hiv and tuberculosis – the deadly combination
TRANSCRIPT
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HIV and Tuberculosis the
deadly combinationPanel discussion
Moderator : Dr.Govindaraju MPanelists: Dr Shivananda
Dr BalasubramaniamDr.Atul Agarwal
Dr. Sharad Thora
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Question - Why is this
combination so deadly?
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Impact of HIV on TB
Palme et al found that TB childrenwho were HIV + were:
- Younger
- Underweight
- 6 fold increase in mortality
- only 58% cure rate
- More severe manifestations
- Progression to death more rapid
Palme et al . Impact of HIV-1 infection on clinical presentation,treatment outcome and survival in a cohort of Ethiopian children withTB. Pediatr Infect Dis J 2002; 21:1053-61
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Question : What are the
possibilities
Dr.Sharad Thora
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Question : What are the
possibilities Fever, Altered sensorium andconvulsions a triad of CNS Infection:
Pyogenic meningitis
TB meningitis
Viral encephalitis
Cerebral malaria
Rickettsial encephalitis
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Case scenario
Family history:
- Father died of tuberculosis 2 yearsback and was being treated for thesame.
- Mother is alive and well, with nocomplaints
Past history:
- He has never been hospitalized
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Case scenario
On examination:
- Grade III PEM
- Cervical lymphadenopathy multiplematted lymph nodes
- Pallor +
- Right sided Facial nerve palsy + withright sided hemiparesis
- Chest clear
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Diagnosis: Right sidedhemiplegia with facial nerve
palsy probably due to
Tuberculous meningitis
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Case scenario
CT scan of the brain showed:
- Hypo dense lesions in left parietallobe and internal capsule
-Two ring enhancing lesions in the leftparietal lobe
- Diffuse cerebral edema +
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A diagnosis ofNeurotuberculosis
meningitis made!
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Question Do yourecommend HIV testing in
all children with TBM?
Dr.Balasubramaniam
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Prevalence
What is the prevalence of TB inHIV +?
What is the HIV seroprevalencein children with TB?
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Prevalence of TB in HIVinfected children
Author N Tuberculosis %
Shah I 2005 317 43.4%
Shah SR 2005 50 38%
Madhivanan P 2004 58 35%
Verghese VP 2002 88 12%
Merchant RH 2001 285 29.47%
Dhurat 2000 55 67.5%
Lodha 2000 27 13%
Tuberculosis is reported in 14 to 54% ofIndian children with HIV/AIDS
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HIV seroprevalence in childrenwith TB
Author Seroprevalence
South African study group 42%
Merchant and Shroff et al 18%
Karande et al 16.2%
Shahab et al 2%
Greater probability of detecting HIVinfection in children with disseminated
TB
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Question What are theclinical signs that suggest
HIV infection in a child?Dr.Atul Agarwal
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Clinical signs suggestive ofHIV
Failure to thrive < 6 months or history ofweight loss > 6 months
Recurrent bacterial infections
Generalized symmetricallymphadenopathy
Extensive oropharyngeal candidiasis
Generalised rash
Bilateral non tender parotid glandenlargement
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Case scenario
As recommended HIV testing wasdone:
- All three samples were found to bepositive
Hence, child is diagnosed to have HIVwith tuberculosis
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What tests do yourecommend for diagnosis of
TB in this child?
Dr.Balasubramaniam
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Pulmonary TB
Mantoux test
Gastric lavage isolation / sputum forculture and smear
Radio logical Chest X-ray
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Extra-Pulmonary TB
Culture of affected body fluid ortissue obtained by fine needleaspiration or biopsy
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Mantoux test/Tuberculintest
Can be done using 5TU intradermally
Induration > 5 mm is consideredpositive
Negative test seen in 50% childrenwith HIV
Hence negative test does not ruleout tuberculosis
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Gastric Lavage/Sputumexamination
50-70% of adults - + ve
Children with TB disease rarely
produce sputum voluntarily and havea low bacterial load.
Three consecutive morning gastric
aspirates have a better yield than asingle sample.
Better diagnostic yield is seen on
culture.
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Chest X-ray
Localized pulmonary infiltrates withhilar adenopathy
Middle lobe collapse andconsolidation
Pleural effusion
In older children cavitatorytuberculosis.
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Culture
Specimens should be cultured for 2-6weeks by radiometric culturemethods (Bactec).
Culture on L-J medium for 8 weeks.
Antimycobacterial drug sensitivityshould be done on the initial positiveculture if treatment fails or relapseoccurs.
