2 rationale for and goals of arv treatment oladunni adeyiga, md, ms star fellow department of...

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Rationale for and Goals of ARV Treatment

Oladunni Adeyiga, MD, MSSTAR FellowDepartment of MedicineDivision of Infectious Diseases

African American HIV University Wednesday, August 26, 2015

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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

Rationale for and Goals of ARV TreatmentOladunni Adeyiga, MD, MS

African American HIV UniversityWednesday, August 26, 2015

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Cases



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Case 1TM 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.



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Case 2SO 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.



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Case 3HK 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.



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Learning Objectives



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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



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HIV and AIDS Classification



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1993 CDC Revised Classification System HIV Infection

Clinical Categories

(A) (B) (C)

Asymptomatic, acute (primary)

HIV or PGL*

Symptomatic, not (A) or (C)

conditions

AIDS-indicator

conditionsAbsolute CD4

+ countCD4

+ % of total T-cells

CD4+

T cell categories

(1) ≥ 500/mL (≥29) A1 B1 C1

(2) 200 - 499/mL (14-28) A2 B2 C2

(3) < 200/mL (<14) A3 B3 C3

Castro, KG. et. al. (1993) CID; 17(4) pp 802-810

*Persistent Generalized Lymphadenopathy

Rationale for and Goals of ARV TreatmentOladunni Adeyiga, MD


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1993 CDC Revised Classification System HIV Infection

• Clinical categories• Category A• Category B• Category C

• CD4+ T cell categories• (1) Absolute # ≥ 500/mL

OR % total # of T-cells ≥ 29

• (2) Absolute # 200 - 499/mLOR % total # of T-cells

14-28• (3) Absolute # < 200/mL

OR % total # of T-cells <14




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• Acute (primary) HIV• Asymptomatic HIV• Persistent generalized lymphadenopathy

1993 CDC Revised Classification System HIV Infection: Clinical Category A




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• 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

1993 CDC Revised Classification System HIV Infection: Clinical Category B




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• 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 disease, particularly if complicated by tubo-ovarian abscess

• Peripheral neuropathy

1993 CDC Revised Classification System HIV Infection: Clinical Category B




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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• CD4

+ count < 200 cells/mm3 OR CD4+ %<14*

• Cervical cancer, invasive*• Mycobacterium tuberculosis, pulmonary*• Pneumonia, recurrent*

*Requires laboratory confirmation of HIV infection




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WHO (World Health Organization) 2005Revised Clinical Staging of HIV/AIDSfor Adults and Adolescents

• Primary HIV Infection• Asymptomatic• Acute retroviral syndrome

• Clinical stage 1• 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

• Clinical stage 3• Conditions where a presumptive

diagnosis can be made on the basis of clinical signs or simple investigations

• Severe weight loss (>10% of presumed or 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 neutropenia (<500/mm3) and/or thrombocytopenia (<50 K/mm3) for more than 1 month



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WHO (World Health Organization) 2005Revised Clinical Staging of HIV/AIDSfor Adults and Adolescents

• Clinical stage 4• Conditions where a presumptive diagnosis

can be made on the basis of clinical signs or simple investigations

• 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

• Clinical stage 4• Conditions where confirmatory diagnostic

testing is necessary• CMV infection (CMV retinitis or infection of

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 HIV-

associated nephropathy



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ARVs: Brief History



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FDA History Timeline**Source: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm117935.htmAccessed August 11, 2014

• 1981: AIDS first reported• 1987: Approval of Zidovudine (AZT)/Retrovir

approved for children in 1989• 1989: Approval of Dideoxyinosine (ddI)/Videx• 1995: April: Saquinavir open label study allowed

Nov: Lamivudine (3TC)/Epivir accelerated approval (to be used in combination with AZT)

Dec: Saquinavir (SQV)/Invirase approved for combination use with nucs (1st PI)

