Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(trials)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Standard care

Increased calorie intake

Death

(at 6 months)

3 per 100

1 per 100
(0 to 4)

RR 0.34
(0.10 to 1.20)

567
(4 trials)

⊕⊝⊝⊝
very low^1,2,3

We don't know if food supplementation reduces mortality from tuberculosis in food‐insecure settings

Cured

(at 6 months)

48 per 100

44 per 100
(28 to 68)

RR 0.91
(0.59 to 1.41)

102
(1 trial)

⊕⊝⊝⊝
very low^2,3,4

We don't know if food supplementation increases cure in tuberculosis patients

Treatment completion
(at 6 months)

79 per 100

85 per 100
(70 to 100)

Not pooled

365
(2 trials)

⊕⊝⊝⊝
very low^3,5,6

We don't know if food supplementation increases treatment completion in tuberculosis patients

Sputum negative

(at 8 weeks)

76 per 100

82 per 100
(65 to 100)

RR 1.08
(0.86 to 1.37)

222
(3 trials)

⊕⊝⊝⊝
very low^3,5,6

We don't know if food supplementation reduces the duration of sputum positivity in tuberculosis patients

Mean weight gain

(At 8 weeks)

—

—

Not pooled

883
(5 trials)

⊕⊕⊕⊝
moderate^7,8

Supplementation probably increases weight gain during treatment

Quality of life
(At 8 weeks)

—

—

Not pooled

134
(2 trials)

⊕⊕⊝⊝
low^9,10

Supplementation may increase quality of life scores during the first 2 months of treatment

*The assumed risk is taken from the mean risk in the control groups in the included studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
Abbreviations: CI = confidence interval; RR = risk ratio; 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.

¹Three trials reported some deaths during the 6 months of treatment (Jahnavi 2010 IND; Jeremiah 2014 TZA; Sudarsanam 2010 IND), and 1 reported that no deaths occurred (Martins 2009 TLS). The trials were conducted in Tanzania, Timor‐Leste, and India in participants with signs of undernutrition. Martins 2009 TLS gave a daily hot meal, Sudarsanam 2010 IND gave monthly ration packs, Jahnavi 2010 IND gave daily locally appropriate supplements, and Jeremiah 2014 TZA gave high energy multivitamin enriched biscuits.
²Downgraded 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.
³Downgraded by 2 for imprecision: the trials and meta‐analysis are significantly underpowered to either detect or exclude an effect if it exists.
⁴Data on successful cure at 6 months is only available from Sudarsanam 2010 IND which randomized tuberculosis patients in India to monthly ration packs or advice only.
⁵Two trials report on tuberculosis treatment completion at 6 months (Jahnavi 2010 IND; Martins 2009 TLS). One trial was conducted in India and 1 in Timor‐Leste in participants with signs of undernutrition. Both trials gave daily locally appropriate supplements.
⁶Downgraded by 1 for inconsistency. Jahnavi 2010 IND found a statistically significant benefit while the larger trial, Martins 2009 TLS, did not.
⁷Five studies reported measures of weight gain but at different time‐points, which prevented meta‐analysis.
⁸Downgraded by 1 for inconsistency. Praygod 2011b TZA included only HIV‐positive patients and although the trend was towards a benefit this did not reach statistical significance. Jeremiah 2014 TZA noted a greater increase in mean weight gain in the supplemented group compared to the non‐supplemented group after 8 weeks; however the difference was not appreciable (1.09 kg, P < 0.6, authors' own figures). The 3 other trials all demonstrated clinically important benefits.
⁹Downgraded by 1 for indirectness. Only 2 small trials, 1 from Singapore (Paton 2004 SGP) and 1 from India (Jahnavi 2010 IND) report quality of life scores. The results can not be generalized to other populations or settings with any certainty.
¹⁰Downgraded by 1 for imprecision. The presented data appear highly skewed and could not be pooled.

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

Multi‐micronutrients

Death

HIV‐negative participants

RR 0.86
(0.46 to 1.6)

1219
(4 trials)

⊕⊕⊝⊝
low^1,2,3

Multi‐micronutrient supplements may have little or no effect on mortality in HIV‐negative tuberculosis patients

40 per 1000

34 per 1000
(18 to 64)

HIV‐positive participants

RR 0.92
(0.69 to 1.23)

1429
(3 trials)

⊕⊕⊕⊝
moderate^4,5

Multi‐micronutrients probably have little or no effect on mortality in HIV‐positive tuberculosis patients not on ARV therapy

357 per 1000

328 per 1000
(246 to 439)

Cure rate

—

—

—

(0 trials)

—

We don't know if multi‐micronutrients improve cure in tuberculosis patients

Treatment completion

970 per 1000

960 per 1000

(920 to 101)

RR 0.99 (0.95 to 1.04)

302

(1 trial)

⊕⊝⊝⊝
very low^6,7

We don't know if multi‐micronutrients improve treatment completion in tuberculosis patients

Remaining sputum positive
(at 4 weeks)

309 per 1000

312 per 1000
(263 to 371)

RR 0.92
(0.63 to 1.35)

1020
(2 studies)

⊕⊝⊝⊝
very low^8,9,10

We don't know if multi‐micronutrients reduce the proportion of patients still sputum positive at 4 weeks

Weight gain

—

—

Not pooled

2940
(5 trials)

⊕⊕⊝⊝
low¹¹

Multi‐micronutrient supplements may not improve weight gain in tuberculosis patients

Quality of life

—

—

—

(0 trials)

—

We don't know if multi‐micronutrients improve quality of life in tuberculosis patients

*The assumed risk is taken from the risk in the control groups of the included studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
Abbreviations: CI = confidence interval; RR = risk ratio; 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.

