European Journal of Integrative Medicine 20 (2018) 90–97

Contents lists available at ScienceDirect

European Journal of Integrative Medicine
journal homepage: www.elsevier.com/locate/eujim

Clinical trial

Adjunctive moxibustion treatment for tuberculosis: A randomised clinical
trial investigating potential eﬃcacy and comparative safety

T

Hood Ahmed Ibandaa, Frank Mubirua, Rogers Musibaa, Sachiko Itayab, Jenny Craigb,⁎
Merlin Youngb, Paul Waakoa,c,aDepartment of Pharmacology and Therapeutics, Makerere University, Kampala, Uganda
Moxafrica, United Kingdom
cBusitema University, Mbale, Ugandab

A R T I C LE I N FO

A B S T R A C T

Keywords:
Moxibustion
Tuberculosis
HIV
MDR-TB
Immuno-modulation
Immunotherapy
Randomised control trial

Introduction: Small cone direct moxibustion (‘moxa’) is known to have been used in Japan at the height of its
tuberculosis (TB) epidemic in the pre-antibiotic era with documented reports of eﬃcacy including one scientiﬁcanimal study. Antimicrobial resistant (AMR) disease is becoming a major threat to global health with drugresistant TB the largest component of this threat, most particularly in Africa and Asia. This study comprises theﬁrst scientiﬁc investigation into whether this simple traditional therapy might help the challenge of reducing thepersistent burden of TB in middle- and low-income countries.
Methods: 180 newly diagnosed TB patients were randomly assigned to two groups, one given standard ﬁrst line
&lsquo;Directly Observed Treatment, Shortcourse’ (DOTS) TB drug therapy, and the other ﬁrst line DOTS alongwith daily self-administered moxibustion. The two groups were carefully monitored for diﬀerences in recovery
rates and serological and immunological markers were compared.
Results: The moxa group responded to the drug therapy faster than the group receiving standard TB therapy as
measured by their becoming sputum negative (P = 0.032 in the ﬁrst month). There were accompanying improved haemoglobin levels of statistical signiﬁcance (P = 0.003) with the same P value seen in a sub-group of TB
patients who were also HIV positive. It was also noted that the moxa patients reported statistically signiﬁcantbetter adherence to their drug therapy (P = 0.001).
Conclusions: The results demonstrate positive eﬀects of moxa treatment on both reduced infectivity and drug
adherence including in HIV co-infected cases. Despite previous reports of a wider range of haematological effects, these were limited to an increase in haemoglobin. There was no evidence that moxa use led to improvements in patients’ well-being, contrary to previous anecdotal evidence.
The paper concludes that more investigations should be developed to provide a broader understanding ofboth eﬀect and potential beneﬁt of moxa therapy in treating human pulmonary TB disease (both with andwithout co-infection with HIV). It further recommends that these should include MDR-, XDR-, (multi-drug resistant and extensively-drug resistant) and programmatically-untreatable TB (including in palliative care scenarios).

1. Introduction
1.1. Background
Tuberculosis (TB) is one of the leading killer diseases in developing
countries. Caused by Mycobacterium tuberculosis it can aﬀect any part ofthe body (most commonly the lungs) and its concomitant risks areclosely associated with both socio-economic factors and weakened hostimmunity [1]. TB itself was oﬃcially declared a global emergency by⁎

WHO in 1993. A quarter century later, the pandemic has yet to bebrought under control in many middle- and low-income countries: infact nearly 2 million are still dying each year (with a case fatality ratioof over 20% in Africa) and there are now estimated to be over 10
million annual new cases of active disease [2].
Antimicrobial resistant disease (and particularly drug-resistant TB) is
well recognised as posing a major threat to global health, particularly where
resources are poor [3,4]. A clinically and diagnostically distinct portion of
the TB pandemic has been designated as multi-drug resistant TB (MDR-TB)

Corresponding author at: Department of Pharmacology and Therapeutics, Makerere University, College of Health Sciences, Box 7072, Kampala, Uganda.
E-mail address: pwaako@chs.mak.ac.ug (P. Waako).

https://doi.org/10.1016/j.eujim.2018.04.006
Received 12 December 2017; Received in revised form 23 April 2018; Accepted 24 April 2018
1876-3820/ © 2018 Elsevier GmbH. All rights reserved.

European Journal of Integrative Medicine 20 (2018) 90–97

H.A. Ibanda et al.

