HIV and Tuberculosis the deadly combination

Panel discussion Moderator : Dr.Govindaraju M Panelists: Dr Shivananda Dr Balasubramaniam Dr.Atul Agarwal Dr. Sharad Thora

Question - Why is this combination so deadly?

Impact of TB on HIV
HIV and TB form a lethal combination speeding the others progress TB accounts for 13% of AIDS deaths worldwide leading cause of death in HIV+ In Africa, HIV is the single most important factor determining increase of TB in past 10 years.

Impact of HIV on TB
Palme et al found that TB children who 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 with TB. Pediatr Infect Dis J 2002; 21:1053-61

Case scenario
A 4 year old was brought to you with complaints of: - Fever 10 days - Headache 10 days - Vomiting 3 days - Convulsions 2 days - Altered sensorium 1 day

Question : What are the possibilities

Dr.Sharad Thora

Question : What are the possibilities

Fever, Altered sensorium and convulsions a triad of CNS Infection: Pyogenic meningitis TB meningitis Viral encephalitis Cerebral malaria Rickettsial encephalitis

Case scenario
Family history: - Father died of tuberculosis 2 years back and was being treated for the same. - Mother is alive and well, with no complaints Past history: - He has never been hospitalized

Case scenario
On examination: - Grade III PEM - Cervical lymphadenopathy multiple matted lymph nodes - Pallor + - Right sided Facial nerve palsy + with right sided hemiparesis - Chest clear

Diagnosis: Right sided hemiplegia with facial nerve palsy probably due to Tuberculous meningitis

Case scenario
Hb 6.8 g% Total counts 16,700 P60 L40 Platelets 1,60,000 Lumbar puncture: Cells: 450 P25% L75% Protein: 450 mg/dl Glucose: 48 mg/dl; RBS 110mg/dl

Case scenario
CT scan of the brain showed: - Hypo dense lesions in left parietal lobe and internal capsule - Two ring enhancing lesions in the left parietal lobe - Diffuse cerebral edema +

A diagnosis of Neurotuberculosis meningitis made!

Question Do you recommend HIV testing in all children with TBM?

Dr.Balasubramaniam

Prevalence
What is the prevalence of TB in HIV +? What is the HIV seroprevalence in children with TB?

Prevalence of TB in HIV infected children

Author Shah I 2005 Shah SR 2005 Madhivanan P 2004 Verghese VP 2002 Merchant RH 2001 Dhurat 2000 Lodha 2000 N 317 50 58 88 285 55 27 Tuberculosis % 43.4% 38% 35% 12% 29.47% 67.5% 13%

Tuberculosis is reported in 14 to 54% of Indian children with HIV/AIDS

HIV seroprevalence in children with TB

Author South African study group Merchant and Shroff et al Karande et al Shahab et al Seroprevalence 42% 18% 16.2% 2%

Greater probability of detecting HIV infection in children with disseminated TB

Question What are the clinical signs that suggest HIV infection in a child?
Dr.Atul Agarwal

Clinical signs suggestive of HIV

Failure to thrive < 6 months or history of weight loss > 6 months Recurrent bacterial infections Generalized symmetrical lymphadenopathy Extensive oropharyngeal candidiasis Generalised rash Bilateral non tender parotid gland enlargement

Case scenario
As recommended HIV testing was done: - All three samples were found to be positive

Hence, child is diagnosed to have HIV with tuberculosis

What tests do you recommend for diagnosis of TB in this child?

Dr.Balasubramaniam

Pulmonary TB
Mantoux test Gastric lavage isolation / sputum for culture and smear Radio logical Chest X-ray

Extra-Pulmonary TB
Culture of affected body fluid or tissue obtained by fine needle aspiration or biopsy

Mantoux test/Tuberculin test

Can be done using 5TU intradermally Induration > 5 mm is considered positive Negative test seen in 50% children with HIV Hence negative test does not rule out tuberculosis

Gastric Lavage/Sputum examination

50-70% of adults - + ve Children with TB disease rarely produce sputum voluntarily and have a low bacterial load. Three consecutive morning gastric aspirates have a better yield than a single sample. Better diagnostic yield is seen on culture.

