co-morbilidadtb-dm: ¿tormentaperfecta? · multidrug-resistant (mdr) tuberculosis (tb) has emerged...

Co-morbilidad TB-DM:¿tormenta perfecta?

CesarUgarteUnidaddeTuberculosis– IMTAvH

Marzo2017

[email protected]@cugartegil

¿Unatormentaperfecta?

S86 • JID 2007:196 (Suppl 1) • Wells et al.

S U P P L E M E N T A R T I C L E

HIV Infection and Multidrug-ResistantTuberculosis—The Perfect Storm

Charles D. Wells,1 J. Peter Cegielski,1 Lisa J. Nelson,2 Kayla F. Laserson,3 Timothy H. Holtz,1 Alyssa Finlay,1

Kenneth G. Castro,1 and Karin Weyer4

1Division of Tuberculosis Elimination, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention (CDC), Atlanta,Georgia; 2Global AIDS Program–Mozambique, CDC, Maputo, Mozambique; 3Kenya Medical Research Institute/CDC Research Center, Kisumu,Kenya; 4Medical Research Council of South Africa, Pretoria, South Africa

Background. Multidrug-resistant (MDR) tuberculosis (TB) has emerged as a global epidemic, with ∼425,000new cases estimated to occur annually. The global human immunodeficiency virus (HIV) infection epidemic hascaused explosive increases in TB incidence and may be contributing to increases in MDR-TB prevalence.

Methods. We reviewed published studies and available surveillance data evaluating links between HIV infectionand MDR-TB to quantify convergence of these 2 epidemics, evaluate the consequences, and determine essentialsteps to address these epidemics.

Results. Institutional outbreaks of MDR-TB have primarily affected HIV-infected persons. Delayed diagnosis,inadequate initial treatment, and prolonged infectiousness led to extraordinary attack rates and case-fatality ratesamong HIV-infected persons. Whether this sequence occurs in communities is less clear. MDR-TB appears notto cause infection or disease more readily than drug-susceptible TB in HIV-infected persons. HIV infection maylead to malabsorption of anti-TB drugs and acquired rifamycin resistance. HIV-infected patients with MDR-TBhave unacceptably high mortality; both antiretroviral and antimycobacterial treatment are necessary. Simultaneoustreatment requires 6–10 different drugs. In HIV-prevalent countries, TB programs struggle with increased caseloads,which increase the risk of acquired MDR-TB. Surveillance data suggest that HIV infection and MDR-TB mayconverge in several countries.

Conclusions. Institutional outbreaks, overwhelmed public health programs, and complex clinical managementissues may contribute to the convergence of the MDR-TB and HIV infection epidemics. To forestall disastrousconsequences, infection control, rapid case detection, effective treatment, and expanded program capacity areneeded urgently.

BACKGROUND

Multidrug-resistant (MDR) tuberculosis (TB)—TBcaused by Mycobacterium tuberculosis strains resistantto at least isoniazid and rifampin—has emerged as aglobal epidemic resulting largely from deficiencies inTB case management and program management [1–3].Approximately 425,000 MDR-TB cases occur annually

Potential conflicts of interest: none reported.Financial support: US government; resources were provided solely in the form

of staff time dedicated to conducting this project. Supplement sponsorship isdetailed in the Acknowledgments.

The findings and conclusions in this report are those of the authors and do notnecessarily reflect the views of the Centers for Disease Control and Prevention.

Reprints or correspondence: Dr. Charles D. Wells, International Research andPrograms Branch, Div. of Tuberculosis Elimination, Centers for Disease Control andPrevention, 1600 Clifton Rd., Atlanta, GA 30333 ([email protected]).

