African American HIV University Tuesday, September 2, 2014 Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD PGY-8 STAR Fellow Department of Medicine Division of Infectious Diseases 2
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Outline • Cases • Learning Objectives • HIV and AIDS classification • ARVs: Brief History • Before ARVs • HIV viral dynamics and AIDS • Effect of ARVs • Cases and Practice Questions • Summary • Questions 3
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Cases 4
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Case 1 TM is a 30 year old male who without any prior known chronic illnesses. A few months ago he developed a cough that has persisted. He has also felt a bit tired, but he’s a writer and has been spending long hours working to meet his publisher’s deadline. At the urging of a friend, he finally decides to see a doctor. His friend noticed that he became extremely short of breath during their usual morning run, which is unusual. The doctor discusses his symptoms with him, performs a physical exam, and orders a few tests. He is told that he is HIV+ and likely has pneumonia as a result of this infection. 5
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Case 2 SO is a 27 year old female who was initially brought in by her male friend. She is back in the doctor’s office today to go over her test results. When she initially came in, she suspected that she was pregnant; she also made it very clear that this was not be discussed while her male friend was in the room. She was somewhat evasive when probed about the nature of their relationship. With regard to her symptoms, she indicated that she had been fatigued, with nausea and vomiting. Her pregnancy test was positive. At that time, the doctor sent routine screening tests, including HIV antibody testing, which was positive. 6
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Case 3 HK is 45 year old male who comes to the doctor’s office in a panic. A few weekends ago he went away with some friends for a bachelor party, the details of which are a bit hazy at this time. There was probably alcohol involved…he can’t remember much else. His concern is that since then he’s developed a fever, a rash, and a slight headache (which is improved when the lights are dim). He’s worried that he may have caught something from someone, though he is sure that he didn’t do anything extremely out of the ordinary. After his evaluation, he is told that testing for HIV and syphilis are both positive. 7
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Learning Objectives 8
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Learning Objectives • Understand the causal relationship between HIV infection and the development of AIDS • Understand the components of an ARV regimen • Understand the effect ARVs have on the health of HIV infected patients • Understand the community benefits of ARV use in HIV infection • Understand the role between the patient and clinician in the use of ARVs 9
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 HIV and AIDS Classification 10
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 1993 CDC Revised Classification System HIV Infection Clinical Categories (A) CD 4+ T cell categories Absolute CD 4+ count (B) (C) Asymptomatic, Symptomatic, AIDSacute (primary) not (A) or (C) indicator HIV or PGL* conditions CD 4+ % of total T-cells (1) ≥ 500/m. L (≥ 29) A 1 B 1 C 1 (2) 200 - 499/m. L (14 -28) A 2 B 2 C 2 (3) < 200/m. L (<14) A 3 B 3 C 3 *Persistent Generalized Lymphadenopathy Castro, KG. et. al. (1993) CID; 17(4) pp 802 -810 11
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 1993 CDC Revised Classification System HIV Infection • Clinical categories • Category A • Category B • Category C • CD 4+ T cell categories • (1) Absolute # 500/m. L % total # of T-cells • (2) Absolute # OR 14 -28 • (3) Absolute # % total # of T-cells OR ≥ 29 200 - 499/m. L % total # of T-cells < 200/m. L OR <14 Castro, KG. et. al. (1993) CID; 17(4) pp 802 -810 12
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 1993 CDC Revised Classification System HIV Infection: Clinical Category A • Acute (primary) HIV • Asymptomatic HIV • Persistent generalized lymphadenopathy Castro, KG. et. al. (1993) CID; 17(4) pp 802 -810 13
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 1993 CDC Revised Classification System HIV Infection: Clinical Category B • Symptomatic conditions that are NOT AIDS defining but • Are attributed to HIV infection or indicative of a defect in cell- mediated immunity • Are considered by physicians to have a clinical course or require management that is complicated by HIV • Example conditions • Bacillary angiomatosis • Candidiasis, oropharyngeal (thrush) • Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy • Cervical dysplasia (moderate or severe)/cervical carcinoma in situ Castro, KG. et. al. (1993) CID; 17(4) pp 802 -810 14
