INT J TUBERC LUNG DIS 27(12):912–917

Q 2023 The Union

http://dx.doi.org/10.5588/ijtld.23.0190

Atorvastatin improves sputum conversion and chest X-ray

severity score

O. O. Adewole,1,2 B. A. Omotoso,2,3 M. Ogunsina,4 A. Aminu,5 O. Ayoola,6 T. Adedeji,7

O. F. Awopeju,1,2 O. M. Sogaolu,8 T. O. Adewole,9 A.O. Odeyemi,10 E. Jiya,11 V. Andero,2
O. Ojo,2 K. Toyin,2 A. O. Akintomide,1,2 G. E. Erhabor1,2
1
Department of Medicine, Obafemi Awolowo University, Ile Ife, 2Department of Medicine, Obafemi Awolowo
University Teaching Hospitals Ile Ife, 3Medical Pharmacology & Therapeutic Department, Obafemi Awolowo
University Ile Ife, 4Department of Medicine, Kaduna State University, Kaduna, 5Department of Medicine, Usman
Fodiyo University, Sokoto, Sokoto, 6Departments of Radiology, and 7Departments of Chemical Pathology,
Obafemi Awolowo University/Teaching Hospitals Ile Ife, 8Department of Medicine, University of Ibadan, Ibadan,
9
Department of Family Medicine, Obafemi Awolowo University Teaching Hospitals Ile Ife, 10Department of
Medicine, Bowen University, Iwo, 11National Tuberculosis Reference Laboratory, Zare, Kaduna, Kaduna State,
Nigeria
SUMMARY

BACKGROUND: We report the results of a phase IIB
study investigating the safety and effectiveness of ator-
vastatin use with standard anti-TB drugs.
M E T H O D S : In this multicentre, open-labelled study, we
recruited treatment-naïve patients with uncomplicated
pulmonary TB aged at least 18 years. Participants were
randomly assigned to standard-of-care or standard-of-
care plus oral dose of atorvastatin (40 mg) daily for 2
months. Primary end points were safety measured by the
number of participants with severe adverse events and
effectiveness measured by the number of participants
with negative sputum culture. Secondary endpoint was
chest X-ray (CXR) severity score.
R E S U L T S : Of the 185 participants screened, 150 were
enrolled and equally assigned to the standard-of-care
and atorvastatin groups. Adverse event severity was similar
in the two groups. There was increased frequency of mus-
cle pain in the trial group (12/75, 16% vs. 4/75, 5%). For
efficacy analysis, respectively 64 (97%) and 57 (85.1%)
patients in the trial and control groups had culture-negative
results (P 5 0.02) and experienced a reduction in CXR
severity score of respectively 37% and 22%, with a mean
difference of 1.4–4.9%.
C O N C L U S I O N : Atorvastatin is safe and associated with
improved microbiological and radiological outcomes in TB.
K E Y W O R D S : safety impact; statin; tuberculosis

TB remains a major global health challenge. Until the
coronavirus (COVID-19) pandemic, TB was the lead-
ing cause of death from a single infectious agent,
ranking above HIV/AIDS.1 COVID-19 pandemic has
also caused reversal of previous gains in the control of
the disease, causing more deaths (1.57 million deaths
among both HIV-negative and HIV-positive people),
at least 18% reduction in number of cases diagnosed
and a drastic fall in global spending on TB diagnos-
tics, treatment and prevention services.1
The fundamental aspect of TB treatment revolves
around the administration of a combination of anti-
TB medications.2 While the creation of novel and
highly efficient anti-TB medications is both costly and
could span decades before reaching practical applica-
tion, repurposing existing drugs offers a cost-efficient
and prompt strategy for utilising medications in con-
ditions beyond their initially intended purposes.3,4
Successful examples of drugs repurposed to treat TB
are linezolid and clofazimine. While linezolid was
initially developed for use for vancomycin-resistant
Enterococcus faecium infections, clofazimine was
originally approved to treat leprosy.4 A panel of other
drugs approved for clinical use such as sulfonamides,
sulfanilamide, statins, doxycycline, and non-steroidal
anti-inflammatory drugs, have been found to have anti-
TB activities. However, their utility as repurposed drugs
for TB have not been exhaustively studied.3–5
Statins are HMG-CoA reductase inhibitors that
were approved as a lipid lowering drug in order to
reduce the risk of stroke and other cardiovascular
events, but have now been identified as having prom-
ising anti-TB effects in vitro by retrospective and
nested case control studies.6–8 Statins displayed a
noteworthy 50% decrease in mycobacterial growth
and relapses compared to treatment solely with anti-
TB drugs, along with a decreased likelihood of devel-
oping active TB, as indicated by a relative risk of

Correspondence to: Professor Olanisun Olufemi Adewole, Respiratory Unit, Department of Medicine, Obafemi Awolowo
University/Teaching Hospitals, Ile Ife, Nigeria. email: ola.adewole@oauife.edu.ng
Article submitted 29 April 2023. Final version accepted 24 June 2023.

