r or LPV/r If TDF used in first-line AZT + 3TC (or FTC) + ATV/r or LPV/r HIV/HBV coinfection + ATV/r or LPV/r AZT + TDF + 3TC (or FTC)
HIV/TB: WHO recommended second-line ART If rifabutin available (150 mg 3x/week) standard 2 nd -line ART If rifabution unavailable same NRTIs + LPV/r or SQV/r with adjusted dose of RTV
When to switch Where available, use viral load to confirm treatment failure A persistent VL > 500 copies/ml confirms treatment failure When VL not available, use immunological criteria to confirm clinical failure
WHO recommended third-line regimens National programs should develop policies for third-line therapy considering funding, sustainability, and equitable access to ART Should include new drugs such as integrase inhibitors and second-generation NNRTIs and PIs Patients on a failing second-line with no new ARV should continue a tolerable regimen
Laboratory monitoring Phase of management Recommended test At HIV diagnosis CD4 count HBsAg Pre-ART CD4 count Desirable test At start of ART CD4 count Hb for AZT, Cr for TDF, ALT for NVP On ART CD4 count Hb for AZT, Cr for TDF, ALT for NVP At clinical failure CD4 count Viral load At immunological failure Viral load Women exposed to sd-nvp with tail within 12 months and without tail within 6 months of ART Viral load 6 months after initiation of ART
Summary: When to start - recommendations CD4 counts 350 cells/mm3 irrespective of the WHO clinical stage All patients with WHO clinical stage 1 and 2 should have CD4 testing to decide when to start WHO clinical stage 3 and 4 irrespective of CD4 count
Summary: What to start First-line therapy AZT + 3TC + EFV AZT + 3TC + NVP TDF + 3TC (or FTC) + EFV TDF + 3TC (or FTC) + NVP
Summary: What to start second-line therapy If d4t or AZT used in first-line therapy TDF + 3TC or FTC + ATV/r or LPV If TDF used in first-line therapy AZT + 3TC or FTC + ATV/r or LPV
Acknowledgements USAID and Higher Education for Development for grant support Associate award # AID-641-LA-11-00001 Lifespan/Tufts CFAR grant # P30AI042853 from the National Institute of Allergy And Infectious Diseases Brown/Tufts AITRP Partner institutions, staff and faculty who have supported the partnership activities Medical knowledge FIESTA 2012 Organizers! THANK YOU FOR YOUR ATTENTION!