CLINICAL MANIFESTATIONS AND OPPORTUNISTIC INFECTIONS IN HIV INFECTION

Clinical manifestations and opportunistic infections in HIV infection July 2009 Dr. Evelien de Jong

Clinical manifestations 1. 2. 3.

4. 5. 6.

Acute HIV-1 infection General manifestations HIV-associated Skin and Mucocuteneous diseases Oral manifestations of HIV HIV and Tuberculosis co-infection PCP

29 year old man, no medical history 2 weeks of malaise, myalgia and since a couple days a rash Four weeks ago unprotected sex Complaints of severe fatigue, no weight loss or mouth sores 1week ago his GP gave him amoxicilline with no effect Physical exam: temperature of 38.3 C, diffuse adenopathy, maculopapular rash

Rash

What is your diagnosis? Mononucleosis infectiosa Acute CMV-infection Acute HIV-infection All of the above are optional

1. 2. 3. 4.

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What is your diagnosis? 1. 2. 3. 4.

Mononucleosis infectiosa Acute CMV-infection Acute HIV-infection All of the above are optional

Test results

HIV RNA: 63.700 copies/ml HIV antibody: negative

What is your diagnosis?

Acute HIV-infection

How long is your diagnostic window? The current HIV-antibody screening tests are able to recognise almost 99.5 % of HIV– infections…… A. B. C. D.

2 weeks 1 month 3 months 1 year

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….after primary HIV infection 30

How long is your diagnostic window? The current HIV-antibody screening tests are able to recognise almost 99.5% of HIV-infections… A. B. C. D.

2 weeks 1 month 3 months 1 year …..after primary infection with HIV

Typical Course of Primary HIV

HIV RNA

HIV-1 Antibodies

1 mil HIV RNA

100,000 10,000 1,000 100

Ab

P24 +

+ _

Exposure

Symptoms

10 0

3

14

21 Days

28

35

Typical Risk of Unprotected Exposures Estimated Average Per Contact Transmission Risk (%) Shared Needles Occupational Needlestick Male to female, vaginal sex Female to male, vaginal sex Insertive anal sex Receptive oral sex with male

0.7% 0.3 % 0.2% 0.1% 0.1% 0.03%

Day 0

Exposure to HIV at mucosal surface (sex)

Day 0-2

Virus collected by dendritic cells, carried to lymph node

Day 3-11

HIV replicates in CD4 cells, released into blood

Day 11 on Kahn JO, Walker BD. N Engl J Med. 1998;339:33-39.

Virus spreads to other organs

Which one of the following statement is true regarding acute HIV infection?

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Less than 5% of persons who acquire HIV develop an acute illness More than 80% of patients with acute HIV present with an aseptic meningitis Patients recently infected with HIV typically have plasma HIV RNA levels greater than 50.000 copies/ml within 4 weeks of acquiring HIV An HIV-RNA level of 800 copies/ml and a negative HIV-antibody test would be diagnostic for an acute HIV infection

Le ss

A.

30

Which one of the following statement is true regarding acute HIV infection? A.

Less than 5% of persons who acquire HIV develop an acute illness

B.

More than 80% of patients with acute HIV present with an aseptic meningitis

C.

Patients recently infected with HIV typically have plasma HIV RNA levels greater than 50.000 copies/ml within 4 weeks of acquiring HIV

D.

An HIV-RNA level of 800 copies/ml and a negative HIV-antibody test would be diagnostic for an acute HIV infection

Northwest AIDS Education and Training Center and the University of Washington

Primary HIV Infection: Signs & Symptoms

80-90% of patients will be symptomatic A mononucleosis-like illness of non-specific signs and symptoms Signs and symptoms typically begin 1-4 weeks post-exposure High index of suspicion is critical

Kahn JO, Walker BD. N Engl J Med. 1998;339:33-39. Schacker T, et al. Ann Intern Med. 1996;125:257-264.