0.76 (95% confidence interval [CI] 0.60–0.97).9 The
chronic use of statins (more than 90 days) was associ-
ated with the lowest risk (risk ratio 0.62, 95% CI
0.53–0.72).10.
Within the limits of the designs of these studies, the
positive role of statins in TB in humans was demon-
strated and this has provided the basis for further
studies of its benefits in TB. Atorvastatin, which is
readily available in Nigeria under various brand names,
is a commonly prescribed antilipidemic drug. There has
been no severe adverse report associated with it, thus
making it suitable for repurposing trial. We therefore
conducted a phase IIB, open-labelled, randomised study
to evaluate the safety, tolerability, and efficacy of
atorvastatin in participants with uncomplicated, drug-
susceptible pulmonary TB in Nigeria.
METHODS
Trial design
This was a phase IIB, open-labelled, controlled rando-
mised clinical trial to evaluate the safety, tolerability
and efficacy of 40 mg of atorvastatin administered
orally daily during the intensive phase of treatment
with standard first-line anti-TB drugs (including rifam-
picin [RIF], isoniazid [INH], ethambutol and pyrazin-
amide) (the trial group). Patients administered only
the standard anti-TB treatment regimen comprised
the active control group. Patients were enrolled across
four chest clinics in Nigeria (Obafemi Awolowo Uni-
versity Teaching Hospitals [OAUTHC], Ile-Ife; Usman
Dan Fodiyo University Teaching Hospital, Sokoto;
Barau Dikko Teaching Hospital, Kaduna; University
College Hospital, Ibadan). A placebo control was not
included due to operational issues. The study was con-
ducted between January 2021 and November 2021.
The 2-month trial end point was in line with recom-
mendations for phase IIB trials for antimycobacterium
effect.11
The trial was approved by the OAUTHC Ethics
and Research Committee and Ethics Committees of
participating institutions. The trial was registered on
www.clinicaltrials.gov (NCT04721795)
Participants
Treatment-naïve, consenting male or female patients
aged 18–64 years with uncomplicated, XpertV MTB/RIF
R
(Cepheid, Sunnyvale, CA, USA) positive (with no RIF
resistance) pulmonary TB were recruited for the study.
Participants had no underlying medical conditions, a
negative HIV test and had to produce at least 10 ml of
sputum. All patients provided written informed con-
sents before study enrolment.
Randomisation and blinding
Participants were assigned a study-generated participant
identification code to ensure anonymity. Participants
were randomised into two groups with a pre-defined
Atorvastatin use for TB treatment 913
allocation ratio of 1:1 based on the Zelen rule.12 The
generation of the allocation sequence was supervised
by the principal investigators and was concealed until
randomisation. Masking of patients and site staff was
partial as the control group had no placebo. Labora-
tory staff assessing microbiological endpoints, as well
as the radiologist were fully blinded.
Study procedure
Patients received supervised drug administration and
were assessed weekly until Week 8. Full blood count,
coagulation studies, serum chemistry, lipid profile,
creatinine phosphokinase and 12-lead electrocardio-
grams (ECGs) were performed prior to drug intake
and at 8 weeks. Anti-TB drugs (four-fixed dose com-
bination of RIF, INH, pyrazinamide and ethambutol)
were given based on weight and in line with current
recommendations of the National Tuberculosis and
Leprosy Control programme.13 Anti-TB drugs were
supplied by the National TB programme, while ator-
vastatin was obtained locally.
Sputum analysis
Sputum specimens were collected before treatment
initiation, and on Days 28 and 56 after treatment ini-
tiation. Sputum collections were completed before
administration of the day’s therapy. Sputum for
culture of M. tuberculosis using solid medium and
colony-forming unit (CFU) counts were sent to the
National TB Reference Laboratory, Zaria, Nigeria,
under cold chain for processing using the modified
Petroff’s method. Serial dilutions of the processed spu-
tum were prepared using the micropipetting method
and phosphate buffered saline (PBS) diluent.14 Each
dilution was inoculated in duplicate using a disposable
loop onto selective plates and incubated at 37! C in
darkness, media-surface upside with tri-weekly shuffling.
Safety assessments to record and monitor for adverse
events (AEs) were done with full clinical evaluations
and laboratory testing, as detailed above. Evaluations
for known adverse effects of anti-TB drugs were also
assessed. 12-lead ECGs were done in the morning
before treatment and on Day 56.We assessed for
rhythm disturbances and changes from the baseline
QT interval corrected by Fridericia’s method (QTcF)
and Bazett’s method (QTcB).15
Participants had a standard posterior anterior chest
X-ray (CXR) done at enrolment and at the end of
the study. CXR severity was documented using the
