First-line antituberculosis drug resistance prevalence and its pattern among HIV-infected patients in the national referral tuberculosis centre, Iran.
ABSTRACT The objective of this study was to determine the drug resistance prevalence and its pattern among tuberculosis (TB)-HIV patients in Iran. In this retrospective study, all admitted TB/HIV patients presenting to our tertiary centre during 2005-2007 were considered. After confirmation for TB-HIV, first-line DST was performed for culture-positive patients. The drug resistance patterns and the treatment outcomes were analysed. Of the total 92 TB/HIV patients, 27 were culture negative, and DST were available in 65. Intravenous drug abuse was seen in 59 (90.8%). Thirty-seven (57%) were 'sensitive' cases and 28 (43%) were 'any drug resistance' cases. Twenty-one (32.3%) were mono-drug, three (4.6%) poly-drug and four (6.1%) were multidrug-resistant TB patients. Previous anti-TB medication was significantly associated with any drug resistance (P = 0.041; 95% confidence interval =0.086-0.984); however, having any drug resistance did not affect the treatment outcome (P = 0.56). Streptomycin showed the highest resistance rate (27%) followed by isoniazid (20%), pyrazinamide (9.8%), rifampin (9.2%) and ethambutol (3%). Drug resistance to antitubercular agents in TB-HIV co-infected patients in Iran is high compared with other reports. Drug resistance is higher among those who have had prior anti-TB medication.
- SourceAvailable from: Mehdi Mirsaeidi[Show abstract] [Hide abstract]
ABSTRACT: To determine the drug resistance pattern to first line antituberculous drugs in National Research Institute of Tuberculosis and Lung Disease and to compare resistant rates with previous studies. An anterograde cross-sectional study was performed. The study includes all adults with documented pulmonary tuberculosis (TB) that were hospitalized in National Research Institute of Tuberculosis and Lung Disease in Tehran, from June 2003 to September 2004. Demographic characteristic, TB categories, and drug susceptibility test results were recorded. Two previous studies regarding drug susceptibility in Iran were selected as historical controls. One hundred and ninety-six new cases and 68 previously treated patients were enrolled in the study. The strains of 61% of new patients and 21% of previously treated patients were fully sensitive to all drugs. The most common resistance was streptomycin (27%) followed by isoniazid (23%) in new cases. Multiple drug resistant strains were noted in 2.6% (95% CI 0.8% to 5.8%) of new cases versus 56% (95% CI 43% to 68%) in previously treated group. The frequency of primary drug resistance to isoniazid was 9.8%-15% or streptomycin 9.8%-13% in the previous studies (p<0.00001). While these rates may not reflect the true prevalence of drug resistance on a national scale, it does partially demonstrate some defects in the existing tuberculosis control program. The significant increase of isoniazid and streptomycin resistance in the last few years would present a serious challenge to effective management of TB.Saudi medical journal 04/2007; 28(4):544-50. · 0.62 Impact Factor
ORIGINAL RESEARCH ARTICLE
First-line antituberculosis drug resistance prevalence and its
pattern among HIV-infected patients in the national referral
tuberculosis centre, Iran
P Tabarsi MD MPH, E Chitsaz MD, A Moradi MD, P Baghaei MD MPH, P Farnia PhD, M Marjani MD MPH,
P Irannejad MD, D Mansouri MD MPH and M Masjedi MD MPH
Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Disease, Masih Daneshvari Hospital,
Shahid Beheshti University of Medical Sciences, Tehran, Iran
Summary: The objective of this study was to determine the drug resistance prevalence and its pattern among tuberculosis (TB)–
HIV patients in Iran. In this retrospective study, all admitted TB/HIV patients presenting to our tertiary centre during 2005–2007 were
considered. After confirmation for TB–HIV, first-line DST was performed for culture-positive patients. The drug resistance patterns
and the treatment outcomes were analysed. Of the total 92 TB/HIV patients, 27 were culture negative, and DST were available in 65.
Intravenous drug abuse was seen in 59 (90.8%). Thirty-seven (57%) were ‘sensitive’ cases and 28 (43%) were ‘any drug resistance’
cases. Twenty-one (32.3%) were mono-drug, three (4.6%) poly-drug and four (6.1%) were multidrug-resistant TB patients. Previous
anti-TB medication was significantly associated with any drug resistance (P ¼ 0.041; 95% confidence interval ¼0.086–0.984);
however, having any drug resistance did not affect the treatment outcome (P ¼ 0.56). Streptomycin showed the highest resistance
rate (27%) followed by isoniazid (20%), pyrazinamide (9.8%), rifampin (9.2%) and ethambutol (3%). Drug resistance to antitubercular
agents in TB–HIV co-infected patients in Iran is high compared with other reports. Drug resistance is higher among those who have
had prior anti-TB medication.