Primary HIV Infection: Common Signs & Symptoms fever

86

lethargy

74

myalgias

59

rash

57

headache

55

pharyngitis

N = 160 patients with PHI in Geneva, Seattle, and Sydney

52

adenopathy

44 0

10

20

30

40 50 60 % of patients

70

Vanhems P et al. AIDS 2000; 14:0375-0381.

80

90

100

Primary HIV Infection: Other Signs & Symptoms aseptic meningitis

24

oral ulcers

15

genital ulcers

10

thrombocytopenia

45

leukopenia

40

transaminitis

21 0

20

40 60 % of patients

Kahn JO, Walker BD. N Engl J Med. 1998;339:33-39.

80

100

Oral Ulcers in Acute HIV Infection

From: Walker, B. 40th IDSA, Chicago 2002.

Genital Ulcer in Acute HIV Infection

From: Walker, B. 40th IDSA, Chicago 2002.

Diagnostic Testing: Viral Load

More sensitive than HIV antibody3 Positive one to three weeks before antibody test1 Typically high level, e.g. greater than 50,000-100,000 copies/mL in acute infection2,3 False positives can occur

Most false positives are low level (<10,000 copies/mL) HIV VL <10,000 copies/mL should probably be considered “indeterminate” 1. Busch MP, Satten GA. Am J Med 1997;102:Suppl 5B:117-24. 2. Kahn JO, Walker BD. N Engl J Med. 1998;339:33-39. 3. Daar ES et al. Ann Intern Med. 2001;134:25-29.

Why do we Care about Diagnosing PHI?

Public Health: Patients with PHI are likely to be highly infectious Diagnosis of HIV infection may lead to safer sex

Personal Health

40% of patients with HIV not diagnosed until they have AIDS

Cellular Immune Response to Acute HIV Infection Acute HIV 100

Weak CTL

80 HIV RNA

Rapid Progression

60

Moderate CTL Moderate Progression

40

Strong CTL

20

Slow Progression

0 0

1

2

3

4

5Time6

7

8

6 months From: Walker BD. Nature 2000;407:313-4.

Slide courtesy David Spach, MD

Primary HIV Infection: Conclusions

PHI is under-diagnosed A high index of suspicion, recognition of key signs & symptoms, and lab testing are required for the diagnosis


4. 5. 6.


Common Clinical Manifestations of Chronic HIV Infection

Constitutional Symptoms fever weight loss/wasting fatigue

Organ/System Specific

virtually all organ systems can be affected

Consider HIV testing for unexplained syndromes

Wasting

Before HAART

After HAART

Wasting syndrome

Involuntary weight loss of at least 10% Accompanied by persistent diarrhea (at least two bowel movements daily for more than 30 days) Or extreme fatigue And/or fever without infectious focus

Exclude other infections like: TB, MAC, cryptosporidiosis and microsporidiosis


4. 5. 6.

Acute HIV-1 infection General manifestations of HIV HIV-associated Skin and Mucocuteneous diseases Oral manifestations of HIV HIV and Tuberculosis co-infection PCP

A 32-year-old HIV-infected man presents to your clinic having noticed his nose is reddish to purple. He is HIV-positive, his CD4 count is 230 cells/mm3, and he has never taken antiretroviral agents.


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Erysipelas (skin infection) He is probably drinking too much alcohol Kaposi’s sarcoma

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What is your diagnosis? A. B. C.

Erysipelas (skin infection) He is probably drinking too much alcohol Kaposi’s sarcoma

Kaposi’s sarcoma

Which of the following is true?

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In some patients HAART alone causes significant improvement of Kaposi’s sarcoma lesions Human herpes virus type 6 is the causative agent of Kaposi’s sarcoma Visceral, but not isolated cutaneous Kaposi’s sarcoma, is an AIDSdefining illness Kaposi’s sarcoma lesions will never involve external genitalia In

A.

30

Which of the following is true? A.

B.

C.

D.