Timika Scoring System, a validated system for report-
ing TB severity on CXR.16 The higher the score the
worse the CXR. The CXR was reviewed and reported
by only one consultant radiologist who was blinded
to the study groups. Scores were compared between
groups.
914 The International Journal of Tuberculosis and Lung Disease
Outcomes
Our primary outcomes were safety and effectiveness
of atorvastatin and anti-TB drug combinations. Safety
was measured based on the number and severity of
adverse effects, QT interval changes, and biochemical
assessment and liver function tests.
Efficacy analysis
Per protocol analysis and intention-to-treat analysis
were done to determine effectiveness. The primary
efficacy endpoint was culture negativity at 8 weeks,
i.e., the number of sputum culture samples that were
negative at the end of 2 months on L€
owenstein-Jensen
solid medium. Secondary outcome measure was CXR
severity score and reduction in CFU/ml of sputum at
the end of 2 months.
Statistical analyses
A sample size of 65–75 patients per group was in line
with previous phase 2B studies.11 The primary effi-
cacy endpoints are presented using frequency distri-
bution and compared between groups using the v2
test, while the Student’s t-test was used to compare
continuous variables between the two groups. The
secondary endpoint (CXR score) was compared using
the Student’s t-test, independent t-tests and frequency
distribution. Univariate analysis was used to examine
the association between independent variables and
sputum negativity at the end of 2 months. All statisti-
cal significance was set at <0.05, and all statistical
analyses were performed using SPSS v21 (IBM Corp,
Armonk, NY, USA).
RESULTS
Between 1 January 2021 and 30 November 2021,
185 patients were screened for eligibility and 150
were enrolled and randomly assigned to standard of
care for PTB (n ¼ 75) or standard of care þ atorvasta-
tin (n ¼ 75). No patient was lost to follow-up; how-
ever, four patients in the control group died due to
advanced disease. Respectively 9 and 4 patients in the
trial and control groups were deemed ineligible for
analysis due to sputum contamination. Respectively
Table 1 Sputum culture and CFU results at the end of study period
Anti-TB þ atorvastatin
n/N (%)
Sputum results
Sputum negativity at 2 months* 64/75 (85.3)
Sputum negativity at 2 months† 64/66 (97)
Sputum CFU/ml
Mean CFU at 2 months 0.780 (0.7)
Mean difference –1.42 to 1.74
Mean fall in CFU/ml/month 0.75 (0.3)
* Intention-to-treat analysis.
†
Per protocol analysis.
CFU ¼ colony forming unit.
66 and 67 patients from the trial and control groups
were included in the final per-protocol effectiveness
analysis. Patients excluded in both groups were simi-
lar in demographics, TB history and medical condi-
tion. Demographic and baseline characteristics were
similar in the two groups (Supplementary Table S1)
At the end of 8 weeks, a significantly higher num-
ber of patients had sputum conversion both in the
intention-to-treat (64/75, 85.3% and 57/75, 76%)
and per-protocol analyses (64/66, 97%) (P ¼ 0.02).
The mean decrease in sputum CFU/ml was signifi-
cantly higher in the trial group than in controls, with
a mean difference of –1.42 to 1.74 (Table 1).
Both treatment regimens were generally safe and
well-tolerated. There were no serious side effects lim-
iting drug administration or discontinuation in either
group. Majority of the participants in the two groups
had Grade 1 AE severity (n ¼ 60, 80% in the atorvas-
tatin and n ¼ 62, 83% in the control group), while
the rest had Grade II severity. The most frequently
reported AE was nausea in the two groups. Respec-
tively 12 (16%) and 4 (5%) participants in the trial
group and control group had muscle pain (P ¼ 0.03,
corrected P ¼ 0.06). Respectively 9 (12%) and 6
(8%) participants in the trial and control groups
had joint pain (P ¼ 0.4, corrected P ¼ 0.4). The con-
trol group reported a significantly higher number of
occurrences of peripheral neuropathy than the trial
group (14/75, 19% vs. 4/75, 5%; P ¼ 0.01; corrected
P ¼ 0.02; Figure). No patient needed to terminate or
discontinue the treatment. Four patients in the control
group who had advanced disease died, while no patient
died in the trial group during the 2-month trial period.
The trial group had significantly lower CXR severity
scores than the control group (n ¼ 202, 13.4% vs.
n ¼ 242, 18.3% at 2 months; P < 0.0001). Further-
more, there was respectively 37% and 22% reduction in
CXR severity in the trial and control groups (Table 2).
The levels of total cholesterol, triglyceride, and
low-density lipoprotein (LDL) at 2 months were sig-
nificantly different between the control and the trial
groups (P < 0.05 each). The mean QTc value was
higher in the trial group than in the control group
(409.4 ms, standard deviation [SD] 620.2 vs. 405.4,
Anti-TB alone
n/N (%) P-value
57/75 (76) 0.02
57/67 (85.1) 0.02
0.94 (1.0)
0.61 (0.2) 0.03