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 1993 CDC Revised Classification System HIV Infection: Clinical Category B • Example conditions cont. • Constitutional symptoms, such as fever (38. 5 C) or diarrhea lasting > 1 month • Hairy leukoplakia, oral • Herpes zoster (shingles), involving at least two distinct episodes or more than one dermatome • Idiopathic thrombocytopenic purpura • Listeriosis • Pelvic inflammatoryd isease, particularly if complicated by tubo- ovarian abscess • Peripheral neuropathy Castro, KG. et. al. (1993) CID; 17(4) pp 802 -810 15
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 1993 CDC Revised Classification System AIDS Surveillance Case Definition • Candidiasis of esophagus, trachea, bronchi, or lungs • Cryptococcosis, extrapulmonary • Cryptosporidiosis with diarrhea > 1 month • Cytomegalovirus disease of any organ other than liver, spleen, lymph nodes • Cytomegalovirus retinitis (with vision loss) • HSV with mucocutaneous ulcer >1 month or bronchitis, pneumonitis, esophagitis • HIV-related encephalopathy • Mycobacterium avium complex or M. kansasii, disseminated • Pneumocystis carinii (P jiroveci) pneumonia • Progressive multifocal leukoencephalopathy • Toxoplasmosis of brain • Wasting syndrome due to HIV • • • Coccidioidomycosis, extrapulmonary Histoplasmosis, extrapulmonary Isosporiasis with diarrhea for >1 month Kaposi's sarcoma Lymphoma • Primary, of brain • Immunoblastic (or equivalent term) • Burkitt’s (or equivalent term) • Mycobacterium tuberculosis, disseminated • Salmonella septicemia (nontyphoid), recurrent • CD 4+ count < 200 cells/mm 3 OR CD 4+ %<14* • Cervical cancer, invasive* • Mycobacterium tuberculosis, pulmonary* • Pneumonia, recurrent* *Requires laboratory confirmation of HIV infection Castro, KG. et. al. (1993) CID; 17(4) pp 802 -810 16
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 WHO (World Health Organization) 2005 Revised Clinical Staging of HIV/AIDS for Adults and Adolescents • Primary HIV Infection • • Asymptomatic Acute retroviral syndrome • Clinical stage 3 • • Clinical stage 1 • Severe weight loss (>10% of presumed or Asymptomatic • Persistent generalized lymphadenopathy (PGL) • • Clinical stage 2 Moderate unexplained weight loss (<10% of presumed or measured body weight) • Recurrent respiratory tract infections (RTIs, sinusitis, bronchitis, otitis media, pharyngitis) • Herpes zoster • Angular cheilitis • Recurrent oral ulcerations • Papular pruritic eruptions • Seborrhoeic dermatitis • Fungal nail infections of fingers Conditions where a presumptive diagnosis can be made on the basis of clinical signs or simple investigations • • measured body weight) Unexplained chronic diarrhoea for longer than one month Unexplained persistent fever (intermittent or constant for longer than one month) Oral candidiasis Oral hairy leukoplakia Pulmonary tuberculosis (TB) diagnosed in last two years Severe presumed bacterial infections (e. g. pneumonia, empyema, pyomyositis, bone or joint infection, meningitis, bacteraemia) Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis Conditions where confirmatory diagnostic testing is necessary • Unexplained anemia (<8 g/dl), and or 3 neutropenia (<500/mm ) and/or thrombocytopenia (<50 K/mm 3) for more than 1 month 17
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 WHO (World Health Organization) 2005 Revised Clinical Staging of HIV/AIDS for Adults and Adolescents • Clinical stage 4 • Conditions where a presumptive diagnosis can be made on the basis of clinical signs or simple investigations • Clinical stage 4 • Conditions where confirmatory diagnostic testing is necessary • CMV infection (CMV retinitis or infection of • Unexplained severe wasting or severe • • malnutrition not adequately responding to standard therapy Pneumocystis pneumonia Recurrent severe presumed bacterial infections (e. g. empyema, pyomyositis, bone or joint infection, meningitis, but excluding pneumonia) Chronic herpes simplex infection; (orolabial or cutaneous of more than one month’s duration) Extrapulmonary TB Kaposi’s sarcoma Oesophageal candidiasis CNS toxoplasmosis (outside the neonatal period) HIV encephalopathy • • • organs other than liver, spleen or lymph nodes; onset at age one month or more) Extrapulmonary cryptococcosis including meningitis Any disseminated endemic mycosis (e. g. extrapulmonary histoplasmosis, coccidiomycosis, penicilliosis) Cryptosporidiosis Isosporiasis Disseminated non-tuberculous mycobacteria infection Candida of trachea, bronchi or lungs Visceral herpes simplex infection Acquired HIV associated rectal fistula Cerebral or B cell non-Hodgkin lymphoma Progressive multifocal leukoencephalopathy (PML) HIV-associated cardiomyopathy or HIVassociated nephropathy 18