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Others
PCR assays are not useful as primarydiagnostic tool
Negative PCR does not rule out TBand
Positive result does not absolutelyconfirm M.Tuberculosis infection.
False positive rates are high withsensitivity ranging from 45-83%.
Serological tests for TB are not verys ecific
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Question What other differentials
would you consider in viewof this child being HIV+ ?
Do you recommend any
other investigationsDr.Shivananda
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Cryptococcal meningitis
< 1% in children
Patients present with fever,headache and altered mental status.
HIV infected children between 6-12years of age with severeimmunosuppression are prone.
Neck stiffness and focal neurologicaldeficit is rare.
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Cryptococcal meningitis
CSF opening pressure should bemeasured.
CSF analysis with INDIA INK a must
Cryptococcal antigen (SF antigen)titres to be obtained.
Fungal cultures from CSF or blood
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Toxoplasmosis
Acquired primary toxoplasmosis israre.
CNS toxoplasmosis may present asheadache, fever, changes in mentalstatus, seizures, psychosis and focalneurological deficits.
Toxoplasma specific IgG +
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Toxoplasmosis
Space occupying lesion on imagingstudies of the brain ring-enhancinglesions in the basal ganglia and
cerebral corticomedullary junction.
Definitive diagnosis requires
histologic or cytologic confirmationby brain biopsy
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Viral encephalitis
HSV encephalitis
CMV encephalitis
Disseminated Varicella infection
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Case scenario
Other tests done:
- CSF IgM Toxoplasma Negative
- CSF AMA Negative
CD4 count - 440/cu.mm
CD4 % - 22%
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Question At what CD4count in HIV does TBM
occur?Dr.Balasubramaniam
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TB an AIDS defining illness
Diagnosing extrapulmonary TBin HIVis important as it is an AIDS definingillness.
Tuberculosis can occur at any CD4count.
The more atypical the clinicalfeatures, the more likely is the CD4count to be low.
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Case scenario
Chest X ray showed bilateral nonhomogenous opacities, diffuselyinvolving all the lobes of the lung.
ABG :
pH 7.52
pCO2 22
pO2 48
HCO3 - 16
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Question - What is yourdifferential diagnosis for non-
homogenous opacities in a HIV +child?
Dr.Shivananda
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Differential Diagnosis
Miliary tuberculosis
Lymphocytic interstitial pneumonia(LIP)
Pneumocystis jiroveci pneumonia(PCP)
Bacterial pneumonia
Rarely:
- Fungal pneumonia
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Miliary tuberculosis
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PCP pneumonia
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Lymphocytic interstitialpneumonia (LIP)
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Fungal pneumonia
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Question Do you treatwith ATT first or with ART
first?Dr.Atul Agarwal
P i i l f t ti TB
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Principles of treating TBwith HIV
1) Treatment of TB takes precedenceover HIV treatment
2) In patients already on HAART,continue the same withmodifications
3) In those not receiving HAART,initiation depends on CD4 countsand t e of TB
P i i l f t ti TB
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Principles of treating TBwith HIV
If CD4 counts > 15% and nosignificant HIV related illness treat for TB first
Monitor carefully for worsening ofimmune status
If CD4 counts < 15% or significantHIV related illness Treat with ATTand HAART
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Initiation of ART
Starting ARV therapy for theindividual child is rarely anemergency!
Management of life-threateningopportunistic infections can be anemergency.
Treat opportunistic infections beforestarting ART
Any child less than 2 years,
irrespective of CD4 count ART is
R d ti f i iti ti
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Recommendations for initiatingART in infants and children
WHOPaediatric
Stage
Availability ofCD4 cell
measurements
Age-specific treatment recommendation
< 2 years 2 years
4 CD4 Treat all
3 CD4 Treat all Treat all, CD4 guided inthose children with TB,
LIP, OHL,thrombocytopenia
2 CD4 Treat all CD4 guided
1 CD4 Treat all CD4-guided
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CD4 criteria of severe HIVimmunodeficiency
Immunological marker
Age-specific recommendation to initiate ART
11 months 12 months-35 months
36 months-59 months
5 years
CD4 % 25% 20% 15% 15%
CD4 count 1500cells/mm3
750cells/mm3
350cells/mm3
200cells/mm3
ART should be initiated by these cut-off levels, regardless of clinical
stage; a drop of CD4 below these levels significantly increases the
risk of disease progression and mortality
% CD4 is preferred for children
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Case scenario
Child was started on RNTCP Category1 treatment:
- 2HRZES + 4HR for 9 months
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Question Is thistreatment sufficient? How
long do we treat?Dr. Sharad Thora
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ATT in HIV + children
American Thoracic society Minimum duration of 6 months andmay be extended if response is
suboptimal
American Academy of Pediatrics 9
months
Indian Academy of Pediatrics 9months
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Treatment
Treatment of TB in HIV infected childis the same as that for an HIVuninfected child.
