HIV / AIDS&

Opportunistic Infections

www.hivma.org

Learning Objectives

• HIV – the basics• Epidemiology and screening• New diagnosis and prognosis• Antiretrovirals• Opportunistic infections – clinical cases

Human Retroviruses

HTLV-1 Adult T-cell Leukemia, HAM/TSP

HTLV-2 Possible association with HAM/TSP

HIV-1HIV-2 Extremely slow progression to AIDS

SIV (Chimpanzee)

HIV-1 Group M

HIV-1 Group N

HIV-1 Group O

SIV (Sooty Mangabey)

HIV-2

HIV Infection

White Blood Cells

Lymphocytes

T - Lymphocytes

CD4+ T – Lymphocytes(Helper)

CD4+ T – LymphocytesCCR5+ (Memory)

T-Cell Panel

• % CD3 63• % CD4 4• % CD8 55

• CD3, Abs 569• CD4, Abs 38• CD8, Abs 494

• Normal CD4% >30%• Normal CD4 >450

• AIDS– CD4 < 200– CD4% < 14%– OI– Malignancy

• Kaposi• NHL• Cervical cancer

Who Should Be Tested?• Routine HIV screening for all individuals ages

13-64 in all health-care settings.

• At least annual screening for high risk patients:– Injection drug use (sex partners)– Persons who exchange sex for money/drugs– MSM and sex partners of HIV infected persons– Heterosexuals (sex partner) with >1 sex partner since

last HIV test

• Repeat test before new sexual relationship.

HIV Test

• Routine HIV ELISA (HIV-1/O/2)- Positive Western Blot

• Rapid HIV ELISA- Negative Routine HIV ELISA- Positive Western Blot

• Window Period:- Routine HIV ELISA ~3 weeks- HIV Quantitative PCR ~7 days

Initial Evaluation of New HIV• HIV ELISA / WB• CD4 count• HIV Viral Load• CBC w/ diff• Comprehensive Chemistry• Lipid profile• Genotype resistance test• Hepatitis A, B, C serologies• RPR• Toxoplasma serology• Testing for GC/Chlamydia• TST or IGRA• HLA-B*5701• Urinalysis

ThrushGenital & peri-anal lesions

Pap smearAnal Pap smear (MSM)

LymphadenopathySkin:

KS lesionsfolliculitispsoriasis

Neurologic:peripheral neuropathyneurosyphilisHAND / neuropsych testing

Ophthalmologic (CD4 < 50)

Prognosis

http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf

3-yr probability of AIDS = AIDS defining illness or death, not CD4<200

Natural Course of HIV Infection

1

10

100

1,000

10,000

100,000

1,000,000

10,000,000

Plas

ma

HIV

RN

A

Plasma RNA Copies

CD4 Cells

4-8 Weeks Up to 12 Years 2-3 Years

CD

4 Cell C

ount

1,000

200

Intermediate Stage AIDS

Primary Infection

Sero-conversion

Opportunistic Infections – CD4 < 200

Pneumocystis pneumonia

Oral candidiasis

Opportunistic Infections – CD4 < 100

Toxoplasma encephalitis

Candida esophagitis

Opportunistic Infections – CD4 < 50

Disseminated cryptococcosis

Kaposi sarcoma

Opportunistic Infections – CD4 < 50

Molluscum contagiosum

CMV Retinitis

Many other…Disseminated Mycobacterium aviumProgressive multifocal leukoencephalopathyCryptosporidiosis & other protozoa

AIDS Defining IllnessesCandidiasis

EsophagealTracheal, bronchial

Cervical Cancer, invasiveCoccidioides – disseminatedChronic diarrhea (>1 month)

Cryptosporidia or Isospora

Cryptococcus – extrapulmonaryCMV

RetinitisOther (not liver, spleen, LN)

HSVChronic ulcer (>1 month)Pulmonary, esophageal

Histoplasma – disseminatedHIV encephalopathy

Kaposi’s sarcomaLymphoma (NHL)

Burkitt’sImmunoblasticPrimary CNS

MycobacteriumTB – anyOther – disseminated/extrapulmonary

PneumoniaPneumocystisRecurrent bacterial (within 1 yr)

PMLNT Salmonella septicemia, recurrentToxoplasmic encephalitisWasting syndrome - HIV

MMWR 1992; 41 (RR17)

When to Start HAART?