¹Five RCTs comparing multi‐micronutrient supplementation with placebo in adults (Range 2005 TZA; Semba 2007 MWI; Villamor 2008 TZA) and children (Lodha 2014 IND; Mehta 2011 TZA), reported deaths during treatment. The exact composition of nutrients varied from 1 to 10 times the DRI. Three studies are from Tanzania, 1 from Malawi, and 1 from India. There is evidence of participants being significantly undernourished at baseline.
²No serious inconsistency: statistical heterogeneity was low. Although the estimate of effect is trending towards a benefit this is due to 1 trial (Villamor 2008 TZA), the remaining trials found non significant trends in the opposite direction. Not downgraded.
³Downgraded by 2 for imprecision: the 95% CI of the pooled effect crosses 1 and includes a 2% absolute reduction in death which might be considered beneficial given the low cost of the intervention. The optimal information size to reliably detect a clinically beneficial effect if there is 1 is greater than 2000.
⁴Downgraded by 1 for indirectness: none of the participants in these trials were receiving antiretroviral therapy (Range 2005 TZA; Semba 2007 MWI; Villamor 2008 TZA). The exact composition of nutrients varied from 1 to 10 times the DRI. Two studies are from Tanzania and 1 in Malawi. There is evidence of participants being significantly undernourished at baseline.
⁵No serious imprecision: the 95% CI of the pooled effect crosses 1 and does includes a 5% absolute reduction in death which might be considered beneficial given the low cost of the intervention. However, the effect estimate is of no difference between the treatments and the optimal information size to reliably detect a clinically beneficial effect is met.
⁶Downgraded by 2 for indirectness: current evidence is limited to 1 small trial (Lodha 2014 IND) conducted in moderately undernourished, HIV‐negative children in India, where treatment completion was very high in both groups. The result is not easily generalized to other settings.
⁷Downgraded by 1 for imprecision: although this trial approaches adequate power to detect a result, the fact that treatment completion was so high in both arm renders the result irrelevant to settings where treatment completion is lower.
⁸Downgraded by 1 for inconsistency. Statistical heterogeneity is high; 1 study found a non‐significant trend in favour of supplementation, and 1 study in favour of placebo.
⁹Downgraded by 1 for indirectness. Both studies were conducted in Tanzania. Different populations may differ in their micronutrient deficiency or requirement.
¹⁰Downgraded by 1 for imprecision. The 95% CI is wide and includes what may be clinically important effects.
¹¹Downgraded by 2 for inconsistency: Statistical heterogeneity is very high. Four studies from Tanzania and India found no evidence of improved weight gain with supplements, while 1 study from Tanzania found large increases in weight with micronutrients at 8 months.

Findings

Interpretation

Equity – Which of the PROGRESS groups examined

The trials included in this review were conducted in a mix of low- and middle-income countries (Egypt, Guinnea-Bissau, Ethiopia, Tanzania, Malawi, Nigeria, South Africa, Singapore, Indonesia, Iran, Bangladesh, India, Timor Leste, Mexico, UK, and Georgia). Undiagnosed tuberculosis is widespread in each of these countries.

There is a higher prevalence of TB in low- and middle-income countries and innovative treatment approaches may decrease prevalence in these endemic areas.

The study provides evidence demonstrating that nutritional supplements may improve weight gain in some settings and improve quality of life, although they may have no effect on mortality, cure, or treatment completion. The included studies were deemed low quality and thus further trials are needed.  

No other PROGRESS-plus groups were

examined in the review

This review did not analyze the effect of nutritional supplements across additional PROGRESS groups. Future research would be required to explore variations in outcome.

Equity Applicability

The review summarized trials addressing treatment of children and HIV+ populations.

Children and individuals with HIV represent a significant portion of new TB cases. These populations are particularly vulnerable to TB due to their lowered levels of adaptive immunity, placing a greater need for trials testing treatment regimens in said populations.

Cost-equity

No studies contributed economic data

The cost and availability of nutritional supplements may vary across countries. Patients in low- and middle-income countries may not be able to acquire this additional food due to economic hardship through illness and loss of work, or due to local food insecurity. Economic context and affordability are important considerations.

Monitoring & Evaluation for PROGRESS Groups

It is unclear from the evidence whether nutritional supplements improve treatment success of active tuberculosis. It is also unclear from the evidence whether nutritional supplements improve treatment completion or decrease mortality rates.

The absence of any benefit may be related to the dose used, as people recovering from tuberculosis may have higher nutrient requirements than healthy people. Further research is needed to make conclusions on the presence or absence of clinically important benefits of nutritional supplements on tuberculosis treatment outcomes. In the meantime, many national and local decisions may be based on pilot studies demonstrating tuberculosis treatment success resulting from nutritional supplements, with the dose and type of supplements modified based on observation and assessment.