Keywords: TB–HIV co-infection, drug resistance, first-line anti-TB
Tuberculosis (TB) infection, which affects almost a third of the
global population, remains a principal factor of morbidity
A horrendous 1.9 million people die of TB annually through-
out the world.2TB is one of the leading mortality factors in
HIV patients, causing at least 11% of deaths in AIDS. Four
million people are co-infected with TB and HIV worldwide.
HIV infection is the most potent activator of the latent
form of TB. Both diseases have been seen to speed up the
progress of the other giving rise to the term ‘co-epidemic’ or
‘dual epidemic’.3TB preys on weakened immune systems
due to HIV infection. Fortunately, it is thought to be the
most curable infectious disease in the young and adults in
the world today.
TB can be treated successfully even if someone is HIV posi-
tive. In fact, TB treatment can prolong the life of co-infected
patients by an average of at least two years. Although there
are several chemotherapeutic measures and various treatment
routines currently used worldwide, drug resistance to anti-TB
agents has become a major health concern.4,5
A drug susceptibility test (DST) indicates an in vitro sensi-
tivity of an isolated bacterial strain to different antibiotics.
Following the drug resistance patterns to Mycobacterium tuber-
culosis can help give rise to more effective, less harmful and
less costly treatment protocols. Because of higher mortality
and morbidity rates, this is especially important in TB/HIV
There exists a body of evidence about the drug resistance
prevalence and pattern in HIV-infected TB patients. Yet, there
still remains considerable contradiction. Some studies have
revealed increased rates of drug resistance to anti-TB agents
among HIV-positive TB cases.6–13Conversely, some others
have reported no significant difference between HIV-positive
and HIV-negative TB patients, with regard to anti-TB drug
resistance. Also, a recent global study on anti-TB drug resist-
ance has advocated the need for further studies on drug resist-
ance in TB–HIV co-infection, an issue that is not yet fully
investigated and understood.14,15
The drug resistance in HIV-positive patients is not yet
addressed in Eastern Mediterranean Region in a conclusive
way. The purpose of this study is to determine the pattern of
DST results in TB/HIV co-infected patients in a tertiary TB
centre in Tehran, Iran.
Correspondence to: Dr E Chitsaz, Masih Daneshvari
Hospital, Darabad, Niavaran Sq, Tehran 1955841452, Iran
International Journal of STD & AIDS 2009; 20: 566–570. DOI: 10.1258/ijsa.2008.008379
MATERIALS AND METHODS
All admitted TB/HIV patients presenting to our centre were
considered for the study. Of the total 117 TB/HIV patients, 27
patients were culture negative, and DST results were available
in 65 cases, while, due to technical problems, the results were
not available in the remaining 25 cases. So, a total of 92 patients
between the years 2005 and 2007 were included in the study,
and analysis of drug resistance was performed for 65 cases
with available DST results. We extracted data from the patients’
medical records ranging from demographic factors, a history of
anti-TB treatment fWHO Category I regimen [2 HRZE/4 HR],
Category II regimen [2HRZES/1HRZE/5 H3R3E3]g, CD4þ
count, albumin levels and treatment outcome.
Primarily, sputum samples (smear, culture) were collected,
chest X-rays were performed, patients were tested for HIV anti-
bodies and positive results were confirmed with Western blot
testing. After initial confirmation for TB/HIV, a first-line DST
was performed for culture-positive patients. TB treatment was
initiated in accordance with standard Category 1 (CAT-1) regi-
mens. For those with a CD4þ count below 200 cell/mL, highly
active antiretroviral therapy (HAART) was initiated 2–8 weeks
after TB treatment commencement.
DST for isoniazid (H), rifampin (R), streptomycin (S) and
ethambutol (E) was performed on Lo ¨wenstein–Jensen media
by the proportion method at a concentration of 0.2, 40, 4.0
and 2.0 mg/mL, respectively. Using a two-phase medium, sus-
ceptibility to pyrazinamide (Z; 900 and 1200 mg/mL) was
tested, and the strain was concluded to be resistant to Z if, on
day 21, the proportion of drug-resistant colonies was higher
than the defined critical proportion.