DHHS Guidelines 2011 (http://aidsinfo.nih.gov)

Antiretrovirals• Nucleoside RTI:Abacavir (Ziagen)Didanosine / ddI (Videx)Emtricitabine / FTC (Emtriva)Lamivudine / 3TC (Epivir)Stavudine / d4T (Zerit)Tenofovir (Viread)Zidovudine / AZT

(Retrovir)

• Non-Nucleoside RTI:Efavirenz (Sustiva)Nevirapine (Viramune)Etravirine (Intelence)Rilpivirine (Edurant)

• Entry/Fusion Inhibitor:Enfuvirtide / T20 (Fuzeon)Maraviroc (Selzentry)

• Protease Inhibitors:Atazanavir (Reyataz)Darunavir (Prezista)Fosamprenavir

(Lexiva)Inidinavir (Crixivan)Lopinavir/Ritonavir (Kaletra)Nelfinavir (Viracept)Ritonavir (Norvir)Tipranavir (Aptivus)

• Integrase Inhibitor:Raltegravir (Isentress)

• Combinations:Atripla (Tenofovir + FTC + Sustiva)Combivir (AZT + 3TC)Epzicom (Abacavir + 3TC)Trizivir (AZT + Abacavir + 3TC)Truvada (Tenofovir + FTC)

HIV Replicative Cycle

ART Basics• General concepts:

– Need 3 active agents: (2 NRTI) + (NNRTI or PI or Integrase inhibitor)– Treatment is life-long. Discontinuing ART results in viral rebound.

• Goal of therapy – HIV VL < 50 = “undetectable viral load”

• ART Resistance– Baseline resistance– Suboptimal medication adherence (90-95% compliance)– Suboptimal pharmacokinetics– Suboptimal potency of the regimen– Resistant strains are “archived” = permanent

• Common initial regimens:Atripla (Tenofovir + FTC + Sustiva) - QDTruvada + Reyataz + Norvir - QDTruvada + Isentress - BIDCombivir + Kaletra - BID

Can We Eradicate Infection?

Nature Medicine 2003; 9:853-860

Common adverse reactions• Rash

– Any antiretroviral– Mild to severe (SJS)– First 2 months

• Nausea/Vomiting– Any antiretroviral– R/O hepatitis– Symptomatic management

• Diarrhea– Any, but usually PIs– Symptomatic management

• Renal failure– Tenofovir (Truvada/Atripla)– First several months

• CNS/Psychiatric– Efavirenz (Sustiva/Atripla)– First several weeks

• Drug-Drug Interaction– New prescriptions

• Fluticasone, Statins• PPIs

– OTC• St. John’s Wort

When Should You Stop HAART?

• Patient clearly non-compliant (active drug abuse) – not “stopping” and actually “starting”

• Severe drug reaction:Abacavir hypersensitivity reaction – fever, rash, GI, and/or pulmonary

symptoms within 6 weeks of initiation, association with HLA-B*5701.Lactic acidosis (ddI/d4T>AZT) – malaise, myalgias, non-specific

symptoms or critically ill, pancreatitis/hepatitis, elevated serum lactate and acidemia.

NNRTI hypersensitivity – occurs within 6 weeks of initiation, hepatitis (fulminant hepatic failure) and/or rash (Stevens-Johnson). Nevirapine hepatotoxicity risk factors: pregnancy, HBV/HCV, CD4 > 250 [F] or CD4 > 400 [M].

HIV-Associated Dyslipidemia

Fat Accumulation HIV Lipohypertrophy Increase abdominal fat Dorsocervical fat pad

Metabolic Changes Increased Triglycerides Increased LDL Decreased HDL Insulin resistance

Case #1

• 31 M with history of HIV presents with fevers and progressive DOE x 3 weeks.