(i.e. strains which are resistant to at least the two strongest ﬁrst line drugs)
which has been oﬃcially described by WHO as having become a new ‘crisis’on its own account [5]. Currently it is estimated that 600,000 new cases of
MDR-TB are occurring each year with “about 240,000” of these dying annually (i.e. roughly a 40% case fatality ratio) [6]. Furthermore a recent
review on global antimicrobial resistance predicted that 75 million lives will
have been prematurely lost just to this drug-resistant part of the pandemic
by 2050, with 2.5 million a year then dying just from MDR-TB (i.e. a tenfold increase on existing levels) [7]. New drugs and vaccines are being investigated, but an eﬀective new vaccine is considered unlikely in the near
future [8], and new drugs, besides being expensive and immensely diﬃcult
to manage in resource-poor environments, will inevitably result in freshdrug-resistance (which has already been seen with both of the two recently
approved new drugs Bedaquiline and Delamanid) [9]. Under such challenging circumstances it is recognised that alternative approaches areneeded [10,12]. This study investigates patient response to one such intervention.
Several studies have underscored the role of the immune system inthe containment of TB infections [1,10,14–17]. It is therefore conceivable that immuno-modulators may have therapeutic potential in
the prevention and treatment of tuberculosis, particularly if they areproved to be safe and simple to administer although it is reported thatno clinically useful innovations are yet on the horizon [11]. Moxibustion (moxa) has been widely believed to improve immune response andis also a very simple treatment.
Moxibustion has been used in Japanese and Chinese traditional medicine for at least two millennia to treat a multitude of illnesses including
tuberculosis [18]. This therapy involves repeated application of brief heat tospeciﬁc points on the body. A variety of approaches have been used anddescribed as moxibustion. In this study the speciﬁcally Japanese tradition
was utilised, using tiny pieces of moxa ﬂoss (dried and reﬁned leaves of
mugwort – Artemisia princeps). The moxa ﬂoss is smouldered on the skin sothat the patient feels the heat [18] with the dosage varied according to thehealth of the patient and the severity of the condition being treated [19].
The smoke from this style of moxa therapy (using small cones) has been
demonstrated to be generally safe [20]. Documentary records from the
1930s state that moxa was used successfully for the treatment of TB in
Japan before the advent of TB drugs including one animal study which
demonstrated its potential clinical eﬀects under controlled conditions [21].
Research from that time and more recently [22] has consistently suggested
that the very slight and locus-speciﬁc heat damage caused by moxa in thedermal layers can stimulate a range of immune responses.
The moxa ﬂoss that was used in this study was the highly reﬁned‘White Fuji’ moxa from the Sennenkyu company of Japan. The regimen
for small cone moxibustion used was the one recommended by theMoxafrica charity [23]. Moxafrica is a UK based registered charity
founded to investigate whether small cone direct moxa might play apositive role in combatting the growing pandemic of drug-resistant TB
in the coming years (www.moxafrica.org). The charity provided ﬁnancial support for this study.

IIb, managed from a single TB clinic in Uganda. 180 newly diagnosed TB
patients were randomly assigned to two equal parallel groups, to receive
either standard (2HERZ/4HE)1 Category I ﬁrst line drug treatment (as acontrol) or the same standard treatment with the addition of daily selfadministered moxibustion.
2.2. Participants and ethical approvals
The study was carried out with permission from Research and Ethics
committee of the School of Biomedical Science at Makerere University,
Kiswa Health Centre II and the Uganda National Council for Scienceand Technology (UNCST). Informed consent of the patient was soughtusing a written consent form that was both in English and the local
Lugandan language. The beneﬁts and possible risks of participating inthe study were carefully explained, patient conﬁdentiality guaranteed
and it was also made clear that participating in the study was not aprerequisite for receiving care from Kiswa Health Centre. Patients
participating in the study, together with their attendants, were given
clear instructions in moxibustion therapy, techniques and requisite
safety measures.
Eligible participants were all aged 18 or over with newly diagnosed
sputum positive TB who met the eligibility criteria for Category I TB
treatment according to the Ugandan national TB treatment guidelines.
Exclusion criteria were pregnancy, previous diagnosis of tuberculosis,
diabetes, and patients already under immune modulating therapy(steroids or hydroxychloroquine).
Patients were included in the study regardless of HIV status (which
was automatically checked at enrolment). This was deliberate because
HIV is recognised as being a frequent confounder for successful TB
treatment and because little is known about response in HIV patients tosmall cone direct moxibustion. These patients were especially carefully
monitored in the early stages for any exacerbation of signs and symptoms of disease.
2.3. Study setting
The study took place at Kiswa Health Centre, one of ten public
primary health care facilities operated by Kampala Capital City
Authority which oﬀer outpatient services including smear microscopy
and DOTS TB treatment. As of 2015, the estimated Ugandan HIV prevalence among adults (aged 15 to 49) stood at 7.1% but this is believed
to be higher in city areas [25]. Uganda is a designated high burdencountry in respect of both TB and HIV with the most recent incident
rate for TB estimated as being 201/100,000 (42% of whom are also HIV
positive) [2].
2.4. Interventions and their implementation
All patients in both treatment groups received standard TB regimen
in exact accordance with national guidelines. The anti-TB drugs were
supplied by the government of Uganda to the study centre and wereused according to WHO recommendation. Adherence to medication wasthen also monitored throughout the study.
The study group (as an adjunct to their drug therapy) applied daily
moxa bilaterally on an acupuncture point on each of their legs (St36, zu
san li). This is an acu-point point with a well-documented record of
stimulating host immunity [26]. This daily treatment was self-administered by the patients. The cone sizes were prepared by the patientsfrom the moxa ﬂoss supplied by the study team to be approx. 1 mg inweight (otherwise described to the patients as needing to be looselyrolled into a shape resembling half a grain of dried rice). Each cone wasthen lit by means of a smouldering taper supplied to the patients by the

