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Tropical Medicine > TB & Pulmonary > Flashcards

TB & Pulmonary Flashcards

1
Q

What sort of sample provides best chance of diagnosing extrapulmonary Tb?

A

Tissue (e.g. pleural biopsy rather than fluid)

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2
Q

What pattern of Tb is more common in immunosuppressed?

A

Disseminated Tb, miliary Tb, extrapulmonary Tb. Atypical chest x-ray findings and negative sputa.

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3
Q

What is standard short course therapy for Tb? What is treatment success rate?

A

2RHZE + 4RH: 2 months of rifampin (R), izoniazid (H), pyrazinamide (Z) and ethambutol (E); followed by 4 months of rifampin and izoniazid. Tx success>95%

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4
Q

TB: What is the standard therapy for CNS disease?

A

2RHZE + 10RH

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5
Q
  • What is the differential diagnosis for pneumonia in HIV infected patients?
A
  • Bacterial pneumonia
    • strep. pneumonia
    • staph
    • others according to local patterns
  • Tb
  • Pneumocystis
    • if CD4<200, not on PCP prophylaxis
  • Viral
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6
Q
  • Pneumonia: What are the similarities and differences of epidemiology in low-income vs high-income settings?
A
  • Similarities
    • Main pathogen still strep pneumonia
    • other bacteria may vary according to local patterns
    • viral pneumonias, chlamydia, mycoplasma need to be considered
    • influenza pneumonia may not show seasonal variation
  • Differences
    • age distribution
      • disease of elderly with comorbid chronic disease in well resourced countries
      • of children and middle-aged in low resourced countries
      • men particularly high in regions of Africa with high incidence of HIV
    • need to consider high prevalence in lower income countries
      • Tb
      • PCP in HIV endemic areas, esp Africa
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7
Q
  • What are the WHO IMAI guidelines for classifying cough or difficulty breating?
A
  • In all pts with cough or difficulty breathing and one or more of
    • very fast breathing or
    • high fever (39o or above) or
    • pulse 120 or more or
    • lethargy or
    • not able to walk unaided or
    • uncomfortable lying down or
    • severe chestpain, THEN
      • ​CLASSIFY AS SEVERE PNEUMONIA or VERY SEVERE DISEASE AND TREAT
        • ​position
        • give Oxygen
        • if wheezing, treat
        • consider and treat ischemia
        • if known heart disease and uncomfortable lying down then give furosemide
        • refer urgently to hsopital
        • consider HIV related illness
        • if on ARV thereapy this could be serious drug reaction
  • If two of the following:
    • fast breathing
    • night sweats
    • chest pain, then classify as
      • pneumonia and
        • give appropriate oral antibiotic
        • exceptions: if 2nd or 3rd trimester pregnancy, HIV clinical stage 4 or low CD4 count, give first dose IM antibiotics and refer urgently to hospital
        • if wheezing present, treat
        • if smoking counsel cessation
        • if on ARV therapy, consider serious drug rxn and consult or refer
        • if cough>2 wks or HIV, send sputum for AFB
        • advise when to return to clinic
        • Follow up in 2 days
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8
Q
  • What are first line treatments for pneumonia due to the following organisms:
    1. S. pneumoniae:?
    2. H. influenza: ?
    3. S. aurues:?
    4. Legionella species: ?
    5. Aerobic gram negative rods: ?
A
  1. S. pneumoniae: narrow spectrum Beta lactam
  2. H. influenza: broad spectrum Beta lactam
  3. S. aurues: flu cloxacillin or flucloxacillin
  4. Legionella species: fluoroquinolone
  5. Aerobic gram negative rods: pip taxo
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9
Q
  1. Describe 1st line antibiotic treatment for non-severe pneumonia.
  2. For severe pneumonia.
A
  1. amoxicillin
  2. ceftriaxone + macrolide
    • ampicillin + gentamycin + macrolide
  3. empirical PCP treatment if HIV-positive
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10
Q
  • What to do in HIV-positive patients with SEVERE PNEUMONIA OR VERY SEVERE DISEASE when referral is impossible
A
  • send sputum for AFB if possible
  • treate empirically fo bacterial pneumonia with IM antibiotics
  • If pt has very fast breathing or unable to walk unaided treat empirically for PCP
    • give SMT-trimethoprim 2 double strength tabs TID x 21 days (15 mg/kg tmp component)
    • give supplemental O2 if available
  • Assess pt daily, consult and discuss case with medical officer if possible and continue to try to refer
  • after 3-5 days, if breathing rate and fever same or worse, start standardized, first lin TB regimen if available or refer to district hospital. Ensure completion of regimen.
  • If breathing slower or less fever, start first line oral antibiotic and finish 7 day course. If PCP tx started then continue for 3 weeks
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11
Q
  • Differential diagnosis of treatment failure in CAP
    • how organized
A
  • Wrong diagnosis
    • Tb and PCP common causes of treatment failure
  • Wrong antibiotic
  • Severe disease +/- comorbidity
  • Complication
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12
Q
  • What is Sputum GeneXpert MTB/RIF?
    • Sensitivity, specificity in non-HIV and HIV pts.
A
  • sensitive, specific sputum DNA analyis by Nucleic Acid Amplification for Tb
    • sensitivity about 90%, specificity about 98% in non-HIV infected pts
    • in HIV infected pts, sensitive 58 to 90% sensitivity
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13
Q
  • Compare and contrast pneumocystis pneumonia with Bacterial pneumonia
A
  • pneumocystis jirovecii pneumonia
    • exertional dyspnea, dry cough, frothy sputum
    • prolonged (>2 wk) symptoms
    • Lack of cotrimoxazole prophylaxis
    • CD4<200
    • LDH>600
    • hypoxia
  • bacterial pneumonia
    • short symptom duration
    • pleuritic pain
    • associated shock, confusion, renal failure
    • raised WCC
    • raised CRP
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14
Q
  • What are first and second line treatments for PCP?
  • Adjuvant treatment?
A
  • 1st Line: TMP-Sulfamethoxazole 120 mg/kg/day x 3 days then 90 mg/kg/day x 18 days
  • 2nd Line:
    • (Clindamycin 600 mg iv/po qid + primaquine 15-30 mg daily) x 21 days
    • pentamidine 4 mg/kg iv for 21 days
    • atovaquone 75 mg po bid x 21 days
    • (trimethoprim 20 mg/kg/day + dapsone 100 mg daily) x 21 days
  • Adjuvant treatment with corticosteroids significantly reduces the risk of death in patients presenting with severe PCP
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15
Q

