Pulmonary diseases in AIDS

Anchalee Avihingsanon, MD
The HIV Netherlands Australia Thailand
Research Collaboration (HIV-NAT)
Bangkok, Thailand

Supported by
SEARCH Regional HIV/AIDS Training A Training Grant
1
8th January to 9th February, 2007 From
 Topics
• Approach to pulmonary manifestation in HIV infected
patients
– Clinical
– Radiographic findings
• Common pulmonary infections
– PCP
– TB
– Fungal infection
– Bacterial infection
• Common non pulmonary infection
– Kaposi sarcoma
– Lymphoma
2
– Pulmonary hypertension
 Pulmonary Diseases in AIDS
• Respiratory symptoms are a frequent complaint in
HIV-infected individuals.
• Spectrum of pulmonary diseases includes both
HIV and non-HIV-related conditions.
• HIV-associated pulmonary conditions include both
OIs and neoplasms, each of which has a
characteristic clinical and radiographic
presentation.
3
• Because of considerable variation and overlap in
the presentation, no pathognomonic or specific
findings for a particular disease.
• Definitive microbiologic or pathologic diagnosis is
preferable to empiric therapy.
• OIs and neoplasms may be limited to the lungs or
pulmonary involvement may be only one site of
multi-organ disease.

4
 General Approach

• Thorough history, physical examination, selected

laboratory tests and chest radiography.

• Specimens from other sites (e.g., skin, lymph

node, bone marrow and CSF) will provide
diagnosis of extrapulmonary or disseminated
disease.

5
History
• Duration of symptoms – acute vs. subacute/
chronic
• Travel to or residence in endemic region of
specific pathogen
• Productive vs. nonproductive cough
• Past pulmonary infection and secondary
prophylaxis
• Adherence to OI prophylaxis
• IVDU pneumonia due to S. aureus
6
Physical signs

• General: wasting, oral thrush

• Lungs: normal, pneumothorax, consolidation,

effusion

• Cutaneous/mucocutaneous lesions

• Peripheral adenopathy

• Neurological signs

• Hepatosplenomegaly
7
• Certain OIs and neoplasms typically develops at
or below a characteristic CD4 cell count range.
• Multiple infections exist.

8
CD4 cell count range for selected HIV-related and non-
HIV-related pulmonary diseases

Any CD4 CD4 < 500

- bacterial pneumonia - Bacterial pneumonia
- tuberculosis (recurrent)
- NHL - pulmonary mycobacterial
- bronchogenic carcinoma pneumonia (TB and NTM)
- pulmonary embolism
CD4 < 200
- PCP
- Cryptococcal pneumonia
- bacterial pneumonia
- disseminated or extrapulmonary TB 9
CD4 cell count range for selected HIV-related and non-
HIV-related pulmonary diseases (cont’)

CD4 < 100 CD4 < 50

- pulmonary KS - diss. Histoplasmosis
- bacterial pneumonia - CMV pneumonitis
- toxoplasma pneumonitis - diss. MAC
- diss. TB
- diss. NTM

10
Investigations:
• Chest x-ray
• lactate dehydrogenase (LDH)
• Sputum : gram stain, acid-fast stain, modified stain, geimsa
stain, silver stain, immunofluorescent stain
• Bronchoscopy - BAL or BW, TBB
• Extrapulmonary samples
blood culture: bacteria, mycobacteria, fungi
serum cryptococcal antigen
lymph node aspiration/biopsy
bone marrow aspiration/biopsy
liver biopsy
skin scraping, biopsy
CSF study
11
 Differential diagnosis of pulmonary complications
based on radiographic findings
Diffuse reticulonodular infiltrates

common uncommon
- P. jiroveci (PCP) • CMV
- TB • H. influenzae
• Nonspecific interstitial
- Histoplasmosis
pneumonitis
- Penicilliosis • Viral pneumonia
• Toxoplasmosis

12
Modified from: Bartlett JG, Gallant JE. 2005-2006Medical Management of HIV Infection.
PCP
13
Miliary TB Miliary TB with pericarditis

14
Consolidation
- Pyogenic bacteria
- TB
- Nocardiosis
Tuberculosis
- M. kansasii
- Cryptococcosis
- Rhodococcosis
- KS

15
Rhodococcosis
Nodules/mass
- TB
- Cryptococcosis
- KS Nocardia

- Lymphoma
- Septic emboli
- Lung cancer

16
Pulmonary lymphoma Pulmonary lymphoma
Cavitary disease
- Bacteria (P. aeruginosa, S. pneumoniae, S. aureus,
K. pneumoniae)
- TB - Rhodococcosis
- Nocardia - Anaerobic bacteria
- M. kansasii, NTM - PCP (rare)
- Cryptococcosis - M. avium complex (rare)
- Histoplasmosis - Lymphoma, malignancies
- Aspergillosis
17
 Cryptococcosis
S. aureus pneumonia