The Journal of Infectious Diseases 2007; 196:S86–107! 2007 by the Infectious Diseases Society of America. All rights reserved.0022-1899/2007/19604S1-0011$15.00DOI: 10.1086/518665

worldwide, representing nearly 5% of the world’s an-nual TB burden [1]. The diagnosis of MDR-TB requiressophisticated laboratories with highly skilled microbi-ologists. Patients with MDR-TB require a much longertreatment period, usually 24 months, compared withthe 6–8 months required for drug-susceptible TB [4].Additionally, treatment requires the use of “second-line” drugs, which are more toxic and prohibitivelymore expensive, with MDR-TB drug costs alone thatare, on average, 100- to 300-fold higher than thoseassociated with drug-susceptible TB [5, 6]. Further-more, patients with MDR-TB have lower cure rates andhigher mortality than do patients with drug-susceptibleTB [7–10]. In well-performing MDR-TB programs insettings with a low HIV infection prevalence, treatmentsuccess is generally 70%–80%; by comparison, treat-ment success for drug-susceptible TB in well-perform-ing TB programs can exceed 90% [11].

Many countries have limited capacity to appropri-

by guest on Decem

ber 13, 2016http://jid.oxfordjournals.org/

Dow

nloaded from

EDITORIALMDR-TB AND HIV: THE PERFECT STORM?

JOSHUA FIERER*University of California, San Diego, California

Tuberculosis has afflicted humans as far back as we haverecords, predating written history. Mycobacterium tuberculo-sis is exclusively a human pathogen, so it has had to adapt toits only host, and we in turn have adapted to it. It is estimatedthat one third of the world’s population is currently infected,but only ∼5% of infected people will develop active tubercu-losis, a tribute to the effectiveness of our innate and acquiredimmune responses to this potentially deadly pathogen. Nev-ertheless, many asymptomatically infected people harbor vi-able tubercle bacilli, possibly for a lifetime, and those are theones who can re-activate their infections later in life. Onlythose with active pulmonary tuberculosis can transmit theinfection, so it is part of the organism’s strategy to remainviable until immunity begins to wane. HIV has completelychanged that balance; patients who are HIV+ with positivetuberculin skin tests have a 30% risk of developing activetuberculosis.1 There are clearly genetic polymorphismsthat make some individuals more susceptible to tuberculosis,2

but the effects of genetic polymorphisms do not approachthe profound effect that loss of CD4 T cells has on the riskof developing active tuberculosis. The good news is thatisoniazid (INH) for 6 months will reduce the risk of devel-oping active tuberculosis by ∼70%, even in patients who areHIV+.3 In addition, conventional four-drug therapy curestuberculosis in patients who are HIV+ who adhere to therapyfor 6–9 months, even those with low numbers of CD4 Tcells or extra-pulmonary tuberculosis.4 This is in sharpcontrast to M. arium complex infections, which are nevercured in patients with AIDS unless T cells are restored, be-cause we do not have effective bactericidal antibiotics for thatorganism.5

The paper from Kawai and others in this issue, reminds usof how important effective anti-tuberculous therapy is whenpatients lack immune defenses against M. tuberculosis. Theauthors prospectively followed two cohorts of patients withnewly diagnosed tuberculosis in Lima, Peru.6 One group hadHIV infection and the other did not (some HIV+ cases mayhave escaped detection because not everyone was tested, butthat would not change the results of the study). AlthoughCD4 T cell counts were not available, almost certainly all thepatients who were HIV+ in the study had advanced immuno-suppression because they were recruited from a unit in a hos-pital that specializes in treating AIDS. The authors tested allisolates for rifampin and INH susceptibility and sub-dividedthe patients into those with resistant bacteria (MDR-TB) andthose with susceptible isolates. Although the number of pa-tients in the different cohorts was relatively small, the differ-ences in outcome were so dramatic that they are worthy ofattention. The shocking observation was that 50% of patientswho were HIV+ infected with MDR-TB died within 2 months

of diagnosis, despite receiving directly observed therapy(DOT) with INH, rifampin, pyrazinamide, and ethambutol.Thus, in the absence of effective antibiotics and an effectiveimmune system, bacterial growth was unchecked and quicklyled to death. The mortality of this group of patients was muchhigher than a cohort from the same hospital that did not havetuberculosis, implying that most of these patients died of tu-berculosis rather than other complications of AIDS, althoughthey do not have direct evidence for that.

