This open-access article is distributed under
Creative Commons licence CC-BY-NC 4.0. IN PRACTICE
COCHRANE CORNER
Nutritional supplements for people being treated for
active tuberculosis: A technical summary
L Grobler,1 PhD, BSc Hons, BSc; S Durao,2,3 MPH, BScDiet; S M van der Merwe,4 MNutr, BDiet; J Wessels,5 BScDiet;
C E Naude,1,2 PhD, MNutr, BScDiet
1
Centre for Evidence-Based Health Care, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
2
Cochrane Nutrition, hosted jointly by the Centre for Evidence-Based Health Care, Faculty of Medicine and Health Sciences, Stellenbosch
University, Cape Town, South Africa, and Cochrane South Africa, South African Medical Research Council
3
Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa
4
Integrated Nutrition Programme, Mpumalanga Department of Health, Nelspruit, South Africa
5
Standerton Tuberculosis Specialised Hospital, Mpumalanga Department of Health, Standerton, South Africa
Tuberculosis and nutrition are intrinsically linked in a complex relationship. Altered metabolism and loss of appetite associated with
tuberculosis may result in undernutrition, which in turn may worsen the disease or delay recovery. We highlight an updated Cochrane
review assessing the effects of oral nutritional supplements in people with active tuberculosis who are receiving antituberculosis drug
therapy. The review authors conducted a comprehensive search (February 2016) for all randomised controlled trials comparing any oral
nutritional supplement, given for at least 4 weeks, with no nutritional intervention, placebo or dietary advice only in people receiving
antituberculosis treatment. Of the 35 trials (N=8 283 participants) included, seven assessed the provision of free food or high-energy
supplements, six assessed multi-micronutrient supplementation, and 21 assessed single- or dual-micronutrient supplementation. There is
currently insufficient evidence to indicate whether routinely providing free food or high-energy supplements improves antituberculosis
treatment outcomes (i.e. reduced death and increased cure rates at 6 and 12 months), but it probably improves weight gain in some settings.
Plasma levels of zinc, vitamin D, vitamin E and selenium probably improve with supplementation, but currently no reliable evidence
demonstrates that routine supplementation with multi-, single or dual micronutrients above the recommended daily intake has clinical
benefits (i.e. reduced death, increased cure rate at 6 and 12 months, improved nutritional status) in patients receiving antituberculosis
treatment. In South Africa, most provinces implement a supplementation protocol based on nutritional assessment and classification of
individuals rather than on disease diagnosis or treatment status.
S Afr Med J 2018;108(1):16-18. DOI:10.7196/SAMJ.2018.v108i1.12839
There is a complex relationship between tuberculosis and nutri treatment for active tuberculosis were included. The review authors
tion.[1] The immunodeficiency caused by undernutrition increases followed standard Cochrane methods for independent screening
the risk of acquiring tuberculosis.[2] Alternatively, tuberculosis may and eligibility assessment, data extraction, risk of bias assessment
cause undernutrition through increased metabolic demands and and data analysis. The quality of the evidence was assessed using
decreased appetite. The resulting nutritional deficiencies may worsen the Grading of Recommendation Assessment, Development and
the disease or delay recovery by depressing immune function.[3,4] A Evaluation (GRADE) approach.[1]
key guiding principle of the World Health Organization guidelines on
nutritional care and support for patients with tuberculosis[5] is that ‘an Results
adequate diet, containing all essential macro- and micronutrients, is Of the 35 eligible trials (N=8 283 participants), four were conducted
necessary for the well-being and health of all people, including those in children (n=739) and 11 specifically presented disaggregated out
with TB infection or TB disease’. However, owing to limited available come data for HIV-positive and HIV-negative participants. Most of
evidence there is still no evidence-based nutritional guidance specific the trials were conducted in Africa and Asia.
to adults and children who are being treated for active tuberculosis.