PCP 18
Rhodococcosis
Pleural effusion
- Bacteria (S. aureus, S. pneumoniae)

- TB - Aspergillosis

- KS (bloody) - Histoplasmosis (rare)

- Cryptococcosis - Lymphoma (rare)

- Rhodococcosis (rare) - M. avium complex (rare)

- Septic emboli - PCP (rare)

- Other noninfectious causes

19
Hilar adenopathy Normal

- TB - PCP

- Cryptococcosis - Endobronchial TB

- M. avium complex

- Histoplasmosis

- KS

- Lymphoma
20
Cough and shortness of breath
Cause Presentation X-ray Sputum

PCP Non-productive Bilateral infiltrates in Induced sputum at

cough (no sputum), the mid zones of the specialized hospital.
shortness of breath lungs Treat for PCP if the
and fever for 1-2 symptoms (and chest
months x-ray) suggest PCP.
Tuberculosis Cough with sputum, Upper lobe infiltrates Acid fast bacilli
fever, weight loss for are typical but (AFB)
1-2 weeks (or longer) patients with HIV
can have atypical X-
ray with lower lung
infiltrates
Bacterial Productive cough, Lobar consolidation Gram-positive
pneumonia purulent sputum and bacteria
fever for 1-2 weeks.
PCP presents more
slowly and there is
normally no sputum
21
 Case 1
• 36 y/o male with AIDS
• AZT, ddI and IDV experienced
• Loss to follow-up for 2 years without taking any
medication
• 2 weeks history of fever, gradually progressive SOB
• Presented with sudden onset of severe SOB
• Exam: T 38oC, P 110/min, RR 32/min
dyspnea, decreased breath sounds both lungs
22
 Case 1

• Chest x-ray: bilateral

pneumothoraces with
diffuse infiltrations of
residual lungs.

• What is the most likely diagnosis?

• What is the appropriate management? 23
 Case 1
• Lt. ICD was inserted.
• Transthoracic needle aspiration of
Rt. pneumothorax was performed.
Oxygen therapy
• Patient was treated with co-
trimoxazole and corticosteroids
for presumptive PCP with prompt
response.

24
 Pneumocystis jiroveci Pneumonia: PCP

 Fungal infection: ubiquitous

organism
– P. carinii infects rodents
– P. jiroveci infects human
 Reactivation or Newly infection

 Diagnosis
– Frequently clinical ( sub-acute
non productive cough with
progressive dyspnea)
– Microscopic demonstration of P.
jiroveci in lung secretions/tissue.
– Special methods to obtain
specimens are necessary
 Induced
sputum/B.A.L./Biopsy

P. Jiroveci from Wright stain

P. Jiroveci cyst from GMS
25
 Pneumocystis jiroveci Pneumonia

 Prognosis:
– 100% fatal untreated.
 Risk factors for a poor clinical outcome
– Hypoxemia, PO2< 70 mmHg
– Extensive bilateral pulmonary involvement
– Concurrent other pulmonary infections
– Recurrent rather than primary disease
– Elevated LDH levels
– An alveolar-arterial (A-a) gradient of greater than 30 mmHg.
– Older age
– Use of treatments other than TMP/SMX
– CD4<50 cells/mm3
– Concurrent culture of CMV from BAL fluid
Benfield TL. Chest. 2001;119:844-851
Brenner M. Am Rev Respir Dis. 1987;136:1199-1206 Dworkin MS. J Infect Dis.2001;183:1409-1412
26
Sullivan JH. Am J Respir Crit Care Med. 2000;162:64-67
Zaman MK. Am Rev Respir Dis. 1988;137:796-800
 Pneumocystis jiroveci Pneumonia : PCP
 Treatment
– Trimethoprim-Sulfamethoxazol(TMP- Prophylaxis (2004 USPHS/IDSA
Guidelines)
SMX) 15-20 mg of
sulfametoxazole/day ( 3-4 tablets TID
Sulfa resistance is common in long
for 21 days
term prophylaxis but TMP-SMX is still
– pentmidine IV, clindamycin+primaquine,
atovaqoune, trimetrexate
drug of choice
Primary prophylaxis until CD4> 200
– Don’t forget steroid in severe cases (add
corticosteroids if hypoxic or O2 cells/ul for at least 3 months
saturation < 70%) co-trimoxazole 1 DS tab daily
 Prednisolone 40 mgBID day1-5 (or 2 SS tabs daily).
 Prednisolone 40 mg OD day6-10 Dapsone 100 mg dail
 Prednisolone 20 mg OD day 11-21
 Treatment failure indicate after 4-8 days after therapy,
aerosilized pentamidine 300
bronchoscope may needed to rule out other causes mg monthly
 13-18% co-infection with other organisms
Secondary prophylaxis until CD4>
200 cells/ul for at least 3-6 months