However, modified treatmentduration schedule and medications
are recommended for specificinstances.
Treatment of TB should be initiated
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Treatment
For HIV infected children with activepulmonary disease, the minimumrecommended duration ofATT is 9
months.
For children with extrapulmonary
disease involving the bones or joints,CNS or miliary disease, the minimumrecommended duration of treatment
is 12 months.
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Question Should steroids
be started? For how long?Dr. Atul Agarwal
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Role of steroids
Adjunctive use of steroids isindicated in patients with:
- TBM
- Serosal TB
- Miliary TB and
- Endobronchial tuberculosis.
Duration: 6 8
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Case scenario
Child was treated with short coursechemotherapy and monitored withCD4 counts.
After 2 months CD4 counts droppedto 128/cu mm (CD% - 8%)
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Question If you arestarting HAART, whatprecautions to take with
ATT?Dr. Shivananda
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Monitoring
In children with HIV and TB coinfection,periodic monitoring of liver enzymes isadvised.
Mild elevations in serum transaminases(e.g., 2-3 times upper limit of normal) doesnot require discontinuation of the drugs.
All patients should be monitored monthlyfor clinical and bacteriological response.
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Monitoring
For patients with pulmonary TB,Chest X-rays should be obtainedafter 2-3 months of therapy to
evaluate response.
Hilar adenopathy might persist for as
long as 2-3 years despite successfulATT and is not a criteria forcontinuation of ATT.
Adverse drug reactions of
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Adverse drug reactions ofATT in HIV
ADRs increase with advancedimmuno suppression and in the first2 months.
Thiacetazone rashes,hepatotoxicity and fatal ADR contraindicated in HIV
INH more prone to develop INH
Adverse drug reactions of
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Adverse drug reactions ofATT in HIV
Rifampicin with Protease Inhibitorscontraindicated due to interactionwith cytochrome p450 enzymes.
Efavirenz can be used withrifampicin.
Malabsorption of ATT is known in
HIV hence monitor response
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What regimen to use if
the child is on rifampicin?Dr. Sharad Thora
What 1st line regimen to
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guse if the child is on
rifampicin?If starting ART after rifampicin-based anti-TB treatment
Preferred regimen Alternative regimen
AZT or d4T + 3TC + ABC 2NRTI + NVP (in children < 3 years old or weigh < 10 kg)2 NRTI + EFV (in children >= 3 years old)
After completing rifampicin-based anti-TBtreatment, consider switching treatment tostandard first line regimen with 2NRTI+NVPor EFV for better efficacy
Continue treatment after completingrifampicin-based anti-TB treatment.
What 1st line regimen to
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guse if the child is on
rifampicin?If already on first-line ART when starting rifampicin-based ATT
Current first line
regimen
Preferred regimen
2NRTI + EFV Continue the same regimen
2NRTI + NVP Switch to either 2NRTI +ABC or 2NRTI +EFV (if age > 3 years and weigh > 10 kg)
2NRTI + ABC Continue the same regimen
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Is there a role forprophylactic ATT in HIV ?
Dr.Shivananda
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Prophylaxis
All HIV infected children with positiveMantoux test and no evidence ofactive TB or no history of previous
treatment for TB should be treatedfor latent TB.
Regimen 6 months of INH +Rifampicin.
There is no role of sin le dru INH
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Prophylaxis
HIV infected children in close contactwith person with Open TB shouldbe treated for latent TB.
Treat regardless of their MT test andprevious treatment for TB after
excluding active TB.
Regimen 6 months of INH +
Rifam icin
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Case scenario
Child was started on HAART usingefavirenz and zidovudine, along withATT
After 1 month of treatment, he wasbrought with complaints of:
- Spiking fever
- Increasing headache and vomiting
- Increase in size of lymph nodes
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Question What are the
possibilities?Dr. Balasubramaniam
IRIS Immune
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Reconstitution Inflammatory
Syndrome It is a paradoxical reaction that occurs in
the course of ATT when HAART restores
the immune function.
