Jason Cronin, MD

Epidemiology

Testing

Clinical Features

Management

In 1981,1 the first cases of AIDS were identified among gay men in the US. However, scientists later found evidence that the disease existed in the world as early as 1959.

Evolved from simian immunodeficiency virus (SIV)

The first documented case of HIV was traced back to 1959 using preserved blood samples, which were analyzed in 1998.

Globally 35.3 million people living with HIV/AIDS, 25 million in sub-Saharan Africa

2.3 million new infections/year

1.6 million deaths due to AIDS/year

1.2 million individuals in the U.S. living with HIV/AIDS

1. UNAIDS Report on the Global AIDS Epidemic. http://www.unaids.org/en/resources/documents2013

1981 -First cluster of homosexual men with pneumocystis and Kaposi’s sarcoma

1983 – Identification of retrovirus eventually known as HIV

1985 - First serologic test for HIV-1

1987 – zidovudine (AZT) approved

1996 – First combination regimen (AZT, lamivudine, indinavir)

N Engl J Med 1997; 337:734-739

9307 1981-2012

5581 Living

64 % MSM, 10% IDU

274 New cases/year last 15 years

Increased rates 20-24 year olds since 2006

County Number

Multnomah 3076

Washington 569

Marion 372

Clackamas 357

Lane 301

Jackson 161

Deschuttes 91

Linn 63

Douglas 62

Josephine 58

Counties with Highest Number People Living with HIV/AIDS

Epidemiologic Profile of HIV/AIDS in Oregon, public.health.oregon.gov/DiseasesConditions/CommunicableDisease/DiseaseSurveillanceData/HIVDat

Modes of transmission

Sexual

IVDA

Transfusions (pre-1985, post-1985 1/1-2 million)

Maternal-fetal transmission

Occupational

Note: For comparison with data for 1999 and later years, data for 1987−1998 were modified to account for ICD-10 rules instead of ICD-9 rules.

Continuous ART arms of SMART and ESPRIT trials

Non-IDU aged 2-70

T cells >350, VL undetectable or very low

No increase in mortality for subgroup with T cells >500 compared with control

31

19

3

47

Causes of Death

CardiovascularDisease

Non-AIDSMalignancy

AIDS-related

Other

AIDS 2013, 27:973–979

CDC Prior Recommendations: Targeted testing based on risk factors

ER screening studies found as many as 43% of positive tests were in individuals with no traditional risk factors

Reduced transmission and long-term morbidity due to earlier diagnosis

Cost-effective even with relatively low-prevalence rates (1/1000)

Routine, voluntary testing for all persons 13-64 (Some groups recommend 75) at all points of care

Annual repeat testing for individuals in higher risk groups (such as high risk sexual behavior, IVDU)

“Opt-out” screening with opportunity to answer questions and decline

No specific informed consent recommended

HIV antibody

ELISA

Rapid tests

Western blot

Combined antibody-antigen

HIV Viral RNA

HIV Test Number of days test positive after RNA detectable Median (95% CL)

4th Generation Laboratory Tests

Architect HIV Ag/Ab Combo 6.2 (3.5, 8.5)

GS HIV Combo Ag/Ab EIA 7.4 (3.8, 11.0)

3rd Generation Laboratory Tests

ADVIA Centaur HIV 1/O/2 9.9 (7.7, 12.0)

Vitros anti-HIV 1+2 10.6 (8.7, 12.1)

GS HIV-1/HIV-2 Plus O EIA

13.7 (11.3, 16.1)

3rd Generation Rapid Test

UniGold Recombigen HIV

21.6 (17.5, 27.8)

2nd Generation Rapid Tests

INSTI HIV-1 Antibody 13.5 (11.3, 14.8)

Multispot HIV-1/2 16.8 (14.5, 18.9)

DDP HIV-1/2 17.5 (14.0, 21.5)

Reveal G2 HIV-1 19.0 (16.5, 20.0)

Clearview Complete HIV-1/2 19.7 (17.5, 23.4)

Clearview HIV-1/2 STATPAK 20.3 (17.4, 25.4)

Oraquick Advance HIV-1/2 23.7 (18.2, 29.9)

Class Interval

4th-Generation Laboratory Tests 6.8 (3.7, 9.7)

3rd-Generation Laboratory Tests 11.4 (9.7, 13.4)

2nd-Generation Rapid Tests 18.5 (16.0, 21.6)

Western Blot Laboratory Test 24.3 (18.8, 31.0)

Types of HIV tests

OraQuick In-Home HIV Test

Symptoms

Primary

Clinical Latency

Long-Term Nonprogressors (4-7%, At least 10 years CD4>500)

Elite Controllers (Absent or very low viremia, 1/300 patients)

