Core Curriculum Review:

HIV

Jason M . Leider, M.D., Ph.D.NBHN Associate Medical Director of HIV

ServicesAssociate Professor of Internal Medicine,

AECOM

Occupational Bloodborne Exposuresfocus on HIV

• HIV, HBV, HCV are the primary agents– Risk of infection:

• HBV = 27-47%• HCV = 1.9% (range 0%-22%)• HIV = 0.32%

• HIV PEP: based on in vitro evidence, maternal-fetal transmission studies, retrospective case-control studies of occup HIV infxn & recent clinical experience

• PEP is based on type of exposure (hollow-bore needles), depth of penetration, type of host

HIV pathogenesis

• High replication rate (even during asymptomatic early phase)

• High mutation rate: abilty to generate mutiple quasi-species

Natural history of HIV-1 infection over time

CD4 = 200

7-10 yrs

Acute Retroviral Syndrome

Asymptomatic

Persistent Generalized LNopathy

Fever

PM sweats

Diarrhea

Wt loss

Clinical Latency Pre-AIDS conditions

A global view of HIV infection33 million people [30–36 million] living with HIV, 2007

2.2

USA HIV facts

• PLWHA = 1.1 million

• 25% PLWHA are unaware of their HIV dx

• AIDS (but not HIV infxn) is reportable in all 50 states

• 2004: 73% new cases in M (globally, M=F)

• 56,300 new HIV infxns occurred in 2006

• AA & Hisp = 70% new cases

Sequence of reactivity of diagnostic tests for HIV in early infection

Rapid HIV tests

• Results in < 20 min

• Oral or blood tests

• Sensitivity & specificity > 99% (similar to conventional HIV enzyme immunosorbent tests

Four FDA-approved Rapid HIV Tests

Sensitivity

(95% C.I.)

Specificity

(95% C.I.)

OraQuick Advance

- whole blood

- oral fluid

- plasma

99.6 (98.5 - 99.9)

99.3 (98.4 - 99.7)

99.6 (98.5 - 99.9)

100 (99.7-100)

99.8 (99.6 – 99.9)

99.9 (99.6 – 99.9)

Uni-Gold Recombigen

- whole blood

- serum/plasma

100 (99.5 – 100)

100 (99.5 – 100)

99.7 (99.0 – 100)

99.8 (99.3 – 100)

US Public Health Service algorithm for serologic diagnosis of HIV-1/HIV-2 infection. 

Risk Assessment Guidelines for HIV+ Patients

• Screen for risk behaviors: IDU, anal intercourse

• Establish past/present h/o psychiatric dz, substance abuse

• Open-ended questions for sx’s of STDs

• Sx’s prompt STD testing

Clinical Evaluation of Patients with Newly Dx’d HIV

Evaluation Frequency

Complete Hx & PE Baseline, as determined clinically (3-4 months)

HIV ab test Confirm on initial visit

CD4 & VL Baseline & q 3-4 months unless changing ARV’s

CBC Baseline & as clinically indicated

Comp metab panel (lytes, gluc, renal, LFTs)

Baseline & as clinically indicated

Fasting lipid profile Baseline & as clinically indicated

Annual assessment of body fat

For pts on HAART

Hepatitis screening Baseline & as clinically indicated

Clinical Evaluation of Patients with Newly Dx’d HIV

Evaluation Frequency

Tuberculin skin test & tb exposure

Baseline & annually

Pap smear Baseline, 6 months & annually if normal

Syphilis, chlamydia, GC, trich

See next slide

Toxoplasmosis Baseline

CMV* Baseline (optional)

CXR Baseline (optional)

Initial, subsequent Visits for STDs in HIV+ Patients

INITIAL• F: screen for syphilis,

trichomonas, GC, chlamydia

• M: screen for syphilis, consider sceening for GC, chlamydia (depending on local STD prevalence)

SUBSEQUENT• Repeat screening at

least annually (or as often as 3-6 months)