Figure Distribution of adverse effects among study participants.
SD 6 41.3; P ¼ 0.3). The highest recorded QTc in the
trial group was 436 ms. The treatment arm was sig-
nificantly associated with sputum culture negativity
at the end of the 2 months of trial (Table 3).
DISCUSSION
This study is a follow-on of our phase IIA trial on the
safety and effectiveness of atorvastatin in pulmonary
TB.16 The study provided additional data on a relatively
larger sample with a follow-up period of 2 months.
We had at least three important findings. First, in
combination with standard anti-TB drugs, atorvastatin
is associated with higher rates of sputum culture nega-
tivity and reduced mycobacterial burden at 2 months.
Second, combining atorvastatin with standard anti-TB
treatment improves CXR severity score. Third, the
combination of atorvastatin with standard anti-TB
medications is safe and not associated with any unto-
ward adverse effects.
Atorvastatin plus standard anti-TB drugs achieved
a significantly higher rate of sputum culture negativity
and reduction in mycobacterial burden in sputum at
2 months compared with anti-TB drugs alone. The
difference in sputum negativity and the mean decrease
in CFU/ml of sputum per month were significantly
higher in the intervention group. The use of atorvasta-
tin was also significantly associated with a negative
sputum result. These may be indicative of the anti-
mycobactericidal effect of atorvastatin, which had
been earlier reported in murine models, other in vitro
studies and is consistent with our earlier phase IIA
results.7–9,17 This finding is, however, in contrast to a
Table 2 Comparison of CXR outcome between the two groups
Atorvastatin þ anti-TB
Variable
Timika score at baseline
Timika score at 2 months
Change in Timika score at 2 months
Mean difference at 2 months
Percentage reduction in CXR score
CXR ¼ chest X-ray; SD ¼ standard deviation.
Atorvastatin use for TB treatment 915
similar study by Cross et al.,18 where rosuvastatin
was administered. Although in the same class of
drugs, atorvastatin and rosuvastatin have distinct
chemical structures with different lipid affinity and
intrinsic activities, which have been shown to be
responsible for their ability to induce variable degrees
of antibacterial activity, with atorvastatin being more
potent than rosuvastatin.19–21 Atorvastatin is particu-
larly noted for its cytotoxic and apoptotic effects.19
This may be responsible for the effects observed in
our study. Atorvastatin may have direct antimycobac-
terial and synergistic effects on the bactericidal activ-
ity of anti-TB drugs, and may therefore enhance
mycobacterial clearance.22,23
Accelerating the rate of sputum conversion is impor-
tant for reducing community and household spread of
TB, especially in disease-endemic areas. The implica-
tions and potentials of this finding in shortening treat-
ment duration for TB should be evaluated further.
It appears the beneficial effect of atorvastatin extends
beyond mycobacterial clearance. These include reduced
incidence of peripheral neuropathy and improvement
in CXR severity. While reduced occurrence of periph-
eral neuropathy may potentially improve adherence,
the impact of the trial on CXR severity scoring is an
important finding that could potentially mitigate the
challenge of non-infectious, structural damages and
sequelae following cure for TB with the current drugs.24
Overall, the rate of improvement and the degree of
improvement in CXR abnormalities were better with
the use of atorvastatin. This may be a dose-dependent
effect of atorvastatin on inflammation.25
Anti-TB only
Mean % 6 SD Mean % 6 SD
53 6 3.32 54 6 3.20
37 6 2.23 40 6 2.95
–16 6 1.09 –14 6 0.65
1.42–4.58
30 25
916 The International Journal of Tuberculosis and Lung Disease