27
 Recurrent Pneumonia
• Definition: > 2 episodes of
pneumonia in a 12 month period
• Epidemiology:
– a common problem in HIV
infected patients.
– S. pneumoniae and H.
influenzae at least 20 times
more common in HIV
– Pneumococcal bacteraemia rate
100 times higher in AIDS vs.
controls
• Clinical:
– clinical presentation is generally
unaltered in HIV
– Acute onset of fever and productive
cough
Organisms
– S.pneumoniae and Haemophilus influenzae are
the most common pathogen for community
acquired pneumonia
– S.aureus is common in IVDU patients
– Pseudomonas aeruginosa is an important cause
of nosocomial infection
– M.TB
– Rhodococcus equi
–
Nocardia asteroides
• Radiographic findings: focal consolidation with a
higher propensity for multilobar and bilateral
disease
• Management : proper antibiotics as per local guidelines
for pneumonia in non HIV
• Prevention:
– Pneumococcal vaccine (ideally when
CD4 > 200 . The impact of vaccine in
HIV-infected adults remain controversial
(Klugman K. Curr Opin Infect Dis 2007;20:11-15)
– H. Influenzae vaccine is not
recommended in adults
– co-trimoxazole prophylaxis protects
against recurrent pneumonia
28
 Case 2
• A 30 y/o HIV-infected male presented with
productive cough, progressive weight loss,
fatigue, and fever for 2 week.

• Exam: T 38.3oC, wasting, oral thrush, OHL

• O2 saturation at room air = 96%

• CBC: Hct 27.8%, WBC 4,900/mm3, N99%, plt
115,000

• TB 1.6, AST 123, ALT 34, alk phos 257 (39-117),

LDH 779 (225-450)

29
 Case 2

What are the differential diagnosis?

• Bacterial pneumonia
• Tuberculosis
• Fungal pneumonitis
• Nocardiosis
• NTM
• What are the appropriate work up?
30
 Case 2
• H/C for bacteria : no growth
• Empirically treated as
• Sputum for AFB + AFB rare
Tuberculosis with INH, RIF,
• Serum cryptococcal antigen:
negative PZA and EMB.
• What is the provisional • 2 weeks later: Rt.
diagnosis?
pneumothorax , ICD,
• What treatment would you
pleurodesis
start while awaiting culture
result?

31
 Case 2

• Sputum culture: M. tuberculosis

• H/C for mycobacteria: M. tuberculosis

32
 Common AIDS-defining
Diseases
Prior to Treating with HAART
Developing Countries Developed Countries
1. TB 1. PCP
2. PCP 2. Toxoplasmosis
3. Cryptococcal 3. CMV retinitis
meningitis 4. TB
4. CMV retinitis
5. MACs
5. Esophageal
candidiasis 6. Cryptosporidiosis
6. MACs 7. Fungal infections
7. Toxoplasmosis 8. Kaposi Sarcoma 33
HIV/TB interaction

 Effect of HIV on TB Effect of TB on HIV

 HIV is high risk of
 HIV disease progression
developing active TB
 Higher rates of
 reactivation disease
 7-10% per year vs 10%
Other OIs
lifetime risk HIV negative
 acute disease
 50% HIV pos vs 5-10% HIV
neg lifelong risk
 skin test (PPD) anergy morbidity, mortality
 extrapulmonary TB

34
 Risk Factors to Develop
Tuberculosis in TB Infection
Relative Risk
200
170
160

120

80

40 30
12 13
0

AIDS Silic Imm H

os is unos emodia
uppr lysis
e s iv
e
35
 Effect of CD4 count on risk of TB
among HIV-infected people
Incidence of TB (per 100 pyrs)
20
CD4 count
>350 200-350 <200
15

10

0
Italy US South Africa
Antonucci JAMA 1995;274:143; Markowitz Ann Int Med 1997;126:123; 36
Badri Lancet 2002;359:2059 Modified from A. Pozniak
 Correlation between CD4 counts and
Clinical Manifestation of Tuberculosis
500 -
Pulmonary TB

400 -
CD4 counts

300 - Lymphatic, serous TB

200 - TB Meningitis

100 -
Disseminated TB
0-
Duration of HIV Infection (yrs) 37
 TUBERCULOSIS
 any CD4 stage
 Prolong fever with weight loss
 Anorexia
 Any organs except hair and nails
 More advanced HIV, more atypical
presentation and sputum tends to be
negative smear / positive culture

38
 HIV/PTB - Clinical Presentation

Early Late (CD4<200cells/uL)

Clinical ‘Typical’ ‘Atypical’
PPD Usually + Usually -
CXR ‘Typical’ ‘Atypical’
Lung site Upper lobe Lower/middle lobes
Hemo c/s rare 20-40%

39
 Treatment
 Total 9 months of anti TB
 adherence is very important*
for
 6Mo vs 9Mo (Similar response
rates 98.5% vs 94.5%*)  delay clinical,
 Induction - 2 months microbiological response
 Isoniazid [INH] (positive C/S at 2 mo.)
Rifampicin [RIF]
Pyrazinamide [PYZ]  cavitary lesion
Ethambutol [EMB]

 Consolidation - 4 months  No PZA during first 2

 Isoniazid + Rifampicin for 4 months
months

 Consolidation – 10 months
 Isoniazid + Rifampicin for 10 Appropriate timing
months in TB meningitis or
tuberculoma of initiation of HAART
 Every effort should be made to use a
rifamycin-based regimen for the
entire course of therapy
40
ATS, CDC, IDSA: MMWR June 20,2003
*Swaminathan S 12th CROI; February 22-25, 2005;. Abstract 141
HIV counseling and testing in TB

patients should be performed .