• F of childbearing potential: routinely test for pregnancy if indicated, counsel on contraception, family planning

Vaccinations of Patients with Newly Dx’d HIV

Vaccinations Frequency

Polyvalent pneumococcal vaccine (esp if CD4>200)

Baseline and at 5 yrs

Influenza Annually during flu season

HBV (for pts at risk) Three-immuniz primary series

HAV (for pts at risk, chronic HBV, HCV, liver dz)

Two-immuniz primary series

According to the US CDC definition, you have AIDS if you are infected with HIV and present with one of the following:

• A CD4+ < 200 cells/µl or CD4+% < 14%• Or one of the following defining illnesses:• Candidiasis of bronchi, trachea, or lungs • Candidiasis esophageal • Cervical cancer (invasive) • Coccidioidomycosis, disseminated or extrapulmonary • Cryptococcosis, extrapulmonary • Cryptosporidiosis, chronic intestinal for longer than 1 month • Cytomegalovirus disease (other than liver, spleen or lymph nodes • Encephalopathy (HIV-related) • Herpes simplex: chronic ulcer(s) (for more than 1 month); or bronchitis, pneumonitis, or

esophagitis • Histoplasmosis, disseminated or extrapulmonary • Isosporiasis, chronic intestinal (for more than 1 month) • Kaposi's sarcoma • Lymphoma Burkitt's, immunoblastic or primary brain • Mycobacterium avium complex • Mycobacterium, other species, disseminated or extrapulmonary • Pneumocystis jiroveci pneumonia (formerly Pneumocystis carinii) • Pneumonia (recurrent) • Progressive multifocal leukoencephalopathy • Salmonella septicemia (recurrent) • Toxoplasmosis of the brain • Tuberculosis • Wasting syndrome due to HIV

Typical relation of clinical manifestations to the CD4+ T-lymphocyte count in HIV-

infected patients

Complications in HAART Era

• Squamous cell cancer of cervix due to HPV

• Chronic HBV• Chronic HCV• Squamous cell cancer of anus due to HPV

(high grade abnlties need f/u w/ hi resolution anoscopy, bx)-> tx is topical imiquimod, podophylotoxin; laser, surgical cold scalpel excision

Follow-up Recommendations for Abnormal Cervical Cytology

Pap Smear ResultRecommendation

ASCUS (with severe inflammation) Evaluate for infection; if found, treat and recheck Pap smear in 2–3 months

ASCUS Follow-up Pap smear every 4–6 months for 2 years (until three consecutive Pap smears are negative)

If another ASCUS, consider colposcopy

ASCUS (neoplastic process suspected) Follow-up Pap smear every 4–6 months; or colposcopy and biopsy if LSIL persists; or immediate colposcopy

LSIL Follow-up Pap smear every 4–6 months; or colposcopy and biopsy if LSIL persists; or immediate colposcopy

HSIL (cervical intraepithelial neoplasia 2 or 3, carcinoma in situ)

Colposcopy and biopsy of abnormal area

or

Squamous cell carcinoma

From Kaplan JE, Masur H, Holmes KK; USPHS; Infectious Disease Society of America. Guidelines for preventing opportunistic infections among HIV-infected persons – 2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. MMWR Recomm Rep 51 (RR-8):1–52, 2002.

HIV+/HBV+ Co-infected Patients

• 10% of HIV+ pts also have HBV

• HIV/HBV pts have incr’d ESLD & death due to HBV than HBV only pts

• HBSAg+ pts: check HBeAg, HBeAb

• Check ast, alt, bili, alb, PT, HBV DNA

• HBV DNA helps monitor response to tx, not prognosis

• Liver bx is best to determine prognosis

Tx of HIV+/HBV+ Patients• Candidates: active liver inflamm, incr’d alt/ast, HBeAg+, HBV DNA >

