30% of DM have TB which is the commonest complicating illness (5.9%).
Management of TB in DM is no different than in non DM patients.
Complication of TB in DM as in non – DM but MDR TB & mortality is more.
Points to remember in TB + DM
Prompt initiation of Pharmacotherapy.
Adequate diet prescription.
Possible failure of sulphonylureas with Rifampicin co-administration.
Augmentation of hepatotoxicity of ATT (esp. with Thiazolidindiones but less with biguanides).
Insulin is always a good option.
TB & HIV ( The Deadly Duo )
Estimates in 2000:
Globally no. of people with TB + HIV = 11.4 mi. (2 mi.).
8.3 million new cases of TB (3.7 mi. is Sp. +ve). Most live in SSA, WP & S.E. Asia where 34 mi. (85%) of estimated 40 mi. people with HIV also live.
9% of 8.3 mi. new TB cases were due to HIV.
4. 12% of 1.84 mi. deaths due to TB were due to HIV.
5. 11 % of all adult AIDS deaths were due to TB.
6. HIV infected pts. has a five time risk of developing TB than non – HIV pts.
7. TB & HIV interaction is bi-directional.
Issues in HAART – ATD
When to start HAART
‘ Virologic, immunologic & clinical responses to HAART of HIV – 1 TB patients treated concurrently with antitubercular therapy & HAART was similar to those of non TB patients’
Hung C. C. et. al AIDS 2003; 17: 2615 - 2622
CD 4 < 100 / µ L or in advanced AIDS – concurrent HAART as early as possible.
CD 4 100 – 200 / µL – Start HAART 4 – 8 weeks after ATD initiation.
CD 4 > 200 / µ L – initiation of HAART based on
Further AIDS defining condition.
CD 4 counts & rate of decline.
Drug toxicity & interactions.
2. Optimal duration of therapy
6 months but prolonged to 9 months in delayed clinical (sym.) / microbiologic response (culture +ve at 2 months)
Treatment failure & relapse is related to:
Advanced immuno deficiency.
Acquired Rifamycin resistance (common in intt. ATD).
So daily ATD.
Overlapping adverse event profile - ZDV CTMX Valganciclovir Bone marrow dysplasia RBT, R Pancytopenia - d4T, ddl & ddc - - H & E Peripheral neuropathy + in pts. With chr. Viral hepatitis NVP, all PI CTMX - ZRH, RBT Hepatitis - Ddl - - E, RBT Ocular Effects + Pancreatitis or Intra – abd. Adenitis ZDV, r, IDV - Do - Other opp infections - Do - Nausea Vomiting - NVP, EVP, ABC CTMX Folliculitis ZRH, RBT Skin Rash IRS ARV drugs Medication other than ARV HIV ATT Possible Causes Adverse Effects
Drug – drug interaction
R reduces PI & NNRTI by increasing CYP3A which metabolises PI & NNRTI. So R never with PI & NNRTI.
RBT also increases CYP3A but less so, so can be used with PI.
PI & NNRTI alters R level by increasing or decreasing CYP3A. PI can increase levels of RBT & it’s metabolites.
So when using NNRTI with RBT, increase dose of RBT & while using PI reduce dose of RBT
H inhibits CYP3A thus increasing levels of PI & NNRTI.
Definition : Restoration of immunity by ARV therapy leading to increased inflammation in TB resulting in significant worsening of S / S (Paradoxical reactions)
Onset – Within days of ARV therapy or months after ARV initiation.
Symptoms : Fever, adenopathy, increased pulmonary infiltrates, serositis. Less common features are worsening of meningitis, increased CNS tuberculomas, soft tissue & bone abscess & diffuse skin lesions.
Diagnosis : Difficult.
BCG & HIV
Role of BCG in preventing TB in HIV +ve pts. is not known.
Conversion to +ve MT after BCG is less frequent but significant
BCG is safe in HIV
In high prevalence – BCG except in children with S / S of HIV / AIDS
In low prevalence – no BCG
Definition : Resistance to H + R + / - other drugs.
Inadequate & inappropiate previous treatment with ATD.
Patients with extensive cavitary disease.
Ineffectual & irrational drug schedule.
Contact with a known MDR patient.
Basic principles of Tt. Of MDR TB
Tt. should be in a specialised centre with C / S facilities.
Careful analysis of past drug history.
Never to add a single to a failing regimen.
Never combine two drugs of the same group or a drug with known cross resistance. (eg. Thioamides / TZN, Km or Am / Sm, R / RBT)
Intt. therapy is not effective in MDR TB
Regimen should contain >= 4 drugs with certain (or nearly so) effectiveness.
No drug should be kept in reserve & the most powerful bactericidal drugs should be used initially in maximum combination.
Tt. should be under direct observation throughout or at least till sputum conversion.
Surgical treatment may be an adjunct.
Injectable drugs for a min. of 6 months. Total duration 18 – 24 months after smear conversion or 12 months after culture becomes negative. Z throughout.
Group 2 + 3 + two to three Group 4 + / - Group 5 + Z
Doses 10 – 12 g. 10 g. 8 g. 150 m/K PAS 750-1000 mg. 750 mg. 500 mg. 15-20m/K Cs 750-1000 mg. 750 mg. 500 mg. 15-20m/K Eto / Pto 400 mg. 400 mg. 400 mg. 7.5–10m/k Mfx / Gfx 750-1000 mg. 750 mg. 750 mg. 7.5–10m/k Lfx 800-1000 mg. 800 mg. 800 mg. 15–20m/k Ofx - - - 15–20m/k AG > 70 Kg. 51-70 Kg. 33–50 Kg. < 33 Kg. Drugs
42 year old male, in whom Cat I / Cat II has failed. DST done. Non diabetic. HIV –ve.