41
 Spectrum of CD4 in HIV- TB Patients
a cohort in NE-Thailand

CD4 <100 CD4 101-250 CD4 >250

12%
CD4 <100
18%

70%

Thus, extra-pulm TB is the most common findings 42

Challenges in Treatment
TB AND HIV

Two Diseases
One Patient
43
Differential Diagnoses of
Pulmonary TB
• Bacterial Pneumonia
• PCP
• Fungal pneumonia
• Non-infectious causes- KS

44
PCP Pen.m Nocardia Crypto. n KS
 ARV in TB/HIV coinfection

TB and HAART - problems

 Pill burden/adherence
 Overlapping toxicity profiles
 nausea, vomiting, rash, hepatitis,
neuropathy
 Drug-drug interactions
 Rifampicin a strong enzyme
inducer
 ‘Paradoxical worsening’ of TB
 immune reconstitution reaction
 more likely if HAART started early
in TB treatment
45
 What are the Benefits of
Antiretroviral Therapy (ART)
on
TB and mortality

46
 Comparison of survival rate among
TB/HIV patients with/without ART
Retrospective study : 01/2000-12/2004
1087 patients, mean CD4 =49(19-129) cells/mm3
p<0.001
99 99 97
ARV
100 89
77 without ARV
80
survival rate

64
60
The mortarity rate
40 was reduced for 80%
20
0
1 year 2 year 5 year
47
Manosuthi W et al J AIDS 2006; 43:42-6
 How to Treat HIV patients co-
infected with Tuberculosis ?
There some Challenges :
• When to start Antiretroviral Therapy
• What ART regimen to start
• Immune Reconstitution syndrome (IRS)
48
When to start HAART in TB-HIV Patients

2 mo 6 mo
4 wk
2 wk

Anti-TB

? Await for Randomized controlled trial results

49
 Randomized “When to Start ART
Treatment in TB” Studies
Trial CD4 ART ART
Sponsor Number Randomization
CAMELIA <200 EFV/D4T/3TC ART 2 vs 8
ANRS1295/NIH N=660 weeks
AA5221 <200 EFV/TDF/FTC ART 2 vs 8-12
NIH N=800 weeks
START >50 DDI/3TC/EFV During vs after
NIH N=592 TB treatment

Blanc, 2006 50
 Potential Benefits and Risks of Starting
ART Immediately With TB Treatment

BENEFITS RISKS
• Reduced morbidity • Increased toxicity to TB
• Reduced mortality and ART therapy
• Improved TB outcome • Drug interactions
between HIV and TB
medications
• Pill burden
• Immune Reconstitution
Syndromes (IRS)

Dean, AIDS, 2002; Pedral-Sampaio,2004, Brazil JID; 51

Harries, Lancet, 2006; Lawn, Lancet ID, 2005 Modified from D. Havlir
 Don’t Wait till it’s too late
• Mortality rate 16-35% in TB-HIV without
ARV (4-9% in HIV negative)
• The lower CD4 is the higher mortality rate
• Mortality rate fell by 72% after
introduction of HAART

Ya DM et al AIDS 2001;15:143-52; Greenberg AE et al. AIDS1995;9:1251-54 Ackah AN et

al Lancet 1995;345:607-10; Kang’ombe CT et al Int J Tuberc Lung Dis 829-36; Dean GL et
al AIDS 2002;16:75-83
52
 Treatment of HIV and TB
Practical Approach

Start 4-drug Currently On HAART ?

TB regimen

No
Yes

CD4 <200 CD4 200-350 CD4 > 350

Continue
and adjust ARV
Begin Begin and dosages
No
HAART HAART HAART
in 2-8 wks in 2-6 mos
53
What ART regimen to start ?

54
 55
D. Havlir 2006
Drug-drug interactions TB/HIV
Absorption Rifampicin
Metabolism ↑CYP3A4
Antiretrovirals
• PIs
Metabolism •  NNRTIs

Elimination
 Effect of Rifamycins on ARV drug levels

Anti-TB SQV IDV NFV APV LPV NVP EFV

Rifampin -84% -89% -82% -82% -75% -37% -25%

Rifabutin -40% -32% -32% -15% 0 -16% 0

Finch et al. Arch Intern Med 2002;162:985-9257

 NNRTIs and RIF
Do we need to adjust the NNRTI doses ?