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 ARVs: Brief History 19
1982: AIDS 1987: AZT 1995: HIV 1981 PIs 1983: 1997: PEPFAR NNRTIs 2006: 2003: 2007: ISTI 2003: ATRIPLA 2014 ENTRY INHIBITORS July: Combivir, Zidovudine May: ABC HSR association with HLA laboratory end-points Generic AZT PEPFAR Saquinavir 5 pills now 2 pills BID for adults and children >6 yo (IDV)/Crixivan approval for AIDS first reported Sept: Oral Generic AZT, FTC Soln June: Oral fosamprenavir soln July: Nelfinavir mesylate (NFV)/Viracept; Jan: single or combination use April: B*5701 allele noted Sept: Kaletra (lopinavir + ritonavir) Generic dd. I out of India, FDC Atripla 1 st tentative approval under a new Approval of Zidovudine (AZT)/Retrovir FDA History Timeline* June: Nevirapine (NVP)/Viramune approved for children in 1989 *Source: http: //www. fda. gov/For. Consumers/By. Audience/For. Patient. Advocates/HIVand. AIDSActivities/ucm 117935. htm Oct: FDA approval process with Norvir approved for 1 mo to 2 yr olds July: (TDF/FTC/EFV), 3 TC/AZT Oct: Generic drugs approved for sale in Generic NVP 5 pills now 2 pills BID Videx EC for combination use Accessed August 11, 2014 the US: AZT, dd. I, d 4 T, copackaged with ABC out of India PEPFAR. Copackaged Combivir approval for combination use, • 1989: Approval of Dideoxyinosine (dd. I)/Videx Aug: Oral generic 3 TC Soln out of India June: Atazanavir sulfate (ATV)/Reyataz Nov: Trizivir (ABC/3 TC/AZT) Maraviroc (MVC)/Selzentry 1 st non-nuc • 2009: Many FDCs (including EFV/3 TC or Aug: and nevirapine Generic NVP out of India, 3 TC/AZT • 1995: April: Saquinavir open label study allowed Dec: Emtricitabine (FTC)/Emtriva, Trizivir • 2001: July: Warning against Zerit and Videx in Jan: approved, combination FDC/TDF and 3 TC/AZT/NVP) Feb: Generic oral d 4 T, generic oral out of South Africa, d 4 T capsules out Caution, avoid SQV/r with rifampin • 1997: Mar: Nelfinavir NFV/(Viracept) 1 st NVP out of India warning (early virologic nonpregnant women Nov: 3 TC/d 4 T/NVP for children Lamivudine (3 TC)/Epivir of India (drug-induced hepatitis) PI labeled for use in children • 2011: FDC Complera (3 TC/RPV/TDF) Oct: response) • 2006: Jan: accelerated approval (to be Oct: Tipranavir traditional approved (for 2 and adults Oct: Caution, atazanavir use with PPI, H Mar: Tenofovir (TDF)/Viread accelerated Oral dd. I, atazanavir 300 mg capsule Alfuzosin (a blocker) contraindicated Rilpivirine (RPV)/Edurant used in combination with AZT) blockers, methadone, rifampin, dd. I Aug: treatment experienced with PI Suggestion that Atazanavir should with norvir. Also norvir interactions April: approval (first nucleotide analog) Nov: Delavirdine (DLV)/Rescriptor, resistance) Viramune XR Dec: Generic ABC, FDC (fixed dose May: be boosted if used with Tenofovir Tentative approval for generic ABC • 2002: Feb: Saquinavir (SQV)/Invirase Once daily EFV, Boosted APV with fluticasone and trazodone for combination use combination) d 4 T/3 TC/NVP approved for combination use with ↑ Rate of bac’t PNA seen w/ Fuseon Oct: Raltegravir(RAL)/Isentress approved June: Combivir (AZT + 3 TC) Tentative approval for another June: Once daily Epivir (3 TC) Sept: Fosamprenavir (FPV)/Lexiva • 2007: Jan: Efavirenz now pregnancy class D Tentative approval FDC 3 TC/d 4 T nucs (1 st PI) Lexiva approved for 1400 mg approved • 2012: FDC Stribild: elvitegravir, cobicistat, Aug: Once daily Kaletra formulation April: general 3 TC solution out of India Nov: Caution on Amprenavir use with Fortovase (new formulation of boosted daily dosing in treatment EFV interaction with FTC, TDF • 2004: Jan: Stavudine (d 4 T) Zerit traditional Avoid atazanavir with indinavir Accelerated approval of darunavir Methadone and OCPs approved Saquinavir (SQV)/Invirase ) naïve. rifampin/diltiazem/azole/statins approval for patients with prior • 2013: Dolutegravir (DTG)/Tivicay Aug: Epzicom (ABC/3 TC) and Truvada Sept: (DRV)/Prezista, boosted (for May: Efavirenz (EFV)/Sustiva • 1998: Sept: Caution on dd. I use w/ ribavirin and • 2008: Jan: Generic 3 TC, Foscarnet Etravirine (ETR)/Intelence FDC 3 TC/AZT/NVP prolonged AZT therapy (prior treatment experienced) (TDF/FTC) June: Accelerated approval of Tipranavir accelerated approval for patients Dec: TDF; ↑dd. I levels Abacavir (ABC)/Ziagen accelerated Feb: accelerated approval already) Combination 3 TC/AZT/NVP, d 4 T, Oct: Entecavir noted to induce M 184 V Dec: Traditional approval for Fuzeon Extended release Zerit (d 4 T) with NNRTI resistance (TPV)/Aptivus, generic EFV • 1996: Mar: approval Mar: Ritonavir (RTV)/Norvir Oral soln dd. I, generic EFV from India Dec: and ABC out of India because of 1 st generic antiretroviral (dd. I), • 2003: Mar: Enfuvirtide (T-20)/fuzeon approved Feb: Tentative approval for genetic d 4 T, July: (children 1997), Indinavir 20 600 mg Prezista tablets 1999: Amprenavir (APV)/Agenerase based on • 1981: 2005: 2000: • 1987:
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 FDA History Timeline* *Source: http: //www. fda. gov/For. Consumers/By. Audience/For. Patient. Advocates/HIVand. AIDSActivities/ucm 117935. htm Accessed August 11, 2014 • 1981: • 1982: • 1983: • 1987: • 1995: • 1997: • 2003: • 2006: • 2007: First cases AIDS terminology used by CDC Identification of HIV as virus leading to AIDS First anti-retroviral (Zidovudine); class: NRTI First PI, beginning of potent ART (HAART) New class: NNRTI PEPFAR announced by US President Bush New class: Entry Inhibitors Atripla (Single pill, daily medication) New class: ISTI 21
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Before ARVs 22
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Clinical course of HIV Infection without therapy: Summary • Acute Infection • Clinical latent period • Long-term nonprogressors • Elite controllers • Early symptomatic HIV infection • AIDS defining illness • Advanced AIDS; death 23
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Clinical course of HIV Infection without therapy: Summary Elite Controllers Acute Infection Long-term nonprogressors 0 Clinical latent period 6 months Early Symptomatic HIV Infection Years Time 24
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Clinical course of HIV Infection without therapy: Clinical latent period • Spans the time when a patient is infected to 6 months • No symptoms • Under examination, there may be enlarged lymph nodes 25
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Clinical course of HIV Infection without therapy: Early symptomatic HIV infection • Class B (formerly called “AIDS-related complex”) 26
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 HIV Viral Dynamics and AIDS 27
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Rapid decline in blood HIV virion levels HIV Replication in Infection “Set point” Schacker, TW. et. al. (1998) Ann Int Med; 128(8): pp 613 -620 28
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 HIV Effect on CD 4+ count without therapy Mean CD 4+ counts for 318 patients from the MACS group Groups Represented Above N: No AIDS developed during 6 years of follow-up; 252 patients L: AIDS developed > 6 years of follow-up; 4 patients M: AIDS developed 3 -6 years of follow-up; 28 patients S: AIDS developed <3 years of follow-up; 20 patients Stein, DS. et. al. (1992) J Inf Dis; 165(2): pp 352 -363 29
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Trends in AIDS Incidence, Deaths, and Prevalence— US, 1996 • 1981 – 1996: 573, 800 persons age ≥ 13 yrs *expanded AIDS surveillance case definition implemented MMWR Morb Mortal Wkly Rep (1997); 46: 165 -73. 30
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Trends in AIDS Incidence, Deaths, and Prevalence— US, 1996 • 1981 – 1996: 573, 800 persons age ≥ 13 yrs *expanded AIDS surveillance case definition implemented **largest number of newly reported cases from Black, non-Hispanic population MMWR Morb Mortal Wkly Rep (1997); 46: 165 -73. 31
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Trends in AIDS Incidence, Deaths, and Prevalence— US, 1996 • 1981 – 1996: 573, 800 persons age ≥ 13 yrs MMWR Morb Mortal Wkly Rep (1997); 46: 165 -73. 32
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Estimated AIDS-opportunistic illness (OI) incidence and estimated deaths among persons with AIDS (AIDS deaths)*, adjusted for delays in reporting, by quarter year of diagnosis/death — United States, 1984–June 1996† AZT PIs MMWR Morb Mortal Wkly Rep (1997); 46: 165 -73. 33
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Number of prevalent AIDS cases among persons aged ≥ 13 years, adjusted for delays in reporting, by quarter year — United States, 1988–June 1996* MMWR Morb Mortal Wkly Rep (1997); 46: 165 -73. 34
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Kaplan-Meier estimates of the cumulative probability of dying according to the number of years from seroconversion. HIV indicates human immunodeficiency virus. *Number of patients remaining at each time point who were at risk Phillips et. al. JAMA (1992); 268(19): pp. 2662 -2666. 35
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Mother to Child Transmission John, GC and Kreiss, J. Epi Reviews (1996); 18(2): pp 149 -157. 36