Summary card for pneumonia case:

Learning points

(no question)

A
  • Non-resolution of pneumonia at 72 hrs should prompt questions:
    • Wrong diagnosis?
    • Wrong antibiotic?
    • Complication?
    • Or due to severe disease? ?Comorbidity
  • HIV testing is major branch point in developing differential for infectious disease: consider esp Tb and PCP
  • Microbiological tests, inc blood cultures and sputum microscopy, often have poor diagnostic value in pneumonia
  • Knowledge of local disease epidemiology - if available - can guide empirical treatment decisions.
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16
Q
  • Childhood TB: some points about epidemiology and patterns of infection
A
  • young children usually contract it from extended family, esp. females
  • Contact tracing and prophylaxis important but seldom done in low and middle income countries.
  • most children asymptomatic
  • young children rarely infectious
  • usually diagnosed as opposed to confirmed (most often smear and culture neg.)
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17
Q
  • TB: What region of the lungs is most prone to reactivation?
A
  • Upper lobes
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18
Q
  • TB children:
    • What ages are at highest risk of developing clinical disease?
A
  • under 5’s esp < 12 months (40%)
  • also adolescence (10-20%)
  • Risk of developing disease is greatest in first 1-2 yrs after infection.
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19
Q
  • TB: How might disease extend from Primary Pulmonary TB?
A
  • Primary pulmonary TB►
    • extension of pulmonary focus
    • extension of hematogenous lesions
      • Brain 6 mo
      • Bone 1-3 yr
      • Kidney 7+ yr
    • complications of regional nodes
    • disseminated dease (miliary), esp if immune suppressed
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20
Q

What is this?

A
  • A Ghon focus is a primary lesion usually subpleural, often in the mid to lower zones, caused by Mycobacterium bacilli (tuberculosis) developed in the lung of a nonimmune host (usually a child).
  • A Ghon focus is a rounded, well-defined focus of calcific density (as dense as bone) usually located in the periphery of the lung
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21
Q

What is miliary TB?

A
  • Miliary tuberculosis (TB) is the widespread dissemination of Mycobacterium tuberculosis via hematogenous spread.
  • Classic miliary TB is defined as milletlike (mean, 2 mm; range, 1-5 mm) seeding of TB bacilli in the lung, as evidenced on chest radiography.
  • This pattern is seen in 1-3% of all TB cases.
  • Miliary TB may occur in an individual organ (very rare, < 5%), in several organs, or throughout the entire body (>90%), including the brain.
  • The infection is characterized by a large amount of TB bacilli, although it may easily be missed and is fatal if left untreated.
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22
Q

Once infected with TB, what is the average lifetime risk of developing TB disease in low-prevalence HIV populations?

A

5-10%

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23
Q

On average, of all cases presenting with TB disease, what percentage will be pulmonary?