HIV-associated symptoms

AIDS Indicator Conditions

Other Comorbidities

Viral load

CD4 count

Genetic Background Long-Term

Nonprogressors (4-7%, At least 10 years CD4>500)

Elite Controllers (Absent or very low viremia, 1/300 patients)

Incubation 2-4 weeks

Fever

Axillary, occipital, cervical lymphadenopathy

Sore throat, shallow mucosal ulceration

Maculopapular rash

Lymphopenia, abnormal LFT’s common

HIV antibody negative, viral load very high

Thrush Persistent vaginal candidiasis Oral hairy leukoplakia Herpes zoster involving two episodes or

multidermatomal Peripheral neuropathy Bacillary angiomatosis Cervical dysplasia Cervical carcinoma in situ Constitutional symptoms (fever or diarrhea >1 mo) Idiopathic thrombocytopenic purpura Pelvic inflammatory disease Listeriosis

CD4>200

Bacterial infections, multiple or recurrent*

Cervical cancer, invasive§

Kaposi sarcoma†

Lymphoma, Burkitt (or equivalent term)

Lymphoma, immunoblastic (or equivalent term)

Pneumonia, recurrent†§

CD4<200

Candidiasis of bronchi, trachea, or lungs

Candidiasis of esophagus†

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Encephalopathy, HIV related

Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia complex*†

Herpes simplex: chronic ulcers (>1 month's duration) or bronchitis, pneumonitis, or esophagitis (onset at age >1 month)

Histoplasmosis, disseminated or extrapulmonary

Mycobacterium tuberculosis of any site, pulmonary,†§ disseminated,† or extrapulmonary†

Pneumocystis jirovecii pneumonia†

Wasting syndrome attributed to HIV

Salmonella septicemia, recurrent

Toxoplasmosis of brain, onset at age >1 month†

Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary†

CD4<50

Cryptosporidiosis, chronic intestinal (>1 month's duration)

Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month

Cytomegalovirus retinitis (with loss of vision)†

Isosporiasis, chronic intestinal (>1 month's duration)

Lymphoma, primary, of brain

Mycobacterium, other species or unidentified species, disseminated† or extrapulmonary†

Progressive multifocal leukoencephalopathy

42%

15% 11%

11%

5%

5%

4%

4%

3% 3%

2% 2% 2% 2% 1% 1% Pneumocystis

Esophageal Candidiasis

Wasting

Kaposi's

Disseminated M. avium

Tuberculosis

CMV

Dementia

Recurrent pneumonia

Toxoplasmosis

Immunoblastic lymphoma

Cryptosporidiosis

Burkitt's lymphoma

Disseminated histoplasmosis

Invasive cervical cancer

Chronic herpes simplex

Malignancies

Cardiovascular

Coinfections

Complex Pathogenesis Immune factors

Behavioral factors

Medication toxicity

Condition Approximate risk Notes

Non-AIDS Defining Malignancies

Hodgkin’s Lymphoma 15 to 30x Increased unfavorable histology and advanced disease

Plasma Cell Disorders 4.5x 2.5% MGUS Younger Age

Hepatocellular 3.8x Coinfection with hepatitis C/B

Lung cancer 2-4x More likely metastatic, less tobacco exposure

Anogenital HPV

Head and Neck 2-3x Younger

Esophagus/Stomach 1.4,1.69x

Cardiovascular

Total 6.76 men, 2.47 women Both effect of HAART as well as direct effects on endothelium

Controlled for other factors

1.26

Diabetes 3x for HIV men on HAART

Protease Inhibitors NRTI’s

1996 – all with CD4+ <500 or CD4 >500 and VL >30,000

1997 – initiate if VL >10,000 copies/mL 2000 – CD4+ <350, or VL >30,000, or CD4 350-500

and VL 5k-30k 2002 CD4 <200, otherwise clinical judtgment 2003 – CD4 <200, offer if 200-350, clinical judgment

>350 and VL >55,000 2004 <200, offer 200-350, most defer >350 and VL >

100k 2008 CD4 <350, otherwise consider 2009 CD4 <500, otherwise consider

• More effective regimens

• More convenient regimens

• Better tolerated therapy

• Less long-term toxicity

• Better immune recovery

• Lower rates of resistance

• More treatment options

• Concerns for uncontrolled viremia

• Decrease HIV transmission

• Lack of RCT data supporting early Rx

• Potential drug toxicity

• Drug and monitoring cost

• Potential negative impact on QOL

Everyone, regardless of CD4 count

Urgency of starting may depend on other factors such as patient readiness, presence of AIDS or AIDS-related comorbidities, pregnancy

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

NRTI

Abacavir (ABC)