Stavudine (d4T) Zerit traditional approval for patients with prior

prolonged AZT therapy (prior accelerated approval already)

• 1996: Mar: Ritonavir (RTV)/Norvir (children 1997), Indinavir

19811982: AIDS1987: AZT1995: PIs(IDV)/Crixivan approval for

single or combination use

June: Nevirapine (NVP)/Viramune approval for combination use, 1st non-nuc

• 1997: Mar: Nelfinavir NFV/(Viracept) 1st PI labeled for use in children and adults

April: Delavirdine (DLV)/Rescriptor, for combination use

Sept: Combivir (AZT + 3TC)

Nov: Fortovase (new formulation of Saquinavir (SQV)/Invirase )

• 1998: Sept: Efavirenz (EFV)/Sustiva

Dec: Abacavir (ABC)/Ziagen accelerated approval

• 1999: Amprenavir (APV)/Agenerase based on

1997: NNRTIs

laboratory end-points • 2000: Sept: Kaletra (lopinavir + ritonavir)

Oct: Videx EC for combination use

Nov: Trizivir (ABC/3TC/AZT)• 2001: Jan: Warning against Zerit and Videx in

pregnant women

Oct: Tenofovir (TDF)/Viread accelerated approval (first nucleotide analog)

• 2002: Feb: Once daily EFV, Boosted APV

June: Once daily Epivir (3TC)

Aug: Caution on Amprenavir use with Methadone and OCPs

Sept: Caution on ddI use w/ ribavirin and TDF;↑ddI levels

Dec: Extended release Zerit (d4T)• 2003: Mar: Enfuvirtide (T-20)/fuzeon approved

for adults and children >6yo

April: Nelfinavir mesylate (NFV)/Viracept;

5 pills now 2 pills BID

June: Atazanavir sulfate (ATV)/Reyataz

July: Emtricitabine (FTC)/Emtriva, Trizivir warning (early virologic non-response)

Aug: Suggestion that Atazanavir should be boosted if used with Tenofovir

Oct: Fosamprenavir (FPV)/Lexiva approved

• 2004: Jan: Avoid atazanavir with indinavir

Aug: Epzicom (ABC/3TC) and Truvada (TDF/FTC)

Oct: Traditional approval for Fuzeon

Dec: 1st generic antiretroviral (ddI),

2003: PEPFAR2003:ENTRY

INHIBITORS

Saquinavir 5 pills now 2 pills BID

2005: Jan: 1st tentative approval under a new FDA approval process with PEPFAR. Copackaged Combivir and nevirapine

Feb: Caution, avoid SQV/r with rifampin (drug-induced hepatitis)

Mar: Alfuzosin (a blocker) contraindicated with norvir. Also norvir interactions with fluticasone and trazodone

Efavirenz now pregnancy class D

April: Once daily Kaletra formulation approved

May: Generic 3TC, Foscarnet

June: Accelerated approval of Tipranavir (TPV)/Aptivus, generic EFV

July: Tentative approval for genetic d4T,

2006: ATRIPLA

Combivir, Zidovudine• 2005: Sept: Oral Generic AZT, FTC Soln

Oct: Norvir approved for 1 mo to 2 yr olds

Nov: Oral generic 3TC Soln out of India

Dec: Generic oral d4T, generic oral NVP out of India

• 2006: Jan: Caution, atazanavir use with PPI, H2 blockers, methadone, rifampin, ddI

May: Tentative approval for generic ABC

June: Tentative approval for another general 3TC solution out of India

Accelerated approval of darunavir (DRV)/Prezista, boosted (for treatment experienced)

