Prevention of relapse in Drug Sensitive Pulmonary Tuberculosis patients with and without Vitamin D3 supplementation: A double blinded randomized control clinical trial

doi:10.21203/rs.3.rs-1331808/v1

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Prevention of relapse in Drug Sensitive Pulmonary Tuberculosis patients with and without Vitamin D3 supplementation: A double blinded randomized control clinical trial

https://doi.org/10.21203/rs.3.rs-1331808/v1

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Background: The immunomodulatory effects of vitamin D are widely recognized and a few studies have been conducted to determine its utility in the treatment of tuberculosis, with mixed results. This study was conducted to see if vitamin D supplementation in patients with active pulmonary tuberculosis (PTB) in the Indian population contributed to sputum smear and culture conversion as well as the prevention of relapse.

Methods: This randomized double-blind placebo-controlled trial was conducted in three sites in India. HIV negative participants aged 15-60 years with sputum smear positive PTB were recruited according to the Revised National Tuberculosis Control Program guidelines and were randomly assigned (1:1) to receive standard anti-tubercular treatment (ATT) with either supplemental dose of oral vitamin D3 (60,000 IU/sachet weekly for first two months, fortnightly for next four months followed by monthly for the next 18 months) or placebo with same schedule. The primary outcome was relapse of PTB and secondary outcomes were time to conversion of sputum smear and sputum culture.

Results: A total of 846 subjects were enrolled between February 1, 2017 to February 27, 2021, and randomly assigned to receive either 60,000 IU vitamin D3 (n = 424) or placebo (n = 422) along with standard ATT. Among the 697 who were cured of PTB, relapse occurred in 14 participants from the vitamin D group and 19 participants from the placebo group (hazard risk ratio 0.68, 95%CI 0.34 to 1.37, log rank p value 0.29). Similarly, no statistically significant difference was seen in time to sputum smear and sputum culture conversion between both groups. Five patients died each in vitamin D and placebo groups, but none of the deaths were attributable to the study intervention. Serum levels of vitamin D were significantly raised in the vitamin D group as compared to the placebo group, with other blood parameters not showing any significant difference between groups.

Conclusions: The study reveals that vitamin D supplementation does not seem to have any beneficial effect in the treatment of PTB in terms to the prevention of relapse and time to sputum smear and culture conversion.

Trial registration: The trial protocol was registered with the ICMR, Clinical Trial Registry – India

Trial registration number: CTRI/2021/02/030977 ( date of first registration-03/02/2021).

Pulmonary Tuberculosis

Vitamin D

Clinical Trial

Placebo

Relapse

Tuberculosis (TB) is a debilitating contagious disease and a major global public health problem(1). A total of 1.5 million people died from TB in 2020 (including 214,000 people with HIV). Worldwide, TB is the 13th leading cause of death and the second leading infectious killer after COVID-19 (above HIV/AIDS).Eight countries account for two thirds of worldwide deaths, with India leading the count, followed by China, Indonesia, the Philippines, Pakistan, Nigeria, Bangladesh and South Africa.(2)

Vitamin D, also called cholecalciferol, is a micronutrient which is recognized primarily for its role in bone mineralization. It has also been under scrutiny lately with respect to its immuno-modulatory properties. In recent years, extensive research has been done to look for other functions of vitamin D and its related metabolites. Many epidemiological studies have shown inverse relation in the levels of vitamin D and incidence of various infectious and chronic diseases(3). The major circulating metabolite of vitamin D is 1,25-hydroxyvitamin D (1,25[OH]D), which supports innate antimicrobial immune responses, thus suggesting a potential mechanism by which adjunctive vitamin D might enhance response to anti-tuberculosis therapy (ATT)(4).

Consequently, in a country with a high TB burden such as India, there is a compelling need to investigate the potential benefits of vitamin D supplementation along with ATT in subjects with active pulmonary TB (PTB), particularly with regards to preventing relapse after successful treatment completion and cure as well as achieving early sputum and culture conversion. If so, it can be helpful in further optimizing the management of PTB. Hitherto few studies have been conducted to investigate the effect of vitamin D in the management of PTB, albeit with small sample sizes, limited dosage of vitamin D and with analysis of limited parameters. This randomized control trial was done to assess the effect of vitamin D in patient with PTB on the time to sputum smear and culture conversion as well as the risk of relapse.