• Small PK studies support dose increase

– EFV to 800 mg qd
– NVP to 300 mg bid
• However, clinical outcome studies to date
do not support dose adjustment of EFV
or NVP

58
 A Randomized Controlled Trial of Efavirenz 600
mg/day versus 800 mg/day in HIV-infected Patients
with Tuberculosis Receiving Rifampicin
Probability of HIV RNA <50 Figure 1a

1.00
copies/mL Efavirenz (EFV) level in plasma
25.0

0.75
22.5

20.0

p = 0.848

Plasma EFV level (mg/L)

17.5

0.50
p = ns
15.0

12.5

10.0

0.25 7.5

5.0
3.39 (median)
2.5 3.02

0.00 0.0
EFV 600 mg EFV 800 mg

0 10 20 30 40 Dose per day

EFV = 600 EFV = 800

Weeks
Manosuthi W. AIDS 2005;19:1481-6. 59
N=42 N=42
Manosuthi W. AIDS 2006;20:131-2.
 NVP+RIF NVP
28
nevirapine concentration (mg/L)

25
22
19
16
12
9
6
3
0
0 2 4 6 8 10 12 14

time (hours)

148 samples collected 2004-2005: 74 on NVP+RIF,

74 GPOvir >85% samples on NVP+RIF level > 3.1 mg/L 60
 NVP 400 mg/day ± Rifampicin
• NVP only n=70, NVP+RIF n=70
• Mean plasma NVP levels at 8 and 12 weeks
were lower in patients receiving rifampicin
(p <.05)
• However, virological and immunological
outcomes at 24 weeks were not different
(p >.05)

Manosuthi W et al. Clin Infect Dis. 2006; 43:253-5. 61

 PK of NVP 400 vs 600 mg/day in HIV-
TB patients treated with RIF
Median NVP plasma concentration versus time
at 2 wks after lead in

NVP 400 NPV 600

10
NVP plasma level (mg/L)

high rate -NVP hypersensitivity

8

4 80% had
suboptimal C12 level
2
Efficacy: pVL<50 c/ml: 50% vs 50% (ns)
0
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (hours) 62
Avihingsanon A, et al CROI 2007
What should we recommend for Asia ?
When combined NNRTI+ RIF
For Asian Populations or Patients with low
body weight
• EFV can be dosed at 600 mg qd
• NVP 200 mg BID is efficacious and should
avoid the first 2 weeks lead-in (because
80% patients had suboptimal NVP levels)

63
HAART is the best option to prevent the
relapse of Tuberculosis
• In industrialised countries, risk of
relapse and reinfection after TB
treatment low, hence “secondary PT”
not required
• in regions with high TB prevalence, risk
of reinfection may be significant
• HAART should be best option

64
 Protease inhibitors

? ! X

Crixivan® Fortovase® Viracept® Norvir®

(indinavir, IDV) (Saquinavir, SQV-sgc) (Nelfinavir, NFV) (Ritonavir, RTV)
400, 200 mg 200 mg 250 mg 100 mg

X X
! Reyataz® Lexiva®
Kaletra® Kaletra
Tablet
Atazanavir, ATV/ATZ) (Fosamplinavir, FPV)
(LPV/r)
200/50 150, 200 mg 700 mg 65
133/33 mg
Lopinavir /rtv Squanavir /rtv
400/400 bid 1000/100 bid

66
 Overlapping toxicities of
Anti-HIV with Anti-TB

67
D. Havlir 2006
Tuberculosis Early After ART Initiation

• Undiagnosed TB
• Activation of latent TB
• Transmitted TB
• Immune reconstitution

Seyler, AJRCC, 2005; Breen, AIDS, 2005;Lawn, AIDS, 2005 68

 ‘Tuberculosis’ after commencing cART is
most common in patients with low baseline
CD4+ T-cells
Incidence rate of tuberculosis

16
(cases per 1000 PYFU)

14
12
10
8
6
4
2
0
<50 50-199 200-349 350-499 >500
CD4+ T-cell count at HAART initiation (cells/uL)

69
The Antiretroviral Therapy Cohort Collaboration. CID 2005;41:1772
 Tuberculosis in patients commencing cART occurs
mostly in the first 3 months of therapy

14
(cases per

12
Incidence rate of tuberculosis

10
1000 PYFU)

0-3 4-6 7-12 13-24 25-36

Duration of HAART (months)

70
The Antiretroviral Therapy Cohort Collaboration. CID 2005;41:1772
When Treating HIV/TB with HAART

What is IRS or IRIS ?

Immune Recovery Inflammatory Syndrome
How is it diagnosed?
How is it managed?