We summarise the evidence from an updated Cochrane review Macronutrient supplementation
assessing the effects of oral nutritional supplements on all-cause Seven trials investigated the effect of providing free food or high-
death and cure at 6 and 12 months in patients receiving treatment for energy nutritional supplements. The trials were too small to reliably
active tuberculosis.[1] demonstrate or exclude clinically important benefits on mortality
(risk ratio (RR) 0.34, 95% confidence interval (CI) 0.10 - 1.20; four
Methods trials, 567 participants, very low-quality evidence), cure (RR 0.91,
The review authors conducted a comprehensive search of eight 95% CI 0.59 - 1.41; one trial, 102 participants, very low-quality
databases up to February 2016, without language or date restrictions. evidence), or treatment completion (data not pooled; two trials,
All randomised controlled trials comparing any oral nutritional 365 participants, very low-quality evidence). Providing free food
supplement, given for at least 4 weeks, with no nutritional inter or high-energy nutritional supplements probably produces modest
vention, placebo or dietary advice only to patients receiving weight gain during treatment for active tuberculosis, although this
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was not consistent across all included trials (data not pooled; five and no studies have assessed the effect on quality of life. The summary
trials, 883 participants, mean weight gain 0.78 - 2.6 kg, moderate- of findings for multi-micronutrient supplementation is available for the
quality evidence). There is some evidence that quality of life may be outcomes death, cure rate, treatment completion, remaining sputum-
improved, but the trials were too small to have much confidence in positive (4 weeks), weight gain and quality of life.[1]
the result (data not pooled; two trials, 134 participants, low-quality
evidence) (Table 1).[1] Single- or dual-micronutrient supplementation
Eighteen trials assessed single- or dual-micronutrient supple
Multi-micronutrient supplementation mentation. Low vitamin A levels are common in tuberculosis, and
Six trials assessed multi-micronutrient supplementation in doses up plasma levels of vitamin A appear to increase following initiation
to 10 times the recommended dietary allowance (RDA).[6] Routine of antituberculosis treatment regardless of supplementation. There
multi-micronutrient supplementation may have little or no effect on is no evidence that vitamin A supplementation in doses up to three
mortality in HIV-negative people with tuberculosis (RR 0.86, 95% times the RDA has a beneficial effect on tuberculosis treatment
CI 0.46 - 1.6; four trials, 1 219 participants, low-quality evidence), outcomes (i.e. death (RR 0.97, 95% CI 0.84 - 1.12; eight trials,
or HIV-positive people not taking antiretroviral therapy (RR 0.92, 3 308 participants), sputum smear- or culture-positive after 4
95% CI 0.69 - 1.23; three trials, 1 429 participants, moderate-quality weeks (RR 0.70, 95% CI 0.33 - 1.48; one trial, 148 participants)) or
evidence). There is insufficient evidence to know whether multi- nutritional recovery (body mass index: RR 0.3, 95% CI –0.44 - 1.04;
micronutrient supplementation improves cure (no trials), treatment one trial, 148 participants). In contrast, supplementation probably
completion (RR 0.99, 95% CI 0.95 - 1.04; one trial, 302 participants, improves plasma levels of zinc, vitamin D, vitamin E and selenium,
very low-quality evidence), or the proportion of people who remain but this has not been shown to have clinically important benefits.
sputum-positive during the first 8 weeks of antituberculosis treatment Of note, despite multiple studies of vitamin D supplementation
(RR 0.92, 95% CI 0.63 - 1.35; two trials, 1 020 participants, very low- in different doses, statistically significant benefits on sputum
quality evidence). Furthermore, multi-micronutrient supplemen conversion have not been demonstrated (number of participants
tation may have little or no effect on weight gain during treatment who were sputum smear- or culture-positive after 4 weeks: RR 0.87,
(data not pooled; five trials, 2 940 participants, low-quality evidence), 95% CI 0.74 - 1.03; five trials, 929 participants).[1]
Table 1. Summary of findings: Food provision (calorie supplementation as food or energy-dense supplements) compared with
standard care (nutritional advice or no intervention) for adults and children with active tuberculosis*
Number of Quality of
Increased calorie participants the evidence
Outcomes Standard care intake Relative effect (trials) (GRADE)
Death (at 6 months) (95% CI) 3 per 100 1 per 100 (0 - 4) RR 0.34 567 (4 trials) Very low†‡§
(0.10 - 1.20)
Cured (at 6 months) (95% CI) 48 per 100 44 per 100 RR 0.91 102 (1 trial) Very lowद
(28 - 68) (0.59 - 1.41)
Treatment completion 79 per 100 85 per 100 Not pooled 365 (2 trials) Very low§||**
(at 6 months) (95% CI) (70 - 100)
Sputum negative (at 8 weeks) 76 per 100 82 per 100 RR 1.08 222 (3 trials) Very low§||**
(95% CI) (65 - 100) (0.86 - 1.37)
Mean weight gain (at 8 weeks) - - MD 0.78 883 (5 trials) Moderate††‡‡
(95% CI) (–0.05 - 1.6)
Quality of life (change in quality At 6 weeks: 13.33 14.47 (25.43) Not pooled 134 (2 trials) Low§§¶¶
of life score), mean (SD) (24.76)
At 24 weeks: 18.75 8.33 (22.49)
(27.38)
CI = confidence interval; SD = standard deviation; RR = risk ratio; MD = mean difference; GRADE: Grading of Recommendations Assessment, Development and Evaluation.