Study design and participants:

We conducted a randomized double-blind placebo-controlled trial at three tertiary care hospitals in India (All India Institute of Medical Sciences, Delhi; National Institute of Tuberculosis and Respiratory Diseases, Delhi and Post Graduate Institute of Medical Education and Research, Chandigarh). Patients were recruited from DOTS (Directly Observed Treatment, Short Course) centres in agreement with Revised National Tuberculosis Control Program (RNTCP) guidelines. New sputum smear positive subjects in the age group of 15–60 years and willing to participate were enrolled for the study. Subjects having any major surgical or medical illness or requiring hospitalization for the same or having chronic kidney disease, Human Immunodeficiency Virus(HIV) infection, BMI < 15kg/m2, diabetes mellitus, chronic alcoholism, pregnant and lactating women, or receiving any kind of vitamin D / calcium supplementation or having any disorder of bone mineral homeostasis, and those refusing consent were excluded from the study.

Subjects were diagnosed as a case of PTB by sputum smear examination for acid fast bacilli (AFB), for which 2 sputum samples were collected- one early morning and the second on the spot. The sputum was treated with N-acetyl-L-cysteine/NaOH and the ensuing sediment was stained by Ziehl Neelsen method. The slides were examined under oil immersion objective, and the number of AFB observed were graded from scanty to 3 + as per the recommendations of WHO. Sputum cultures were done using the Mycobacteria Growth Indicator Tube (MGIT-960) non radiometric automated isolation system (Becton Dickinson), and drug resistance was determined using the line probe assay (LPA) method. To ensure eligibility of subjects, pre-randomization investigations for hepatic and renal assessment, serology for HIV, Hepatitis B and Hepatitis C as well as fasting blood glucose were done. Other investigations like chest radiograph, electrocardiogram, complete hemogram and urine microscopy were also done.

The primary outcome was rate of relapse of PTB in both arms assessed up to 24 months of follow up. Secondary outcomes included time to sputum smear and culture conversion in months.

Randomization:

Subjects were randomly assigned (1:1) into two groups by using block randomization via a computer program. Packets containing the two interventions were prepared in accordance with the randomization numbers and were arranged serially, and then distributed consecutively to subjects according to their entry into the trial. Both the groups received standard DOTS ATT as per RNTCP guidelines. The intervention group received supplemental dose of oral vitamin D3 (60,000 IU/sachet every week for first two months, then every fortnight for next four months and then every month for next 18 months), and the control received only placebo with an identical schedule. The vitamin D and placebo sachets were identical in terms of their taste and physical appearance. The codes of the interventions were kept secure by an investigator who was not involved in the distribution of the packets and none of the patients, clinical and laboratory investigators were informed of the treatment assignment.

The protocol was followed as per the Good Clinical Practice standards and Institutional Ethical Guidelines. The protocol was approved by DHR, ICMR and institutional ethics committee of all three centers. Written informed consent was taken from all the participants. For participants below the age of 18, written informed consent was provided by their legal guardians. The trial protocol was registered with the Clinical Trial Registry – India.

Procedures:

Sputum smear for AFB was taken every fortnight during the intensive phase (two months), every month during the continuation phase (four months) and once every six months thereafter till the 24th month of follow up. Samples for MGIT culture were taken every fortnight for the initial 2 months and every month thereafter till 6 months of follow up. Blood and urine investigations were conducted every fortnight till two months, then every month till six months and then every six months till the 24th month follow up. Chest radiograph was done at baseline, at the end of the intensive phase, end of treatment and every 6 months thereafter. Ultrasound abdomen done at baseline, end of treatment and at 24 months. Disease severity was graded on chest radiographs as minimal, moderately advanced, and far advanced according to the American Thoracic Society recommendations.(5)

Statistical analysis:

As per Revised National Tuberculosis Control Program annual report (2013), 12% of PTB patients receiving category-I ATT relapsed. Assuming that vitamin D supplementation for 24 months (6 months with ATT and 18 months post ATT), would reduce the relapse by 5% by the end of two years from diagnosis. To detect a 5% reduction (12% vs 7%) in the relapse between the two arms in a two-sided test with 5% alpha error and 80% power, 539 participants in each group (as per the nQuery Advisor Version 2.0). Giving an allowance of 15% each for losses in follow-up and MDR detection after randomization, 772 participants would be required per group. Therefore we need to randomize about 1550 participants.