• He reports he was diagnosed with HIV about 10 years ago when he developed shingles. He never followed-up and has never been on HAART.

• He does not know his last CD4 count or viral load.

Case #1

ROS:20 lbs weight loss x1 yearNight sweats for past monthDiarrhea

SH:Acquired by MSMBorn & raised in OhioMoved to AZ 2 yrs agoVisits homeless shelters

Physical Exam:101.80F 94 110/60 16Pulse Ox 92%

GEN – appears comfortableOP – thrushLUNGS – diffuse cracklesABD – soft, non-tenderSKIN – no lesionsMS – alert & oriented

CXR

Laboratory Results• CD3 87• CD4 9• CD8 75• CD3, Abs 610• CD4, Abs 64• CD8, Abs 530• HIV VL 500K

Differential Diagnosis?

Differential DiagnosisPneumonia in HIV

• CAP – Pneumococcus, Influenza• Pneumocystis• TB• Coccidioides• Histoplasma• Cryptococcus

Diagnostic Tests• Nasal Influenza swab - negative• Blood cultures - negative• Urine S.pneumonia antigen - negative• Sputum culture - normal flora• Sputum AFB smear - negative x3• Sputum fungal smear - negative• Induced sputum PCP DFA - negative• Serum Cryptococcal antigen - negative• Coccidioides ELISA - negative

Pneumocystis jiroveci• Subtle – symptoms for weeks to months• 90% with CD4 < 200 or CD4% < 15%• CXR findings variable – possibly negative• Negative CXR – role of HRCT• Diagnosis:

– Induced Sputum DFA 50-90%– BAL DFA 90-99%– Transbronchial Bx 95+%

Therapy

• PaO2 < 70 mmHg

• A-a > 35 mmHg

• Corticosteroids• IV TMP/SMX• IV Pentamidine

• PO TMP/SMX• Clinda + Primaquine• TMP/Dapsone• Atovaquone

- Clinical deterioration common within 3-5d of initiation of therapy, particularly in those not receiving corticosteroids.

- Treatment failure if no improvement or worsening after at least 4-8d of therapy.

ProphylaxisTMP/SMX, Dapsone, Atovaquone, Aero

PentamidineStop prophylaxis when CD4 > 200 x 3 months

20 Prophylaxis:- Requires QD TMP/SMX, not QMWF

10 Prophylaxis:- CD4 < 200, or CD4% < 14%- History of thrush- AIDS defining illness

Pneumonia in HIV• S.pneumoniae remains most common cause. Other

organisms = H.influenza, S.aureus, P.aeruginosa.• Give Pneumovax and revaccinate when CD4 > 200.

• Pulmonary TB in HIV patients with CD4 > 350 similar to that in non-HIV infected individuals.

• Pulmonary TB in AIDS patients – typically no cavitation, appears more like consolidation or diffuse infiltrates.

• TB in HIV patients – at higher risk of extrapulmonary disease at all CD4 counts.

• AIDS patients and HIV patients with unknown CD4 count presenting with pneumonia Respiratory Isolation.

Coccidioides• Common cause of pneumonia in Arizona

• CD4 < 250, past history NOT a risk factor• Radiographs – diffuse or focal infiltrates• Serologic tests ~60% sensitivity• Diagnosis – fungal culture, smear ~40%• Disseminated disease frequent:

lymph nodes, meningitis, skin

Case #2

• 42 M with history of IVDA presents with complaints of intermittent fever, HA, and increasing lethargy over the past 4 weeks.

• He is subsequently found to be HIV + with a CD4 count of 23.

• He reports having been in and out of jail on several occasions.

• Poor historian, appears confused.

MRI Brain

Differential Diagnosis?

