High level of MDR-TB among HIV-infected persons in Mumbai

[Guest guest]

Dear Moderator,

The enclosed BMJ publication revealed a high level of MDR-TB among

HIV-infected persons in Mumbai. Infact, resistance to 4/5 first-line

drugs and 4/5 drugs of the second-line regimen was seen in 72% and

60% of patients, respectively. This is an omnious trend because these

will be considered highest rates of MDR-TB reported from anywhere in

the world. This will be of interest to forum members.

Dr. Subhash Hira

e-mail:arcongov@...

________________________________

A preliminary report on initial mycobacterial drug resistance in HIV-

TB dual infection in Mumbai.

Authors: Tannaz J. Birdi, Yatin Dholakia, T. B. D'souza,

Bhakti B. Oza, Subhash Hira, Noshi H. Antia. BMJ December 2002, Vol

18: 879-881.

Abstract

Objective: The study was undertaken to determine the patterns of

initial drug resistance in HIV patients TB suspects. Apart from the

fact that they are a population particularly susceptible to TB

infection, the data obtained would be representative of the current

drug resistance trends in TB patients in general, in the city of

Mumbai.

Design:Sputum and/or blood samples from HIV positive freshly

diagnosed TB persons were collected for smear examination, culture

and drug susceptibility testing using the radiorespirometric

Buddemeyer assay. Setting/Participants: Patients attending the

outpatient department at the AIDS Research and Control Centr (ARCON)

at Sir JJ Group of Hospitals, in the city of Mumbai were selected as

a sub cohort for the study.

Results: Smear positivity was 80% and 30% for the sputum and blood

samples respectively. All sputum and blood samples were culture

positive in Dubos medium. Twenty-three of twenty-five isolates were

confirmed as Mycobacterium tuberculosis. Initial resistance levels

were highest to ethionamide (100%) and lowest to amikacin (50%).

Conclusion:The study highlights the occurrence of primary multi drug

resistance in newly diagnosed infected patients despite a small

patient number. High levels of primary drug resistance would effect

the TB control programme in terms of case categorization, management,

cure rates as well as resources for therapy.

Introduction

Tuberculosis (TB) has re-emerged as a global emergency due to

increasing drug resistance and HIV-TB coinfection. In India, despite

the National Tuberculosis Programme operating since 1962, problems in

case - holding and treatment are possible contributors to emerging

drug resistance. Preliminary information on initial drug resistance

in patients with HIV-TB dual infection in Mumbai is presented.

Materials and Methods

Patients attending the outpatients department at AIDS Research and

Control Centre(ARCON) were tested for HIV by ELISA (Genelavia,

Sanofi, France) and rapid test (Serodia, Fujirabio, Japan). AIDS

defining criteria were as per National guidelines. Seropositive

patients at enrollment were subjective to clinical examination and

investigations - complete blood count, Mantoux test, chest x-ray,

sonography (if required) and sputum examination. The aforementioned

tests were repeated every three months.

Twenty-five patients formed a selected sub cohort for the study over

a 6 month period. They revealed no history of TB/TB treatment, nor

were the investigation including chest X-ray suggestive of TB at the

time of enrollment in the HIV cohort. Clinical history was elicited

and documented as per WHO recommendations. These patients only

developed TB subsequently and were classified as fresh cases of TB.

The average duration from the time of enrollment into the HIV

programme upto development of TB was around 1-1.5 years. Table 1

shows the clinical profile of these patients.

Sputum was collected from 15 patients with productive cough, while

from the remaining 10 patients, 10ml of heparinized blood was

collected at the time of diagnosis. Both sampled types were subjected

to culture and sensitivity testing. All 25 patients being newly

diagnosed cases of TB were then started on treatment comprising

Rifampicin®(10mg/kg), Isoniazid (H) (5mg/kg), Pyrazinamide(Z)

(30mg/kg), Ethambutol(E)(20 mg/kg) for the initial 2 months and R and

H for 7 months as per World Health Organisation guidelines. No

antiretroviral therapy was given to the patients due to financial

constarints.

Sputum was processed by the Modified Petroff's Method whereas blood

was processed by the method of Kiehn et all. The samples were

cultured using Dubos' broth and Lowenstein-Jensen (LJ) (Himedia)

slants.

Tests for niacin production, nitrate reduction and catalase activity

at68°C were performed to differentiate between Mycobacterium

tuberculosis and other mycobacteria.

The samples from Dubos' medium were used for the radiorespirometric

Buddemeyer assay2. The following drugs (Sigma) at their respective

concentration expressed in µg/ml were tested : Isoniazid (INH)-8,

Rifampicin (RIF)-80, Pyrazinamide (PZA)-5, Streptomycin (S)-160,

Ethambutol (ETB)-200, Amikacin (AMI)-160, Cycloserine (Cyclo)-2000,

Ethionamide (ETA)-5, Kanamycin (K)-5 and Para-aminosalicylic acid

(PAS)-160. Growth was monitored using a liquid scintillation counter

for eight days. The growth index (G.I) was calculated as count on

eighth day / zero day. Viable isolate without drugs and uninoculated

medium served as positive and negative controls respectively. A G.L.