The data was analyzed using STATA version 16.0.0. Blood, urine and radiological parameters were analyzed using parametric and non-parametric analysis. Parametric data was analyzed using Student’s t-test, while non-parametric data was analyzed using Wilcoxon rank sum test. Sputum smear and culture data was analyzed using Wilcoxon (Breslow) test for equality of survivor functions. Relapse data was analyzed using Log-rank test for equality of survivor functions in STATA.

A total of 1996 subjects were screened from February 1, 2017 and followed up till February 27, 2021 at three tertiary care hospitals in India. Of these 1150 subjects were excluded and 846 were randomly assigned to the vitamin D group (n = 424) and placebo group (n = 422). (Figure.1) Baseline and demographic characteristics did not demonstrate any significant difference between the two groups. Baseline BMI is shown in Table 1, with an overall mean of 19.3 ± 3.7 kg/m2. The baseline BMI amongst the two groups did not display any statistically significant difference (p-0.95). A majority of the participants in both groups were deficient in Vitamin D with average value of 14.2 ± 8.7ng/ml (Normal:25–80 ng/ml). Vitamin D levels amongst the two groups also did not reveal any statistically significant difference (p = 0.156). Similar trends were observed for calcium levels (p = 0.951), phosphate (p = 0.335), urea (p = 0.175), creatinine (p = 0.160), iPTH (p = 0.377) and hemoglobin (p = 0.957). Analysis of the chest radiographs revealed 46% of individuals having moderately affected lungs with no significant difference amongst the two groups at baseline (p = 0.151). Sputum smear profile at baseline showed 49% of subjects had 1 + bacilli (AFB), 21% had 2 + and 30% had 3+, with no significant difference seen among both groups (p = 0.46).

Table 1

Baseline and demographic characteristics
Demographic Profile ( n = 846) (MEAN ± SD)
Observations	Vitamin D arm (424)		Placebo arm (422)		p-value	Overall (n-846)
Gender	Male – 276(65%)	Female – 148 (35%)	Male – 279 (66%)	Female – 143 (34%)	p-value	Male – 555 (65%)	Female – 291 (35%)
Age (in years)	29.2 ± 11.6		29.4 ± 11.4		0.821	29.3 ± 11.5
Weight (Kg)	48.7 ± 9.5		49.1 ± 9.8		0.553	48.9 ± 9.6
Height (cm)	158.3 ± 11.1		158.9 ± 10.8		0.457	158.6 ± 10.9
BMI (Kg/m²)	19.3 ± 3.9		19.3 ± 3.6		0.955	19.3 ± 3.7
Calcium (mg/dl)	8.8 ± 0.6		8.7 ± 0.6		0.951	8.8 ± 0.7
Phosphate(mg/dl)	3.5 ± 1.0		3.4 ± 0.9		0.335	3.4 ± 1.0
25OH Vitamin D₃ (ng/ml)	(3–63.5 ) 12.4		(2.6–61.1) 11.6		0.156	14.2 ± 8.7
iPTH	(1–229.3 ) 17.8		(4–115.8 ) 15.4		0.377	21.3 ± 16.3
Hemoglobin (gm/dl)	11.9 ± 1.9		11.8 ± 1.8		0.957	11.9 ± 1.9
Urea (mg/dl)	24.3 ± 6.7		24.9 ± 6.5		0.175	24.6 ± 6.6
Creatinine (mg/dl)	0.7 ± 0.3		0.8 ± 0.3		0.160	0.7 ± 0.3
Chest X-ray severity	Normal − 8 Mild – 117 Moderate- 202 Severe − 97		Normal − 6 Mild – 144 Moderate- 194 Severe − 78		0.151	Normal − 14 Mild – 261 Moderate- 396 Severe − 175
Sputum Smear Profile	1 + − 212 2 + − 92 3 + − 120		1 + − 200 2 + − 86 3 + − 136		0.461	1 + − 412 2 + − 178 3 + − 256

