31st Annual Winter Update

Indiana Osteopathic Association

December 7, 2012

Indianapolis, IN

cgenske@ecommunity.com

Outline History Epidemiology Transmission Natural History Testing Recommendations Diagnosis Clinical Manifestations Treatment Health Maintenance Hot Topics

Pre-exposure prophylaxis (PrEP)Post-exposure prophylaxis (PEP)

June 5, 1981: MMWR published 5 cases of PCP

in homosexual men from California

July 3, 1981: 26 additional cases

Dec 10, 1981: 3 NEJM papers describe cases

41 cases Kaposi’s Sarcoma (KS)

GRID = Gay-related Immune Deficiency

20 states with disease

AIDS = Acquired ImmunoDeficiency Syndrome

Hemophiliacs died

1292 of 3064 people died

James Mason isolated LAVRobert Gallo isolated HTLV-III

First test to identify HIV antibodies developed

July 1981

1982

June1982

July1982

Dec1982

1983

April1984

March1985

1985

Rock Hudson died of AIDS

50% of hemophiliacs infected

Surgeon General’s first report on AIDS

FDA approved first drug (AZT)

Ryan White died

FDA approved second drug (ddI)

1985

1986

1986

March1987

April1990

1991

1986 Drug trials begin (ACTG)

1988 45,000/83,000 patients had died

Ryan White CARE Act passed

AZT reduces MTCT

2 drugs are better than 1

HAART in use (3+ drugs)

DHHS guidelines recommend initiation of ART for CD4 <500

New hope for HIV prevention (PrEP)

1990

1994

1994

1996

2009

2010+

1995 First HIV viral load testing

2006 First one pill once daily regimen approved

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1995 1996 1997 1998 1999 2000 2001

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USE OF ART

Mortality vs. ART utilization

Courtesy: AETC

AIDS Mortality Rates: 1995-2001

Adult HIV Prevalence, 2010

Courtesy: UNAIDS

Courtesy: UNAIDS

Courtesy: UNAIDS

Changes in HIV Incidence, 2001-2010

Epidemiology – Worldwide 34 million living with HIV / AIDS

~2/3 in Sub-Saharan Africa, mostly heterosexual60% unaware of being infected7,000 new infections each day (2.5 million/yr)

○ 900 of these are children < 15 yo○ 47% in women○ 39% in young people (15-24)○ African Americans 8x rate of HIV cases compared

to whites1.7 million died in 2011

Only 25% are receiving treatment !!

www.unaids.org

Epidemiology – U.S. 1,180,000 HIV+ (1 in 200)

20% undiagnosed488,000 living w/ AIDS21,000 die each yr

50,000 newly infected each yr61% MSM1 of every 5 homosexual urban males HIV+1 of every 22 African Americans will be

infected

Incidence in Washington D.C. is 3%!

Epidemiology – U.S.

Only 1 of 5 have undetectable virus -> (close to) non-contagious.

Over 800,000 have detectable virus -> CONTAGIOUS!

Individuals unaware of their HIV+, particularly those recently infected, are major contributors to the ongoing epidemic

Epidemiology – Indiana Persons living with HIV/AIDS in Indiana

as of June, 30, 2012Total = 10,420

○ 80% Male (8,388)○ 20% Female (2,032)

Race/Ethnicity of HIV patients53% White (5,541) 0.1% infected36% Black (3,764) 0.6% infected7% Hispanic (780) 0.2% infected

Spotlight on HIV/STD/Viral Hepatitis, Indiana Semi-Annual Report, June 2012: http://www.in.gov/isdh/files/At_A_Glance-Dec.pdfIndiana IN Depth Profile. http://www.stats.indiana.edu/c2010/dp1/FactfinderINandUS.pdf

HIV Transmission/Acquisition Found in blood, semen, or vaginal fluid of an

infected person

HIV is transmitted/acquired by:Having sex (anal, vaginal, or oral) with someone

infected with HIVSharing needles, syringes with someone who has

HIVExposure (in the case of infants) to HIV before or

during birth, or through breast feeding

Probability of HIV Transmission

INFECTION ROUTE RISK OF INFECTIONSexual IntercourseMale-to-male transmission 1 in 10 - 1 in 1,600Male-to-female transmission 1 in 200 - 1 in

2,000Female-to-male transmission 1 in 700 - 1 in

3,000

Transmission from mother to infantWithout AZT 1 in 4With AZT Less than 1 in 10With HAART 1-2 in 100