72
 Paradoxical Reactions
(Immune Restoration Syndromes)
• Transient worsening of condition or new
clinical symptoms after initiation of
treatment
• not the result of treatment failure
• 13-36 % of MTB/HIV infections after
initiation of HAART developed
paradoxical clinical deterioration
Narita M, et al: Am J Respir Crit Care Med 157-61, 1998; McCormack JG, et al: CID 1008-9, 73
1998; Hirsch HH, et al CID 38:1159-66, 2004; Avihingsanon A, et al. CROI 2007
 Paradoxical Reactions
(Immune Restoration Syndromes)
Common manifestations :
(new or worsening)
• Adenopathy
• Pulmonary infiltrates
• Serositis
• Cutaneous or CNS lesions (spots)
• Prolong fever (>101.5°F)
Median time : 6 weeks (4-80 days)
Narita M, et al: Am J Respir Crit Care Med 157-61, 1998; McCormack JG, et al: CID 1008-9, 74
1998; Hirsch HH, et al CID 38:1159-66, 2004; Avihingsanon A, et al. CROI 2007
 Paradoxical Reaction or IRIS
Worsening Radiograph
Active TB

After Anti-TB
IRIS
After HAART

75
 Immune Reconstitution Inflammatory Syndrome (IRIS)

76

Courtesy of Anton Pozniak

XDR-TB Warning !!!

77
• XDR tuberculosis has been transmitted to
HIV co-infected patients
• is associated with high mortality
• warrant urgent intervention for the success
of treatment programmes for TB and HIV

78
 HIV and TB Drug-Drug Interactions
 Rifampin-based regimens:
 PIs: data is limited Rifabutin
 Lopinavir/r (Kaletra) 400/100  PI regimen
BID+Ritonavir (300 mg bid) +
2NRTIs +usual dose Rifampin  Decrease dose of Rifabutin
(600 mg) to 150mg/d
 SQV/r 400/400 BID +2NRTIs
 NNRTI regimen
 Rifampin should not be used with
unboosted PIs or with low-dose  EFV : increase dose of
ritonavir/PI combinations Rifabutin to 300-450mg/d
 NNRTIs  NVP 200mg BID
 Efavirenz (600-800 mg daily) +
usual dose Rifampin (600 mg) (  NRTI regimen
preferred regimen)  TDF+3TC+ ABC
 Nevirapine (200 mg bid) + usual
dose Rifampin (600 mg) (limited
data; optional regimen)
WHOGuidelines, August 200679
 Case 3
• 32 y/o newly diagnosed HIV-infected male
• 2 weeks history of fever, productive cough,
weight loss, SOB
• Exam: T 39.2oC, RR 24/min, BP 110/80
mmHg, oral thrush
• multiple small cervical nodes
• O2 saturation at room air = 97%
• CBC: Hct 25%, WBC 4,100/mm3, plt 125,000
• CD4 39/mm3
• LDH 570
• Chest x-ray: RUL infiltrates

What are your differential diagnosis?

82
 Case 3
• What are the appropriate
work up?
• Tuberculosis
– Sputum exam. for gram stain,
• NTM pneumonitis
modified acid-fast and acid-
• Nocardiosis
fast stains were negative.
• Rhodococcosis
– Sputum cultures for bacteria,
• Cryptococcosis mycobacteria, fungus are
pending
• What would you do?

83
 Case 3

• Bronchoscopy:

BAL positive for gram-positive

branching filamentous bacilli and
modified acid-fast positive
branching bacilli

Acid-fast stain was negative.

84
 Case 3

• What is your provisional diagnosis?

• What would you recommend for empiric
treatment?

85
 Case 3

• Co-trimoxazole was given.

• Patient gradually improved.

• BAL culture grew Nocardia asteroides; no

mycobacteria isolated.

86
 Nocardiosis (Nocardia asteroides)

 Environment, soil
 Clinical
– Acute, subacute, chronic lung
infection
– Fever, fatique, night sweat

 1. ability to disseminate to any

virtually organs esp CNS
 2.tendency to relapse or
progress
 Diagnosis : gram stain, culture

87
 Nocardiosis
 Treatment
 Sulfonamide 6-12 gm /day
(divided q 4-6 hours)
 Trimetroprim (2.5-10mg/kg)/
sulfamethoxazole 12.5-50
mg/kg q 6-8 hours
 Duration of treatment
– 6-12 mos
– At least 12 months for central
nervous system involvement and
all immunocompromised host
 Primary prophylaxis
– Cotrimoxazole 800/160 mg po
daily until CD4 > 200 cells/uL
 Secondary prophylaxis
– Cotrimoxazole 800/160 mg po
daily until CD4 > 200 cells/uL
for at least 3-6 months
88
 Case 4
• 26 y/o HIV-infected female
• 2 weeks history of fever, productive cough,
chest pain, fatigue and anorexia.
• Exam: T 39oC, RR 24/min
OHL, pruritic papular eruption
small cervical nodes
• O2 saturation at room air = 98%

• CBC: Hct 31%, WBC 3,000/mm3, N 50%,

plt 110,000

• CD4 = 75/mm3

• LDH 452

89
 Case 4

• What are the differential diagnosis? • What are the appropriate

– Nocardiosis investigation?
– Rhodococcosis
– Sputum for gram stain,
– Tuberculosis
– NTM modified acid-fast and acid-
– Fungal infection: Aspergillosis, fast stains
Cryptococcosis
– Sputum cultures for bacteria,
– Lymphoma
mycobacteria and fungi

90
 Case 4
• What is the diagnosis?

• What are the treatment of choice?