1.2. Objectives
WHO has set a goal to eradicate TB by 2035 with one of the strategies being to intensify research directed towards ﬁnding new eﬀective
and aﬀordable treatments [24]. The current study set out to test the null
hypothesis that use of adjunctive moxa with standard WHO-approved
drug treatment for TB would produce no measurable diﬀerences in effectiveness when compared with the use of standard drug regimen
alone.
2. Methods
2.1. Trial design

1
2 months daily Rifampicin, Isoniazid, Pyrazinamide and Ethambutol followed by(subject to successful sputum conversion) 4 months daily Isoniazid and Ethambutol.

The study was an open-label randomised controlled clinical trial phase91

European Journal of Integrative Medicine 20 (2018) 90–97

H.A. Ibanda et al.

2.9. Statistical methods

study nurse. The moxa was snuﬀed out by the patient a few seconds
after lighting as soon as he/she felt any heat.
The patients on adjunctive moxibustion were trained in its administration at the start of their drug therapy by the designated TB nurse,
and were given medication counselling covering both anti-TB treatment
and possible moxibustion side-eﬀects. Moxa application as used in the
study is described in detail on the website https://www.moxafrica.org/
copy-of-uganda-project-1.
Before leaving from the ﬁrst visit, the moxa patients were asked toself-administer moxa in the presence of the study nurse and to complete
it to her satisfaction. They were then instructed to self-administer it ona daily basis. Patients were instructed to begin using three cones at eachpoint each day, increasing to a maximum daily dosage of seven cones.
Patients were instructed to discontinue moxa therapy and to contact thecentre if they believed they were suﬀering any ill-eﬀects from the moxa.
Individual patient safety was regularly monitored both by the senior
study nurse (who was not blinded to the allocation of patients) and by
the study doctor (who was blinded) and whose decision in the event of
stopping therapy would be ﬁnal. No patients were stopped for thisreason.

The data was analysed using STATA version 13.0, Texas, USA.
Baseline characteristics were described using frequencies, medians andproportions and stratiﬁed by treatment group (moxa and no-moxa).
Pearson and Fishers exact Chi-square test were used to test the association between categorical variables both before and after treatment.
T-test and Kruskal-Wallis tests were respectively used to test for differences in mean and medians of numeric variables across the diﬀerent
levels of categorical variables.
3. Results
3.1. Recruitment and participant ﬂow
All participants were recruited between January 2012 and January
2014. Each one initially attended clinic at the time of randomisation(baseline) and then at designated intervals for the following 6 months(Diagram 1).
3.2. Losses and exclusions

2.5. Outcomes
By the end of month 2 (a primary way marker for sputum conversion) 14 patients had either been lost (died, self- referred to anothercentre or lost to follow up) or excluded from the study. By the end ofmonth 6 a total of 36 had been lost (including either failed treatment or
excluded as conﬁrmed MDR-TB).
These changes meant that the number of patients compared in eachanalysis depend upon the stage of the study. Accordingly, N values arestated in each Tables 2–9.

The primary outcome measure was sputum conversion. Since
sputum microscopy remains the gold standard for diagnosis of TB in
Uganda this was considered to the most useful measurement of outcome. Other measurements included full blood counts, radiologicalanalysis (intended to be the subject of a second paper) and renal andhepatic function for reasons of patient safety. Well-being was alsomeasured using the Karnofksy scoring method, conducted by patientinterview with the designated study doctor who was blinded to thestatus of the patient.
The well-being outcome measure was set as either achieving normal
daily functioning (a Karnofsky score 80 or more) or a clinically signiﬁcant improvement in functioning (a change in Karnofsky score of 20
or more) by the end of treatment.

3.3. Baseline data
Details of the baseline characteristics are shown in Table 1. Based onthese characteristics there were no statistical diﬀerences between the
two treatment groups.

2.6. Changes to outcomes

3.4. Outcomes and estimations

There were no changes to outcomes.

3.4.1. Karnofsky score
The median average at enrolment was scored at 70%. There was analmost universal improvement of more than 20 in both groups with nosigniﬁcant diﬀerences so no data is reported.

