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HIV INFECTION

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HIV INFECTION

HIV : Chronic and Fatal Infection if not treated.: Progressive Immunodeficiency: Long clinical latency period: O.Is.: Hallmark: infection and viral replication

within T.Lymphocytes Expressing CD4 HG (helper-inducer lymphocyte)

: CD4 Critical Component of Normal Cell-mediated Immunity

: Risks of Ois. Increased as Quolitative defects in CD4 and its progressive depletion increase.

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: Ois • pcp [p. carinii/jiroveci

• kapesi sarcoma

• lymphoma/I CNS lymphoma/.

: HIV Disrupt: Monocytes, tissue macrophages and B-Lymphocytes (Humoral Immunity), thus predisposition to infectious with Encapsulated bacteria.

: HIV Meningitis:

peripheral neuropathy

dementia

: 40 Million people worldwide infected

CD4, attacking CNS

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: If not treated: Average time from:

Acquision to Aids defining Ois = 10 yrs

: Survival 1- 2 years

: Patients however differs regarding time interval:

Ac. HIV to Death 1 – 2 yrs.

Other patients – 20 yrs.

: ART and OIs prophylaxis markedly improved prognosis

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APPROACH TO HIV INFECTION

HIV INFECTION

DX and Evaluation

HX, exam, labsHIV Ab. TestingCD4 CountPlasma HIV RNA(viral load)

Treatment

ART OIs

InitiationOptimal treatmentDrug Failure

ProphylaxisTreatment

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STAGES OF HIV INFECTIONA. Viral TX

sexual intercourseblood/blood productperinatal TX

• Risk of TX by single encounter with HIV 1 in 150Needle sharing 1 in 300Occupational percutaneous expesure 1 in 300-1000

• Mode of TX does not affect HIV natural HX.

B. Acute (primary) HIV infection• 1-4 wks following TX• Viral replication and CD4 decline• Infect. Mono-like SX (often overlooked)• Confimation by high viral load and absent HIV-Abs.

C. Sero ConversionHIV-Abs 4 wks (usu) and invariably 6 mon (few exception)

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D. Asymptomatic HIV infection

8 – 10 yrs

gradual decline in CD4 counts

relatively stable viral load (HIV RNA level)

E. Symptomatic HIV infection (previously called ARC)

thrush/candidiasis

cervical dysplasia/Ca. in situ

HZ. Recurrent, multiple dermatomes

O H L

periph. Neuropathy

ch. Diarrhea

Constitutional SX.

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F. AIDS: CD4 < 200 (CD4% < 14 %)AIDS related Ois

pcpcryptococcal meningitisEsoph. CandidiasisRecur. Bact. PneumoniaCNS TOXOTB, Reur. Salmonella – BSILymphoma (N.H.)Ch. Intestinal cryptospondosisisosporiasiskaposi sarcomaMAC, PML, HIV wasting

G. Advanced HIV DiseaseCD4 < SOMost Aids-related deathsCommon Late Stage OisCMV Retinitis, ColitisMAC

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ACUTE/PRIMARY HIV INFECTIONA. • 1 – 4 wks post TX (6d – 6w).

• SX in 50 – 90% but mistaken for flu, I.M., others.• Severe SX may correlate to rapid HIV progression• Most patient recover (even without treatment) ?-----------Develop. of partially effective immune Response and Depletion of Susceptible CD4.

B. DDX: EBV CMV, viral hepatitis, enteroviral inf. 2° S, toxo, HSU to E. Multiforme drug reaction, Behcet’s dis. Acute Lupus.

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C. SX/SX: Hematogenous to lymphoreticular/neurologic• Fever 97%• Pharyngitis 73% non-exudative• Rash 77% Maculopap. face/trunk• Arthralgia/riyalgia 58%• Neuro. SX 12% Headache, Neuropathy Bell’s palsy,

mening. Encephalitis• Oral/genital ulceration, trush, diarrhea, vomiting, wt.

loss.D. Lab. Findings• CBC: Lymphopenia followed by lymphocytosis

(common) atypicol lympho < in EBV (>20-30%) Thrombocytopenia

• High Transaminases (not all patients)• Depressed CD4• HIV - ABS

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E. AC. HIV infection Confirmation

1. HIV – Abs (informed consent-----??)

2. Viral Load (HIV RNA DCR)/RT-PCR

confirms acute HIV prior to serconversion

- most patient > 100,000 copies/ml

- if < 20,000, suspect false positive

- any positive test, Repeat HIV RNA and HIV. Ab.