A

85%

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24
Q

On average, of all cases with TB, what percentage of pulmonary disease presentations will be smear positive?

A

50%

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25
Q
  • Describe the natural hx of untreated TB?
    • What percentage will be ill and chronically infectious?
    • What percentage will be dead?
    • What percentage will be healthy and non-infectious?
A
  • Ill and infectious: 25%
  • Dead: 50%
  • Healthy and non-infectious: 25%
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26
Q

What is DOTS?

A
  • Directly Observed Treatment: Short course (WHO, 1999)
  1. Government commitment to sustained TB control activities.
  2. Case detection by sputum smear microscopy among symptomatic patients self-reporting to health services.
  3. Standardized treatment regimen of six to eight months for at least all confirmed sputum smear positive cases, with directly observed treatment (DOT) for at least the initial two months.
  4. A regular, uninterrupted supply of all essential anti-TB drugs.
  5. A standardized recording and reporting system that allows assessment of treatment results for each patient and of the TB control programme overall.
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27
Q

What are the standard antituberculous drugs and their abbreviations?

A
  • R: rifampicin
  • H: izoniazid
  • Z: pyrazinamide
  • E: ethambutol
  • S: streptomycin
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28
Q

What is the significance of gibbus deformity?

A
  • >90% specific for TB spine
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29
Q

What is the typical pattern of TB spine pathophysiology leading to Gibbus?

A

Tends to invade anterior aspect of vertebral body first leading to marked angular deformity and gibbus.

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30
Q

What are definitions of Cure following treatment of TB

A
  • smear or culture
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31
Q

WHO 2017 Guidelines for treatment of Drug-susceptible TB:

What is recommended treatment regimen?

A
  • 6 month rifampicin based regimen remains recommended regimen
    • i.e. 2HRZE/4HR
      • (Strong rec, moderate certainty)
    • favour fixed drug combi tabs
    • daily (vs 3/wk) dosing recommended
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32
Q

WHO 2017 Guidelines for treatment of Drug-susceptible TB:

What are recommendations for patients co-infected with HIV?

A
  • start ART in all TB/HIV patients regardless of CD4 count
    • start TB treatment first, then ART ASAP within 8 weeks (strong rec, high cert)
    • profoundly immunosuppressed pts (CD4<50 cells/mm3) should start ART within 2 wks
    • 6 months standard tx recommended over extended 8 mo tx
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33
Q

WHO 2017 update on drug sens TB:

What are recommendations re adjuvant steroids in TB meningitis?

TB pericarditis?

A
  • adjuvant steroids (dex or prednisolone x 6-8 wks)
    • should be used in TB meningitis
    • may be used in TB pericarditis
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34
Q

WHO 2017 update on drug sens TB:

What are the category II regimens previously recommended?

What are the updated recommendations regarding their use.

A
  • Previously rec Cat II regimens:
    • 2HRZES/1HRZE/5HRE or
    • 2HRZES/1HRZE/5(HRE)
  • No longer recommended. Instead recommend drug-susceptibility testing
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35
Q

What are the main microbes causing pneumonia in Europe?

(Lim. Brit Thor Soc 2011. Welte et al. Thorax 2012. Gutierrez et al. J Infect 2006)

A
  1. Unknown
  2. Strep. pneumonia
  3. Viruses
  4. Chlamydophilia pneumoniae
  5. Hemophilus influenzae
  6. Mycoplasma
  7. Legionella
  8. Coxiella burnetti
  9. Enterobacter
  10. Staph
  11. Pseudomonas
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36
Q

Outline a pragmatic approach to teatment of acute pneumonia using WHO AMAI Guidelines for severity of cough or dyspnea.

If HIV +ve?

A
  • pneumonia
    • oral abx: amoxicillin
  • severe pneumonia
    • ceftriaxone plus macrolide
    • amp + gent + macrolide
  • If HIV +ve empirical PCP treatment
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37
Q

What is the Curb 65 Scoring system and why important?

A

Predictor of morbidity and mortality.

severity assessment essential to pneumonia management.

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38
Q

Outline the pragmatic approach to HIV +ve patient with severe pneumonia or very severe diseases when referral to hospital is impossible.

A
  • send sputum for AFB if possible
  • treat empirically for bacterial pneumonia with IM antibiotics
  • if very fast breathing or unable to walk unaided, treat empirically for PCP.
    • 3 ds tabs tid (15 mg/kg tmp) x 21 days
  • supplemental O2
  • reassess daily
  • if T & RR no better after 3-5 days start first line TB tx or refer. Ensure completion of TB tx.
  • if improving complete oral course abx or PCP tx
39
Q

What pneumoccal vaccine is effective in HIV?