91
 Case 4

• Sputum culture grew Rhodococcus equi.

• The patient was treated with vancomycin +
rifampicin.
• Fever subsided with clinical improvement after 2
weeks, azithromycin + rifampicin were given as
out-patient treatment.

92
 Rhodococcus equi
 Clinical
– Pulmonary: most common (70%):
subacute fever, cough, hemoptysis,
chest pain, prominent fatique
– Extrapulmonary:brain abscess, skin
abcess
 CXR: cavitary lesion and often with
associated pleural effusion
 Diagnosis
– Suspicious
– Gram stain ( gram-positive
coccobacillus), culture
 Treatment
– Multiple antibiotics ( 2 drugs
combination from the lists)
– Imipenem 500 mg iv q 6 hr
– Vancomycin 1 g q iv 12 hr
– Ofloxacin 500 mg po bid
– Ciprofloxacin 750 mg po bid
– Rifampicin 600 mg po qd
– Azithromycin 250 mg po qd
– Clarithromycin 500 mg po bid
– Erythromycin 500 mg po qid
93
 Case 5
• 26 y/o HIV-infected female
• On TMP/SMX DS 1 tab OD
• 2 weeks history of fever, headache, productive
cough, myalgia, 2-3 small volume watery diarrhea
per day
• Exam: T 40.2oC, RR 20/min,BP 120/80 mmHg,
oral thrush, wasting.
Otherwise unremarkable
• CBC: Hct 25.2%, MCV 72.9, WBC 4,600
N 88%, plt 383,000,
• LDH 818 U/L (normal 225-450) 94
 Case 6

• Treatment: ciprofloxacin 500 mg

PO BID

• H/C for bacteria, mycobacteria

serum cryptococcal Ag

stool for parasites and modified AFB

stain

• Chest x-ray: RUL cavitating lesion

with adjacent focal alveolitis and

RLL infiltrates.

95
 Case 5
• What are the differential diagnosis?
– Tuberculosis
- NTM infection
- Nocardiosis
- Fungal pneumonia
- Rhodococosis
- lymphoma
96
 Case 5
• Stool: RBC 1-10/HPF, WBC 1-10/HPF, no
parasite, mod. acid-fast stain negative

• Sputum negative for AFB x 2

• Sputum for Gram stain: numerous Gram +

cocci, few budding yeasts with capsules,

bacterial culture - moderate growth of

yeasts

97
 Case 5
• BAL: C. neofromans

• Serum cryptococcal Ag + 1:256 • TBB: acute and chronic

• L.P. inflammation with yeasts

CSF open pressure 8 cmH2O
WBC 1, RBC 12,650, protein 67
mg/dL, glucose 42 mg/dL, india
ink negative, cryptococcal Ag
negative
suggestive of Cryptococcus
• H/C for bacteria: C.
neoformans
• H/C for mycobacteria: C.
neoformans

• H/C for fungus: C.

neoformans

98
 Cryptococcal pneumonia
 Exposure
– Ubiquitous
 CD4 < 100
 Clinical features:
– fever (80-90%)
– cough
– dyspnea
– Chest pain, hemoptysis
– Non pulmonary symptoms: headache, papular
skin lesions
– > 50 % of patients are fungemic, and
90% have concomitant CNS infection Encapsulated yeast of C.
 Radiographic findings: diffuse interstitial neoformans
infiltrates, focal consolidation, cavitary
disease, nodules, adenopathy and
pleural effusion
 Diagnosis:
– Lumbar puncture:
India ink staining(76%), Cryptococcal
antigen, and culture(95%).

99
 CRYPTOCOCCOSIS
 Prognosis:  Primary prophylaxis:reduces
 mortality rates as high as 30% disease frequency in advanced disease
despite therapy
 Recommended in Thailand
 Not routinely recommended in US
 Treatment (USPHS/IDSA)
 Induction  CD4 < 100 /mm3
 amphotericin B iv daily for 14  Exclusion of cryptococcal
days meningitis
 Negative serum crypto Ag (if
 Fluconazole 400-800mg/day available)
in mild case  History & Clinical examination
 Consolidation  Regimen
 fluconazole 400 mg po daily  Fluconazole 400 mg weekly
for 8 -10week  Secondary prophylaxis :until
 repeat LP, with measurement CD4> 200 for at least 6 months
of opening pressure, if
patient remains symptomatic  fluconazole 200 mg/day
(especially persistent  amphotericin B 1 mg/kg//eek (less
effective than fluconazole)
headache)
 itraconazole 100-200 mg po bid
(less effective than fluconazole) 100
 Histoplasmosis (Histoplasma capsulatum)