Combination 3TC/AZT/NVP, d4T, and ABC out of India because of

PEPFAR

July: Generic ddI out of India, FDC Atripla (TDF/FTC/EFV), 3TC/AZT

copackaged with ABC out of India

Aug: Generic NVP out of India, 3TC/AZT out of South Africa, d4T capsules

out of India

Oct: Oral ddI, atazanavir 300 mg capsule

Nov: Generic ABC, FDC (fixed dose combination) d4T/3TC/NVP

• 2007: Jan: Tentative approval FDC 3TC/d4T

EFV interaction with rifampin/diltiazem/azole/statins

FDC 3TC/AZT/NVP

Feb: Entecavir noted to induce M184V

Mar: Oral soln ddI, generic EFV from India

2007: ISTI

May: Generic AZT

June: Oral fosamprenavir soln

July: Generic NVP

Aug: Maraviroc (MVC)/Selzentry approved, combination 3TC/d4T/NVP for children

Oct: Tipranavir traditional approved (for treatment experienced with PI resistance)

Raltegravir(RAL)/Isentress approved

Lexiva approved for 1400 mg boosted daily dosing in treatment naïve.

• 2008: Jan: Etravirine (ETR)/Intelence accelerated approval for patients with NNRTI resistance

Feb: 600 mg Prezista tablets

July: ABC HSR association with HLA-B*5701 allele noted

Generic drugs approved for sale in the US: AZT, ddI, d4T,

• 2009: Many FDCs (including EFV/3TC or FDC/TDF and 3TC/AZT/NVP)

• 2011: FDC Complera (3TC/RPV/TDF)

Rilpivirine (RPV)/Edurant

Viramune XR

↑ Rate of bac’t PNA seen w/ Fuseon • 2012: FDC Stribild: elvitegravir, cobicistat,

FTC,TDF• 2013: Dolutegravir (DTG)/Tivicay

1983: HIV

2015

http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm117935.htm

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• 1981: First cases• 1982: AIDS terminology used by CDC• 1983: Identification of HIV as virus leading to AIDS• 1987: First anti-retroviral (Zidovudine); class: NRTI• 1995: First PI, beginning of potent ART (HAART)• 1997: New class: NNRTI• 2003: PEPFAR announced by US President Bush• 2003: New class: Entry Inhibitors• 2006: Atripla (Single pill, daily medication)• 2007: New class: ISTI

FDA History Timeline**Source: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm117935.htmAccessed August 11, 2014



http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm117935.htm

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Before ARVs



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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

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Advanced HIV Infection

Early Symptomatic HIV Infection

Clinical course of HIV Infection without therapy: Summary

Time0 Years

Clinical latent period

Long-term nonprogressors

Elite Controllers



6 months

Acu

te In

fect

ion

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• Spans the time when a patient is infected to 6 months• No symptoms• Under examination, there may be enlarged lymph nodes

Clinical course of HIV Infection without therapy: Clinical latent period



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• Class B (formerly called “AIDS-related complex”)

Clinical course of HIV Infection without therapy: Early symptomatic HIV infection



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HIV Viral Dynamics and AIDS



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HIV Replication in Infection



Schacker, TW. et. al. (1998) Ann Int Med; 128(8): pp 613-620

Rap

id d

ecli

ne

in b

loo

d H

IV v

irio

n l

evel

s

“Set point”

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HIV Effect on CD4+ count without therapy



Stein, DS. et. al. (1992) J Inf Dis; 165(2): pp 352-363

Mean CD4+ counts for 318 patients from the MACS group

Groups Represented AboveN: No AIDS developed during 6 years of follow-up; 252

patientsL: AIDS developed > 6 years of follow-up;

4 patients

M: AIDS developed 3-6 years of follow-up; 28

patientsS: AIDS developed <3 years of follow-up;

20 patients

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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.