Which one is not?

A
  • pneumococcal conjugate vaccine is effective in HIV (Prevnar 13)
  • pneumococcal polysaccharide vaccine (pneumovax and pneumovax II) are not effective. (Lancet 2000 RCT in HIV infected Ugandan adults)
40
Q

What are the usual presenting symptoms of TB?

What is the negative predictive value of the 4 key symptoms in a setting of high TB prevalence?

A
  • Key sx
    • cough (usually productive)
    • fever
    • wt loss
    • night sweats
  • absence of these in a setting of high TB prevalence has a high negative predictive value for active TB
  • Subacute or chonic presentaiton
  • cough”>2-3 weeks” (but must start at some time)
  • less common sx:
    • chest pain
    • breathlessness
    • hemoptysis
    • fatigue
    • symptoms of co-existing pulmonary disease
41
Q

How are sputum smears graded?

A
  • 0 per 100 fields = 0
  • 1-9 per 100 fields = scanty (record #)
  • 10-99 per 100 fields = +
  • 1-10 per field =++
  • more than 10 per field = +++
42
Q

What is the sensitivity & specificity of SSM?

Using ZN smear?

Using flourescent microscopy + auramine stain.

Gene Xpert?

A
  • ZN smear:
    • Sensitivity 61% (31-89%)
    • Specificity 98% (93-100%)
  • FM adds 9% to sensitivity, not specificity.
  • GeneXpert
    • Sensitivity 92% (70-100%)
    • Specificity 99% (91-100%)
    • PLUS allows detection of Rifampin Resistance
    • WHO recommends for use in diagnosis of pulmonary and extrapulmonary TB in adults and children.
    • 21 Studies
      8880 participants
    • Xpert 23% increase in sensitivity versus microscopy
    • “Xpert MTB/RIF should be used rather than conventional microscopy, culture and DST as the initial diagnostic test in adults suspected of having MDR-TB or HIV-associated TB (strong recommendation, high- quality evidence)
      • sensitivity about 90%, specificity about 98% in non-HIV infected pts
      • in HIV infected pts, sensitivity 58 to 90%
43
Q

Outline an algorithm for the diagnosis of TB in a patient with cough for >2 wks in an HIV-prevalent setting.

A
  • see attached image
44
Q

Describe the pathogenesis of TB meningitis.

A
  • usually not hematogenous, rather granulomata adjacent to meninges or in brain parenchyma (Rich foci) rupture into subarachnoid spread and diffuse throughout CSF and leptomeninges
  • associated vasculitis
  • arachnoiditis, esp around base of brain
  • tuberculomas may be deep in brain parenchyma or adjacent to ventricles, in which case they may rupture and lead to meningitis
  • hydrocephalus may be communicating or non-communicating
45
Q

TB meningitis: outline the clinical features.

A
  • Subacute onset (1-3 weeks)
  • headache
  • vomiting
  • decreased loc
  • confusion
  • constitutional symptoms
  • seizures
  • epidemiological risk (origin, travel, contact)
  • risk of drug resistance (treatment, origin, prison)
46
Q

TB meningitis: outline possible findings on clinical exam

A
  • diminished LOC: Glasgow coma scale
  • Ophthalmoscopy: papilledema, or later, optic atrophy, sometimes choroid tubercles, hemorrhage
  • CN lesions: CN VI most frequently affected, followed by CNs III, IV, VII, and, less commonly others
  • Spinal/radiculopathies
  • sphincter function
  • look for TB elsewhere eg. scrofula
47
Q

Outline staging and prognosis of TB meningitis.

A
  • mortality rate high, approaches 50% in some populations
48
Q

Describe CSF findings in TB meningitis.

A
  • moderately raised cell count
  • lymphocytic pleocytosis
  • raised protein, often very high
  • reduced CSF: plasma glucose ratio
  • raised opening pressure
  • AFB’s rarely seen in routine samples
49
Q

Other than CSF, what other investigations for suspected TB meningitis?

A
  • cxr
  • fundoscopic exam r/o papilledema, choroidal tubercles
  • mycobacterial blood cultures
  • HIV test
  • CrAg on blood or CSF
50
Q

TB Meningitis: Differential Diagnosis

A
  • viral meningitis
  • viral encephalitis
  • TBM
  • Listeria
  • Fungal -cryptococcal
  • partially treated bacterial meningitis
  • parameningeal bacterial infections (cerebral abscesses etc …)
  • mycoplasma
  • HIV
  • syphilis
  • Drugs e.g.
    • NSAIDS
    • trimethoprim
  • Autoimmune encephalitis
  • ADEM
  • MS
  • neoplastic/paraneoplastic
  • vasculitis
  • other autoimmune disorders e.g. SLE
  • migraine
  • sarcoid
  • HaNDL (headache with neurologic deficits and CSF lymphocytosis)
51
Q

How good is Xpert in CSF?