Once the DST results were acquired, treatment was modified
according to the resistance pattern (multidrug resistant [MDR],
polydrug resistant, monodrug resistant, etc.).
MDR is defined as concomitant resistance to both isoniazid
and rifampin. Polydrug resistance is notified as resistance to
more than one anti-TB agent that does not fulfil MDR criteria
(i.e. resistance to isoniazid and pyrazinamide, etc.). Monodrug
resistance is defined as any single resistance to anti-TB agents.
Sensitive case is considered as showing resistance to none of the
tested anti-TB agents.
It should be noted that all patients received co-trimoxazole
and azithromycin as prophylaxis.
TB treatment outcomes were measured in accordance with
A statistical analysis of the collected data was performed by
using SPSS v. 13.0 software (SPSS Inc., Chicago, IL, USA).
The x2test was utilized for nominal variables, and when
necessary, the Fisher’s exact test was used. The Student’s
t-test and the Mann–Whitney U test were used for variables
with a normal distribution and non-normal distributed data,
respectively. Factors with a P value of less than 0.05 were con-
sidered statistically significant.
The Scientific and Ethics Committee of the NRITLD
approved the study protocol.
Of the total 92 TB/HIV patients, 27 patients were culture nega-
tive, and DST results were available in 65 cases. All 65 patients
were men. The mean age was 38+8 years (range 23–58).
Patients were divided into ‘sensitive’ and ‘any drug resistance’
subgroups. Data showed the route of transmission to be pri-
marily intravenous drug abuse that was present in a total of
59 (90.8%) patients. All 65 male patients were smokers and all
but one had a history of drug abuse. Thirty-three (50.8%)
showed a history of alcohol abuse. Sixty (92.3%) of the patients
were formerly imprisoned. The mean weight of the patients
was 53.3+9.1 (range 37–78 kg) (Table 1).
Fifteen (23.4%) had a history of CAT-I treatment, 10 of which
carried some kind of drug resistance while all of those who
received CAT-II treatment (2 [3.1%]) showed drug resistance.
Thirty-five (53.8%) of the patients had received HAART;
adverse effects were seen in 25 (38.5%) patients; 42.9% of which
showed some kind of drug resistance (Table 2).
Totally, 37 (57%) were ‘sensitive’ cases while the remaining
28 (43%) were classified as ‘any drug resistance’. In the latter
group, 21 (32.3%) were monodrug, three (4.6%) were ploydrug
and four (6.1%) were MDR TB patients (Table 3).
In terms of frequency of resistance, streptomycin showed the
highest resistance rate (27% of the patients) followed by isonia-
zid (20%), pyrazinamaide (9.8%), rifampin (9.2%) and etham-
butol (3%) (Tables 4 and 5).
On performing a univariate analysis, it was found that ‘sen-
sitive’ and ‘any drug resistant’ strains showed no significant
association with the route of transmission, cigarette use, drug
abuse (P ¼ 0.37), alcohol abuse (P ¼ 0.87), imprisonment (P ¼
0.375), age and weight. Similarly, the drug resistance status
showed no significant association with CD4þ count mean
or its cut-off ,200 (P ¼ 0.56), adverse effects (P ¼ 0.435) and
HAART (P ¼ 0.57).
However, having a prior history of treatment was signifi-
cantly associated with ‘any drug resistance’ (P ¼ 0.041, 95%
confidence interval ¼0.086–0.984).
Outcomes were classified into successful outcome (cure,
treatment completed) and unsuccessful outcome (death, treat-
ment failure, default). Most patients (46 [71.9%]) were cured
and 26 of them carried sensitive bacterial strains. Among the
eight (12.5%) who died, five carried sensitive strains and only
three had drug-resistant ones. Three cases were categorized
as treatment completed and eight cases were defaulters.
Interestingly, the drug resistance status was not significantly
associated with the outcome (P ¼ 0.56).