Given the rapid progression of the tuberculosis infection,the current practice of initiating tuberculosis therapy using astandard four-drug regimen is clearly inadequate treatment ofnearly one half of the patients who were HIV+ with tubercu-losis in Lima. Because so many patients with AIDS withMDR-TB died in less time than it usually takes to completesusceptibility studies, the authorities will have to invest in newrapid methods for doing drug susceptibility testing, such asthe one used by the authors of this paper.7 The governmentwill also have to be ready to provide second-line drugs for thetreatment of these patients. Although second-line treatmentof tuberculosis is expensive and more toxic than treatmentwith first-line drugs, the alternative is to allow patients withsmear positive pulmonary MDR-TB to essentially go un-treated. That increases the risk of the spread of MDR-TB toothers with AIDS, health care workers, and family members.Even the use of second-line drugs is no guarantee of successin this battle against tuberculosis, because resistance to sec-ond-line drugs is becoming a problem in countries that usethem extensively. New, cheaper, more effective drugs are des-perately needed to treat tuberculosis.8

Prevention is at least as important as treatment, so it isimportant to understand the epidemiology of MDR-TB inPeru to try to limit its spread. Tuberculosis is endemic in Peru,and 50% of Peruvians with AIDS will develop tuberculosis atsome point in their illness.9 One striking feature of tubercu-losis in Lima is that nearly 50% of tuberculosis in patientswith AIDS in Lima are infected with MDR strains as docu-mented in this and another recent study.9 In both studies, thepatients with AIDS with tuberculosis were recruited from thesame public hospital in Lima that treats the largest number ofHIV-infected patients. In both studies, the authors found anassociation between receiving care at this hospital and havingMDR-TB, suggesting nosocomial transmission of the resis-tant bacteria. The use of molecular typing could easily con-firm this hypothesis. Because nosocomial acquisition ofMDR-TB has been previously documented and confirmed byrestriction fragment length polymorphism (RFLP) analysis inat least one South American country, this would have majorimplications for the practice of cohorting patients with AIDSin specialized treatment facilities that lack negative pressurerooms, especially if they also care for patients with tubercu-losis.10 Even in the United States, which has hospital facilitiesfor negative pressure isolation, this led to disastrous out-breaks of MDR-TB.11

* Address correspondence to Joshua Fierer, University of California,San Diego, CA. E-mail: [email protected]

Am. J. Trop. Med. Hyg., 75(6), 2006, pp. 1025–1026Copyright © 2006 by The American Society of Tropical Medicine and Hygiene

1025

Diabetes and tuberculosis:a gathering storm?John Moore-GillonThe number of cases of active tubercu-losis (TB) continues to rise in the UK andin many other parts of the world.1 2 Inanalysing the reasons behind this rise, itneeds to be kept in mind that onlya small proportion of those who becomeinfected with TB will progress to becomeill with active TB disease in the weeksand months after infection. They do,however, remain at risk of reactivation oftheir latent TB infection in the years (andindeed decades) to come. Clearly, a co-existing medical condition which impairsthe immune response to the TB bacte-rium might increase the likelihood ofdirect progression to active diseaseshortly after infection, or increase thelikelihood of latent TB infection in laterlife. Co-infection with HIV is a strikingexample; the relative risk of developingTB in HIV-positive individuals comparedwith HIV-negative individuals (the inci-dence rate ratio) is between about 20and 35.2

In this issue of Thorax, Walker andUnwin (see page 578) consider theimpact on numbers of TB cases inEngland of another increasingly commonconditiondnamely, diabetes mellitus.3 Alink has long been suggested, the authorspointing out that combined clinics forthose with diabetes and TB were beingheld more than half a century ago,4 andrecent analyses suggest that the associa-tion is indeed genuine.5 Walker andUnwin focus their attention on pulmo-nary TB, choosing this because theyconsider the evidence for an associationto be strongest for this type of TB. Theyconstructed an epidemiological modelusing data on the incidence of TB, theprevalence of diabetes, the populationstructure and data on the age-specificrelative risk of TB associated with dia-betes from a cohort study. Theyacknowledge that there are limitations totheir approach: the estimate of the totalprevalence of diabetes in England is basedon old and relatively small population-based studies and the age-specific relative