GRADE Working Group grades of evidence:
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.
*This technical summary is an adapted version of a Cochrane Review Summary of Findings table previously published[1] in the Cochrane Database of Systematic Reviews 2016, Issue 6, https://
doi.org/10.1002/14651858.CD006086.pub4 (see www.cochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback, and
the Cochrane Database of Systematic Reviews should be consulted for the most recent version of the review.
†
Three trials reported some deaths during the 6 months of treatment (Jahnavi 2010; Jeremiah 2014; Sudarsanam 2010), and one reported that no deaths occurred (Martins 2009). The trials were
conducted in Tanzania, Timor-Leste, and India in participants with signs of undernutrition. Martins 2009 gave a daily hot meal, Sudarsanam 2010 gave monthly ration packs, Jahnavi 2010 gave
daily locally appropriate supplements, and Jeremiah 2014 gave high-energy multivitamin-enriched biscuits.
‡
Downgraded by 1 for indirectness: trials are only available from limited settings. Food supplementation would plausibly have its biggest effect in highly food-insecure or emergency settings,
which are not reflected in these trials.
§
Downgraded by 2 for imprecision: the trials and meta-analysis are significantly underpowered to either detect or exclude an effect if it exists.
¶
Data on successful cure at 6 months are only available from Sudarsanam 2010, which randomised tuberculosis patients in India to monthly ration packs or advice only.
||
Two trials report on tuberculosis treatment completion at 6 months (Jahnavi 2010; Martins 2009). One trial was conducted in India and one in Timor-Leste in participants with signs of
undernutrition. Both trials gave daily locally appropriate supplements.
**Downgraded by 1 for inconsistency. Jahnavi 2010 found a statistically significant benefit, while the larger trial, Martins 2009, did not.
††
Five studies reported measures of weight gain but at different time points, which prevented meta-analysis. The relative effect was derived from three trials (Jeremiah 2014; Martins 2009 and
Praygod 2011b) that provided change and/or actual mean weight data at 8 weeks.
‡‡
Downgraded by 1 for inconsistency. Praygod 2011b included only HIV-positive patients, and although the trend was towards a benefit, this did not reach statistical significance. Jeremiah 2014
noted a greater increase in mean weight gain in the supplemented group compared with the non-supplemented group after 8 weeks; however, the difference was not appreciable (1.09 kg, p<0.6,
authors’ own figures). The three other trials all demonstrated clinically important benefits.
§§
Downgraded by 1 for indirectness. Only two small trials, one from Singapore (Paton 2004) and one from India (Jahnavi 2010), report quality-of-life scores. The results cannot be generalised to
other populations or settings with any certainty.
¶¶
Downgraded by 1 for imprecision. The presented data appear highly skewed and could not be pooled.