- p24 Hg Caube diagnostic But less sensitive than HIV RNA PCR.

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3. Other tests/serologies if HIV RNA negative- throat culture- EBV- CMV- HHV-6- viral hepatitis

F. Management of Ac. HIV infection1. Initiate ART2. HIV Resistance genotype3. Rationale for treating ac. HIV infection

• Hastens SX. Resolution• Reduces viral TX. Other organs involvement• preserve CD4 but viral eradicaton unlikely

1gm/ 1gG

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APPROACH TO HIV TESTINGSuspected HIV infection

Acute Infection

HIV – Ab &HIV RNA

AB (-)RNA (-)

AB (+)RNA (+)

AB (-)RNA (+)

AB (+)RNA (-)

NO HIVinfection

Ch. HIVor lateAc. HIV

AcuteHIV

RepeatTest

Chronic infection

HIV AB

(+) intermediate (-)

HIV Infection HIV RNA No HIVInfection,no furthertestive(-)

HIV Extrem. Unlikely repeatHIV AB at 3 mon. to ensureno sero conversion

Acute HIV seroceuversion in prog.Repeat HIV RNA and followup HIVAB at 1, 3, 6 mon. or untilseroconversion documented

(+)

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APPROACH TO HIV TESTINGA. HIV-AB

Most patients produce AB 6-8 wk of exposure. Half patients positive AB 3-4 wk nearly 100% detectable AB 6 mon.

1. Elisa: usu screeningpositive patients must be confirmed by western blot/other specific tests.

2. Western BlotCDS criteria• positive: At least 2 of following bands: - p24, p41, gp 160/120.• Negative no bands• Intermediate: Any HIV band, but doesnot meet positivity criteria.

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3. Test performance

Elisa: Standard screening with western blot confirmation.

a. Elisa Negative: W.B. not required 99.7% sensitive and 98.5% specific obtain HIV RNA if ac. HIV suspected.

b. Elisa positive: confirm with W.B. having both Elisa and W.B. false positive extremely low < 1/140,000 absent p31 band clue to false positive W.B.

c. Unexpected Elisa/W.B.

repeat test to exclude clerical/computer error.

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d. Intermediate W.B.• Common clinical problem affecting 4-20% reactive Elisa.• Usu. due to single p24 band or weak other hands.• Causes include:

Seroconversion in progressAdvanced HIV disease with loss of AB responseCross-reacting AB from pregnancy, blood TX,

organ TX, auto AB from collagen vase dis infection with HIV2, influenza vacc. Or recipient of HIV vaccine.

• In low-risk patients intermediate result: Almost never represents true HUV infection options include:

Repeating test 2-3 with 6 mon., if still intermediate: Reassure, or do HIV RNA high: seroconversion in progress.

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B. Quantitative plasma HIV RNA [HIV viral load Assay]

1. Measures amount of HIV RNA in plasma.

High sensitivity of assay allows virus detection in most patients not on ART. Used to diagnose acute HIV infection and more commonly to monitor response to ART.

2. Uses of HIV RNA Assay

a. Confirms acute HIV infection diagnosis.

b. Helpful in initial evaluation of HIV infection establishes baseline HIV RNA and helps to initiate/defer therapy (together with CD4 count) [HIV RNA correlate with CD4 decline rate]

c. Monitor response to ART

Rapidly decline 2-4 wk after starting or changing effective ART, with slower decline thereafter.

Patient with greatest HIV RNA response have best clinical outcome.

No change in HIV RNA suggest ART ineffective.

d. Estimates Risk for Ois.

In patients similar CD4: Risk of OI higher with higher HIV RNA.