OtherTransfusion of infected blood 95 in 100Needle stick 1 in 250Needle sharing 1 in 150

Royce, et al

Natural History

Acute Infection (days to weeks) Partial Control of HIV (weeks to months) Asymptomatic HIV Infection (1-10+

years) Symptomatic HIV Infection & AIDS

(years)

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Primaryinfection

Possible acute HIV syndromeWide dissemination of virusSeeding of lymphoid organs

Clinical latency

Death

Opportunisticdiseases

Constitutionalsymptoms

Natural History of HIV Infection

CD4 Lymphocyte Count

Reflects immune status Normal CD4 count: 500 - 1,500 cells/mm3 CD4 count decreases as HIV disease

progresses CD4 counts differ daily Overall trend of CD4 counts over time

most important

CD4 < 200 = AIDS (or opportunistic infection)

HIV Viral Load

Number of HIV RNA copies per mL of blood

“High” viral load: 5,000 to >1,000,000 copies High reproduction rateDisease will progress faster

“Low” viral load: 200 to 500 copies Low reproduction rateRisk of disease progression is low

“Undetectable” viral loads: <50 or <400Below the threshold needed for detection

2006 CDC HIV Testing Recommendations

CDC Testing Guidelines, 2006 Offer routine testing in all health care

settings to:13- to 64-year-olds

Anyone with Tuberculosis (TB)

All patient seeking treatment for STDs

All pregnant females

Any health care worker exposed to blood or body fluids

Anyone who requests testing

CDC Testing Guidelines, 2006

Who should be tested at least annually?IVDA and their sex partnersPersons who exchange sex for money or

drugsSex partners of HIV-infected personsPersons with multiple sex partners

Why emphasize early diagnosis? Individuals unaware of their HIV+,

particularly those recently infected, are major contributors to the ongoing epidemic

Earlier treatment: Lowers mortality

○ “Delayed Therapy” group (<500) had 94% higher mortality!* Decreases risk of transmission by 96%** May improve immune system by (partially) restoring CD4

count more towards normal May lower long-term complications associated w/

inflammation (though biomarkers of inflammation may never return to normal )

*Kitahata et al **Cohen et al

Diagnosis Screening: ELISA antibody (or other rapid

tests) Now recommended to be part of routine medical care

(yearly if high risk) Time to + : ~ 3 wks Newer assays may detect infection as early as 10 - 14

days; still, very early infection will not be detectable

Confirmation: Western Blot Time to + : ~4-5 weeks Any two: p24, gp41, gp120/160 -> positive One + band, or other + bands -> “indeterminate”

○ Either wait and repeat, or obtain quantitative assay for HIV by PCR = “viral load”

Some causes of False-Negative HIV Antibody Tests Acute HIV Infection

Advanced HIV Infection

Antiretroviral Therapy

Some causes of False-Positive HIV Antibody Tests Liver Disease Autoimmune Disorders CKD/ESRD Congenital bleeding disorders Recent Infection with dengue, malaria,

hepatitis B, leprosy Immunizations

Diagnosing Acute HIV: Window Period

Window Period = Time between infection and detectable HIV antibodiesWindow Period = Time between infection and detectable HIV antibodies

Courtesy: AETC

Diagnosing Acute HIV: Acute HIV

Acute HIV = patients may present with acute retroviral syndrome/illnessAcute HIV = patients may present with acute retroviral syndrome/illness

Acute HIV

Laboratory Diagnosis of Acute HIV

Acute HIV

• Positive HIV-1 RNA Assay• Negative HIV Antibody Test

• Positive HIV-1 RNA Assay• Negative HIV Antibody Test

Course of HIV Infection Chronic and progressive infection

Acute Retroviral Syndrome (Acute Infection)Flu-like symptoms Period of active viral replicationHIV Ab levels may be below the limit of detection

(negative ELISA), however the patient is HIGHLY CONTAGIOUS!