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD HIV/AIDS Outcomes Prior to ART Summary African American HIV University Tuesday, September 2, 2014 • Ongoing HIV viral replication • Destruction of CD 4+ T cells • Resulting cell-mediated immunity defect • Transmission of HIV • To sexual contacts • In utero • Development of • Recurrent Infections • Malignancy • Death 37
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 HIV Infection Ongoing HIV viral replication AIDS 38
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 HIV Infection ARVs Ongoing HIV viral replication AIDS 39
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 OVERALL RATIONALE SUPPRESS ONGOING VIRAL REPLICATION to STOP THE PROGRESSION from HIV INFECTION to the development of AIDS 40
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Effect of ARVs 41
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 ARVs: 1986 -1997 • 1986: First clinical trial with Zidovudine 1 • 1993: Two drug therapy 2 • 1996: Saquinavir, 1 st PI used in combination therapy 3 • 1997: Indinavir (also a PI) used in combination therapy 4, 5 1 Fischl, MA et. al. (1987) NEJM; 317(4): pp. 185 -91 2 Collier, AC et. al. (1993) Ann Intern Med. ; 119(8): pp. 786 -793 3 Collier, AC et. al. (1996) NEJM; 334(16): pp. 1011 -7 4 Hammer, SM et. al. (1997) NEJM; 337(11): pp. 725 -733 5 Guilick, RM et. al. (1997) NEJM; 337(11): pp. 734 -739 42
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD ARVs: 1986 -1997 What did we learn? African American HIV University Tuesday, September 2, 2014 • Multiple drugs needed • Potent drugs needed • Antimicrobial prophylaxis for opportunistic infections Corey, L and Holmes, KK. (1996) NEJM; 336(16): pp. 1142 – 1143 Girard, PM et. al. , (1989) Lancet; 333(8651): pp 1348 -53 Ruskin, J and La. Riviere, M. (1991) Lancet; 337(8739): pp. 468 -71 43
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 • In general: • base = INSTI, Maraviroc, NNRTI, PI PLUS • backbone = 2 N[t]RTIs (nucleoside/nucleotide reverse transcriptase inhibitors) TWO Nucleoside/ Nucleotide Reverse transcriptase Inhibitors BACKBONE + Integrase Inhibitor OR CCR 5 Antagonist OR Non-nucleoside Reverse Transcriptase Inhibitor OR Protease Inhibitor BASE 44
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 HIV Life Cycle 1. Cell entry ENTRY INHIBITORS (CCR 5 3. Integration ANTAGONISTS) INTEGRASE FUSION INHIBITORS 4. Protein assembly INHIBITORS 2. Reverse Transcription PROTEASE NON-NUCLEOSIDE REVERSE INHIBITORS TRANSCRIPTASE INHIBITORS NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS 5. Budding Tsibris, AMN and Hirsch, MS. (2010). Chapter 128. Antiretroviral Therapy for Human Immunodeficiency Virus Infection Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases ( 7 th Ed. ). Philadelphia, PA: Churchill Livingstone/Elsevier 45
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 HIV Life Cycle • Cell entry • Fusion Inhibitors • Entry Inhibitors (CCR 5 antagonists) • Reverse Transcription • Nucleoside/Nucleotide Reverse Transcriptase Inhibitors • Non-nucleoside Reverse Transcriptase Inhibitors • Integration • Integrase Inhibitors • Protein production and virion assembly • Protease Inhibitors • Budding Tsibris, AMN and Hirsch, MS. (2010). Chapter 128. Antiretroviral Therapy for Human Immunodeficiency Virus Infection Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases ( 7 th Ed. ). Philadelphia, PA: Churchill Livingstone/Elsevier 46
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Rationale #1: In general, three active drugs from two different classes are needed to suppress viral replication. 47
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 ARVs: 1997 -2006 • Highly active antiretroviral therapy = HAART • Establishment of target viral load • Risk vs. Benefit • Benefits • Increased CD 4+ counts, decreased viral load • Delay in progression to AIDS, reduction in perinatal transmission • Risk • Metabolic complications • Drug interactions • Cost • Treatment failure 48
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Effect of ARVs: ↓ in HIV Viral Replication; ↑ in CD 4+ counts Evolution of viremia and CD 4+ counts under different treatment regimens. Mean changes from baseline of HIV RNA and of CD + counts are given. 4 Vertical bars represent standard deviations. Monotherapy = 1 RTI; RTI Combination = 2 RTI; HAART = 1 RTI + 2 PI OR 2 RTI + 1 PI *RTI = NRTI Erb, P. et al. , JAMA (1996); 18(2): pp 149 -157. 49
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Effect of ARVs: Patient Adherence Paterson, DL. et al. , Ann Intern Med (2000); 133(1): pp 21 -30. 50
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Rationale #2: Compliance with medications is CRITICAL for suppression of HIV viral replication. 51
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Effect of ARVs: PMTCT Prevention of Mother to Child Transmission n = 250 (22%) n = 396 (25. 7%) n = 186 (16%) n = 710 (62%) Cooper, ER. , et. al. JAIDS (2002); 29(5): pp 484 -494. 52