Sensitivity and Specificity?

A
  • Pooled sensitivity 80.5%
  • Specificity 97.8%
52
Q

What are the typical CT findings in TB meningitis?

A
  • basal enhancement, hydrocephalus
  • tuberculoma may show as ring-enhancing (or not)
53
Q

Complications of TB meningitis

A
  • cranial nerve entrapment
  • hydrocephalus
  • infarction
  • enlargement of tuberculomas
  • adhesive arachnoiditis/spinal block
  • one or more in > 90%
54
Q

Outline treatment of TB meningitis

A
  • almost always started empirically
    • 2HRZS/7-10 HR (WHO)
    • 2HRZE/7-10 HR (ATS, NICE)
  • IV/NG route may be necessary
  • recovery prolonged and variable
  • supportive care challenging
55
Q

Additional Drugs for Tb Meningitis

CSF: Plasma Ratio

Side Effects

A
  • Drug CSF:Plasma Ratio Side Effects
  • Ethambutol 20-30% optic neuropathy
  • Streptomycin 10-20% oto and nephrotoxicity
  • Ethionamide 80-90% GI, hypothyroidism
  • Moxifloxacin 80-90% Tremor, confusion, seizures
  • Levofloxacin “ “
56
Q

Summarize Heemskirk et al N Engl J Med 2016; 374:124-134

“Intensified Antituberculosis Therapy in Adults with Tuberculous Meningitis”

A
  • randomized double blind placebo-controlled trial of intensified anti-tb therapy
    • ​​​​location Vietnam
    • standard 2HRZE treatment vs intensified arm with 15 mg/kg Rifampicin vs standard 10 mg/kg + addition of levofloxacin (2HRZEL)
    • primary outcome death at 9 months
  • Conclusion: No difference in survival
  • (previous 2013 open label phase 2 trial in Indonesia had shown survival benefit.)
57
Q

What is the role of LTA4H (Leukotriene A4 hydroxylase) Polymorphism in TB-IRIS?

A
  • Unknown
  • presence of pro-inflammatory TT mutation in non HIV infected pts appears to improve survival in cases of TB meningitis, but has no effect on survival in HIV patients with TB
  • This may be related to a possible increased severity (but not frequency) of TB-Iris in HIV +ve infections in one study, although the IRIS in all cases appeared to respond to steroids.
  • It could simply be that the immune suppression in HIV prevents the pro-inflammatory gene from exerting its beneficial effect on TB meningitis.
58
Q

Pathophysiology, diagnosis and management of Communicating Hydrocephalus in TB and cryptococcal meningitis.

A
  • inflammatory infiltration of basal cisterns interferes with resorption of CSF
  • total CSF volume is ~125 ml and ~500 ml is generated per day
  • diagnosis is formally demonstrated by pneumoencephalography or MRI CSF-flow study
  • Management:
    • BP, Na, O2
    • Repeated LP
    • Acetazolamide
59
Q

Non-communicating hydrocephalus:

What causes it?

How is it managed?

A
  • obstruction of the aqueduct of 4th ventricle foramina
  • Treated with VP shunt
    • good outcomes in 60%
    • Poor outcomes in HIV +ve pts
      • Endoscopic 3rd ventriculostomy is an alternative
      • fewer long term complications, but lower success rate
60
Q

What portion of the global population is latently infected with TB?

A

1/3

61
Q

How much higher is the risk of progressing from latent to active TB in HIV coinfection than in the non-HIV infected population?

A

20-40 times higher

62
Q

What are the advantages of IGRA over TST for the detection of latent TB?

A
  • excellent specificity in low prevalence TB setting: 98% +
  • no cross reactivity with BCG
  • however neither TST or IGRA are reliable in HIV +ve patients
63
Q

What is the most common OI in HIV patients?

The most ocmmon cause of death?

A

TB to both

the incidence of active TB is 20-40 times higher in HIV pts (WHO 2009)

64
Q

What effect does TB have on HIV replication and disease progression?

A

It increases both.

65
Q

How many TB infections worldwide?

HIV infections?

HIV-TB coinfections?

From this:

What proportion of TB patients have HIV?

What proportion of HIV patients have TB?

What proportion of HIV and TB in Africa and SE Asia?

A
  • 9.3 Million TB
  • 33 Million HIV
  • 1.4 million co-infected
  • Therefore 15% of TB pts have HIV
    • 4% of HIV pts have TB
  • 80% Africa; 10% Asia
66
Q

Discuss the incidence of TB in HIV infected pts.