In some patients HAART alone causes significant improvement of Kaposi’s sarcoma lesions Human herpes virus type 6 is the causative agent of Kaposi’s sarcoma Visceral, but not isolated cutaneous Kaposi’s sarcoma, is an AIDS-defining illness Kaposi’s sarcoma lesions will never involve external genitalia

Kaposi’s sarcoma

Vascular malignant tumour nodular lesions Mostly skin lesions; oral/genital/GI-tract/longs can be involved

Due to infection HHV-8 KS is an AIDS-defining illness Since HAART: frequency of KS decreased 90% HAART= first line treatment Local therapy/chemotherapy

A 28-year-old HIV-infected man with at presentation a CD4 count of 26 cells/mm3, and a 4 week history of genital lesions. At first there were vesicles and for the past week, the lesions have become more painful.



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Herpes zoster Syfilis Herpes simplex virus Molluscum contagiosum

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What is your diagnosis? A. B. C. D.

Herpes zoster Syfilis Herpes simplex virus Molluscum contagiosum

HSV

80% seropositive for HSV-1 and/or -2 Normal cell-mediated function: Grouped vesicles; heal spontaneously Cold blister lip (mostly HSV-1) Genital lesions (mostly HSV-2) Genital HSV asymptomatic shedding

Advanced HIV (CD4 cell< 100/µl)

After grouped vesicles painfull deep ulcerations mostly anogentital and face

48-year-old HIV-infected man comes in for routine care and evaluation of skin lesions on his face. His most recent labs showed a CD4 count of 38 cells/mm3 and HIV RNA of 87,000 copies/ml. He is an active intravenous heroin user and has not been able to stay on antiretroviral therapy. The patient describes a 2-3 month history of persistent papules on his face that have gradually increased in number and size.


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HSV-1 Herpes Zoster Acne Vulgaris Molluscum Contagiosum

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HSV-1 Herpes Zoster Acne Vulgaris Molluscum Contagiosum

Molluscum contagiosum

Benign viral infection of the skin Pox virus Diagnosis made on clinical grounds HIV-patients high number of lesions, typically face and neck, otherwise rare location Presence of multipele mollusca on face; indicating CD4 cell < 100/µl

1. 2.

3. 4. 5.

Acute HIV-1 infection HIV-associated Skin and Mucocuteneous diseases Oral manifestations of HIV HIV and Tuberculosis co-infection PCP-infection

A 33-year-old HIV-infected man with a CD4 count of 120 cells/mm3 visits the clinic for a routine appointment. On examination, white papular lesions are seen bilaterally on the lateral side of his tongue, which do not rub off


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Candidiasis Oral hairy leukoplakia Herpes simplex Aphthae

C

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30

Oral manifestations

A. B. C. D.

A 33-year-old HIV-infected man with a CD4 count of 120 cells/mm3 visits the clinic for a routine appointment. On examination, white papular lesions are seen bilaterally on the lateral side of his tongue, which do not rub off What is your diagnosis? Candidiasis Oral hairy leukoplakia Herpes simplex aphthae

Oral hairy leukoplakia



Which of the following statements is true regarding oral hairy leukoplakia?

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It occurs in approximately 5% of persons infected with hepatitis C, who are not co-infected with HIV It is caused by an infection with human herpes virus type 8 It is caused by an infection with Epstein-Barr virus Approximately 15% of lesions develop into premalignant lesions that require surgical removal

It

A.

30

Which of the following statements is true regarding oral hairy leukoplakia? A.

It occurs in approximately 5% of persons infected with hepatitis C, who are not co-infected with HIV

B.

It is caused by an infection with human herpes virus type 8

C.

It is caused by an infection with Epstein-Barr virus

D.