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3. Assays and interpretation:

a. 3 main assays widely used

• RT-PCR amplicor (roche)

• RT-PCR ultra sensitive 1.5 (roche)

• b DNA versant 3.0 (Bayer).

b. Correlation between HIV RNA and CD4. [Inverse correlation]

• For any given CD4: higher HIV RNA correlates with more rapid CD4 decline

• In response to ART, HIV RNA changes precede CD4 changes.

4. Indication for HIV RNA Testing

• Use done with CD4 counts

• Indicated to AX acute HIV infection

• Initial evaluation of newly diagnosed HIV

• Recommended 2-8 wk after ART initiation and every 3-4 mon. in all HIV patients.

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5. When to avoid RNA testinga. During acute illnesses and vaccination in

patient with acute infection RNA rises > 5-folds, and return to base line 1-2 mon.

b. When results of test would not influence theraphy: patients with advanced with no ART or cannot tolerate theraphy.

c. To diagnose HIV infection except if acute/primary disease suspected during AB window [first 3-6 wk after seroconversion].

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INITIAL ASSESSMENT OF HIV-INFECTED PATIENTS

A. Clinical evaluation: HX/EX. HW patients have more severe, frequent, and longer duration of disease.

1. Dermatology: HS, HZ, molluscum contogiosum, staph abscesses, nail tenia, k. sarcoma (HHS8)

2. Oropharyngeal: Candidasis, OHL, k. sarcoma.3. Constitutional SX4. Lymphatic: gen., persistant adenopathy.5. Others: TB (EPT), NHL, neurolgic, GBS.

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TESTRATIONALE

HIV Serology Elisa/W.B.

Patients unable to document prior test “patients with low risk” with test (detect computer/clerical error rept. Serology now less imp. (HIV RNA confirmation)

CBC with Diff. and PLTS.Detects cytopenias, calculation of CD4.

ChemistryRenal dysfunction, electrolytes, LFT to detect HCV, HIV nephropathy [assoc. infections]

CD4 CountDetermines need for ART and OIs prophylaxis best test for defining OIs risk and prognosis

HIV RNA

(Viral Load)

Provides marker for pace of HIV progression determines indication for and response to ART

TST

(Standard 5 TU PPD)

Detects Latent TB inf. and targets patients for preventive theraphy HIV most powerful co-factor to develop active TB

PAP smearCervical cancer risk x2 high in HIV women

GGPD ScreenDapsone, primaquine induced hemolysis

Toxo, Seklogy syph (VDRL/RPR Anti HCV/HBV CMV Seklogy gG VZU gG

CXRHealed granuloma, indicated for ALL TST Baseline for future comparison

B. Baseline Lab Testing

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C. CD4 Count1. • CD4 decline characterises acute HIV infection

• This decline followed by gradual rise assoc. with clinical recovery• Ch HIV infection assoc. with CD4 progressive decline (50-80 cells/yr) if no treatment.• Then rapid decline 1-2 yr prior to OIs (THE AIDS-defining diagnosis)• In 5% of patients CD4 caint remained stable 5-10 yrs others show rapid decline (300 cells/yr)• Because of these variability, repeating CD4 count prior to making management decision maybe useful.

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2. Uses of CD4 Count• Assess degree of immune suppression and interpretation of SX/SX.• Guide theraphy

CD4 < 200 klythreshould to initiate ART, regardless of viral load or symptoms

CD4 < 350: consider treatment• Guide OIs prophylaxis

count < 200 --- pcpcount < 50 --- CMV and MAI

• Estimation of OIs risk or deathcount < 50: marked increase death risk

with one year median survival

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USE OF CD4 COUNT TO INTERPRET PATIENT SX/SX

CELL COUNTASSOC. CONDITIONS

> 500

Most illnesses similar to HIV-negative patients some increased risk of bactgerial infection: - pneumonia, sinusitis HZ, TB …… etc.

200 – 500Bacterial infection (sinusitis, pneum. Pneumonia) K.S. ITP, vag, candidiasis

50 - 200Trush, OHL, HIV-assa. OIs, crypto, mening, toxo. if patient receiving OIs prevented until CD4 < 100.