Differential DiagnosisCNS Lesions in HIV

• Toxoplasma Encephalitis• Primary CNS Lymphoma• Bacterial brain abscess • Progressive Multifocal Leukoencephalopathy • TB• Cryptococcus• CMV Encephalitis• Chagas disease

Diagnostic Tests

• Blood cultures - negative• Serum Cryptococcal antigen - negative• Toxoplasma IgG positive, IgM negative• LP: 8 WBC (90%L), 64 G, 60 P

– Toxoplasma DNA PCR negative– CMV and JC virus PCRs negative– TB PCR negative– Cryptococcal antigen negative

Toxoplasma Encephalitis• 80% have CD4 < 100• 95+% Toxoplasma IgG+• ~30% single lesion• CSF PCR sensitivity 50%• Definitive dx = brain bx

• Therapy – 6 wksPyrimethamine/SulfadiazinePyrimethamine/Clindamycin

• 10 Prophylaxis (CD4 < 100)DS TMP/SMX QDPyrimethamine/Dapsone

Adapted from http://www.cdc.gov

Cryptococcal Meningitis• Majority of cases occur in patients with CD4 < 50.• Classic meningeal symptoms/signs (neck stiffness &

photophobia) infrequent.• Disseminated disease common: pulmonary, blood, skin.

• Elevated opening pressure > 75% (> 20cm H2O).

• Cryptococcal antigen 90+% sensitive (serum & CSF).

• Treatment:Ampho B +/- Flucytosine x 2wks FluconazoleRepeated LP for symptomatic elevated ICP

Case #3

• 29M diagnosed with AIDS ~2 months ago (Thrush), started on HAART 6 weeks ago.

• Presents with acute onset of fever, cough, pleuritic chest pain, and dyspnea.

• He looks well despite Temp 102.60F. Exam only notable for L sided bronchial breath sounds.

• CD4 count 29 146.

CXR

CT Chest

Laboratory Studies• Blood cultures• Fungal BC • Mycobacterial BC• Serum Cryptococcal Ag• Urine Histoplasma Ag• RPR

• LDH 188• WBC 12.9 (88%N)

• BAL Bacterial Cx -• BAL Fungal Cx -• BAL Mycobacterial Cx -• BAL PCP DFA -• BAL Viral Cx -• BAL Cytology: WBC/RBC, benign bronchial cells

• Transbronchial Bx:Bronchial mucosa - crush artifact

Diagnosis?

• Lymph node biopsy reveals caseating granulomata with rare acid fast organisms

• LN Mycobacterial culture - MAC

Disseminated MAC• Occurs in advanced AIDS, CD4 < 50.• Vast majority – fevers, weight loss, night sweats, severe

anemia (Hct < 25%). • Organ involvement: spleen, LN, liver, intestines, and

bone marrow. Lung involvement rare (< 10%).• Diagnosis:

– Blood culture – single 90-95%, two 99%.– May take 2-6 weeks to grow.

• Treatment: Clarithromycin + Ethambutol +/- Rifabutin• 10 Prophylaxis (CD4 < 50): Azithromycin 1200mg Qwk

Immune Reconstitution Inflammatory Syndrome

• Paradoxical worsening of clinical or laboratory parameters despite rising CD4 counts and declining viral loads.

• Inflammatory reaction to a subclinical infection.

• Estimated to occur in 10-25% of those initiating ART (weeks to months).

CID 2004; 38:1159-66

Summary• HIV

– HIV-1/0/2 strains. CD4 T-cell, CCR5 > CXCR4. LN damage.• Epidemiology and screening

– About 50,000 new cases / yr. MSM > heterosexual > IVDA.– HIV EIA HIV WB. Check VL for acute retroviral syndrome.

• New diagnosis and prognosis– Screen for other STIs. Baseline genotype resistance testing.

• Antiretrovirals– Indications: CD4 < 350, AIDS, HIVAN, HBV trmt, pregnancy– Need 3 active agents, strict compliance, lifelong treatment

• Opportunistic infections– Primary Prophylaxis: PJP, Toxoplasma, MAC– Cryptococcus, CMV, Cryptosporidia– IRIS – unmasking versus paradoxical