Chest X-ray
Localized pulmonary infiltrates with hilar adenopathy Middle lobe collapse and consolidation Pleural effusion In older children cavitatory tuberculosis.

Culture
Specimens should be cultured for 2-6 weeks by radiometric culture methods (Bactec). Culture on L-J medium for 8 weeks. Antimycobacterial drug sensitivity should be done on the initial positive culture if treatment fails or relapse occurs.

Others
PCR assays are not useful as primary diagnostic tool Negative PCR does not rule out TB and Positive result does not absolutely confirm M.Tuberculosis infection. False positive rates are high with sensitivity ranging from 45-83%. Serological tests for TB are not very specific

Question What other differentials would you consider in view of this child being HIV+ ? Do you recommend any other investigations
Dr.Shivananda

Cryptococcal meningitis
< 1% in children Patients present with fever, headache and altered mental status. HIV infected children between 6-12 years of age with severe immunosuppression are prone. Neck stiffness and focal neurological deficit is rare.

Cryptococcal meningitis
CSF opening pressure should be measured. CSF analysis with INDIA INK a must Cryptococcal antigen (SF antigen) titres to be obtained. Fungal cultures from CSF or blood

Toxoplasmosis
Acquired primary toxoplasmosis is rare. CNS toxoplasmosis may present as headache, fever, changes in mental status, seizures, psychosis and focal neurological deficits. Toxoplasma specific IgG +

Toxoplasmosis
Space occupying lesion on imaging studies of the brain ring-enhancing lesions in the basal ganglia and cerebral corticomedullary junction. Definitive diagnosis requires histologic or cytologic confirmation by brain biopsy

Viral encephalitis
HSV encephalitis CMV encephalitis Disseminated Varicella infection

Case scenario
Other tests done: - CSF IgM Toxoplasma Negative - CSF AMA Negative CD4 count - 440/cu.mm CD4 % - 22%

Question At what CD4 count in HIV does TBM occur?

Dr.Balasubramaniam

TB an AIDS defining illness

Diagnosing extrapulmonary TB in HIV is important as it is an AIDS defining illness. Tuberculosis can occur at any CD4 count. The more atypical the clinical features, the more likely is the CD4 count to be low.

Case scenario
Chest X ray showed bilateral non homogenous opacities, diffusely involving all the lobes of the lung.
ABG : pH 7.52 pCO2 22 pO2 48 HCO3 - 16

Question - What is your differential diagnosis for nonhomogenous opacities in a HIV + child?
Dr.Shivananda

Differential Diagnosis
Miliary tuberculosis Lymphocytic interstitial pneumonia (LIP) Pneumocystis jiroveci pneumonia (PCP) Bacterial pneumonia Rarely: - Fungal pneumonia

Miliary tuberculosis

PCP pneumonia

Lymphocytic interstitial pneumonia (LIP)

Fungal pneumonia

Question Do you treat with ATT first or with ART first?

Dr.Atul Agarwal

Principles of treating TB with HIV

1) Treatment of TB takes precedence over HIV treatment 2) In patients already on HAART, continue the same with modifications 3) In those not receiving HAART, initiation depends on CD4 counts and type of TB

Principles of treating TB with HIV

If CD4 counts > 15% and no significant HIV related illness treat for TB first Monitor carefully for worsening of immune status If CD4 counts < 15% or significant HIV related illness Treat with ATT and HAART

Initiation of ART
Starting ARV therapy for the individual child is rarely an emergency! Management of life-threatening opportunistic infections can be an emergency. Treat opportunistic infections before starting ART Any child less than 2 years, irrespective of CD4 count ART is

Recommendations for initiating ART in infants and children

WHO Paediatric Stage Availability of CD4 cell measurements Age-specific treatment recommendation < 2 years 2 years

4 3

CD4 CD4 Treat all

Treat all Treat all, CD4 guided in those children with TB, LIP, OHL, thrombocytopenia

2 1

CD4 CD4

Treat all
Treat all

CD4 guided
CD4-guided

CD4 criteria of severe HIV immunodeficiency

Immunologi cal marker Age-specific recommendation to initiate ART 11 months 12 months- 36 months35 months 59 months CD4 % CD4 count 25% 1500 cells/mm3 20% 750 cells/mm3 15% 350 cells/mm3 5 years

15% 200 cells/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 <5 yrs.