Drug resistance to antitubercular agents is a major global health
concern and its importance in TB–HIV co-infection is further
highlighted due to the increasing HIV infection paralleling
the TB incidence. Despite the fact that drug resistance in HIV
patients has been widely addressed in several reports, there is
still no consensus on several issues and many data are contra-
dictory.6–10,15–17In this study, we evaluated drug resistance
in TB–HIV co-infected patients in Iran. This study accounts
as the first investigation of drug resistance among HIV patients
in Iran and almost the first in the Eastern Mediterranean
Our study showed that the rate of any drug resistance among
HIV-positive TB patients is 43%. This is relatively a high rate
compared with 17.1% and 22.3% reported in other studies
worldwide.18,19However, this figure closely matches that of
49.2% of any drug resistance in new and retreatment cases of
Tabarsi et al. Anti-TB drug resistance in TB-HIV
Drug susceptibility with regard to demographic characteristics of the patients
Sensitive Any drug resistanceTotal
CountColumn N% CountColumn N%CountColumn N%
Route of transmission
100 64 98.5
39+9 38+7 38+8
Weight (kg) 52.5+8.1 54.2+10.2 53.3+9.1
None of the parameters showed significance
P value .0.05
IV ¼ intravenous; DU ¼ drug use
Drug susceptibility with regard to epidemiologic and laboratory characteristics of the patients
SensitiveAny drug resistanceTotal
CountColumn N% CountColumn N%CountColumn N%
History of CAT-I
History of CAT-II
87.7 3225 57
CAT-I ¼ category 1; CAT-II ¼ category-II; HAART ¼ highly active antiretroviral therapy
International Journal of STD & AIDS Volume 20August 2009
general TB population in our centre reported by Mirsaeidi
It is of note that, the majority of the patients (76.6%) in our
study were new TB cases with no previous exposure to
anti-TB drugs, which is also close to 74.2% of new cases in
the aforementioned study.20So, the similar consistency of the
patients in our TB–HIV population compared with general
TB population makes our findings of drug resistance more
reliable and poses more accurate and straightforward data
from drug resistance in TB–HIV patients.
Our findings demonstrate that the rate of drug resistance in
HIV-infected patients may not be different from what is
expected in non-HIV TB cases; the resistance pattern in this
group follows its corresponding schema in the whole popu-
lation for any given region. The rationale for this is the nature
of acquiring drug resistance. It can develop as a result of treat-
ment with anti-TB agents or through direct transmission of
the mutant-resistant strain from an infected patient to one
who has never been exposed to anti-TB medication (e.g.
primary resistance). However, the effect of higher likelihood
of close contact among opium users, intravenous drug users
and imprisoned patients who comprised the majority of our
cases should be kept in mind.
Our study revealed that drug resistance is higher in those
who have previously received anti-TB treatment.
Accordingly, as reported by other studies, the drug resist-
ance, i.e. MDR-TB,19is found to be significantly higher in
those TB–HIV patients who had received prior anti-TB.
Our data showed that the unsuccessful outcome of the
patients was not significantly higher in those who had any
drug resistance (P ¼ 0.56). It is now proven that MDR-TB
yields less successful outcomes compared with non-MDR
cases.21Although the overall outcome in ‘any drug resistance’
population was not shown to be significantly different in our
study due to our somewhat small sample size, particularly
the small number of MDR-TB cases, further outcome analysis
in subgroups such as MDR-TB was not feasible.
This is the first study of drug resistance among HIV patients
in Iran carried out in the national referral centre for TB. Our
study supported the findings of several previous studies.
However, it carries some limitations; the study is conducted
in a tertiary referral centre, and the sample size of the study
is not sufficient for some analysis particularly in drug resistance
Therefore, this mandates further future investigations, cer-
tainly with larger sample sizes, to give a more comprehensive
perspective of the subject.
Drug resistance to antitubercular agents in TB–HIV co-infected
patients is close to the figure in the population of TB patients in
Iran. However, it is substantially higher compared with those
reported in other regions worldwide. Although the drug resist-
ance is higher among those who had had prior anti-TB medi-
cation, having drug resistance did not affect the treatment
outcome in TB–HIV patients.
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and previously treated patients
Drug susceptibility and its subtypes in new cases
History of treatment
Previously treatedNew case Total
MDR¼ multidrug resistant
Distribution of drug resistance to each anti-TB agent
?DST for PZA is not performed for all patients due to technical difficulties
TB ¼ tuberculosis; DST ¼ drug susceptibility testing
agents in TB–HIV patients
Drug resistance pattern of the tested five anti-TB
Drug resistance pattern
H ¼ isoniazid; R ¼ rifampin; E ¼ ethambutol; Z ¼ pyrazinamide; S ¼ streptomycin;
TB ¼ tuberculosis
Tabarsi et al. Anti-TB drug resistance in TB-HIV
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International Journal of STD & AIDS Volume 20August 2009