1981-1992 1992-1996*0

50000

100000

150000

200000

250000

300000

350000

400000

Reported Cases

*expanded AIDS surveillance case definition implemented

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• 1981 – 1996: 573,800 persons age ≥13 yrs




1992 1993* 1994 1995 1996**0

20000

40000

60000

80000

100000

Yearly Reported Cases

MenWomen

*expanded AIDS surveillance case definition implemented**largest number of newly reported cases from Black, non-Hispanic population

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• 1981 – 1996: 573,800 persons age ≥13 yrs




Race/Ethnicity of Total Reported Cases

White, non-HispanicBlack, non-HispanicHispanicAsian/Pacific IslanderAmerican Indian/Alaskan NativeUnknown Ethnicity

34.6%

46.6%

17.6%

1.8%

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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

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Number of prevalent AIDS cases among persons aged ≥13 years, adjustedfor delays in reporting, by quarter year — United States, 1988–June 1996*




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Kaplan-Meier estimates of the cumulative probability of dying according to the number of years from seroconversion. HIV indicates human immunodeficiency virus.



Phillips et. al. JAMA (1992);268(19): pp. 2662-2666.

*Number of patients remaining at each time point who were at risk

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Mother to Child Transmission



John, GC and Kreiss, J. Epi Reviews (1996); 18(2): pp 149-157.

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HIV/AIDS Outcomes Prior to ARTSummary• Ongoing HIV viral replication• Destruction of CD4

+ T cells

• Resulting cell-mediated immunity defect• Transmission of HIV

• To sexual contacts• In utero

• Development of • Recurrent Infections• Malignancy

• Death



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Ongoing HIV viral replication



HIV Infection

AIDS

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Ongoing HIV viral replication



HIV Infection

AIDS

Ongoing HIV viral replicationARVs

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SUPPRESS ONGOING VIRAL REPLICATION

to

STOP THE PROGRESSION from

HIV INFECTION to the development of

AIDS



OVERALL RATIONALE

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Effect of ARVs



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ARVs: 1986-1997• 1986: First clinical trial with Zidovudine1

• 1993: Two drug therapy2

• 1996: Saquinavir, 1st PI used in combination therapy3

• 1997: Indinavir (also a PI) used in combination therapy4,5



1Fischl, MA et. al. (1987) NEJM; 317(4): pp. 185-912Collier, AC et. al. (1993) Ann Intern Med.; 119(8): pp. 786-7933Collier, AC et. al. (1996) NEJM; 334(16): pp. 1011-74Hammer, SM et. al. (1997) NEJM; 337(11): pp. 725-7335Guilick, RM et. al. (1997) NEJM; 337(11): pp. 734-739

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ARVs: 1986-1997What did we learn?• Multiple drugs needed• Potent drugs needed• Antimicrobial prophylaxis for opportunistic infections



Corey, L and Holmes, KK. (1996) NEJM; 336(16): pp. 1142 – 1143Girard, PM et. al., (1989) Lancet; 333(8651): pp 1348-53Ruskin, J and LaRiviere, M. (1991) Lancet; 337(8739): pp. 468-71

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• In general: • base = INSTI, Maraviroc, NNRTI, PI

PLUS• backbone = 2 N[t]RTIs (nucleoside/nucleotide reverse transcriptase inhibitors)

Base



Integrase Inhibitor ORCCR5 Antagonist OR

Non-nucleoside Reverse Transcriptase InhibitorOR Protease Inhibitor

BASE

TWO Nucleoside/Nucleotide

Reverse transcriptaseInhibitors

BACKBONE+

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HIV Life Cycle



1. Cell entryENTRY INHIBITORS

(CCR5 ANTAGONISTS)

FUSION INHIBITORS2. Reverse Transcription

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

NUCLEOSIDE/NUCLEOTIDE REVERSE

TRANSCRIPTASE INHIBITORS

3. IntegrationINTEGRASE

INHIBITORS4. Protein assembly

PROTEASE 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 (7th Ed.). Philadelphia, PA: Churchill Livingstone/Elsevier

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HIV Life Cycle• Cell entry

• Fusion Inhibitors• Entry Inhibitors (CCR5 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 (7th Ed.). Philadelphia, PA: Churchill Livingstone/Elsevier

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Rationale #1: In general, three active drugs from two different classes are needed to suppress viral replication.