2.7. Sample size
The sample size was chosen using the formula for sample size estimation in a randomized control trial: N = 2 [(z1-α + z1-β)/(d- δ0)] 2P(1-P). The study was designed to have a power of 0.8 and α = 0.05,
using a response rate of 70% based on WHO reports. A loss-to-follow-up
rate of 5% was estimated.

3.4.2. Eﬀect of adjunctive moxibustion on sputum conversion rate (allpatients)
Table 2 shows sputum conversion among all 180 patients on ﬁrstline TB treatment, with and without moxa.
In the ﬁrst month of treatment, 10 patients using moxa and only 2
patients in the control arm had converted to sputum negative, showing
a statistically signiﬁcant diﬀerence among the two arms (p = 0.032).
After 2 months of treatment, most patients (83.9%) had converted
to negative. The conversion rate was slightly higher, however, (87.8%)
for the cohort using moxa compared with the control treatment (79%)
although this diﬀerence was not statistically signiﬁcant.

2.8. Randomisation generation, type, concealment mechanism,
implementation and blinding
Participants were randomly assigned following a simple randomization procedure to 1 of the 2 treatment groups, one group all treatedwith standard TB drugs, the other treated with standard TB drugs andadjunctive daily moxa. A total of 180 identical envelopes were preparedwith designations of either moxa or no-moxa clearly identiﬁed on paper
within them. These envelopes were in no speciﬁc order and each patient was asked to choose an envelope by the senior study nurse, as aresult of which the patient was inducted into one of the groups and thenmonitored by the study nurse accordingly.
Since almost all outcome measurements were remotely made byscientiﬁc measurements there was considered to be no reason for more
complex randomisation. The study doctor (who conducted Karnofsky
assessment and adherence questionnaires) was blinded and was neverpresent at the randomisation.

3.4.3. Changes in CD4 count (all patients)
Table 3 shows the CD4 values for all 180 patients on ﬁrst-line TB
treatment, with and without moxa.
Both groups saw improved CD4 counts with no statistically signiﬁcant eﬀects although the changes in the moxa group were larger at 6
months with the median values of diﬀerences between the two groups –273 vs 151–showing an 80% diﬀerence.
3.4.4. Haemoglobin levels (all patients)
At baseline all the median levels of haemoglobin were borderline
92

European Journal of Integrative Medicine 20 (2018) 90–97

H.A. Ibanda et al.

Diagram 1. Study Participant ﬂow.
Table 1Baseline Characteristics of patients included in both study arms. N values
shown indicate numbers of patients. (Comparisons were made using Pearson
and *Fishers exact chi-square test statistic and Wilcoxon rank sum test of
medians).
Baseline characteristics Overall

Gender-n (%)
Male
FemaleAge in complete
years–n (%)
15–30
31–45
Above 45 years
Body mass index-n (%)
Underweight
Normaloverweight
HIV sero status- n (%)
Positive
Negative
Not done/unknown
Weight in kgsmedian(IQR)
Karnofsky scoremedian(IQR)
Cd4- median(IQR)
Haemoglobin −median(IQR)

Randomization

Table 2
Sputum conversion rates among patients in both study arms over 6 months oftreatment. (Comparisons made using Pearson and Fisher’s Exact chi-square
exact test) totals showing numbers (and percentages in brackets).

p-value

N = 180

No Moxa n = 90 Moxa n = 90

112(62.2)
68(37.8)

59(65.6)
31(34.4)

0.356
53(58.9)37(41.1)
0.297
103(57.2)64(35.6)13(7.2)56(62.2)
27(30.0)7(7.8)

47(52.2)
37(41.1)
6(6.7)

91(50.6)80(44.4)9(5.0)

40(44.4)
43(47.8)7(7.8)

51(56.7)
37(41.1)2(2.2)

49(27.2)
128(71.1)3(1.7)
51(46–57)

24(26.7)
63(70.0)3(3.3)
53(47–58)

25(27.8)65(72.2)0(0.0)
50(46–57)

0.360

70(70–80)

70(70–80)

70 (65–80)

0.220

Total nnumbernumbersOverall(%)

No Moxa

Moxa

p-value

1
2
3
4
5
6

12(6.7)151(83.9)
164 (91.1)
166(92.2)
171(95.0)172(95.6)2(2.2)
72(80.0)79(87.8)
79(87.8)
82(91.1)
83(92.2)

10(11.1)
79(87.8)
85(94.4)
87(96.7)
89(98.9)89(98.9)

0.032
0.156
0.202
0.130
0.120
0.210

Table 3
Changes in CD4 levels among patients on ﬁrst-line TB treatment with andwithout adjunctive moxibustion over 6 months treatment period. (All comparisons were made using the Wilcoxon rank sum test) N values shown are
numbers.