 Endemic in northen part

 CD4 < 100 cells/uL
 Exposure : soil; particularly soil associated
with bird roosts, and caves
 most common: fever and weight loss, ~ 75%
of patients
 Respiratory complaints ( cough and
dyspnea), abdominal pain or
gastrointestinal bleeding
 5-10% have an acute septic shock-like
syndrome, very poor prognosis
 Skin lesions: uncommon, molluscum
contagiosum-like
 Typical radiographic findings are diffuse
interstitial or reticulonodular infiltrations
with hilar or mediastinal adenopathy.

101
tum

Diagnosis
Presumptive: 1.microscopy on
smear. : small budding yeasts
intracellular and extracellular,
grapelike
2.polysaccharide antigen in urine
or blood ( sensitivity 93% and
89%, respectively.)

Definitive: blood/ BAL fluid

culture
DDx:
other disseminated
mycobacterial or
fungal disease

102
 Histoplasmosis
USPHS/IDSA 2004 Thailand
 Treatment: Histoplasmosis Peniciliiosis
– amphotericin iv for 2 weeks then
itraconazole 200mg po bid for 10
weeks

– amphotericin 0.7 mg/kg/day iv for Primary Optional in Endemic Optional in Endemic

3-10 days then itraconazole prophylaxis area Itraconazole 200 mg
200mg po bid for 12weeks [2004 Itraconazole 200 mg po
daily
po daily
USPHS/IDSA Guidelines for
histoplasmosis]

Secondary Strongly recommended: Strongly

prophylaxis Itraconazole 200 mg po recommended:
 In mild cases: daily until CD4> 150-200 Itraconazole 100-200
– Itraconazole 200 mg po bid for 12 cells/uL for at least 6 mg po daily until
weeks months CD4> 150-200 cells/uL
for at least 6 months

2004 USPHS/IDSA Guidelines 103

 Case 6
• 32 y/o homosexual HIV-infected male with history of
PCP, CD4 = 75/mm3
• Medications: TMP/SMX DS 1 tab OD, fluconazole
400 mg/wk
• Developed violaceous nodules and plaques on face,
extremities, back and ears that progressively
increased in number and size over the past 3
months.
• He has had dry cough, increasing SOB for 2 weeks

104
 Case 6
• Exam: T 37.5oC, RR 28/min,
skin lesions as stated
violaceous lesion on the palate
Lungs – crackles both lungs
• O2 saturation at room air = 89%
• Chest x-ray

What is the most likely

diagnosis?

105
 pulmonary KS
• 16% had disease limited to the lungs
(Aboulafia DM. Chest 2000:117:1128-1145)

• The disease may be asymptomatic

even with extensive abnormalities on
CXR
• Typical radiographic findings: nodular
infiltrates + pleural effusions
• Diagnosis
– Visualization of characteristic
purplish plaques on bronchoscopy
• Treatment :
– HAART can induce significant
improvement in pulmonary KS and
sustained remissions (aboulafia DM. Mayo Clin
Proc 1998;73:439-443, Holkova B. J Clin Oncol.
2001;19:3848-3851.)
– Chemotherapy is indicated for
symptomatic pulmonary disease

106
 Pulmonary lymphoma

• Radiographic findings : nodules, masses, and pleural effusions

• Nonspecific findings that suggest lymphoma
– Elevated LDH
– A positive gallium scan corresponding to the area of abnormality on chest
imaging.
• HAART ( Aboulafia DM. AIDS Read 2004;14:605-617, Ratner L. J Clin Oncol 2001;19:2171-2178, Powles T, AIDS 2002;16:531-
536)

– increases the response rate to chemotherapy

– maintains the immune function
– Improves patients’ survival rates

107
 Pulmonary hypertension

• It occurs at all stage of HIV disease

• Variable CD4 and HIV RNA levels at the time of presentation.
• The pathogenesis of HIV-related pulmonary HT remains unclear.
• Clinical symptoms : progressive dyspnea, cough, fatique, pedal edema and
chest pain
• PE: right ventricular hypertrophy or failure is helpful
• Echocardiogram: right atrial hypertrophy elevated pulmonary pressures
• Management: same as for HIV negative patients
– Prostaglandin agonists (epoprostenol and iloprost) and bosantan*( McLaughlin VV.
Am J Respir Crit Care Med. 2006;174:1257-63)
– Diuretics for RHF
– Anticoagulantion
– Sildenafil ( drug interaction with PI)
– HAART may be beneficial ( Nunes H. Am J Respir Crit Care Med 2003;167:1433-1439, Zuber JP. Clin
Infect Dis; 38:1175-1185.)
• Prognosis is grave, 70% of patients died from PAH related mortality such as RHF

108