When does it start?

As HIV progresses?

Impact of ART?

What is the impact of TB on HIV progression?

A
  • risk of TB rises immediately with HIV infection, before CD4 falls appreciably
  • increases progressively as CD4 falls
  • ART reduces the risk, but never falls to baseline, remains 4 times higher than non HIV infected pt
  • TB accelerated HIV replication and progression.
67
Q
  • What is the role for Isoniazid Preventive Therapy (IPT) in HIV infected pts in areas of high prevalence?
    • Discuss effects on TB incidence
      • On mortality
    • Discuss issue of duration of therapy
A
  • IPT should be offered to all HIV pts are Mantoux positive and who don’t have active TB.
  • RCT data back to 70’s, most recent sysematic review 2015
  • However, studies have not shown statistically sig red in TB in non-TST +ve patients given IPT (trend only)
  • Despite reduction in TB incidence no studies have demonstrated sig difference in mortality, likely because, although TB the most common cause of death, there are multiple comorbidities at play in HIV infection and it is possible these have not been optimally addressed
  • Duration of IPT?
    • WHO recommends IPT for at least 36 months of all HIV infected adults (WHO Guidelines 2016)
    • Children older than 1 year living with HIV should receive 6 months of IPT
    • children <12 months old living with HIV should only receive IPT if they have had contact with Tb infected person and have been investigated for TB
    • All HIV infected children after completing course of treatment for TB should receive a further 6 months of IPT
    • recommendations are conditional because of infrastructure and economic restraints (e.g. cost of 36 months over 6 months approx $3000 and ‘bought’ 1 extra month of life expectancy from 136 to 137 months.
    • other unsettled concerns are impacton on INH resistance
68
Q

What particular concerns pertain to the clinical features and treatment of HIV/TB co-infection?

i.e. How does presence of HIV affect presentation and diagnosis?

Considerations for treatment?

A
  • IPT should be offered to all TST+ve patients
  • Altered clinical presentation:
    • increase in smear neg pulmonary disease
    • increase in extra-pulmonary disseminated forms as CD4 falls
  • Sputum smear microscopy less sensitive during HIV-infection
  • Typical and atypical chest xray features depending on severity of immunosuppression
  • Risk of IRIS
  • Drug-drug interactions
69
Q

What is the significance of Extra-Pulmonary TB and HIV?

A
  • more common as CD4 falls
  • presence of EPTB classifies HIV as Clinical Stage 4
  • associated with higher mortality
  • normal cxr does not exclude TB, get samples if possible
  • often presents in atypical fashion so empiric treatment may be needed in order to save lives
70
Q

Discuss the use of empiric anti-TB therapy in patients with advanced HIV

A
  • incidence of TB and death due to TB with advanced HIV very common, and may be difficult to diagnose because sputums more commonly neg in HIV, as is sensitivity of GeneXpert.
  • so in a patient who is symptomatic and ill, empiric treatment of unconfirmed TB is essential strategy
  • On the other hand, a strategy of empirically initiating ATT in pts with CD4<50 and starting ARV who did not have suspected or confirmed TB showed no benefit over standard IPT (Hosseinipour et all, Lancet 2016).
  • This was the REMEMBER study. REMEMBER not to treat for HIV infected people for TB empirically unless you think they probably have TB.
71
Q

Early vs Late Start to ART with TB co-infection?

What are the issues.

A
  • treating ART early associated with increased risk of Tb-associated IRIS
    • Drugs:
      • problems with synergistic toxicity
      • drug interactions
      • adherence
  • treating late may be associated with early mortality associated with poor immune response
    • progression of HIV
    • other OI’s
72
Q

How soon should ART be started after onset TB treatment?

A
  • WHO guidelines call for start from 2-8 weeks after start of TB treatment for all patients found to be coinfected with HIV
  • studies to date indicate consistent benefit of ART within 2 weeks when CD4<50
  • however at higher CD4 levels, no evidence of benefit with early start
  • however, evidence of harm with TB meningitis: should be deferred until completion of intensive phase of TB therapy (i.e. 8 wks)
73
Q

Outline the treatment of IRIS.

What is the mortality rate associated with IRIS?

A
  • no treatment needed in most cases
  • no need to stop arv’s
  • continue TB treatment
  • symptomatic treatment
  • Anti-inflammatory drugs - NSAIDS
  • consider steroids
  • consider drainage of abscesses
  • mortality with IRIS is low <3%
74
Q

What is IRIS?