0.102

0.350

519(330–740) 530(345–764)
12(9–13)
12(10–13)

Time(Months)
hshhs)(Cd4 count in cells/μL)

All

No Moxa

Moxa

Baseline CD4 –median (IQR)(range) N = 180

519 (330–740) 530 (345–764) 518 (318–709)

p-value
0.460

752 (520–991) 681 (541–904) 791 (474–1059) 0.56
Cd4 count at 6
months – median(IQR) (range)
N = 139518(318–709) 0.460
10(9–13)0.052

93European Journal of Integrative Medicine 20 (2018) 90–97

H.A. Ibanda et al.

Table 4
Haemoglobin levels among patients on ﬁrst-line TB treatment with and without
adjunctive moxibustion over 6 months treatment period. (All comparisons
made using the Wilcoxon rank sum test) N values shown are numbers.
All

No moxa

Baseline Haemoglobin (ctHB g/L) – 12 (9–13)
median(IQR) (N = 180)
Haemoglobin at 6 months(N = 139)Moxa

12 (10–13) 10 (9–13)

Table 6
Eﬀect of adjunctive moxibustion on sputum conversion rate among HIV-positive patients in the study. (Comparisons made using Pearson and Fisher’s Exactchi-square exact test) N values shown are numbers of patients with percentagesof cohort in brackets.

p-value15 (14–16) 14 (14–15) 15 (14–16) 0.003

anaemic or below as deﬁned by the WHO technical working group of ahemoglobin concentration of less than13 g/dl for men and less than
12 g/dl for females. [27] (See Table 4). After 6 months the median levels of both treatment groups had increased to healthy status, but witha signiﬁcantly larger improvement in the moxa group. Comparing themedians of individual changes in haemoglobin over this period produced a signiﬁcant eﬀect of moxa (P = 0.03).

68(76.4)
21(23.6)

84(94.4)
5(5.6)

1
2
3
4
5
6

2(4.1)
33(67.4)
41(83.7)
43(87.8)
46(95.0)47(95.9)

1(4)13(54)
19(79)
19(79)
21(87)
22(92)

1(4)20(80)
22(88)
24(96) 24(96)25(100)25(100)

1.00
0.07
0.40
0.07
0.11
0.24

The proportion of patients experiencing any adverse event was similar between the two groups. (See Table 9).
It should furthermore be noted that there were no reports of harms
speciﬁcally related to moxa applications (i.e. burns or blisters).
4. Discussion
4.1. Interpretation of results
Previous unpublished pilot studies by Moxafrica had provided
Table 7
CD4 counts among HIV positive patients in the two study arms. (All comparisons were made using the Wilcoxon rank sum test) N values shown are numbers.

Table 5Adherence rates among the two study arms over 6 months of treatment.
(Comparisons are made using Pearson and Fishers exact chi-square test statistic
and Fishers exact test p-value) N values shown are numbers of patients withpercentages of cohort in brackets.

152(85.4)26(14.6)

p-value

3.6. Adverse eﬀects of moxa

3.5.1. Sputum conversion in HIV-positive cases
The median conversion rate for these patients was slower than for
the whole study set shown in Table 2 although in the ﬁrst month oftreatment there was no diﬀerence between the two treatment groups(See Table 6). However after 2 months of treatment, 80% of moxa
patients had converted to sputum negative as opposed to 54% in thecontrol group although this was not statistically signiﬁcant. Given thestatistically signiﬁcant diﬀerence that appeared in the moxa groupcompared with the no-moxa patients in the whole cohort (see Table 3)
it seems possible that a similar moxa-provoked response might have

Adherence n (%)
Good adherence
Poor adherenceMoxa(n = 25)

3.5.3. Haemoglobin levels in HIV positive cases
Similarly to ‘all TB cases’ at baseline the median levels in HIV positive cases were borderline anaemic or below (See Table 8). However,median baseline levels were signiﬁcantly lower in moxa patients. After
6 months both groups had recovered to similar median values, with therise in haemoglobin of the moxa group being signiﬁcantly larger(P = 0.003).

On the basis that the eﬀects of adjunctive moxa might diﬀer in HIV
positive cases, and knowing that co-infection is a hallmark of TB in
Africa, we pre-speciﬁed a secondary subgroup analysis with respect toboth sputum conversions and blood results of HIV positive patients. HIV
status was not taken into account at all at randomisation and a total of
25 of the 90 no-moxa patients were HIV positive, compared with 24 of
the 90 moxa patients.