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Effect of ARVs: PMTCT Prevention of Mother to Child Transmission Number of children acquiring HIV infection in low- and middle-income countries, 1996 -2012 Global Update on HIV Treatment 2013: Results, Impact, and Opportunities. WHO Report. June 2013 53
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Effect of ARVs: Transmission Donnell, D. , et. al. Lancet (2010); 375(5): pp 2092 -98. 54
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD Effect of ARVs: Decline in AIDS and death rates African American HIV University Tuesday, September 2, 2014 • ACTG 1751 • Euro. SIDA study 20032 • Swiss HIV Cohort Study 20053 1 Katzenstein, DA. et. al. (1996) NEJM; 335(15): 1091 -8 2 Mocroft, A. et. al. (2003) Lancet; 362(9377): pp. 22 -29 3 Sterne, JAC et. al. (2005) Lancet; 366: pp. 378 -384 55
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 ARVs: 2006 -2014 *Era of Single Pill, Once a day Regimen • Atripla® • Efavirenz + Tenofovir + Emtricitabine • Gilead Sciences and Bristol-Myers Squibb • Complera® • Rilpivirine + Tenofovir + Emtricitabine • Janssen Therapeutics and Gilead Sciences • Stribild® • Elvitegravir + Cobicistat** + Tenofovir + Emtricitabine • Gilead Sciences • Triumeq® • Dolutegravir + Abacavir + Lamivudine • Vii. V Healthcare *For those patients who are appropriate candidates **Cobicistat is NOT an ARV, it is used to maintain appropriate blood levels of Elvitegravir 56
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 ARV Recommendations: Who should be treated? • International Antiviral Society-USA Panel (IAS—USA)1 • Everyone should be offered treatment regardless of CD 4+ count (Rating: AIa-BIII) • Reasons: lack of demonstrated harm from early therapy, cost- effective in resource –rich and –poor nations, more than 20 drugs are expected to become generic in the next 4 years. • US Department of Health and Human Services (DHHS)2 • Everyone should be offered treatment regardless of CD 4+ count (Rating: AI-BIII) • Reasons: reduce risk of disease progression, to prevent HIV transmission. 1 Gϋnthard, HF. et. al. (2014) JAMA; 312(4) pp 410 -425 2 http: //aidsinfo. nih. gov/guidelines 57
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 World Health Organization (WHO) 2013 Consolidated ARV Guidelines Population Adults and adolescents (≥ 10 years) Children ≥ 5 years old Children 1 -5 years old* Infants < 1 year old* Recommendation Initiate ARV if CD 4+ cell count ≤ 500 cells/mm 3 • As a priority, initiate ARV in all individuals with severe/advanced HIV disease (WHO clinical stage 3 or 4) or CD 4+ count ≤ 350 cells/mm 3 Initiate ARV regardless of WHO clinical stage and CD 4+ cell count • Active TB disease • HBV coinfection with severe chronic liver disease • Pregnant and breastfeeding women with HIV • HIV-positive individual in serodiscordant partnership (to reduce HIV transmission risk) Initiate ARV if CD 4+ cell count ≤ 500 cells/mm 3 • As a priority, initiate ARV in all children with severe/advanced HIV disease (WHO clinical stage 3 or 4) or CD 4+ count ≤ 350 cells/mm 3 Initiate ARV regardless of CD 4+ cell count • WHO clinical stage 3 or 4 • Active TB disease Initiate ARV in all regardless of WHO clinical stage and CD 4+ cell count • As a priority, initiate ART in all HIV-infected children 1 -2 years old or with severe/advanced HIV disease (WHO clinical stage 3 or 4) or with CD 4+ cell count ≤ 750 cells/mm 3 or <25%, whichever is lower Initiate ARV in all infants regardless of WHO clinical stage and CD 4+ cell count *Initiate ARV in all HIV-exposed children below 18 months of age with presumptive clinical diagnosis of HIV infection http: //www. who. int/hiv/pub/guidelines/arv 2013/download/en / 58
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Rationale #3: In general, in the US everyone who has been infected with HIV should be offered ARV treatment. 59
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Evidence of rebound viremia after stopping ARVs Felipe, G. , et. al. AIDS (1999); 13(11): pp F 79 – F 86. 60
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Cumulative Probability of the Primary End Point (Panel A); Death from Any Cause (Panel B); Major Cardiovascular, Renal, or Hepatic Disease (Panel C); and Grade 4 Adverse Events (Panel D) The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med 2006; 355: 2283 -2296 The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med (2006); 355: 2283 -2296 61
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Rationale #4: ARV Treatment should be LIFELONG. 62