>15% of the positive control was considered resistant. As part of a

routine practice, 10% of the samples were sent to national and

international reference laboratories for quality assurance of the

drug susceptibility results.

Results

The smear positivity was 80% (12/15) for the sputum samples and 30%

(3/10) for the blood samples respectively. All 25% patients were

culture positive in Dubos' media. Niacin production, nitrate

reduction and a lack of catalase activity at 68°C in 23/25 isolates

confirmed them as M. tuberculosis.

The initial resistance levels to the drugs were: INH-92%, RIF-65%,

PZA-96%, S-81%, ETB-77%, AMI-62%, Cyclo-50%, ETA-100%, K-85%, PAS-

89%. Resistance to 4 or 5 first line drugs and 4 or 5 second line

drugs was seen in 72% and 60% of patients respectively.

Though the objective was to study the prevalence of initial drug

resistance in HIV positive patients, clinical follow-up was possible

in 12 out of the 25 patients (Table1) – 2 died during treatment. 10

completed their treatment successfully. Of these, 4 relapsed on

further follow-up. Of the remaining 13 patients, some may have

migrated to their village and / or died. Definitive information of

migration to the village was received for 2 patients. An active

follow - up of the remaining 11 patients could not be done due to

issues related to confidentiality.

Discussion

The extent of drug resistance seen in the isolates is not due to low

drug concentrations in the assay since the concentration used are

amongst the highest reported in literature3.

A study by WHO4 has recorded initial drug resistance to any drug

ranging from 9.8% to 3.6%. Increasing acquired drug resistance is

being reported in Mumbai in tertiary care hospitals with levels

ranging from 25% to 58%5. With the exposure of immunocompromised

patients to these strains it is not surprising that such high levels

of initial drug resistance are observed. A study undertaken in

Bangkok also reports higher levels of initial drug resistance in HIV

positive patients6.

The study highlights the occurrence of primary multidrug resistance

in dually infected patients despite a small patient number.

Preliminary DNA fingerprinting of some of the isolates by the

spoligotyping method does not indicate the occurrence of a mini-

outbreak due to a common source of exposure7. High levels of primary

drug resistance would affect the TB control programme in terms of

case categorization management as well as resources for therapy.

What is already known on this topic:

The WHO report No.2 on anti - tuberculosis drug resistance in the

world, reports amongst new cases, a level of 10% for mono drug

resistance and 3% for multi drug resistance in Tamil Nadu, India.

There is however a dearth of information from the rest of India, on

the prevalence of drug resistance in persons who have no previous

exposure to either TB disease or therapy (primary drug resistance).

===========================================

What this study adds:

The levels of primary drug resistance revealed in this study are

significantly higher than earlier reports.

This fact assumes importance since it has direct impact on the TB

control Programme, categorization of cases, the drug regimens

currently used and outcome of the treatment.

References

1. Kieha TE, FF, Brannon P, Tsang AY. Infections caused by

Mycobacterium avium complex in immunocompromised patients. Diagnosis

by blood culture and fecal contamination, antimicrobial

susceptibility tests and morphological and seroagglutination

characteristics. J Clin Microbiol 1985; 21:168-73.

2. Boonkitticharoen V, Elabardt JC, Kirchner PT. Radiometric assay of

bacterial growth : Analysis of factors determining system performance

and optimization of assay techniques. J Clin Med 1987: 28: 209-17.

3. Rastogi N, HL,. Mode of action of antituberculosis drugs and

mechanisms of drug resistance in Mycobacterium tuberculosis. Res

Microbiol 1993; 144: 133-42.

4. WHO Anti-tuberculosis drug resistance in the World (the WHO/IUATLD

Globalproject on anti-tuberculosis drug resistance surveillance 1994 -

1997) WHO/TB/ 97-229.

5. Udwadia ZF, Hakimiyan A, Rodrigues C et al. A profile of drug –

resistant tuberculosis in Bombay. Chest 1996: 110: 2285.

6. Punnotok J. Shaffer N, Naiwatanakul T et al. Human

immunodeficiency virus-related tuberculosis and primary drug

resistance in Bangkok. Thailand. Int J Tuberc Lung Dis 2000: 4(6):

537-43.

7. Mistry N F. Iyer A M, D'souza D T et al. Spoligotyping of

Mycobacterium tuberculosis isolates from multiple drug resistant

tuberculosis patients from Bombay, India. J Clin Microbiol 2002, 40

(7): 2677-79.

[Guest guest]

Dr Hira and others in this list,

One interesting follow up with this cohort study from Mumbai would be some

mapping of their pharmacology history. Some questions that occur to me is a

history of incomplete medicine intake or a lack of adequate monitoring of

adherence to the regimes in earlier treatment histories.

Maybe we have some adherence lessons that we need to learn. Medicine is only as

effective as the appropriate dosage and rate adherence. I worry about MDR-HIV in

the foreseeable future also, and I have reason to think that prescribing

practices might become a contributing factor.

Geoffrey

E-mail: <gheaviside@...>