risks for TB in those with diabetes arederived from a Korean study. The authorspoint out, however, that these appear tobe the best tools available for the job theywished to do, and it is indeed arguablethat a line of scientific enquiry should notbe ignored simply because the availabletechniques for its investigation are as yetimperfect.With the frank admission that ‘given

the nature of the data available, consider-able uncertainty surrounds these esti-mates’, the authors go on to suggest thatthe population attributable fraction (PAF)of diabetes for pulmonary TB in Englandis 19.6% for Asian men (95% CI 10.9% to33.1%) and 14.2% for Asian women (95%CI 7.1% to 26.5%). The figures for whiteand black men are similar to each other ataround 7%, and about 8.5% for white andblack women. Expressed differently, theauthors estimate that about 11% of thenew cases of pulmonary TB whichoccurred in England in 2005 may beattributed to diabetes.These figures aredor should bedof

even greater concern than they mayappear. It is pulmonary TB which ispotentially infectious to others, and publichealth efforts to control TB have focusedon the early identification and treatmentof infectious pulmonary cases. Perhapsmore importantly, we are confronted withan explosive and apparently inexorablerise in the prevalence of diabetes.6 7 Thisrise in diabetes is, moreover, particularlymarked in ethnic minority popula-tions8dthat is, those who are in any casemost at risk of having pre-existing latentTB infection and of fresh exposure toother infectious cases. It is also associatedwith a sharp rise in the numbers of indi-viduals with chronic renal failure, anindependent risk factor for TB.9 Even ifthe figures from Walker and Unwin are anoverestimate, it seems likely that theysoon won’t be. If they are already anunderestimate, then the interactionbetween diabetes and TB is rapidlybecoming a major issue for TB control andone which, as the authors point out,appears to be receiving little attention.Diabetes does not achieve a mention inthe ‘TB Action Plan’10 nor, indeed, in the2009 Annual Report.1

What can be done? TB services in mostcountriesdeven wealthy onesdare hardpressed, and tackling the rising tide ofobesity (the principal cause of the rise indiabetes) may be a task too far. Thismeans dealing with the consequenceswhile others struggle, probably unsuc-cessfully, with the underlying cause.Walker and Unwin suggest that, based ontheir figures, around one-third of Asianswith newly diagnosed TB in England willhave diabetes. There seems no reason tosuspect that the figure would be markedlylower in other parts of the UK nor, prob-ably, in other socioeconomically similarcountries. In the UK there are probablyaround half a million undiagnosed dia-betics11 and, although their rates of TBmay well be less than among diagnoseddiabetics, we can at least ensure that newlydiagnosed TB patients have a documentedassessment of the presence or absence ofdiabetes. Active screening for evidence oflatent TB in diabetics is part of US guide-lines,12 but not those from the NationalInstitute for Health and Clinical Excellence(NICE).13 Indeed, the NICE guidelinessuggest that, although the relative risk ofTB is increased in diabetics, the absoluterisk of TB in diabetics is sufficiently lowthat there is no need to educate them aboutsymptoms suggestive of disease (section10.2.4 of the NICE guidelines).Given the calculations set out in Walker

and Unwin’s paper in this issue of Thorax,these two issuesdspecific screening forlatent TB in diabetics and health educa-tion regarding TBdare ones which shouldbe reviewed by NICE or another expertgroup. Indeed, an expectation that thosehealthcare professionals who deal withdiabetic patients should educate themabout the symptoms suggestive of TBwould mean that the professionals them-selves would have to have the possibilityof TB in mind, and this secondary effectmay actually turn out to be of moreimportance than the apparent primaryaim of such education. Whatever steps aretaken, it seems highly likely that, at leastfor the foreseeable future, TB services willbe managing increasing numbers of dia-betics with tuberculosis.Competing interests None.

Provenance and peer review Commissioned; notexternally peer reviewed.