Resistant to – S R H
Sensitive to – E Km Ofx Eto Cs PAS
On RHE since DST has been sent. Sensitivity to Z was not possible.
What would you give?
+ / - PAS
36 year old female in whom Cat I / Cat II has failed. Non diabetic. HIV –ve. DST sent for.
Resistant to – S R H E Z Km
Sensitive to – Cm Ofx Pto Cs PAS
Not on any drugs since DST was sent.
What would you give?
Option 1 – Cm Ofx Pto Cs
Option 2 – Cm Ofx Pto Cs + / - PAS
35 year old male on Km Ofx Eto Z remains sputum +ve after eight months of treatment. DST done four months ago.
Resistant to – R H E Z Eto
Sensitive to – Km Cm Ofx Cs PAS
What would you give?
one of Group 5 drugs
Management of contacts of MDR TB patients
Identify & Evaluate
If contact Sp. +ve / CXR +ve – DST
If DST NA – Protocol of the index case.
If contact Sp. –ve (but symptomatic) & CXR –ve
If symptoms persist
FOB / CT
If all NA – rpt. work-up monthly if patients remains symptomatic.
Chemoprophylaxis – 2 nd line not recommended – close FU.
XDR TB (Extensively drug resistant TB)
Defintion : MDR TB + resistance to any FQ + resistance to at least one of three injectables ( Cm Am Km.) 1 to 2 % of MDR TB in India are XDR TB. This figure is 4% in the US, 19% in Latavia.
Incorrect drug prescription by doctors.
Poor quality drugs.
Erratic supply of drugs.
Patient non – adherence.
Actions to prevent XDR TB
Strengthen basic TB care to prevent emergence of drug resistance.
Ensure prompt diag. & Tt. of DR TB to cure existing cases & prevent further transmission.
Increase HIV TB control programme collaboration.
Increase investment in lab. infrastrutures to enable better detection & management.
DOTS PLUS & Green Light Committee
DOTS PLUS is a comprehensive management strategy that includes five tenets of DOTS strategy. It considers specific issues (eg. use of reserve drugs) that needs to be addressed in high MDR TB areas.
Green Light Committee is a working group that has made arrangement with the pharmaceutical industry to provide concessionally - priced 2 nd line anti TB drugs to DOTS PLUS pilot projects for management of MDR TB.
TB & Pregnancy
No adverse effect of pregnancy on TB & vice – versa.
Effect of maternal TB on baby. Examine placenta.
Treatment is the same (avoid Sm Eto Pto).
Management of new born
Don’t separate (unless mother is desperately ill)
If mother Sp. –ve give BCG
If mother is / was Sp. +ve during pregnancy / delivery
If baby ill & TB suspected – full ATD
If baby well - give INH 5 mg. / Kg. X2 months. Then MT done. If MT –ve – stop INH. Give BCG. If MT +ve – give INH upto 6 months.
If mother MDR – start Tt. in 2 nd trimester with 3 – 4 oral drugs (except Am, Eto, Pto)
Management of latent TB – Indications of Tt. Silicosis / DN / malignancy Chr. immunosupression Lab personnel Prior TB (fiibrosis) Residents & employees of high risk setup. Recent contact No risk persons Immigration HIV +ve 15 mm. induration 10 mm. induration 5 mm. induration
Treatment of latent TB
HIV –ve – INH 9 months
MT +ve – INH 9 months.
MT –ve – no INH
RZ x2 months – not given
RH x3 months – not given
R x4months – exclude active TB 1 st
Toxicity with Tt. of latent TB
HIV -ve – Low risk. Hepatitis (fatal), PN (use B 6 )
HIV +ve – Toxicity > that of HIV –ve pts.
Problems with treatment of latent TB
Low rate of Tt. inititation.
Low Tt. completion rates.
Monitoring for toxicity is a must.
RPT + INH x3 months
Pregnant / breast feeding females – INH
Children – INH
Contacts with MDR – Z + E / Z + FQ x6 – 12 months
Newer drugs in TB
Why is it required?
To improve current Tt. Of active TB by
Shortening duration of treatment
Providing more widely spaced intt. therapy.
To improve MDR TB Tt.
To provide more effective Tt. of latent TB.
First used in MAC prophylaxis.
Now, used as a substitute for R & for patients who can’t be given R for drug drug interaction.
Given twice weekly, it increases acquired drug resistance.
Acts by reducing enzyme induction.
Reduces drug drug interaction
Flu like syndrome
It is not indicated in advanced TB & HIV infection (acquired Rifamycin resistance)
It’s chief indication is LTBI where it is combined with H.
Dose is 900 mg. / day.
It’s bactericidal activity is better than R but = H
5. Diarylquinoline (R 207910)
Effective against drug sensitive bacilli & strains resistant to SRHEZFQ.
It is effective against other myco bacteria. It may be combined with any standard ATD (RHZ).
It’s ability to shorten duration is under trial.
Pyrrole (LL 3858) – It’s a good steriliser.
Dihydroimidazo – oxazoles (OPC – 67683)
No cross resistance or antagonistic action against other ATD.
Better than the first line drugs.
Nitroimidazopyrans (PA – 824)
Effective against sensitive & resistant TB.
It is highly selective.
Active against non replicating bacilli (cf ‘H’).
Active against MDR TB.
Does not demonstrate mutagenicity.
Min. effective dose is 12.5 mg. / day.
It is not genotoxic.
SQ 109 – Active against MDR TB
It is very active against MDR TB
May rarely cause peripheral & optic neuropathy.
Where youth grows pale, and spectre-thin, and dies; Where but to think is to be full of sorrow And leaden-eyed despairs, Where Beauty cannot keep her lustrous eyes, Or new Love pine at them beyond to-morrow.