Primary Outcome:

For the final analysis, we took patients who had successfully completed their six months of treatment and 18 months of follow up (697 out of 846). 149 subjects were censored of which 87 were lost to follow-up, 57 individuals provided insufficient sample, 3 had adverse event and 2 patients expired.

There were 14 (4%) relapses in vitamin D arm and 19 (5.5%) relapses in placebo arm (n = 697 patients, n = 149 censored), which was however not statistically significant (p = 0.29). Bivariate Cox regression revealed a hazard ratio of 0.68 (95% CI: 0.34 to 1.37) having a log rank p-value of 0.29 (Table 2), thus implying a 32% reduction in relapses amongst individuals receiving vitamin D, which is not statistically significant. Upon testing for drug resistance, none of the relapsed participants were found to be harboring resistant organisms. All the relapsed patients were again initiated on ATT. Most of the individuals relapsed were male (n = 25) compared to female (n = 8).

Table 2

Primary outcome of the study
No. of subjects cured at 6 month	No. of Relapse in Placebo arm (n-343)	No. of Relapse in Vitamin D arm (n-354)	Hazard Ratio (Bivariate Cox Regression)	95% CI	P- Value
n-697	19 (5.5%)	14 (4%)	0.68	0.34–1.37	0.290

Secondary Outcomes:

Median time to sputum smear conversion in both groups was two weeks (95% CI 1.7 to 2.2 in vitamin D arm; 95% CI 1.7 to 2.6 in placebo arm) with hazard risk ratio of 1.06 (95% CI 0.92 to 1.23) and log rank p value 0.35 (Table 3). There was no significant difference observed between vitamin D and placebo groups with respect to median time to sputum smear conversion (n = 779 patients, n = 67 censored). Median time to culture conversion for both groups was four weeks (95% CI 3.6 to 4.3 vitamin D arm; 95% CI 3.7 to 4.3 placebo arm) with hazard risk ratio of 1.06 (95% CI 0.91 to 1.24) and log rank p value of 0.42. Again, there was no significant difference seen in the median time to culture conversion (n = 703 patients, n = 143 censored) between the two groups (Table 3).

Table 3

Secondary outcomes of the study
Group (s)	Subject(s)	Median Time to Conversion (In Weeks)	95% CI	Hazard Ratio (Bivariate Cox Regression)	95% CI	p-value
Time to Sputum smear conversion (n-779)
Placebo	385	2	1.7–2.6	1.0	0.92–1.23	0.35
Vitamin D	394	2	1.7–2.2	1.06	0.92–1.23	0.35
Time to Culture Conversion (n- 703)
Placebo	347	4	3.7–4.3	1.0	0.91–1.24	0.418
Vitamin D	356	4	3.6–4.3	1.06	0.91–1.24	0.418

The intervention arm saw a significant increase in vitamin D levels compared to the placebo arm following supplementation, which was maintained throughout the follow-up at 6th, 12th, 18th and 24th month (p-value < 0.001 at each interval).

None of the subject in either group developed hypercalcemia. There was no significant difference observed in calcium level during follow up at 6th month (p = 0.62), 12th month (p = 0.52), 18th month (p = 0.17) and 24th month (p = 0.13).

Further sub group analysis was done to see the relationship between BMI (Asian Indian Criteria and relapse rate.(6) It was observed that no relapse occurred in the BMI range of ≥ 25 while 63% (n = 21) of relapse cases were seen in BMI range < 18.5, 33% (n = 11) in BMI range 18.5–22.9 and 3% (n = 1) relapse case was seen in BMI range 23–24.9. On Cox regression analysis, hazard ratio was 0.50 (95% CI: 0.2–1.3, p-0.19) which shows more than 50% of relapse cases were observed in < 18.5 BMI but results are not statistically significant (p = 0.19).