105 c/mL

• PEG IFN

• Lamivudine (3TC) leads to HBeAg seroconv in 22% of tx’d pts, but

easy to develop resistance

• Tenofovir + 3TC or Adefovir + 3TC are better than 3TC monotx

• Baraclude (Entecavir) Not Recommended for HIV/HBV Co-Infected

Patients Who Are Not Also Receiving HAART Due to Potential for

Development of HIV Resistance

HIV+/HCV+ Co-infected Patients

• 30-40% of HIV+ pts also have HCV• HIV/HBV pts have incr’d ESLD & death

due to HCV than HCV only pts• 70% HCV+ pts are geno 1• Response rate to tx best for geno 2,3;

worse for geno 1, 4• HCV RNA helps for response to tx, not

prognosis• Liver bx is best to determine prognosis

Tx of HIV+/HCV+ Patients

• PEG IFN/RBV

• HCV only, geno 1: Cure rates = 30-40%

• HCV only, geno 2,3: Cure rates = 70-80%

• APRICOT study: SVR = 40% (62% for geno 2,3; 29%

geno 1)

• For geno 1, HCV VL > 800,000 c/mL: SVR = 19%

Progression of HIV disease to AIDS or death by initial CD4 count 

HAART strategy in 1996

• Hit early, hit hard: CD4<500, VL > 10,000 c/mL

• Changed due to:– toxicities assoc w/ HAART, – failure to demonstrate clinical benefit,– concerns about resistance

• Cost of HAART = $10k to $15k/yr in USA

Likelihood of progression to AIDS or death in the pretreatment (A) and treatment (B)

era. 

Indications for Initiation of Therapy: Chronic Infection

Clinical Category

CD4+ T Cell Count

Plasma HIV RNA

Recommendation

Symptomatic (AIDS, severe symptoms)

Any value Any value Treat

Asymptomatic, AIDS

<200 cells/µL

Any value Treat

Asymptomatic >200 cells/µL but

<350 cells/µL

Any value Treatment should be offered, with consideration of pros and cons

Indications for Initiation of Therapy: Chronic Infection

Clinical Category

CD4+ T Cell Count

Plasma HIV RNA

Recommendation

Asymptomatic >350 cells/µL

≥100,000 copies/mL

Most clinicians recommend deferring therapy; some will treat

Asymptomatic >350 cells/µL

<100,000 copies/mL

Defer therapy

Current Antiretroviral Medications

NRTI• Abacavir ABC• Didanosine DDI• Emtricitabine FTC• Lamivudine 3TC• Stavudine D4T• Zidovudine ZDV

• Tenofovir TDF

NNRTI• Delavirdine DLV• Efavirenz EFV• Nevirapine NVP• Etravirine ETV

Integrase Inhibitor• Raltegravir RAL

PI• Amprenavir APV• Atazanavir ATV• Darunavir DRV • Fosamprenavir FPV• Indinavir IDV• Lopinavir LPV• Nelfinavir NFV• Ritonavir RTV• Saquinavir SQV

– hard gel HGC– tablet INV

• Tipranavir TPV

Fusion Inhibitor/Entry Inhibitor• Enfuvirtide T-20• Maraviroc MVC

Initial Treatment: Preferred Components

*Avoid in pregnant women and women with significant pregnancy potential.**Emtricitabine can be used in place of lamivudine and vice versa.

•Efavirenz*

OR

•Atazanavir + ritonavir

•Fosamprenavir + ritonavir (BID)

•Lopinavir/ritonavir (BID)

NNRTI Option

PI Options

Tenofovir + emtricitabine**

Zidovudine + lamivudine**

+

NRTI Options

Use of HIV RNA & CD4+ T Cell Levels to Guide Therapy

Decisions• Syndrome consistent with acute HIV infection• Initial evaluation of new HIV diagnosis• Every 3-4 months in the untreated patient• Immediately prior to initiating therapy• 2-8 weeks after initiating therapy• Every 3-4 months in patients on therapy• As clinically indicated

Testing for Drug Resistance• Adjunct to guide antiretroviral therapy

• Combine with obtaining a drug history and maximizing drug adherence

• Research supports use in certain settings

• Genotyping vs. phenotyping

• Limitations of resistance testing and specific indications

The Use of Drug Resistance Testing

RECOMMENDED COMMENT

Acute HIV infection, if treatment is to be started

•To determine if resistant virus was transmitted; guide treatment decisions.