Thorax 2010;65:571e572.doi:10.1136/thx.2009.134247

REFERENCES1. Health Protection Agency Centre for Infections.

Tuberculosis in the UK: annual report on tuberculosissurveillance in the UK 2009. London, 2009.

Correspondence to John Moore-Gillon, Department ofRespiratory Medicine, St Bartholomew’s and RoyalLondon Hospitals, London EC1A 7BE, UK;[email protected]

Thorax July 2010 Vol 65 No 7 571

Editorial

group.bmj.com on December 13, 2016 - Published by http://thorax.bmj.com/Downloaded from

11

Interacción TB-DM

12

TB-DM:3x

Susceptible TBLatente TBActiva

😀 😳 😷Fagocitosis ↓

Inflamasoma desreguladoInflamación Crónica

Respuesta innata retardada

Hiperglicemia Crónica⬇

Respuesta adaptativaretardada

⬇Peor presentación

clínica

Articles

www.thelancet.com/diabetes-endocrinology Vol 3 May 2015 325

Baker and colleagues6 noted that diabetes increased the risk of death in individuals with active tuberculosis (RR 1·89) and the risk of relapse after treatment

completion (RR 3·89). Finally, diabetes is associated with increased risk of all-cause mortality because it aff ects a number of other disorders (RR 3·48).22 We did not

Defi nition Average diabetes prevalence in 2035

Explanation

Large rise (worst case scenario)

Diabetes prevalence in 13 countries will reach 20·6% by 2035

20·6% The upper bound of diabetes prevalence in all scenarios; diabetes prevalence is expected to increase worldwide because of ageing, urbanisation, and increased prevalence of obesity, physical inactivity, smoking, and unhealthy diet;7,15 the diabetes prevalence of 20·6% is based on the fi nding in women in the Oceania region7

Continue current trend (base case scenario)

Diabetes prevalence will follow the present rising trend, with an upper bound of 20·6%

16·0% Without further intervention the age-specifi c prevalence of diabetes will continue its present trend in each country

Stop rise Diabetes prevalence will stop rising after 2015

9·4% Assume the new global non-communicable disease target for diabetes will be reached by 201516

Aggressive intervention

The incidence rate of diabetes will be reduced by 35% between 2015 and 2025

7·4% Findings of previous studies showed that diff erent intervention strategies can reduce the progression of pre-diabetes to diabetes17,18

To background level (best case scenario)

By 2035, diabetes prevalence will gradually decrease to the 1990 background level

2·2% The lower bound and ideal scenario of diabetes prevalence; the background prevalence in 1900 was derived from external prediction with recorded diabetes prevalence in 1980–20087

Table 1: Scenarios of diabetes used in the analysis

Diab

etes

pre

vale

nce (

%)

0

5

10

15

20

Tube

rcul

osis

incid

ence

(per

100 0

00)

0

50

100

150

200

Tube

rcul

osis

mor

talit

y (pe

r 100

000

peop

le)

2015 2020 2025 2030 20350

10

20

30

40

Tube

rcul

osis

prev

alen

ce (p

er 10

0 000

)

2015 2020 2025 2030 20350

50

100

150

200

250

Year Year

A

C

B

D

Large riseContinue current trendStop riseAggressive interventionTo background level

Figure 2: Scenarios of diabetes prevalence aggregated for 13 countries with high tuberculosis burden (A) and projected tuberculosis incidence (B), mortality (C), and prevalence (D) in these countries under diff erent scenarios of diabetes, 2015–35The lines in panels B, C, and D represent the means of posterior simulations from the calibrated models. Table 1 shows defi nitions of diabetes scenarios. The appendix shows country-specifi c results.