Approximately 15% of lesions develop into premalignant lesions that require surgical removal

Oral hairy leucoplakia

Clinical manifestation of EBV Exclusively in patients with untreated advanced HIV (median CD4 cell of 230/µl) White verrucous plaques, especially lateral parts of tonque, do not rub off Treatment: antiviral drugs: aciclovir, ganciclovir No respond on antifungal

A 39-year-old HIV-infected male presents to the clinic with a 14-day history of a mild burning sensation in his mouth. He was diagnosed with HIV infection in 2001, but has remained asymptomatic up until now. Most recent laboratory studies performed 2 months earlier showed a CD4 count of 250 cells/mm3. By inspection of the mouth you see creamy white plaques or patches on oral tissues that can be scraped off


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Oral Candidiasis Oral hairy leukoplakia Herpes simplex virus Aphthae

O

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30


Oral Candidiasis Oral hairy leukoplakia Herpes simplex virus Aphthae

Oral candidiasis

Oral candidiasis

Oral candidiasis

Commensal microbe in oral cavity and female genital tract Vaginal candidiasis also in immunocompetent female Candida oesophagitis usually CD4count<100/µl KOH: prep showing yeast, however usually clinical diagnosis

What kind of treatment will you start?

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Fluconazol 100 mg/d PO x 14 days Nystatine oral suspension 4 a 6 mg qid Amphotericin IV 03-05 mg/kg/d x 1-2 wks Caspofungin 70 mg day 1, then 50 mg/d IV x 1-2 wks A and B are optional

Fl

A.

30

What kind of treatment will you start? A. B. C. D.

E.

Fluconazol 100 mg/d PO x 14 days Nystatine oral suspension 4 a 6 mg qid Amphotericin IV 03-05 mg/kg/d x 1-2 wks Caspofungin 70 mg day 1, then 50 mg/d IV x 1-2 wks A and B are optional

What is your diagnosis? A 36-year-old HIV-infected man with at presentation a CD4 count of 350 cells/mm3

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Candidiasis Oral hairy leukoplakia Herpes simplex virus aphthae

C

A.

30


A. B. C. D.

A 36-year-old HIV-infected man with at presentation a CD4 count of 350 cells/mm3 Candidiasis Oral hairy leukoplakia Herpes simplex virus aphthae


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Candidiasis Oral hairy leukoplakia Herpes simplex virus aphthae

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Candidiasis Oral hairy leukoplakia Herpes simplex virus Aphthae


4. 5. 6.


The Dual Epidemic

HIV 40 Million

TB 2 Billion

WHO estimates, 2005

HIV and TB: Global Epidemiology

Proportion of TB cases with HIV infection increased dramatically in 1990s Burden per capita highest in sub-Saharan Africa >50% of TB cases HIV infected

HIV-Infected Patients Are at Increased Risk

To acquire TB To develop active TB once infected with TB To become re-infected with a second strain of TB

Extrapulmonary Tuberculosis 80

% of patients

70 60 50 40 30 20 10 0 0-100

101-200

201-300

CD4 cells / uL

>300

MTB Pulmonary Disease in AIDS Patients

75 % of patients have pulmonary disease 20 – 59 % have hilar or mediastinal adenopathy 12 – 28 % have pleural effusions 7 – 18 % have miliary pattern 12 % have normal CXR, positive sputum culture Other diseases masquerade as TB

TB Treatment

Treat HIV+ same as HIV– INH, RIF, PZA x 2 months, INH, RIF x 4 months Use EMB initially while sensitivities pending if INH resistance > 4 %

TB Treatment in HIV Coinfected Patients

Response rates similar between HIV+ and HIV– patients Components of successful therapy: Resistance testing DOT

Multiple-drug-resistant TB will emerge and spread with inadequate treatment programs

A 32-year-old man with pulmonary TB is treated with INH, PZA, EMB, RIF At first there is a good response, however two weeks after starting treatment he’s getting fever of 38.3C, cervical lymfadenopathy and shortness of breath


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He’s not taking his medicine Resistance for the prescribed medicine IRIS All of the above are optional H

A.

30

A. B. C. D.

What is your diagnosis? He’s not taking his medicine Resistance for the prescribed medicine IRIS All of the above are optional

“Paradoxical Reactions” in Tuberculosis (IRIS) Transient worsening of clinical signs and symptoms after initial response to anti-tuberculosis therapy

“IRIS” in Tuberculosis

First recognized in 1950s Lymphadenitis (12 – 25 %), pulmonary disease, central nervous system, tuberculomas 1 – 6 months post initiation of therapy May require steroids

“IRIS” in Tuberculosis and HIV Co-infection

Can happen with any antiretroviral regimen Mean onset of symptoms is 2 weeks Mean duration of symptoms is 3 weeks Most common symptoms include fever, cervical lymphadenopathy, intrathoracic lymphadenopathy Associated with restoration of immune responses to M. tuberculosis

TB and HIV: Immediate vs. Delayed HAART

TB treatment must be given urgently.