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Summary: Rationale for ARV Treatment Suppress viral replication • In general, three active drugs from two different classes are needed to suppress viral replication. • Compliance with medications is critical for suppression of HIV viral replication. • In general, in the US, everyone who has been infected with HIV should be offered ARV treatment. • ARV Treatment is LIFELONG. 1 Bartlett, JG. The stages and natural history of HIV Infection. (2012) ww. uptodate. com 2 http: //aidsinfo. nih. gov/guidelines 63
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Goals of ARV Treatment • Laboratory goals • Reduce viral replication • Increase CD 4+ counts; restore and preserve immunologic function • Clinical goals • Reduction is AIDS defining events • Reduction in opportunistic infections • Reduction in AIDS associated malignancies • Reduction in hospitalizations • Reduction in mortality; prolong duration and quality of survival • Reduction in transmission (including Pre & Post Exposure Prophylaxis) • Improvement in non-AIDS associated malignancies, TB, HIVAN + ESRD, cardiovascular health, TB 1 Bartlett, JG. The stages and natural history of HIV Infection. (2012) ww. uptodate. com 2 http: //aidsinfo. nih. gov/guidelines 64
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 HIV Treatment Cascade/HIV Care Continuum 1, 2 • HIV testing and diagnosis • Linkage to care • Retention in care • Initiation of effective ARVs • Adherence to treatment 1 http: //aids. gov/federal-resources/policies/care-continuum/ 2 Gardner, EM, et. al. CID (2011); 52(6): pp 793 -800. 65
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 HIV Care Continuum: Best Case Scenario— Everyone is successfully diagnosed and treated! 66
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 HIV Care Continuum: Current Data http: //aids. gov/federal-resources/policies/care-continuum/ 67
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 HIV Care Continuum http: //aids. gov/federal-resources/policies/care-continuum/ 68
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 HIV Care Continuum http: //aids. gov/federal-resources/policies/care-continuum/ 69
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 OVERALL GOAL To build a thriving long term PARTNERSHIP between the PATIENT AND CLINICIAN so that HIV can be managed SUCCESSFULLY. 70
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Practice Questions! 71
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 OVERALL RATIONALE SUPPRESS ONGOING VIRAL REPLICATION to STOP THE PROGRESSION from HIV INFECTION to the development of AIDS 72
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 In general, __ active drug(s) from at least __ class(es) are needed to suppress HIV virus replication A. In general, 1 active drug from at least 1 class is needed to suppress HIV virus replication B. In general, 2 active drugs from at least 2 classes are needed to suppress HIV virus replication C. In general, 3 active drugs from at least 2 classes are needed to suppress HIV virus replication D. In general, 3 active drugs from at least 3 classes are needed to suppress HIV virus replication E. In general, 4 active drugs from at least 4 classes are needed to suppress HIV virus replication 73
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 How often must a patient take ARVs to ensure success? A. B. C. D. E. Never At least 3 times a week Only when feeling sick Everyday I’m ready for a coffee break 74
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 True or False A. After taking ARVs for an extended period of time, it’s generally okay for a patient to decide to stop therapy, since their viral load is not detectable. B. Taking ARVs can stop the progression from HIV infection to AIDS. C. A pregnant woman should not be offered ARV Treatment because ARVs may harm the baby. D. A patient taking ARVs has been cured and no longer has HIV. E. Key to successful treatment is a partnership built on trust between the patient and clinician. FALSE TRUE 75
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 The HIV Care Continuum A. is a model that is used by federal, state and local agencies to identify issues and opportunities related to improving the delivery of services to people living with HIV across the entire continuum of care. B. tells us that 25% of the 1. 1 million Americans living with HIV are virally suppressed, based on analysis of the latest CDC data using this model. C. tells us that African-Americans are the least likely to be in ongoing care or have their virus under control based on analysis of the latest CDC data using this model. D. tells us that younger Americans are least likely to be retained in care or have their virus in check based on analysis of the latest CDC data using this model. E. All of the above 76