A
  • Immune reconstitution syndrome
  • a paradoxical worsening of symptoms of an opportunistic infection after commencing treatment of the infection or of the immune-suppressing disorder esp HIV.
  • TB-IRIS may occur in HIV negative persons
  • asociated with low CD4 count at onset of treatment
  • and varies with the interval between TB and HIV treatment
    • occurs overall in 12% of HIV patients treated for TB
    • in 30% of those starting ART within 2 months
    • 4% overall hospitalized
    • 1% died
    • usually manageable with steroids
75
Q

What are the TB-IRIS Case Definition Criteria?

(Meintjes Lancet ID 2008)

A
  • A) Antecedents: Both of
    • dx of TB fulfils WHO critera pre-ART
    • initial response to treatment prior to ART
  • B) Clinical criteria (1 major or 2 minor)
    • Major
      • New/enlarging LNs, cold abscesses or other focal tissue involvement
      • New/worsening xray features of TB
      • New/worsening CNS TB
      • New/worsening serositis (pleural/pericardial effusion)
    • Minor
      • New/worsening constitutional symptoms (fever, wt loss, night sweats)
      • New/worsening resp sx (cough, dyspnea, stridor)
      • New/worsening abd pain (peritonitis, hepato/splenomegaly, abdominal adenopathy)
  • C) Exclude alternative explanations if possible:
    • poor adherence
    • TB resistance
    • another OI or neoplasm
    • Drug toxicity
76
Q
  • Name 4 risk factors for IRIS and one for Tb IRIS
A
  1. low cd4 count
  2. high viral load
  3. rapid reduction in viral load
  4. rapid rise in cd4 count
  5. ARVs started early <2 months after treatment of TB
77
Q

What is Rifampicin Auto-Induction?

What effect may this have on co-administered drugs?

A
  • rifampicin is the most potent known inducer of cytochrome p450
  • it induces expression of cytochrome 2B6 by 9 fold and 3A4 by 55 fold
  • may reduce blood levels of co-administered drugs
  • co-administered drugs may also affect rifampicin level
78
Q

What effect does Rifampicin have on NRTI’s.

A
  • none, but a regimen made up of 3 NRTI’s is less effective
79
Q

What is the interaction between Rifampicin and nevirapine what are it’s clinical implications.

What is a preferred drug in such circumstances in place of nevirapine?

A
  • Nevirapine is metabolized by cytochrome P450 and 3A4 and 2B6
  • it leads to a 20-55% reduction in NVP levels
  • the usual 2 wk dosing in schedule of 200 mg bid should therefore be omitted and dosing proceed directly to 300 mg bid
  • there is a risk of hepatotoxiciy if the dose of nevirapine is increased
  • ideally nevirapine should be avoided if possible. If already taking may continue
  • higher virological failure on NVP during TB treatment may be the possible effect of dosin in
  • EFV is preferred
80
Q

Outline interaction between Rifampicin and Efavirenz and its clinical significance.

A
  • Efavirenz primarily metabolized by CY P2B6, therefore less interaction
  • auto-induction milder, with 20-30% reduction in levels
  • higher interindividual variability due to polymorphism
  • no evidence for dose adjustment
  • concerns about increasing the dose of efavirenz to 800 mg because of neurotoxicity
81
Q

What is the interaction between Rifampicin and Protease Inhibitors?

A
  • main enzyme for PI metabolism is Cytochrome 3A4
  • Co-administration is contraindicated in all except ritonavir
  • Rifampicin AUC increases by 25-73%
  • SEVERE HEPATOTOXICITY IN STUDIES OF HEALTHY VOLUNTEERS
  • severe interaction, AVOID. If needed, consider rifabutin (but cost a major problem)
82
Q

Discuss the advantages and disadvantages of Rifabutin for combined treatment of HIV/TB.

A
  • weakest inducer of PXR among current rifamycins
  • may be used cautiously with some protease inhibitors, but not ritonavir, which markedly increases Rifabutin AUC
  • adverse effects: Hepatotoxicity, Uveitis
  • Adjustment: reduce rifabutin dose to 150 mg 3x/weekly
  • some recommend 300 mg 3x/week or 150 mg daily b/c risk of insufficient rifabutin levels and resistance
83
Q

Rifabutin ?Rifampin & Integrase inhibitors & CXCR5 antagonists.

A
  • avoid raltegravir as levels reduced by 40-60%
  • double doses of raltegravir and dolutegravir if they must be used
  • also reduces level of maraviroc by 78% - avoid or increase dose if must be used
84
Q

What are the 6 classes of Antivirals?

A
  1. Nucleoside reverse transcriptase inhibitors (NRTIs).
  2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs).
  3. Protease Inhibitors (PI).
  4. Attachment inhibitor (CCR5).
  5. Fusion inhibitors (T20).
  6. Integrase inhibitors.
85
Q

What are the currently available antiretrovirals?

abbreviations?