Case scenario
Child was started on RNTCP Category 1 treatment: - 2HRZES + 4HR for 9 months

Question Is this treatment sufficient? How long do we treat?

Dr. Sharad Thora

ATT in HIV + children

American Thoracic society Minimum duration of 6 months and may be extended if response is suboptimal American Academy of Pediatrics 9 months Indian Academy of Pediatrics 9 months

Treatment
Treatment of TB in HIV infected child is the same as that for an HIV uninfected child. However, modified treatment duration schedule and medications are recommended for specific instances. Treatment of TB should be initiated

Treatment
For HIV infected children with active pulmonary disease, the minimum recommended duration of ATT is 9 months. For children with extrapulmonary disease involving the bones or joints, CNS or miliary disease, the minimum recommended duration of treatment is 12 months.

Question Should steroids be started? For how long?

Dr. Atul Agarwal

Role of steroids
Adjunctive use of steroids is indicated in patients with: - TBM - Serosal TB - Miliary TB and - Endobronchial tuberculosis. Duration: 6 8

Case scenario
Child was treated with short course chemotherapy and monitored with CD4 counts. After 2 months CD4 counts dropped to 128/cu mm (CD% - 8%)

Question If you are starting HAART, what precautions to take with ATT?
Dr. Shivananda

Monitoring
In children with HIV and TB coinfection, periodic monitoring of liver enzymes is advised. Mild elevations in serum transaminases (e.g., 2-3 times upper limit of normal) does not require discontinuation of the drugs. All patients should be monitored monthly for clinical and bacteriological response.

Monitoring
For patients with pulmonary TB, Chest X-rays should be obtained after 2-3 months of therapy to evaluate response. Hilar adenopathy might persist for as long as 2-3 years despite successful ATT and is not a criteria for continuation of ATT.

Adverse drug reactions of ATT in HIV

ADRs increase with advanced immuno suppression and in the first 2 months. Thiacetazone rashes, hepatotoxicity and fatal ADR contraindicated in HIV INH more prone to develop INH

Adverse drug reactions of ATT in HIV

Rifampicin with Protease Inhibitors contraindicated due to interaction with cytochrome p450 enzymes. Efavirenz can be used with rifampicin. Malabsorption of ATT is known in HIV hence monitor response

What regimen to use if the child is on rifampicin?

Dr. Sharad Thora

What 1st line regimen to use 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-TBContinue treatment after completing treatment, consider switching treatment torifampicin-based anti-TB treatment. standard first line regimen with 2NRTI+NVP or EFV for better efficacy

What 1st line regimen to use if the child is on rifampicin?

If already on first-line ART when starting rifampicin-based ATT

Current first regimen 2NRTI + EFV 2NRTI + NVP

linePreferred regimen Continue the same regimen Switch to either 2NRTI +ABC or 2NRTI + EFV (if age > 3 years and weigh > 10 kg) Continue the same regimen

2NRTI + ABC

Is there a role for prophylactic ATT in HIV ?

Dr.Shivananda

Prophylaxis
All HIV infected children with positive Mantoux test and no evidence of active TB or no history of previous treatment for TB should be treated for latent TB. Regimen 6 months of INH + Rifampicin. There is no role of single drug INH

Prophylaxis
HIV infected children in close contact with person with Open TB should be treated for latent TB. Treat regardless of their MT test and previous treatment for TB after excluding active TB. Regimen 6 months of INH + Rifampicin

Case scenario
Child was started on HAART using efavirenz and zidovudine, along with ATT After 1 month of treatment, he was brought with complaints of: - Spiking fever - Increasing headache and vomiting - Increase in size of lymph nodes

Question What are the possibilities?