Pan S-C, et al. Lancet Diabetes Endocrinol. 2015

IncidenciaTBproyectada(B)bajodiferentesescenariosdecontroldeDM(A)

Articles





Explanation
















Diab

etes

pre

vale

nce (

%)

0

5

10

15

20

Tube

rcul

osis

incid

ence

(per

100 0

00)

0

50

100

150

200

Tube

rcul

osis

mor

talit

y (pe

r 100

000

peop

le)

2015 2020 2025 2030 20350

10

20

30

40

Tube

rcul

osis

prev

alen

ce (p

er 10

0 000

)

2015 2020 2025 2030 20350

50

100

150

200

250

Year Year

A

C

B

D



Prevalen

ciaDiabetes(%

)

Incide

nciaTB

(pe

r100000)

Articles





Explanation
















Diab

etes

pre

vale

nce (

%)

0

5

10

15

20

Tube

rcul

osis

incid

ence

(per

100 0

00)

0

50

100

150

200

Tube

rcul

osis

mor

talit

y (pe

r 100

000

peop

le)

2015 2020 2025 2030 20350

10

20

30

40

Tube

rcul

osis

prev

alen

ce (p

er 10

0 000

)

2015 2020 2025 2030 20350

50

100

150

200

250

Year Year

A

C

B

D



15

Articles





Explanation
















Diab

etes

pre

vale

nce (

%)

0

5

10

15

20

Tube

rcul

osis

incid

ence

(per

100 0

00)

0

50

100

150

200

Tube

rcul

osis

mor

talit

y (pe

r 100

000

peop

le)

2015 2020 2025 2030 20350

10

20

30

40

Tube

rcul

osis

prev

alen

ce (p

er 10

0 000

)

2015 2020 2025 2030 20350

50

100

150

200

250

Year Year

A

C

B

D



Mortalidad/Prevalencia proyectada deTB(C/D)bajodiferentesescenariosdecontroldeDM

Articles





Explanation
















Diab

etes

pre

vale

nce (

%)

0

5

10

15

20

Tube

rcul

osis

incid

ence

(per

100 0

00)

0

50

100

150

200

Tube

rcul

osis

mor

talit

y (pe

r 100

000

peop

le)

2015 2020 2025 2030 20350

10

20

30

40

Tube

rcul

osis

prev

alen

ce (p

er 10

0 000

)

2015 2020 2025 2030 20350

50

100

150

200

250

Year Year

A

C

B

D



Mortalidad

TB(p

er100000)

Prevalen

ciaTB

(pe

r100000)

Pan S-C, et al. Lancet Diabetes Endocrinol. 2015

16

www.thelancet.com/diabetes-endocrinology Vol 2 September 2014 747

Series

age, patient capabilities and treatment preferences, and available resources.75

Frequent monitoring is needed to ensure good glycaemic control. Self-measurement of blood glucose is not feasible in many settings and for some patients. Clinic-based measurement of fasting blood glucose is not ideal for ambulatory care in busy clinics in tuberculosis-endemic settings, and random blood glucose and glycosuria measurements are less accurate than fasting blood glucose.76

With respect to the choice of diabetes drugs, possible drug–drug interactions should be taken into account, especially for rifampicin, the most important antituberculosis drug because it helped to shorten tuberculosis treatment time from 18 to 6 months. Drug resistance to rifampicin is associated with poorer treatment outcomes, worse than for any other tuberculosis drug. Rifampicin increases the hepatic metabolism of all sulphonylurea derivatives, the most widely used class of oral diabetes drugs worldwide. This eff ect on sulphonylurea derivatives has great inter-individual variation, which makes dose adjustments diffi cult and increases a patient’s risk of hyperglycaemia or hypoglycaemia. Inter-individual variation in the induction of the metabolism of diabetes drugs makes dose adjustment diffi cult when rifampicin treatment is interrupted or stopped; the same is true for most other oral antidiabetes drugs (appendix). Less is known about newer antidiabetes drug classes, and no data have been published from patients with tuberculosis treated with these drugs. Rifampicin probably has no eff ect on the exposure of glucagon-like peptide-1 receptor agonists and only a slight eff ect on dipeptidyl peptidase-4 inhibitors;77 however, poor availability and high costs of these drugs will restrict their use in tuberculosis-endemic settings.