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Cases 77
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Case 1 TM is a 30 year old male who is without any prior known chronic illnesses. A few months ago he developed a cough that has persisted. He has also felt a bit tired, but he’s a writer and has been spending long hours working to meet his publisher’s deadline. At the urging of a friend, he finally decides to see a doctor. His friend noticed that he became extremely short of breath during their usual morning run, which is unusual. The doctor discusses his symptoms with him, performs a physical exam, and orders a few tests. He is told that he is HIV+ and likely has pneumonia as a result of this infection. 78
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Case 2 SO is a 27 year old female who was initially brought in by her male friend. She is back in the doctor’s office today to go over her test results. When she initially came in, she suspected that she was pregnant; she also made it very clear that this was not be discussed while her male friend was in the room. She was somewhat evasive when probed about the nature of their relationship. With regard to her symptoms, she indicated that she had been fatigued, with nausea and vomiting. Her pregnancy test was positive. At that time, the doctor sent routine screening tests, including HIV antibody testing, which was positive. 79
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Case 3 HK is 45 year old male who comes to the doctor’s office in a panic. A few weekends ago he went away with some friends for a bachelor party, the details of which are a bit hazy at this time. There was probably alcohol involved…he can’t remember much else. His concern is that since then he’s developed a fever, a rash, and a slight headache (which is improved when the lights are dim). He’s worried that he may have caught something from someone, though he is sure that he didn’t do anything extremely out of the ordinary. After his evaluation, he is told that testing for HIV and syphilis are both positive. 80
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Cases: Discussion 81
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Summary 82
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Summary • We have experience with a broad range of ARVs that have been shown to be effective with regard to suppressing HIV viral replication. • ARV treatment is currently the only way we are able to stop the progression from HIV infection to AIDS that will occur in the majority of patients who are not treated over time. • A successful ARV treatment strategy includes building a trusting relationship between the clinician and the patient. 83
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Questions? 84
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Thank You! oadeyiga@mednet. ucla. edu 85
Rationale for and Goals of ARV Treatment Oladunni Adeyiga, MD African American HIV University Tuesday, September 2, 2014 Additional References • Update: trends in AIDS incidence, deaths, and prevalence — United States, 1996. MMWR Morb Mortal Wkly Rep 1997; 46: 165 -73. • Phillips AN, Elford J, Sabin C, et al. Immunodeficiency and the risk of death in HIV infection. JAMA 1992; 268: 2662 • Valdiserri, R. (2012, July 19). HIV/AIDS Treatment Cascade Helps Identify Gaps in Care, Retention. Retrieved August 31, 2014, from http: //blog. aids. gov/2012/07/hivaids-treatmentcascade-helps-identify-gaps-in-care-retention. html • Gardner, EM et al. The Spectrum of Engagement in HIV Care and its Relevance to Test-and. Treat Strategies for Prevention of HIV Infection. Clinical Infectious Diseases 2011; 52(6): 793800 • Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 -infected adults and adolescents. Department of Health and Human Services. Available at http: //aidsinfo. nih. gov/contentfiles/lvguidelines/Adultand. Adolescent. GL. pdf Initiating Antiretroviral Therapy in Treatment-Naïve Patients [insert date] pp. E 1 -E 2 • World Health Organization. Interim WHO Clinical Staging of HIV/AIDS and HIV/AIDS Case Definitions for Surveillance. Geneva, Switzerland: World Health Organization; 2005 • Bartlett, JG. The stages and natural history of HIV infection. Up. To. Date. June 2012. • Pedersen, C. et. al. Clinical course of primary HIV infection: consequences for subsequent course of infection. BMJ 1989; 299: 154 -7 • Weekly Epidemiological Record. 1994; 69 (37): pp. 273 -275. World Health Organization, Geneva. • Bartlet, JG. Ten years of HAART: Foundation for the Future. Medscape. February 2006. • A Timeline of AIDS. Accessed August 28, 2014. http: //www. aids. gov/hiv-aids-basics/hiv-aids 101/aids-timeline/ 86
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