Features include hectic fevers,lymphadenopathy and worsening of TB
Treatment patients generally feel well.Can treat with short term steroids rarely
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How do you treat drugresistant tuberculosis in
this child?Dr.Shivananda
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Drug resistant TB
Minimum of three drugs should begiven, including at least 2bactericidal drugs to which the
organism is susceptible.
Multidrug resistant tuberculosis (i.e.
resistant to INH and RIF) aggressive treatment with a regimean amino glycoside or capreomycin
and a fluoroquinolone
Suggested Regimens
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Suggested RegimensPattern of
drugresistance
suggest
regimen
Minimum
duration oftreatment
comments
H (+/- S) R , Z and E 6 - 9 A fluroquinolonecan be added forpts with extensivedisease
H and Z R ,E and
fluroquinolones
9 - 12 A longer durationfor those with
extensivedisease.
H and E R ,E and
fluroquinol
9 - 12 A longer durationfor those withextensive
disease.
Suggested Regimens
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Suggested RegimensPattern of
drugresistance
suggest
regimen
Minimum
duration oftreatment
comments
R H , E
fluroquinolones plusatleast2 monthsof Z
12 - 18 An injectableagent maystrengthen theregimen for ptswith extensivedisease.
R andE(+/- S)
H , Zfluroquinolones plus aninjectable agent
for at least the
18 A longer course( 6 months) of theinjectable agentmay strengthenthe regimen forpts with extensive
disease.
Suggested Regimens
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Suggested RegimensPattern of
drugresistance
suggest
regimen
Minimum
duration oftreatment
comments
R and Z
(+/- S)
H , E
fluroquinolones plus aninjectable agentfor at least thefirst 2-3months.
18 A longer course( 6 months) of theinjectable agentmay strengthenthe regimen forpts with extensivedisease.
H , E , Z
(+/- S)
R,Fluroquinolones , plusan oral secondline plus an
18 A longer course( 6 months) of theinjectable agentmay strengthen
the regimen for
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When will you suspectatypical mycobacterial
infectionDr. Atul Agarwal
Mycobacterium avium
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Mycobacterium aviumcomplex (MAC)
MAC - M. avium, M. intracellulare,and M. paratuberculosis.
MAC can appear as isolated
lymphadenitis among HIV infectedchildren.
CD4 count < 50 cells/cumm is an
important risk factor for developmentof MAC.
Lungs, liver, spleen, GI tract, bone
marrow and l m h nodes are
Cli i l F
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Clinical Features
Isolated pulmonary disease is rare.
Patients present with recurrent fever, weight
loss or failure to thrive, night sweats, fatigue,chronic diarrhea and recurrent abdominalpain.
Patients have lymphadenopathy,hepatomegaly and splenomegaly.
Associated laboratory findings of neutropenia,anemia and leuko enia are seen
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What investigations willyou consider in MAC with
HIV?Dr.Balasubramanium
Di i
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Diagnosis
Is accomplished by isolation oforganism from blood or biopsy sites(bone marrow, lymph node or other
tissues).
Culture can yield the organisms in 2
weeks.
Culture is necessary for species
identification.
Di i
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Diagnosis
Anemia out of proportion to thestage of the HIV disease
Elevated serum alkaline phosphatasemay be seen.
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What is the treatment of
MAC with HIV?Dr.Shivananda
T t t
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Treatment
Combination therapy with aminimum of 2 drugs isrecommended.
Clarithromycin or Azithromycin plusEthambutol is recommended.
Additional drugs such asCiprofloxacin, Amikacin or
Stre tom cin ma be considered
T t t
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Treatment
For disseminated disease, 3 or 4drugs are essential.
Most patients show improvementwithin 4-6 weeks.
Treatment should then be continuedwith 2 drugs.
P h l i
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Prophylaxis
Age CD4 count(cells/cumm)
WHO Stage CDC Class
< 12 months < 750 - -
1-2 years < 500 - -
2-6 years < 75 - -
> 6 years < 50 - -
Any Age - IV C
After initial treatment, secondary prophylaxis isrecommended for life time
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Prophylaxis may be stopped if CD4
percent is more than 15% for 6months and ART has been continuedfor more than 12 months and child isasymptomatic
Drugs Dosage
Clarithromycin 15 mg/kg/day PO BD (max 500 mg/day)
Azithromycin 20 mg/kg/day weekly (max 1.25 gm/day
Ethambutol 15-20 mg/kg/day PO OD (max 1.5gm/day)
Ciprofloxacin 20-30 mg/kg/day PO/IV OD/BD (max 1.5gm/day)
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THANK YOU !!! to all the
panelists!