Several other factors determine the choice of antidiabetes drugs to be used in patients with tuberculosis, such as availability, cost, ease of administration, and safety. Safety concerns include hypoglycaemia with sulphonylureas and insulin, lactic acidosis (especially under hypoxic conditions) with beguanides, and gastrointestinal complaints wih biguanides, meglitinides, and alpha-glucosidase inhibitors, and hypersensitivity to sulphonylureas (which might overlap with side-eff ects of antituberculous drugs). Insulin use at the start of tuberculosis treatment has been suggested;74 some national treatment guidelines (for instance in Indonesia) strongly suggest the use of insulin for diabetes in patients with tuberculosis even though no evidence base lends support to that approach. Because insulin is not metabolised, it has no pharmacokinetic interactions with rifampicin or other antituberculous drugs, but insulin has several potential drawbacks when used in under-resourced settings including cost, availability, storage, and delivery.

Metformin is a fi rst-line drug for type 2 diabetes and does not usually lead to hypoglycaemia. Metformin is not

metabolised by P450 enzymes,78 and thus its con-centrations should not be decreased by an inductive eff ect of rifampicin on these metabolic enzymes. However, exposure to metformin could be aff ected because metformin is a substrate for human organic cation transporters and other transporters.77 Rifampicin increases the expression of organic cation transporter (OCT1) and hepatic uptake of metformin, leading to an enhanced glucose-lowering eff ect in healthy indi viduals.79 Possible disadvantages of metformin use in patients with tuberculosis include the risk of gastrointestinal side-eff ects and, very rarely, lactic acidosis.80,81

Drug–drug interactions are even more probable when patients with tuberculosis also have HIV, because many anti-HIV drugs are substrates of metabolic or transporter enzymes, or can change the activity of these enzymes. Similarly, toxicity profi les and side-eff ects of HIV, tuberculosis, and diabetes drugs might overlap. To our knowledge, no studies on the combined treatment of these three diseases have been published.

What is needed for patients with concurrent tuberculosis and diabetes?Patients with tuberculosis and diabetes might need alternative interventions besides changes to their drug regimens. Counselling and education are advised for patients with tuberculosis and newly diagnosed diabetes. In an Indonesian study, 60% of cases of diabetes in patients with tuberculosis were newly diagnosed.82 To refer a patient with active tuberculosis to a separate diabetes clinic is not an option that appeals, both from a patient’s and an infectious control point of view. However, patients that need insulin, in particular, need to learn about glucose measurements and the symptoms and necessary action in case of hypoglycaemia. Intense engagement of patients with tuberculosis with the health system, especially early on in their treatment, provides an opportunity for repeated counselling including about lifestyle interventions (eg, nutrition, weight loss, smoking

Figure 2: Factors that aff ect glycaemic control for patients with diabetes during treatment for tuberculosis

Active tuberculosisInflammation leading to:weight loss; loss of appetite;insulin resistance

BehaviourVariable food intake;physical activity;treatment compliance

Health systemsAccess and affordability of health services;collaboration between tuberculosis and diabetes physicians; laboratory facilities;continuous medicaton supply

Drug therapySide-effects (eg, vomiting); drug–drug interactions;weight gain during treatment

Riza AL,PearsonF,Ugarte-GilC,etal.LancetDiabetes2014

Factores queafectan elcontrolglicemico depacientes conDMdurante eltratamiento deTB

AsociaciónentreDMymuerteenpacienteentratamientoTB

NOTE: Weights are from random effects analysis

Overall (I-squared = 84.2%, p = 0.000)