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ARVs: 1997-2006• Highly active antiretroviral therapy = HAART• Establishment of target viral load• Risk vs. Benefit

• Benefits• Increased CD4

+ counts, decreased viral load

• Delay in progression to AIDS, reduction in perinatal transmission• Risk

• Metabolic complications• Drug interactions• Cost• Treatment failure


African American HIV UniversityTuesday, September 2, 2014

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Effect of ARVs:↓ in HIV Viral Replication; ↑ in CD4

+ counts



Erb, P. et al., JAMA (1996); 18(2): pp 149-157.

Evolution of viremia and CD4+ counts under different treatment regimens. Mean changes from baseline of HIV RNA and of CD4+ counts are given.

Vertical bars represent standard deviations. Monotherapy = 1 RTI; RTI Combination = 2 RTI; HAART = 1 RTI + 2 PI OR 2 RTI + 1 PI*RTI = NRTI

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Effect of ARVs: Patient Adherence

≥95 90 - 94.9 80 - 89.9 70 - 79.9 <700

20

40

60

80

100

21.7

54.666.7 71.4 82.1

Adherence to antiretroviral therapy and viro-logic failure

Adherence, %

Pa

tie

nts

wit

h V

iro

log

ic F

ailu

re, %



Paterson, DL. et al., Ann Intern Med (2000); 133(1): pp 21-30.

51

Rationale #2: Compliance with medications is CRITICAL for suppression of HIV viral replication.



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Effect of ARVs: PMTCTPrevention of Mother to Child Transmission



Cooper, ER., et. al. JAIDS (2002); 29(5): pp 484-494.

n = 396 (25.7%)

n = 710 (62%)

n = 186 (16%)

n = 250 (22%)

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Effect of ARVs: PMTCTPrevention 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

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Effect of ARVs: Transmission



Donnell, D., et. al. Lancet (2010); 375(5): pp 2092-98.

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Effect of ARVs:Decline in AIDS and death rates• ACTG 1751

• EuroSIDA study 20032

• Swiss HIV Cohort Study 20053

1Katzenstein, DA. et. al. (1996) NEJM; 335(15): 1091-8 2Mocroft, A. et. al. (2003) Lancet; 362(9377): pp. 22-293Sterne, JAC et. al. (2005) Lancet; 366(9483): pp. 378-384



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ARVs: 2006-2015*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• ViiV Healthcare



*For those patients who are appropriate candidates**Cobicistat is NOT an ARV, it is used to maintain appropriate blood levels of Elvitegravir

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2015 ARV Recommendations: Who should be treated?• International Antiviral Society-USA Panel (IAS—USA)1

• Everyone should be offered treatment regardless of CD4+ 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 CD4+ count

(Rating: AI-BIII)• Reasons: reduce risk of disease progression, to prevent HIV transmission.



1Gϋnthard, HF. et. al. (2014) JAMA; 312(4) pp 410-4252http://aidsinfo.nih.gov/guidelines

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World Health Organization (WHO) 2013 Consolidated ARV Guidelines



Population Recommendation

Adults and adolescents (≥10 years)

Initiate ARV if CD4+ cell count ≤500 cells/mm3

•As a priority, initiate ARV in all individuals with severe/advanced HIV disease (WHO clinical stage 3 or 4) or CD4

+ count ≤350 cells/mm3

Initiate ARV regardless of WHO clinical stage and CD4+ 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)

Children ≥ 5 years old

Initiate ARV if CD4+ cell count ≤500 cells/mm3

•As a priority, initiate ARV in all children with severe/advanced HIV disease (WHO clinical stage 3 or 4) or CD4

+ count ≤350 cells/mm3

Initiate ARV regardless of CD4+ cell count

•WHO clinical stage 3 or 4•Active TB disease

Children 1-5 years old*

Initiate ARV in all regardless of WHO clinical stage and CD4+ 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 CD4

+ cell count ≤750 cells/mm3 or <25%, whichever is lower

Infants < 1 year old*

Initiate ARV in all infants regardless of WHO clinical stage and CD4+ 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/arv2013/download/en/

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Rationale #3: In general, in the US everyone who has been infected with HIV should be offered ARV treatment.