Table 3 Univariate analysis of factors associated with sputum negativity at 2 months

Sputum negativity
Negative Positive
(n ¼ 121) (n ¼ 12)
Variables n (%) n (%) P-value
Age groups, years
<30 65 (54) 7 (58)
>30 56 (46) 5 (42) 0.9*
Sex
Female 43 (36) 4 (33.3)
Male 78 (64) 8 (66.3) 0.8*
Previous treatment for TB
Yes 6 (5) 2 (16)
No 115 (95) 10 (84) 0.3*
Smoking
Yes 18 (15) 4 (33.3)
No 103 (85) 8 (66.6) 0.2*
Treatment group
Anti-TB only 57 (47) 10 (83)
Anti-TB þ atorvastatin 64 (53) 2 (17) 0.01*
Median CFU/ml, log10
0–0.9 66 (55) 5 (42)
$1.0 55 (45) 7 (58) 0.3

* Fisher’s exact.
CFU ¼ colony forming unit.

Combining atorvastatin presents no serious side
effects as shown in this study. Bioavailability of ator-
vastatin and exposure to the drug may be reduced by
about 90% when co-administered with RIF, which
can be mitigated by administering both drugs together
as done in this study.26 The often-feared myalgia was
not sufficiently severe to warrant drug discontinua-
tion and like some other side effects, this was not long
lasting. To note, the frequency of neuropathy was
reduced among participants on atorvastatin. We are
not sure about the underlying mechanism for this,
although it is well known that atorvastatin and INH
interaction may cause neuropathy. This will require
further studies with objective documentation through
nerve conduction tests.
Patients in the control arm had significant increase
in lipid profiles in contrast to patients in the trial arm.
In addition, deaths were only recorded in the control
group. These deaths were due to TB, although autop-
sies were not done. However, in general, the use of
atorvastatin may be associated with a reduction in
atherogenic lipids and TB-associated cardiovascular
events, with its attendant mortality.27,28
Additional research is required to assess the endur-
ing effects of the intervention and to address certain
study limitations. These include establishing a correla-
tion between atorvastatin’s effectiveness and serum
concentration, exploring other pharmacokinetic data,
and determining the ideal dosage for a consistent
anti-mycobactericidal impact. We did not test for
resistance to anti-TB drugs other than rifampicin as
routinely done in clinical practice using GeneXpert.
The number of patients with previous exposure to
anti-TB drugs in this study was low, and the preva-
lence of primary resistance to anti-TB drugs is also
low in our environment. In addition, the inability to
evaluate the time to stable sputum culture conversion
or time to sputum positivity makes it difficult to deter-
mine the optimal duration to achieve the desired effect.
Despite these limitations, this study has provided
evidence for the beneficial impact of atorvastatin on
TB treatment. It has provided strong evidence for a
phase IIC/III trial with a large cohort to further evalu-
ate these findings in unbiased patients’ groups. At this
time, adding atorvastatin to anti-TB drug treatment
could not be made a standard practice, however, its
use in people living with HIV or diabetes mellitus
who are co-infected with TB or those with elevated
lipids could be beneficial and should be further explored.
This study has demonstrated the safety, tolerabil-
ity, and effectiveness of atorvastatin, which appears
to extend beyond microbiological benefit, and has
opened opportunities for more studies and evidence
for its use in treating TB.
Acknowledgements
The authors thank the following for their support: Cures Within
Reach (Chicago, IL, USA) for funding, Synlab Laboratory (Lagos
Nigeria), staff of Chest Clinics, Cardiac Care Clinic, Obafemi
Awolowo University Teaching Hospitals, research staff, National
Tuberculosis Reference Laboratory (Kaduna, Nigeria) and all the
study participants.
AOO received funding from Cures Within Reach.
Cures Within Reach was not involved in study design, data
collection, data analysis, and did not participate in data interpre-
tation and writing of this report.
Conflicts of interest: none declared.
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