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Conclusion In SA, the burden of tuberculosis disproportionately affects people
The review authors concluded that based on the current research who are chronically impoverished, hungry and malnourished, who
they do not know whether routinely providing free food or have an increased risk not only of developing tuberculosis but also of
energy supplements results in better antituberculosis treatment poor tuberculosis treatment outcomes.[12,13] National data show that
outcomes (decreased tuberculosis-related mortality, increased cure almost a third (28.3%) of all adults are at risk of food insecurity and just
rate, increased tuberculosis treatment completion rate); however, over a quarter of all adults (26%) are food insecure.[14] Approximately
limited evidence suggests that it probably improves weight gain 70% of patients (n=100) admitted to a specialist tuberculosis hospital
in some settings. There is also no reliable evidence that routine in Mpumalanga were from food-insecure households (J Wessels,
supplementation with multi-micronutrients or specific individual unpublished data). Patients with tuberculosis also incur substantial
micronutrients above recommended daily amounts has clinical direct (e.g. transport to and from the clinic for consultation and
benefits. Of note for future research, according to the review authors’ treatment) and indirect (e.g. time and income loss due to absence
calculations, none of the included trials or meta-analyses of trials from work) costs related to their condition,[15] further exacerbating the
were sufficiently powered to detect clinically important effects on the social inequity. Currently, only 5% of all tuberculosis patients access
outcomes of interest.[1] the disability grant provided through the South African Social Security
Agency.[15] Improving access to the disability grant, as well as a possible
This evidence in the South African expansion thereof to tuberculosis patients contingent on treatment
context adherence or other relevant improved health behaviours associated
Tuberculosis is the leading cause of underlying natural deaths in with tuberculosis risk (e.g. stopping smoking),[16] along with effective
South Africa (SA), even through the proportions of natural deaths implementation of nutritional supplementation when indicated,
attributed to tuberculosis have declined over time (8.8% in 2013, deserves due attention in the fight to improve the concomitant and
8.3% in 2014, 7.2% in 2015).[7] The 2016 Global Tuberculosis Report intergenerational burden of poor nutrition and tuberculosis in SA.
estimated that SA had the sixth-greatest number of incident cases and
third-greatest incidence in relation to population.[8] The incidence Acknowledgements. S Nagpal, T D Sudarsanam and D Sinclair, co-authors of the
of multidrug-resistant (MDR) and extensively drug-resistant Cochrane review, are acknowledged for all their input into the review.
tuberculosis is increasing, and SA is deemed at risk of having a MDR Author contributions. LG summarised the evidence from the Cochrane Review
tuberculosis-dominated tuberculosis pandemic.[9] with the assistance of SD and CEN. SMvdM and JW drafted the section on the
According to the 2015/2016 District Health Barometer,[10] the
evidence in the SA context.
incidence of tuberculosis in SA has decreased over the past 5 years,
Funding. Partly supported by the Effective Health Care Research Consortium,
with the most notable decline in KwaZulu-Natal Province. The
which is funded by UK aid from the UK Government for the benefit of developing
Eastern Cape, KwaZulu-Natal and Western Cape have the highest
incidence of tuberculosis, while Mpumalanga, Gauteng and Limpopo countries (grant 5242). The views expressed in this publication do not necessarily
provinces rank the lowest. Districts with the highest tuberculosis reflect UK government policy.
incidence were Sarah Baartman (Eastern Cape), Pixley ka Seme Conflicts of interest. None.
(Northern Cape) and Nelson Mandela Bay (Eastern Cape).[10]
While the national guiding document on nutritional supple 1. Grobler L, Nagpal S, Sudarsanam TD, Sinclair D. Nutritional supplements for people being treated
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2008;46(10):1582-1588. https://doi.org/10.1086/587658
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6. Institute of Medicine, The National Academies of Science, Engineering and Medicine, Health and
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criteria for nutritional supplementation differ between provinces and from Death Notification. Pretoria: Stats SA, 2017. http://www.statssa.gov.za/?page_
id=1854&PPN=P0309.3&SCH=6987 (accessed 17 July 2017).
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‘Nutritional status of patients with tuberculosis and TB/HIV 11. Lombardo CC, Swart R, Visser ME. The nutritional status of patients with tuberculosis in comparison
with tuberculosis-free contacts in Delft, Western Cape. S Afr J Clin Nutr 2012;25(4):180-185. http://
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pregnant women, tuberculosis is associated with high mortality rates
and poor treatment outcomes, and as such these women may require
additional nutritional support. Accepted 7 September 2017.
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