Moxa(n = 89)

No Moxa(n = 24)

3.5.2. CD4+T cells in HIV positive cases
As expected, the CD4 baselines were much lower in these co-infected patients (Table 7).
The CD4 counts improved with treatment in both groups, with themedian values of diﬀerences between the two groups – 263 vs
209–showing a 26% diﬀerence, but this diﬀerence was not statisticallysigniﬁcant. Given the impact of HIV infection on the progression of
tuberculosis, this is considered by the authors as still being worth reporting.

3.5. Ancillary analyses

No Moxa(n = 89)

Overall n (%)

appeared slightly later in these HIV+ patients. Although this did notshow as being statistically signiﬁcant the authors consider it to be
worth reporting because the trends in both tables look similar. It should
also be noted that at all times during the study the conversions remained higher in the moxa patients, though these diﬀerences wereagain not statistically signiﬁcant.

3.4.5. Adherence rates
Adherence was assessed on every clinic visit in line with standardised methods as practised at tuberculosis treatment centres in the
Ugandan National TB Programme. Patients were asked whether they
forgot to take their medicine, whether they were careless at taking their
medicine, whether (when they felt better) they sometimes stopped
taking their medication, or whether they felt worse and stopped taking
their medication. If a patient declared none of these in any all theirvisits, then they were designated as having good adherence.
Results (See Table 5) indicated that adherence was statisticallydiﬀerent across the treatment arms and that patients using moxa had
improved adherence to treatment compared to those on the standard TB
treatment (p = 0.001).

Overall(n = 178)

Time(Monthshs)
0.052

p-value(Cd4 count in cells/μL)

all

No Moxa

Moxa

p-value

Baseline CD4- median(IQR) Range
N = 49369 (230–653) 392 (238–667) 366 (230–587) 0.670

CD4 count at 6 months 615 (397–811) 601 (495–763) 629 (301–823) 0.56
− median (range)
N = 250.001

94European Journal of Integrative Medicine 20 (2018) 90–97

H.A. Ibanda et al.

to be shown to support or promote recovery from these more dangerous
strains (as well as from drug-susceptible strains as suggested by thisstudy – strains which are normally curable) this could be of signiﬁcantpublic health beneﬁt. In this respect, the study’s authors conceive of
future similar small studies conducted in a variety of TB endemic
countries as part of existing TB projects which are already speciﬁcallytreating local epidemics of drug-resistant TB. This could be a highly
eﬃcient and economical way of eliciting more information of thistherapy’s potential value in a variety of environments with ethnicallydiﬀerent patients infected with genetically diﬀerent strains of disease. It
would be of extraordinary value of the results were shown to generally
improve either treatment outcome, treatment adherence or both. The
authors also suggest this therapy’s potential as a palliative tool for
supporting patients who have failed all therapy (who frequently havelittle or no care at all and remain infectious with lethal strains of disease
up until their death) and suggest urgent investigation in this situation as
well given the paucity of care available for such patients and theirprecarious epidemiological status.
Given the relatively high success rates (83%) of treating drug-susceptible TB [2], it can only be suggested that there would only be amodest public health pay-oﬀ if moxa was used as part of standard care.
However, with the much lower reported success rates of MDR- and
XDR-TB (54% and 30% respectively) [2] the use of moxa could provide
a proportionately far more signiﬁcant therapeutic advantage if similareﬀects were to be seen in these patients – or indeed if a larger eﬀect
could be elicited with a larger moxa dosage.

Table 8
Haemoglobin levels among HIV positive patients in the two study arms. (Allcomparisons made using the Wilcoxon rank sum test). N values shown are
numbers.
All

No Moxa

Moxa

p-value

Baseline Haemoglobin − (ctHB g/L)
median(IQR) N = 49

10(9–13)

12(10–13) 10(8–12)

Haemoglobin at 6 months N = 25

15(14–16) 14(14–15) 15(14–16) 0.003

0.040

Table 9Prevalence of adverse events among patients on ﬁrst-line TB treatment with andwithout adjunctive moxibustion over the 8 months period of treatment N values
shown are numbers with percentages in brackets.
Adverse events

PulmonaryAbsentPresent
Abdominal pain
AbsentPresent
Neurologic problems
AbsentPresent
Skin infections
AbsentPresent
Cardiovascular problems
AbsentPresent
Musculoskeletal problems
AbsentPresent

Overall n(%)

Treatment
No Moxa

Moxa

68(76.4)
21(23.6)

19(76.0)6(24.0)49(76.5)
15(23.4)

85(95.5)4(4.5)

25(100.0)0(0.0)

60(93.8)4(6.25)71(79.8)
18(20.2)

19(76.0)6(24.0)52(81.3)
12(18.7)

75(84.3)
14(15.7)

19(76.0)6(24.0)56(87.5)8(12.5)75(84.3)
14(15.7)21(84.0)4(16.0)54(84.4)
10(15.6)50(56.2)
39(43.8)