Acute Retroviral Syndrome

80 - 90% with acute HIV infection report symptoms consistent with acute retroviral syndrome“Mononucleosis-like” syndrome

Onset of symptoms typically 2-4w after exposure

Median duration of symptoms is 2 weeks

Fever (96%), adenopathy (74%), pharyngitis (70%), rash (70%), myalgia (59%), night sweats (50%), thrombocytopenia (45%), leukopenia (45%), diarrhea, headache

May also present as “aseptic/viral meningitis”

Acute Retroviral Syndrome Most acutely infected patients seek

medical attention

This syndrome may be missed in up to 75% of presenting patients

HIV antibody levels usually negative Check HIV RNA PCR

Course of HIV Infection Asymptomatic Phase (6 months - >10 years)

Host immune response controls viral replicationCD4 cell count gradually declines

Symptomatic PhaseHost immune response begins to waneCD4 cell count < 500 cells

○ Bacterial pneumonia, thrush, vaginal candidiasis, shingles, oral leukoplakia

CD4 cell count < 200 cells○ Opportunistic infections

Pneumocystis jirovecii pneumonia, CMV retinitis, Candida esophagitis, Toxoplasma encephalitis, Histoplasmosis, Cryptococcal meningitis, MAC, lymphoma, etc

CD4 Count & Risk of Clinical Disease

Clinical Findings in HIV Infection General

Generalized LAD

Thrombocytopenia (ITP)

Elevated total protein

DermatologicSeborrheic dermatitis

Zoster (shingles)

Superficial fungal infections

Warts

Eosinophilic folliculitis

MucocutaneousOropharyngeal candidiasisOral or genital herpesGingivitis/peridontitisOral Hairy Leukoplakia

RespiratoryRecurrent sinusitis

Community acquired pneumonia

Tuberculosis

Images courtesy of: AIDS Images Library www.aidsimages.ch

Images courtesy of: AIDS Images Library www.aidsimages.ch

Other clues to possible HIV Unusual presentation of a common illness

Pneumococcal pneumonia w/ bacteremia in a young person

Salmonella, shigella, campylobacter bacteremia

Presentation of an unusual illnessMore advanced/severe dx than expectedUnusual age for illness

TB, especially w/ unusual presentation Other STDs

Other clues to possible HIV Common complaints

Persistent fatigue, recurrent fevers, chills/night sweats, persistent diarrhea, weight loss

Routine lab abnormalitiesLeukopenia (low WBC)Lymphopenia (low lymphocytes)Thrombocytopenia (low platelets)Mild transaminitisElevated protein

Goals of HIV Therapy Maximal and durable suppression of viral load

– reduces the risk of disease progression Restoration and/or preservation of

immunologic function Improvement in quality of life Reduction in HIV-related morbidity and

mortality Prevent vertical transmission of HIV

Over 90% of HAART Regimens PI Based100

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1994 1995 1996 1997 1998 1999

HOPS: Mortality and Frequency HOPS: Mortality and Frequency of HAART Useof HAART Use

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Use of HAART

HA

AR

T, % patient-days

Palella. N Engl J Med 1998;338:853. Update: Palella. Personal Communicat ion, 1999.

When to Treat?* Symptomatic, or “AIDS-defining” illness CD4 at 500 or less Pregnancy HIV-associated nephropathy (to preserve kidney

function) Active hepatitis B co-infection (10% of U.S. HIV+) HIV RNA > 100,000 copies/mL High risk for secondary transmission Age > 50

*March 27, 2012 - NIH Guidelines for the use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents

When to Treat?*

When circumstances permit, offer to ALL individuals, regardless of CD4 count

*Thompson et al.

Predictors of Inadequate Adherence Regimen complexity & pill burden Poor clinician-patient relationship Active drug use or alcoholism Unstable housing Mental illness Lack of patient education Medication adverse effects Fear of medication adverse effects

Current Treatment Options 31 drugs currently

6 classes

Now 3 options for 1 pill once dailyAtripla ®Complera ®Stribild ®

Treatment

Benzodiazepines Antidepressants Anticonvulsants Rifampin OCPs

Statins Erectile dysfunction

agents Antifungals Acid reducers Nasal steroids

Common drug interactions with HAART to consider:

Health Maintenance

ImmunizationsInfluenza Annually (IM route)Pneumovax (entry into care and 5 years

later)Hepatitis A vaccine seriesHepatitis B vaccine seriesTdap/Td

Annual PPD/quantiferon

CDC. 2011 ACIP Guidelines

Health Maintenance

Immunizations to AVOID:Live vaccines to avoid:

○ Intranasal Influenza vaccine○ Smallpox○ OPV (no longer available in U.S.)○ BCG

May be ok if CD4 >200 and pt asymptomatic:○ MMR○ Varicella○ Zoster

CDC. 2011 ACIP Guidelines

Health MaintenancePatients trust their primary care providers. Your support of is

critical in keeping HIV patients healthy.