A
  • NRTIs (all nucleoside analogues except TDF, which is nucleotide analogue
    • pyrimidine analogues
      • emtricitabine (FTC)
      • lamivudine (3TC)
      • zidovudine (AZT)
      • stavudine (D4T)
    • purine analogues
      • tenofovir (TDF) (nucleotide analogue)
      • abacavir (ABC)
      • didanosine (DDI)
  • NNRTIs
    • efavirenz (EFV)
    • nevirapine
    • rilpivirine
    • etravirine
  • PIs
    • atazanavir
    • darunavir
    • fos-amprenavir
    • lopinavir
    • saquinavir
    • tipranavir
  • PK booster
    • ritonavir/cobistat
  • Fusion Inhibitors
    • enfuvirtide (T20)
  • Entry Inhibitors
    • maraviroc
  • Integrase inhibitors
    • raltegravir
    • elvitegravir
    • dolutegravir
86
Q

Tenofovir

Abbreviation

Class

Adverse effects

A
  • TDF
  • NRTI - nucleotide analogue - purine
    • proximal renal tubulopathy
    • Fanconi ‘s syndrome
    • loss of BMD
87
Q

D4T, AZT, DDI

adverse effects

A
  • lipodystrophy
  • lactic acidosis
  • pancreatitis
  • peripheral neuropathy
  • macrocytic anemia
  • liver cirrhosis
88
Q

NNRTI’s

adverse effects

A
  • EFV - Efavirenz - CNS toxicity
  • NVP - Nevirapine - rash, liver
  • ETR - Etravirine - Rash
  • RPV - Rilpiravine
89
Q

Protease Inhibitors

Names, abbreviations

major toxicity

A
  • potent viral suppression
  • SAQ: saquinavir
  • LPV: lopinavir
  • RIT: ritonavir
  • ATZ: atazanavir: jaundice, renal stones
  • DRV: darunavir
  • ALL CAUSE DIARRHEA
    • insulin resistance, diabetes, dyslipidemia
    • lipodystrophy
    • hepatitis
    • avascular necrosis
90
Q

Integrase Inhibitors

names

mech of action

efficacy

tolerability

drug interactions

A
  • Raltegravir, Elvitegravir, Dolutegravir
  • strand transfer inhibitors
  • rapid viral load drop
  • good tolerability
  • durable
  • fewer drug interactions
91
Q

Fixed dose combinations

Which are available?

Which most useful?

A
  • Triple
    • Trioday & Viraday: TDF, 3TC, EFV
    • Trizivir: AZT, 3TC, ABC
    • Triomune: D4T, 3TC, NVP - less useful because toxicities
  • Dual
    • Combivir: AZT, 3TC
    • Kivexa: ABC, 3TC
    • Truvada: TDF, FTC
    • Kaletra: Lop/r
92
Q

What was the START study and what were its implications?

A
  • Strategic Timing of Antiviral Terhapy (START) study 2015
  • international randomised trial comparing immediate CD4>500 to deferred CD4<350 cells
  • primary endpoint serious AIDS event, serious non-AIDS event or death from any cause
  • Outcomes: 57% risk of serious events or death with immediate ART
  • 68% of primary endpoints occured in pts with CD4>500
  • 72% reduced risk of serious AIDS events with immediate ART
  • reduced risk of cancers with immediate ART
  • trial stopped early
  • Foundation for WHO recommendation for immediate ART in all HIV patients
93
Q

What was the SAPIT study and what were its implications?

A
  • Starting ART at 3 Points in TB treatment (standard 4EIRP then 6EI
  • open label randomized 3 arm controlled trial
  • in South Africa, reported in 2011 NEJM
  • pts newly diagnosed with TB & HIV all treated for TB with standard 2mo RHEP then 4 mo RI. Pts prev treated for tb had intensified regimen
  • In terms of ART randomized to 3 treatment arms
    • early integrated to start ART (ddi, 3TC, EFV) within 4 wks of start TB
    • late integrated to start within 4 wks of completion of 8 wk intensive treatment arm
    • sequential to start after completion of TB tx (i.e. after 24 wks)
  • study halted early because of 56% lower mortality in integrated treatment arms.
  • then followed to differentiate the outcomes in early vs late integrated arms
  • outcomes for CD4<50 there was a 68% reduction in AIDS or death
  • no difference for those with CD4>50
94
Q
  • How useful is the absence of pulmonary and systemic symptoms in ruling out TB.
A
  • In settings of high prevalence of TB, absence of the four key symptoms cough, fever, weight loss and night sweats (often with chest X-ray) has been shown to have high negative predictive value for active TB.

Tropical Medicine (17 decks)

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