Didanosine (ddI)

Emtricitabine (FTC)

Lamivudine (3TC)

Stavudine (d4T)

Tenofovir (TDF)

Zidovudine (AZT, ZDV)

NNRTI

Delavirdine (DLV)

Efavirenz (EFV)

Etravirine (ETR)

Nevirapine (NVP)

Rilpivirine (RPV)

PI

Atazanavir (ATV)

Darunavir (DRV)

Fosamprenavir (FPV)

Indinavir (IDV)

Lopinavir (LPV)

Nelfinavir (NFV)

Ritonavir (RTV)

Saquinavir (SQV)

Tipranavir (TPV)

Integrase Inhibitor

(II)

Dolutegravir (DTG)

Elvitegravir* (EVG)

Raltegravir (RAL)

Fusion Inhibitor

Enfuvirtide (ENF, T-20)

CCR5 Antagonist

Maraviroc (MVC)

May 2014 32 www.aidsetc.org

* EVG currently available only in coformulation with cobicistat (COBI)/ TDF/FTC

NNRTI-Based Regimen • EFV/TDF/FTC1 (AI) PI-Based Regimens (in alphabetical order) • ATV/r + TDF/FTC1 (AI) • DRV/r (once daily) + TDF/FTC1 (AI) INSTI-Based Regimen • DTG plus ABC/3TC (AI) – only for patients who are HLA-B*5701 negative •DTG plus TDF/FTC (A1) •EVG/cobi/TDF/FTC – only for patients with pre-ART CrCl>70 mL/min (A1) •RAL plus TDF/FTC (A1) In addition to above, following regimens recommended only for patients with pre-ART plasma HIV RNA <100,000 copies/mL NNRTI-Based Regimen • EFV plus ABC/3TC (A1) only for patients who are HLA-B*5701 negative • RPV/TDF/FTC – onlyfor patients with CD4 count >200 PI-Based Regimens (in alphabetical order) •ATV/r plus ABC/3TC (A1) – only for patients who are HLA-B*5701 negative

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

Fusion inhibitors

Entry inhibitors

NRTI’s

NNRTI’s

Protease inhibitors

Integrase inhibitors

Condition NRTI’s NNRTI’s PI’s Integrase Inhibitors

Dyslipidemia D4T, AZT, ABC

EFV All, ATV, DRV are less

EVG/cobi/TDF/FTC

Nephrotoxicity TDF EVG/cobi/TDF/FTC

Insulin Resistance

D4T, AZT, DDI IDV, LPV-rit

Cardiovascular ABC, DDI Older PI’s, limited data on ATV, DRV

Lactic Acidosis D4T, AZT, DDI

Lipodysrophy D4T, AZT ? ? ?

Decreased bone density

TDF

Neuropsychiatric

D4T/DDI/AZT PN

EFV depression, insomnia, vivid dreams

Insomnia

Toxicity of Antiretrovirals

Medical comorbidities

AIDS-associated

Non-AIDS associated

Coinfections (hepatitis C, hepatitis B, Other STD’s)

Substance dependence and abuse, including tobacco

Psychosocial

Mental health

Relational strain due to diagnosis

Economic

Patient Primary

Care Provider

Case Management

Other Specialty

Care

HIV Provider

Addiction Recovery

Mental Health Provider

HIV-trained pharmacist

Family/Social support network

Multidisciplinary Approach

Little change in new cases despite current preventative measures AND increased in some subgroups

Large scale trials in multiple populations showing benefit without emergence of resistance

Now recommended by CDC for certain higher risk groups as one preventative option

Study Drug Population Results Notes

Pre-exposure Prophylaxis Initiative (iPrEX)

TDF-FTC 2499 HIV-seronegative MSM

100 infected, (36 I, 64 placebo)

Drug detected in only 9% of treatment arm

Partners-PrEP TDF TDF-FTC

4758 discordant heterosexual couples in Africa

TDF-3TC with 75% reduced risk

TDF2 TDF-FTC 1200 heterosexual women

62% reduced risk

TDF-FTC 2413 IVDU Thailand

50 infected (17 intervention, 33 placebo), 49% reduction

Lancet. 2013 June;381 (9883):2083-90 N. Engl J Med. 2010;363(27):2587 N Engl J Med. 2012;367(5):399

MSM: Non-monogamous sexual activity past 6 months involving unprotected anal intercourse or recent bacterial STI

Heterosexual: Infrequent condom use with partners of unknown HIV status expected high risk for HIV, recent bacterial STI

Discordant couples where infected partner not well-controlled

Active IV drug users with history sharing needles

Preexposure Prophylaxis for the Prevention of HIV Infection in the United States – 2014 Clinical Practice Guideline