You can:• Manage co-morbid conditions (Diabetes, Cardiovascular Health)• Provide routine preventative care – (PAPs, Immunizations, Colonoscopy,

etc..)• Encourage routine dental and vision care• Provide support messages about reducing tobacco use, EtOH use and/or

other drug use• Drive home the importance of proper diet, exercise and rest• Promote “Safer Sex” prevention practices• Support adherence (meds and follow-up with ID)• Provide emotional support, recommend counseling if needed• Referral to local AIDS service organizations: Damien Center, Concord

Center, Step-Up, etc

You are the Experts!

Pre-Exposure Prophylaxis (PrEP) In PrEP, an HIV uninfected individual

takes antiretroviral medication (oral or topical) ahead of ongoing HIV exposures. By having these medications in the bloodstream/tissues, HIV may be unable to establish infection.

Pre-Exposure Prophylaxis (PrEP)

Select, high-risk circumstancesOnce daily Truvada ®

(FTC/TDF)75+% effective among those w/

detectable drug levelsControversial ExpensiveSee Truvada.com

○ Includes a 17-point check list, agreement form, training guide, etc

Pre-Exposure Prophylaxis (PrEP) Vaginal gel (Tenofovir)

Initial study (CAPRISA 004) showed it to be >50% effective when used regularly*

Also showed decreased genital herpes transmission

Less effective in other studiesMore studies ongoingNot yet ready for “Prime Time”

*Karim et al.

Post-Exposure Prophylaxis (PEP) Needle stick

Determine status of both source and patient at baseline if possible for:○ HIV, HBV, HCV, RPR

If source is HIV positive, ideally treatment should be started within 2 hours (72 hours max)○ Treatment continued for 28 days○ Choice of regimen complex, based on many

factors (typically 3 drugs)○ Post Exposure Prophylaxis (PEP) hotline:

1-888-448-4911 (24 hours a day)

Post-Exposure Prophylaxis (PEP) Needle stick (cont’d)

Risk of transmission is 1 in 300 (0.3%)○ Highly correlated with viral load

Close monitoring of patient while on PEP○ Weekly visits

Rechecking labs up until 6-12 months post exposure○ 6 weeks, 3 months, 6 months, 12 months

Post-Exposure Prophylaxis (PEP) Sexual encounter

May be unable to determine source patient status

Risk of transmission dependent on sexual act (0.01-0.5%)

If felt to be a high risk situation, may decide to start PEP○ Check baseline status on patient○ Start PEP within 72 hours (3 drug regimen)○ Monitor closely (weekly appts)

Continued f/u for 6-12 months after exposure

Summary

20-25% of HIV infected individuals do not know they are infected

Test often, treat early Effective treatment can:

Reduce risk of transmission to near zero!Better long term survival

HIV is evolving into a chronic disease, PCPs play a prominent role in overall health

References http://www.aidsetc.org http://www.aidsinfo.nih.gov http://www.unaids.org Spotlight on HIV/STD/Viral Hepatitis, Indiana Semi-Annual Report, June 2012:

http://www.in.gov/isdh/files/At_A_Glance-Dec.pdf Indiana IN Depth Profile. http://www.stats.indiana.edu/c2010/dp1/FactfinderINandUS.pdf Royce, et al. NEJM 336:1072-1078, 1997 CDC. Revised guidelines for HIV counseling, testing, and referral. MMWR 2006;55[No. RR-14]:1-

17 CDC. General Recommendations on Immunization. Recommendations of the Advisory Committee

on Immunization Practices (ACIP). MMWR January 28, 2011;60 (RR02); 1-60 Thompson et al. Antiretroviral Treatment of Adult HIV Infection. JAMA 2012;308: 387-402 Kitahata M et al, NEJM 2009; 360:1815-26 Cohen et al. Medical Progress: Acute HIV Infection. NEJM 2011;364:1943-54 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. March 27, 2012. Available at http://aidsinfo.nih.gov/Guidelines/HTML/1/adult-and-adolescent-arv-guidelines/0

Interim Guidance for Clinicians Considering the Use of Preexposure Prophylaxis for the Prevention of HIV Infection in Heterosexually Active Adults. MMWR. August 10, 2012 / 61(31);586-589

Q Abdool Karim et al. Science 2010;329:1168-1174 Grant R et al, N Engl J Med 2010;363:2587-99