The urgency of HIV treatment depends on predictors of HIV disease progression especially the CD4 cell count.

<100 cells/mm3 HAART ASAP 100-200 cells/mm3 - HAART after 2 months >200 cells/mm3 - HAART after TB RX finished

Antiretroviral Therapy Options

Triple NRTI with Rifampin NNRTI (EFV) 800 mg* with Rifampin Ritonavir + saquinavir with rifampin Protease inhibitor (IDV, NFV, APV)* with Rifabutin

*Dose adjusted


4. 5. 6.

Acute HIV-1 infection General manifestations HIV-associated Skin and Mucocuteneous diseases Oral manifestations of HIV HIV and Tuberculosis PCP

A 23 year old male presents with dry cough since three weeks and dyspnoe. He was tested HIVpositive three years ago. Then with a CD4 count of 300. He stopped taken his medicine in 2007 because of side effects What is your most likely diagnosis? A. Pneumococcal pneumonia B. PCP-infection C. VZV-pneumonia

Pneumocystis jiroveci Pneumonia: Epidemiology

Caused by P jiroveci (formerly P carinii) Before widespread use of PCP prophylaxis and effective ART, PCP seen in 70-80% of AIDS patients Risk factor: CD4 count <200 cells/µL

PCP: Clinical Manifestations

dyspnea, fever, nonproductive cough, chest discomfort Subacute onset, worsens over days-weeks Chest exam may be normal, or diffuse dry rales, tachypnea CXR: Typical: diffuse bilateral, symmetrical interstitial infiltrates

PCP: Diagnosis

Clinical presentation, blood tests, radiographs suggestive but not diagnostic

Organism cannot be cultured

Hypoxemia: characteristic, may be mild or severe (PO2 <70 mmHg) LDH >500 mg/dL is common

PCP: Diagnosis (Imaging)

Chest X ray: PCP with bilateral, diffuse granular opacities

Chest X ray: PCP with bilateral perihilar opacities, interstitial prominence, hyperlucent cystic lesions

PCP: Diagnosis

Definitive diagnosis requires demonstrating organism:

Induced sputum (sensitivity <56%) Spontaneously expectorated sputum: low sensitivity

Bronchoscopy with bronchoalveolar lavage (sensitivity 90-99%)

PCP: Diagnosis (Histopathology)

silver stain: P jiroveci organisms in tissue

PCP: Primary Prophylaxis

Initiate:

Discontinue:

CD4 <200 cells/µL On ART with CD4 >200 cells/µL for >3 months

Reinitiate:

CD4 decreases to <200 cells/µL

PCP: Primary Prophylaxis (2)

First choice:

Trimethoprim-sulfamethoxazole 480 mg QD

PCP: Primary Prophylaxis (3)

Alternative

TMP-SMX DS 1 tablet PO 3 times Q week Dapsone 100 mg PO QD or 50 mg BID Aerosolized pentamidine 300 mg Q month Atovaquone 1,500 mg PO QD*

* Effective as toxoplasmosis prophylaxis (for CD4 count <100 cells/µL + positive serology)

PCP: Treatment

Duration: 21 days for all treatment regimens Preferred: TMP-SMX 1980 mg tid

Adjust dosage for renal insufficiency

PCP: Treatment

Adjunctive:

Corticosteroids For moderate-to-severe disease (room

air PO2 <70

mmHg) Give as early as possible (within 72 hours) Prednisone 40 mg BID days 1-5 40 mg QD days 6-10 20 mg QD days 11-21

Questions?

CLINICAL MANIFESTATIONS AND OPPORTUNISTIC INFECTIONS IN HIV INFECTION

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