•Consider resistance testing if treatment is deferred.

Chronic HIV infection before starting ART

•Transmitted drug-resistant virus is common in some areas; is more likely to be detected earlier in the course of HIV infection; consider resistance testing earlier in the course of infection

Pregnancy •Recommended before initiation of ART or prophylaxis, or if incomplete viral suppression on ART

Virologic failure during ART •To assist in selecting active drugs for a new regimen.

Suboptimal suppression of VL after starting ART

•To guide treatment decisions.

The Use of Drug Resistance Testing

NOT USUALLY RECOMMENDED

COMMENT

After discontinuation of drugs • Resistance mutations may become minor species in the absence of selective drug pressure.

Plasma VL <1000 HIV RNA copies/mL

• Resistance assays unreliable if HIV RNA is low.

Complications of HAART

• Metabolic– Insulin resistance

• Protease inhibitors

– Hyperlipidemia (high chol/LDL/trig)• Assoc w/ most PI’s except unboosted ATV

– Body fat redistribution (lipodystrophy)• Lipoatrophy: loss of facial fat/limbs

– Esp assoc with stavudine

• Low long-term risk for CV dz?

Prognosis with HAART tx

• HAART can:– Suppress viral replication– Permit adquate immune system recovery

• Lasting concerns: – long-term adherence– SE mgmt (esp CV events)

• HAART is not a cure (cannot eliminate long-lived T-cell population)

Four FDA-approved Rapid HIV Tests

Sensitivity

(95% C.I.)

Specificity

(95% C.I.)

Reveal G2

- serum

- plasma

99.8 (99.2 – 100)

99.8 (99.0 – 100)

99.1 (98.8 – 99.4)

98.6 (98.4 – 98.8)

Multispot

- serum/plasma

- HIV-2

100 (99.9 – 100)

100 (99.7 – 100)

99.9 (99.8 – 100)

OraQuick Advance HIV-1/2

• CLIA-waived for finger stick, whole blood, oral fluid; moderate complexity with plasma

• Store at room temperature

• Screens for HIV-1 and 2

• Results in 20 minutes

Obtain finger stick specimen…

Insert loop into vial and stir

Collect oral fluid specimens by swabbing gums with test device.

Gloves optional; waste not biohazardous

Insert device; test develops in 20 minutes

PositiveNegative

Reactive Control

Positive HIV-1/2

Read results in 20 – 40 minutes

Uni-Gold Recombigen

• CLIA-waived for finger stick, whole blood; moderate complexity with serum, plasma

• Store at room temperature

• Screens for HIV-1

• Results in 10 minutes

Add 1 drop specimen to well

Add 4 drops of wash solution

Read results in 10 -12

minutes

Positive Negative

Reveal G2

• CLIA moderate complexity with serum, plasma

• Reconstitute and refrigerate reagents

• Screens for HIV-1

• Perform test in 5 minutes

Centrifuge to obtain serum or plasma

Add buffer to reconstitute conjugate. (Sufficient for 15 tests;

Refrigerate to store)

Add 3 drops buffer to moisten membrane

Add one drop of serum or plasma, followed by 3 drops of

buffer.

Add 4 drops of Colorimetric Detection Agent

Add 3 drops of buffer to wash

Read results immediately

Reactive

Negative

Multispot HIV-1/HIV-2

• CLIA moderate complexity with serum, plasma

• Refrigerate reagents

• Distinguishes HIV-1 from HIV-2

• Perform test in 15 minutes

Dilution of plasma or serum

Remove and discard pre-filter

Several timed reagent & wash steps

Negative HIV-1 & HIV-2 Positive

Peptide HIV-2

Recombinant HIV-1

Peptide HIV-1

Reactive Control