17(68.0)8(32.0)33(51.6)31(48.4)

p-value
0.90

0.20

0.56

0.18

anecdotal evidence of improved appetite and energy as well as a reduction in joint pains. However, monthly monitoring throughout thisstudy did not reveal any evidence of such eﬀects. At the same time,
however, no adverse eﬀects of moxa were reported, indicating that thetreatment is safe as an adjunctive therapy for those taking both ﬁrst-line
TB drugs and Highly Active Anti-Retroviral Therapy (HAART).
The results of this study suggest that the use of adjunctive moxa
enables a faster sputum conversion rate, allows greater recovery of
haemoglobin levels and may lead to some increases in CD4. These
would all be generally considered to be beneﬁcial eﬀects in TB patients’recoveries if they are conﬁrmable in the future.
If this type of moxa therapy is indeed immunomodulatory (as issuggested by other previous research [22]) it is likely that some or all ofthese changes may have been elicited by a moxa-provoked host-directed immune response. If this was indeed the case, then (despite there
being no direct evidence from this study) it is reasonable to further
suggest that similar eﬀects might be seen in all types of TB patients
regardless of TB strain (i.e. particularly those patients who will be at
most critical risk in the coming years from MDR-TB and XDR-TB, including those co-infected with HIV). Furthermore it can be suggested
that such eﬀects may also be dependent on dosage.

4.1.2. Dosage
It is important to note that the moxa dosage was deliberately
minimised in this study so that the patients could self-administer theirtreatment (added dosage would have necessitated administration of themoxa by a helper since the extra treatment points would have been on
the back). This choice was made based on anecdotal evidence from theunpublished pilot studies (that moxa only on the two leg points would
be enough to see measurable diﬀerences emerge in drug-susceptible
cases treated with ﬁrst line TB drugs). It was reasonably assumed that
this would maximise completion rates and therefore produce more
rigorous results. It is quite possible, therefore, that increased moxa
dosage could provoke a stronger immune response.
These current ﬁndings could be of particular relevance because
moxa has been found to be safe, and is so cheap and potentially sustainable. Furthermore (because it is inherently a low-tech intervention)
it is highly adaptable for even the most resource-poor or remote pointof-care environments. This latter issue is a challenge even for ﬁrst line
drug treatment of TB but is of a diﬀerent order entirely for DR-TB. The
most regularly identiﬁed problems with existing second-line treatments
for DR-TB are that they are too expensive, too lengthy, have limited
treatment success rates, are extremely challenging to manage (even in
middle-income countries where so much of the burden of MDR-TB is
believed to exist), and/or are too toxic for the patient to tolerate [28].
The emerging ﬁndings point to the possibility that moxa might beshown to mitigate one or more of these problems and (if so) should do
so without the risk of stoking further drug-resistances in the mycobacterium in the process.
Table 10 suggests the possible add-on costs of moxa in the context ofthe existing regimens, their costs and their relative success rates. The
costs in the moxa row include material for a higher dosed regimen.

4.1.1. Drug-resistant TB
Tuberculosis mycobacteria vary globally in terms of genetic strains
and these in turn confer varying degrees of virulence. Since the adventof TB drugs some of these strains have evolved even further to vary interms of their respective capacities to resist the anti-TB drugs themselves (varying from resistance to a single anti-TB drug to strains thatare resistant to all available anti-tuberculosis medication). If moxa were

4.1.3. HIV co-infection
HIV-positive anaemic TB patients, especially those with low CD4
cell counts, have been shown elsewhere to have poor recovery during
TB treatment, though studies have also conﬁrmed the ability of HAART
to correct or improve the anaemia alongside the other haematologicalparameters of HIV infection [29].
When HIV+ patients were examined as a separate sub-group in thisstudy, there were some indications that beneﬁcial eﬀects of moxa might

0.99

0.16

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H.A. Ibanda et al.

beneﬁt of the data from this study relating to drug-susceptible disease it
seems quite reasonable to use these as corroborative evidence formaking a case for further research looking at MDR or XDR disease.
The authors furthermore recognise that the low ‘N’ values for HIV
cases in the Hb and CD4 tables (see Tables 7 and 8) only emerged at theﬁnal review of the data and it was realised immediately that thesenumbers were unexpectedly low. This was, of course, not one of theplanned primary outcomes anyway but nevertheless it still is, in theopinion of the authors (despite the low numbers), important to report.
Dosage issues: as discussed previously, the protocol was deliberately
set so that it would require self-administration of the moxa therapy (andtherefore maximise treatment adherence by the TB patients andtherefore enable more robust statistical outcomes). This made for an
obvious limitation of the study in that the dosage of moxa stimulation
was deliberately set relatively low: were it to have been increased it
could possibly have made for more signiﬁcant data outcomes but could
also have resulted in higher drop-out rates.
Finally during the course of the study GeneXpert was added to theonsite laboratory facility; GeneXpert is a more speciﬁc and sensitivebacteriological test for TB than sputum microscopy and can also diagnose Rifampicin resistance. It would have possibly improved the resulting data if it had been included as the base diagnosis. It was not
added to the diagnostic algorithm of the study design, however, because it had not been available for all enrolled patients (although it wasused once it was available to conﬁrm Rifampicin resistance andtherefore exclude some cases from the study).