< 50OIs final common pathway CMV, DISSIM. MAI, HIV-wasting neuro. Dis, (neuropathy, encephalopathy

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ARTINITIATION OF ART

HIV – Infected Patient

Acute HIVHIV-related SXPregnancyAIDS

Asymptomatic

Treat

AIDS orCDU < 200

CD4: 201-349 CD4 > 350

Any viral load Any viral load

Offer treatmentTreat

HIV RNA > 100,000(RT – PCR or b DNA)

Offer treatmentor observe/defer

HIV RNA < 100,000

Observe/defer

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A. Initiation of ART

• Combination ART provides dramatic reduction in HIV-related M/M. For patient with severe immunosupr. [CD4 < 200 or AIDS-defining illness]

• Treatment of Asymptomatic patient more controversial

• Potential benefits of starting ART with high CD4

– Controlling viral replication

– Reducing HIV RNA [viral load]

– Preventing immunodeficiency

– Delaying time to AIDS onset

– Decreasing viral transmision and selecting resistant virus.

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• Portential Risks of early ART- reduced life quality [from SE/in convinience]- early development of drug resistance- TX of resistance virus- limitation in future ART choices- unknown long-term drug toxicity- unknown duration of effectiveness

• Primary goals ART- prolonged viral replication suppression [250-75]- restoration/preservation of immune function- improved clinical out come.

• Once initiated, ART continued indefinely

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B. Selection of ART

• DHHS and IAS – USA guide lines/www.aidsinfo.gov/guidelines/ October 2006

All recommend 3 active agents: NRTI pair [continuing 3TC or FTC] plus either NNRTI or PI

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A.R. AGENT FOR HIV INFECTION1. Nucleoside/Nucleotide analogue reverse transcriptase

inhibators [NRTI]1. Abacavir [Zlagen]2. Abacavir + Lamivudine [Epzicom]3. Didanosine (ddl, videx)4. Emtricitabine + [3 tc, epivir]5. Emtricitabine + Tenofovir [Truvada]6. Lamivudine [3tc, Epivir]7. Stavudine [dut, zerit]8. Tenofovir [viread]9. Zidovudine [ZDV + 3TC]10. Combivir [ZDV + 3TC]11. Trizivir [abacavir + zidovudine + lamivudine]

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2. Non-nucleoside reverse transcriptase inhibators [NNRTI]

1. Delavirdine [rescriptor]

2. Efaviren [sustiva]

3. Nevirapine [viramune]

3. Protease Inhibators [PI]

1. Atazanavir [reyataz]

2. Darunavir [prezista]

3. Fosamprenavir [lexiva]

4. Indinavir [crixivan]

5. Kaletra [lopinavir + ritonavir]

6. Nelfinavir [viracept]

7. Ritonavir [norvir]

8. Saquinavir [invirase]

9. Tipranavir [aptivus]

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4. Combination NRTI/NNRTI

1. Artripla [efavirenz + emtricitabine + tenofovir]

5. Fusion inhibitor: enfuvirtide [fuseon]

6. Integrace Inhibators: Few under trials

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ART Recommended for HIV-Naïve patient (DHHS guidelines)

Select NRTI pair + NNRTI or PI

NRTINNRTIPI

Preferred

• Tenofovir/

Emtricitabine

• AZT/ LamivudineEfavirenz

• Atazanavir + Ritonavir

• Fosamprenavir +

Ritonavir

• Kaletra

[lopinavir/ ritonavir]

Alternative

• Abacavir/ Lamivudine

• ddl + emtricitabine or lamivudine

Nevirapine

• Atazanavir

• Fosamprenavir + Ritonavir

• Kaletra

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INITIAL A.R. REGIMENS [IAS-USA guidelines]

NRTI PAIRNNRTIPI

Recommended

• tenefovir/ emtricibaine

• AZT + 3TC

• Abacavir + 3TC

Efavirenz Nevirapine

• Kaletra [Lopinavir/ ritonavir]

• Saquinavir + ritonavir

• Fosamprinavir + ritonavir