Safety profile (non-serious and serious adverse events) and mortality profile (all-cause deaths) analysis between the two groups (Table 4) showed that 10 (1.1%) patients died during the study (five in the vitamin D group and five in the placebo group). No death was directly attributable to the study intervention. Excluding death, seven serious adverse events were recorded (4 in placebo and 3 in vitamin D arms). Two patients in vitamin D arm had drug induced liver injury, with 1 patient developing liver abscess, while 4 participants in the placebo arm had serious side effects (one developing ethambutol ototoxicity, one developed allergic reaction to the placebo, one had drug induced liver injury and one developed DRESS syndrome). A total of 14 adverse events were recorded, eight in the vitamin D group and six in the placebo group, all having renal calculi, with none requiring a change in medical therapy (Table 4).

Table 4

Adverse events profile
	Vitamin D (n-424)		Placebo (n-422)		COX Regression	p-value
Variable	No. of Events	Event / 100 person-month	No. of Events	Event / 100 person-month	Hazard Ratio (Vitamin D vs Placebo) 95% CI	p-value
Death	5	0.10	5	0.11	0.96 (0.2–3.3)	0.95
Serious Adverse Event	3	0.06	4	0.06	0.96 (0.1–4.7)	0.96
Adverse Event (Renal Calculus)	8	0.17	6	0.13	1.3 (0.4–3.7)	0.61
Hypercalcemia	0	0	0	0	NC	-
Hypervitaminosis D	0	0	0	0	NC	-
*NC indicates that the risk ratio could not be calculated due to no events in both the groups

At the initiation of our study, we observed most of our patients suffering from active PTB being deficient in vitamin D with average value at 14.2 ± 8.7ng/ml (Normal:25–80 ng/ml). This is in agreement with similar studies across the globe; a study in US adults acknowledged the inverse relationship of vitamin D levels with the risk of latent TB infection (LTBI) (7) and another in Sudan connected low vitamin D Levels with increased risk of PTB (8). In view of its anti-inflammatory and anti-microbial qualities as elucidated by Coussens et al, one can make the assumption for Vitamin D deficiency to be a risk factor for the development of PTB.(9). However, a large study in Mongolia involving 8851 children revealed no beneficial effect of Vitamin D supplementation in limiting the risk of TB infection despite the Vitamin D levels reaching physiologic levels.(10) In our study, supplementation of high-dose oral vitamin D was safe and led to a substantial increase in plasma vitamin D concentrations in the intervention arm, but did not contribute significantly towards prevention of relapse. Although the number of relapses in the group without vitamin D supplementation was less, the difference was not statistically significant. Similar findings were seen in a metaanalysis of 8 trials, where despite a significant increase in vitamin D levels, there was no beneficial effect of vitamin D as adjunctive treatment for TB(11). We observed relapses in our study to be more common in male subjects (n = 25) compared to female subjects (n = 8), which is concordant with the similar trend observed in the general population(12). Individuals having BMI > 25 in both the groups were observed to be have no relapse, a phenomenon which is also commonly seen in our clinical practice. A possible explanation for such a phenomenon may be due to the differential biophysical stresses in the lungs of these individuals, wherein young males having lower BMI are more predisposed to enlarging apical bullae, which are easy targets for TB reactivation. Studies in this purview also suggest the same.(13)