Table 10
A comparison of treatment complexities between diﬀerent types ofTuberculosis.

Resistance to:Total treatment time
Intensive phase
Continuation phase
Success rate
median costi
Adjunctive moxa cost

Drug-susceptible
TB

MDR-TB

XDR-TBn/a
6–8 months
2 months (4drugs)
4–6 months (2drugs)
83%$1253i< $10

2 drugs
24 month
8 months(5–6 drugs)
12? months(4 drugs)
52%$9529ic. $30–40

4 + drugs
24 + months
12 months (5–6 drugs)
18? + months (4–6
drugs)
28%$2000–200,000
c. $30–40iWHO. Global Tuberculosis Report 2017. Geneva, Switzerland: World
Health Organization, p, 107.

be greater than in the study group as a whole although this turned out
to be a smaller sub-group than anticipated because of disproportionate
drop out between months 2 and 6 in this group. These indications included suggestions of a more rapid sputum conversion rate after 2
months (with the sputum conversion data appearing not to have beenaﬀected by the disproportionate drop-out), an improved rate of haemoglobin reconstitution that was statistically signiﬁcant (P = 0.03) anda possible greater increase in CD4 compared with control group. While
this eﬀect on CD4 was not statistically signiﬁcant it still suggests aninteresting potential considering the devastating eﬀect that the HIV
pandemic has on the prognosis of TB.
All HIV positive cases were also on anti-retroviral medication, andas a consequence the data further tentatively suggest the possibility thatmoxa may help improve the eﬀects of the anti-retroviral ARV drugs
while at the same time supporting the TB drugs.

Registration
The trial is registered at the Pan African Trials Registry no:
PACTR201504001033387.
Protocol4.2. Limitations
Full details of the trial protocol can be found on the moxafrica
website. https://www.moxafrica.org/copy-of-uganda-project-1.

Blinding of the patient had been initially considered to increasescientiﬁc rigour (i.e. to add a third ‘sham’ arm) but, because of thenature of the intervention itself and the uncertainty of its mechanism ofaction, it was concluded that it was eﬀectively impossible to add aplacebo which would involve use of heat if any of the eﬀects were
thermoceptive.
There were unavoidable limitations in the study design relating to
the blinding of the doctor and the non-blinding of the study nurse. In
the case of the doctor there were inevitable possibilities that a patient
would reveal which arm of the study he/she was on during interview.
With regard to the senior study nurse, there were possibilities that her
usual management of the intervention patients might have been biased
given that she knew which arm of the study they were on. Generally
constant eﬀorts were made to minimise the risks that this limitation
might have had on the ﬁnal data. It can have little or no impact on theserological and sputal outcome data (which forms the bulk of the report) of course, although we recognise that it is possible that it could
have had an eﬀect on the adherence data about which there was also
statistically signiﬁcant data.
A loss-to-follow-up rate of 5% had been originally estimated whichtranspired to be an under-estimation (in the event the total loss-tofollow up at 6 months was 23% which had obvious impact on much of
the data). It should be noted, however, that the key data on sputum
conversion all fell within the 5% that had been estimated at outset.
The authors furthermore accept that much of the discussion section(speciﬁcally relating to the potentials of using moxa for supporting
treatment of MDR-TB) is not substantiated directly by the data presented. Given the scale of the public health threat from MDR-TB and thelack of eﬀective response, however, this limitation was unavoidable: itwould have been both unreasonable and unethical to conduct an RCTlooking at responses of MDR cases at ﬁrst instance; however with theFunding
This study was funded by Moxafrica (UK based charity no.
1128408). Moxafrica was involved in the design of the study and provided logistical support during the trial but were not involved in the
preparation of the statistical analysis plan. The analyses themselves
were performed by the University of Makerere’s School of Health
Sciences. The manuscript was prepared by the authors led by Professor
Paul Waako. Moxafrica was permitted to review the manuscript andsuggest changes, but the ﬁnal decision on content was exclusively retained by the authors.
Conﬂicts of interests
There were no conﬂicts of or competing interests.
Acknowledgements
The authors thank the eﬀorts and dedication of Rehema Kigongo,
Dorothy Nabuule and Denis Kayanja at Kiswa Health Centre for helping
to see this study completed. The authors also acknowledge the supportof the North American Journal of Oriental Medicine which donated themoxa ﬂoss that was used in the study.
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