Dr. Balasubramaniam

IRIS Immune 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

How do you treat drug resistant tuberculosis in this child?

Dr.Shivananda

Drug resistant TB
Minimum of three drugs should be given, including at least 2 bactericidal drugs to which the organism is susceptible. Multidrug resistant tuberculosis (i.e. resistant to INH and RIF) aggressive treatment with a regime an amino glycoside or capreomycin and a fluoroquinolone

Suggested Regimens
Pattern of drug resistance H (+/- S) suggest Minimum regimen duration of comments treatment R , Z and E 6-9
A fluroquinolone can be added for pts with extensive disease A longer duration for those with extensive disease. A longer duration for those with extensive disease.

H and Z

R ,E and fluroquinol ones R ,E and fluroquinol

9 - 12

H and E

9 - 12

Suggested Regimens
Pattern of drug resistance R suggest Minimum regimen duration of comments treatment H,E fluroquinol ones plus at
least 2 months of Z

12 - 18

An injectable agent may strengthen the regimen for pts with extensive disease. A longer course ( 6 months) of the injectable agent may strengthen the regimen for pts with extensive disease.

R and E(+/- S)

H,Z fluroquinol ones plus an

injectable agent for at least the

18

Suggested Regimens
Pattern of drug resistance R and Z (+/- S) suggest Minimum regimen duration of comments treatment H,E fluroquinol ones plus an
injectable agent for at least the first 2 -3months.

18

A longer course ( 6 months) of the injectable agent may strengthen the regimen for pts with extensive disease.

H,E,Z (+/- S)

R,Fluroquin olones , plus

an oral second line plus an

18

A longer course ( 6 months) of the injectable agent may strengthen the regimen for

When will you suspect atypical mycobacterial infection

Dr. Atul Agarwal

Mycobacterium avium complex (MAC)

MAC - M. avium, M. intracellulare, and M. paratuberculosis. MAC can appear as isolated lymphadenitis among HIV infected children. CD4 count < 50 cells/cumm is an important risk factor for development of MAC. Lungs, liver, spleen, GI tract, bone marrow and lymph nodes are

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 abdominal pain. Patients have lymphadenopathy, hepatomegaly and splenomegaly. Associated laboratory findings of neutropenia, anemia and leukopenia are seen

What investigations will you consider in MAC with HIV?

Dr.Balasubramanium

Diagnosis
Is accomplished by isolation of organism 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.

Diagnosis
Anemia out of proportion to the stage of the HIV disease Elevated serum alkaline phosphatase may be seen.

What is the treatment of MAC with HIV?

Dr.Shivananda

Treatment
Combination therapy with a minimum of 2 drugs is recommended. Clarithromycin or Azithromycin plus Ethambutol is recommended. Additional drugs such as Ciprofloxacin, Amikacin or Streptomycin may be considered

Treatment
For disseminated disease, 3 or 4 drugs are essential. Most patients show improvement within 4-6 weeks. Treatment should then be continued with 2 drugs.

Prophylaxis
After initial treatment, secondary prophylaxis is recommended for life time
Age CD4 count (cells/cumm) WHO Stage IV CDC Class C

< 12 months < 750 1-2 years 2-6 years > 6 years Any Age < 500 < 75 < 50 -

 Prophylaxis may be stopped if CD4 percent is more than 15% for 6 months and ART has been continued for more than 12 months and child is asymptomatic
Drugs Clarithromycin Azithromycin Ethambutol Ciprofloxacin Dosage 15 mg/kg/day PO BD (max 500 mg/day) 20 mg/kg/day weekly (max 1.25 gm/day 15-20 mg/kg/day PO OD (max 1.5 gm/day) 20-30 mg/kg/day PO/IV OD/BD (max 1.5 gm/day)

THANK YOU !!! to all the panelists!