With regards to the therapeutic value of vitamin D in the treatment of TB, increase in vitamin D levels in serum as a result of supplementation did not translate to significant improvement in time to sputum smear and culture conversion in comparison with the placebo group. This is in agreement with similar studies investigating the relationship between vitamin D and PTB.(14) Wejse et al, did not observe any beneficial outcome of vitamin D supplementation on TB score, weight gain, sputum conversion, or mortality (15). A study in Georgia confirmed the inverse relationship between vitamin D levels and risk of TB, but failed to show enhanced sputum Mycobacterial clearance in patients receiving high dose vitamin D(16). According to Martineau et al, vitamin D did not improve time to sputum conversion in the study population, however, sputum conversion was significantly faster in patients with the tt genotype of the TaqI polymorphism of the Vitamin D Receptor gene(4). In contrast, Tukvadze et al, could not confirm whether the allele resulted in a faster sputum culture conversion for patients on vitamin D treatment. However, their study was significantly underpowered.(16)(4) Certain peers attributed the negative results in the studies of Martineau et al and Wejse et al to the low dosage of the intervention (4)(15). In order to address this limitation, as well as keeping in mind the higher prevalence of vitamin D deficiency in our country as compared to the western world,we supplemented our intervention group with high dose of Vitamin D (60,000 IU), but even this change did not translate to a faster sputum mycobacterium clearance.(17)

No significant difference was detected in the safety profile (non-serious and serious adverse events) and mortality profile (all-cause deaths) between the two groups. The most reported non-serious adverse event in 14 patients out 846 was renal calculi. Adverse events and deaths were evenly distributed between the two groups.

Our study has several strengths, including a large sample size (n = 846) with an appropriate period of follow up (2 years). Participants also received a substantial dose of vitamin D to avoid the possibility of false negative results as criticized by some in the earlier mentioned studies. The participants were closely followed up regularly throughout the study period and the administration of the intervention was directly observed, ensuring good compliance to medications and thus eliminating the confounding effect of non-compliance contributing to relapse. The proportion of missing outcome data was small and comparable in both the groups. Therefore, our findings have a high degree of validity.

Vitamin D supplementation showed no benefit over placebo in preventing relapse of PTB and in reducing time to sputum smear and culture conversion. There were no major adverse reactions observed in either the vitamin D or placebo arm which could be ascribed to the intervention.

AIIMS

All India Institute of Medical Sciences

PTB

Pulmonary Tuberculosis

Tuberculosis

ATT

Anti-tubercular treatment

DOTS

Directly Observed Treatment, Short Course

RNTCP

Revised National Tuberculosis Control Program

ICMR

Indian Council of Medical Research

DHR

Department of Health Research

BMI

Body Mass Index.

Ethics approval and consent to participate: This study has been approved by the Institute Ethics committee, All India Institute of Medical Sciences, New Delhi. Before the start of the study, all participants provided written informed consent. For participants below the age of 18, written informed consent was provided by their legal guardians. Participants were informed that they had the right to discontinue their participation or withdraw from the study at any time. We confirm that all methods were performed in accordance with the relevant guidelines and regulations (e.g., Declaration of Helsinki).

Consent for publication: Not Applicable

Availability of data and materials: De-identified participant data will be provided upon reasonable request to [email protected].

Competing Interests: The authors declare that they have no competing interests.

Funding: Department of Health Research, Ministry of Health and Family Welfare, Government of India.

Author contributions:

SS conceptualized the study, determined methodology, recruited participants at AIIMS New Delhi, collated / analyzed data and wrote the first draft of the manuscript.

HT contributed to participant recruitment at AIIMS New Delhi, data analysis and manuscript writing.

IS and DD contributed to data analysis and manuscript writing.

BS,SuS,RY and BKD performed the laboratory work and contributed to manuscript editing.

SD,AK,ANA,SB and DB contributed to patient recruitment at PGIMER Chandigarh as well as analysis and editing of the manuscript.

SKM, RSi and RS contributed to patient recruitment at NITRD New Delhi as well as analysis and editing of the manuscript.

RMP and SP performed data analysis, creating the figures and tables and manuscript editing.

SS and HT accessed and verified the data.

All authors approved of the final manuscript.

Acknowledgements: We thank the staff members of the DOTS clinic for their help during patient enrolment and follow-up. We acknowledge the support and coordination of all staff of the project and laboratory staff of Department of Medicine and Microbiology. We thank Department of Health Research, Ministry of Health and Family Welfare, Government of India for funding this project.

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No competing interests reported.

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Prevention of relapse in Drug Sensitive Pulmonary Tuberculosis patients with and without Vitamin D3 supplementation: A double blinded randomized control clinical trial

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