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Evidence of rebound viremia after stopping ARVs



Felipe, G., et. al. AIDS (1999); 13(11): pp F79 – F86.

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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

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Rationale #4: ARV Treatment should be LIFELONG.



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Summary: Rationale for ARV TreatmentSuppress 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.



1Bartlett, JG. The stages and natural history of HIV Infection. (2012) ww.uptodate.com2http://aidsinfo.nih.gov/guidelines

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Goals of ARV Treatment• Laboratory goals

• Reduce viral replication• Increase CD4

+ 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



1Bartlett, JG. The stages and natural history of HIV Infection. (2012) ww.uptodate.com2http://aidsinfo.nih.gov/guidelines

Early HIV Infection: Treatment*Clinical trial outcome data is limited

Possible benefits: • Decreased severity of acute

disease• Lower viral “set point”• Reduced viral reservoir• Reduced rate of mutation• Preserved immune function• Lower risk of HIV transmission

Risks:Drug-related toxicityEarlier emergence of drug

resistanceAdverse effects on

quality of life

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April 2015

www.aidsetc.org



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HIV Treatment Cascade/HIV Care Continuum1,2

• HIV testing and diagnosis• Linkage to care• Retention in care• Initiation of effective ARVs• Adherence to treatment



1http://aids.gov/federal-resources/policies/care-continuum/2Gardner, EM, et. al. CID (2011); 52(6): pp 793-800.

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HIV Care Continuum: Best Case Scenario—Everyone is successfully diagnosed and treated!

0

20

40

60

80

100100 100 100 100 100

HIV Care Continuum: Best Case Scenario

Pe

rce

nt

of

all

Pe

op

le w

ith

HIV



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HIV Care Continuum1:



1http://aids.gov/federal-resources/policies/care-continuum/Accessed August 14, 2015

2JAMA Intern Med. 2015;175(4):588-596.

Regarding HIV transmission, hose not retained in care are more likely to transmit2

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To build a thriving long term

PARTNERSHIP between the

PATIENT AND CLINICIAN so that HIV can be managed

SUCCESSFULLY.



OVERALL GOAL

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Practice Questions!



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SUPPRESS ONGOING VIRAL REPLICATION

to

STOP THE PROGRESSION from

HIV INFECTION to the development of

AIDS



OVERALL RATIONALE

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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



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How often must a patient take ARVs to ensure success?

A. Never

B. At least 3 times a week

C. Only when feeling sick

D. Everyday

E. I’m ready for a coffee break



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True or FalseA. 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

FALSETRUE

TRUEFALSE

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The HIV Care ContinuumA. 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 30% of the 1.2 million Americans living with HIV are virally suppressed, based on analysis of the latest CDC data using this model.

C. Those who are not retained in care are more likely to transmit HIV, based on analysis of the latest CDC data using this model.

D. All of the above



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Cases



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Case 1TM 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.



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Case 2SO 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.



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Case 3HK 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.



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Cases: Discussion



81

What are some issues that may prevent someone from accessing care or taking medications?



82

Using what you’ve learned, how might you get this person to agree to therapy?

Rationale for and Goals of ARV TreatmentOladunni Adeyiga, MD


83

Summary



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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.



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Questions?



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Thank [email protected]



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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-treatment-cascade-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):793-800

• 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/AdultandAdolescentGL.pdf Initiating Antiretroviral Therapy in Treatment-Naïve Patients [insert date] pp. E1-E2

• 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. UpToDate. 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/



2 rationale for and goals of arv treatment oladunni adeyiga, md, ms star fellow department of...

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