Kitahara, 1994

Centis, 1998 report

Moosazadeh, 2014

Nandakumar, 2013

Magee, 2014

Burgielski, 1985

Uchimura, 2013

Reed, 2013

Ambrosetti, 1997 report

Jiménez-Corona, 2013

Kourbatova, 2006

Chen, 2015

Alo, 2014

Reis-Santos, 2013

Orofino Rde, 2011

Oursler, 2002

Chiang, 2015

Maâlej, 2009

Wu, 2015

Amnuaiphon, 2009

Tabarsi, 2014

Sulaiman, 2013

Alavi-Naini, 2013

Cavanaugh, 2015

Pina, 2006

Mboussa, 2003

Tatar, 2009

Mathew, 2006

Wang, 2009Dooley, 2009


Viswanathan, 2014

Chiang, 2009

Alisjahbana, 2007

Mi, 2013

Singla, 2006

Hasibi, 2008

Viswanathan, 2014

Sangral, 2012

Bashar, 2001


Study

Fielder, 2002

Touré, 2007

Lin, 2014

Ribeiro Macedo, 2013

Vasankari, 2010

Vasankari, 2007

Centis, 1999 report

Japan

Italy

Iran

India

United States

Poland

Japan

South Korea

Italy

Mexico

Russia

China

Fiji

Brazil

Brazil

United States

Taiwan

Tunisia

Taiwan

Thailand

Iran

Malaysia

Iran

Kiribati

Spain

Congo

Turkey

Russia

TaiwanUnited States

Italy

India

Taiwan

Indonesia

China

Saudi Arabia

Iran

India

India

United States

Italy

Country

United States

Senegal

Taiwan

Brazil

Finland

Finland

Italy

3/71

5/41

26/140

42/667

16/151

38/90

1193/5622

21/162

1/41

11/363

5/20

9/182

3/53

73/703

4/14

8/18

79/705

5/60

1645/7637

376/4188

1/37

19/342

40/108

4/101

8/73

8/32

2/78

8/44

13/746/42

3/32

0/96

52/241

2/94

2/97

1/134

3/6

1/89

2/23

7/50

4/50

n/N

13/22

18/86

65/182

39/323

7/26

22/92

2/40

TB-DM

14/449

49/1059

123/824

71/2127

66/1167

19/90

6282/28077

30/495

43/666

36/847

87/440

9/944

11/335

995/17047

15/294

14/108

61/768

0/82

3939/26214

19/290

1/67

42/914

35/607

2/174

97/1438

8/100

0/78

75/1872

11/14320/255

29/737

5/149

137/886

0/540

2/483

3/384

6/44

1/120

16/257

1/105

19/773

n/N

29/152

6/88

184/565

712/12472

25/205

86/537

26/852

TB-nonDM

2.10 (1.76, 2.51)

1.37 (0.38, 4.90)

2.86 (1.08, 7.62)

1.30 (0.81, 2.07)

1.95 (1.32, 2.88)

1.98 (1.11, 3.51)

2.73 (1.42, 5.27)

0.93 (0.87, 1.00)

2.31 (1.28, 4.16)

0.36 (0.05, 2.70)

0.70 (0.35, 1.40)

1.35 (0.48, 3.82)

5.40 (2.12, 13.81)

1.77 (0.48, 6.56)

1.87 (1.45, 2.40)

7.44 (2.09, 26.51)

5.37 (1.81, 15.91)

1.46 (1.03, 2.08)

16.35 (0.89, 301.66)

1.55 (1.46, 1.66)

1.41 (0.87, 2.27)

1.83 (0.11, 30.19)

1.22 (0.70, 2.13)

9.61 (5.72, 16.15)

3.55 (0.64, 19.72)

1.70 (0.79, 3.65)

3.83 (1.30, 11.27)

5.13 (0.24, 108.62)

5.32 (2.39, 11.85)

2.56 (1.08, 6.03)1.96 (0.74, 5.20)

2.53 (0.73, 8.77)

0.14 (0.01, 2.49)

1.50 (1.05, 2.15)

29.22 (1.39, 613.44)

5.06 (0.70, 36.39)

0.95 (0.10, 9.26)

6.33 (1.03, 38.98)

1.35 (0.08, 21.92)

1.43 (0.31, 6.67)

16.93 (2.02, 141.78)

3.45 (1.13, 10.56)

Odds ratio (95% CI)

6.13 (2.39, 15.70)

3.62 (1.36, 9.62)

1.15 (0.81, 1.63)

2.27 (1.61, 3.20)

2.65 (1.01, 6.94)

1.65 (0.97, 2.80)

1.67 (0.38, 7.31)

100.00

1.36

1.91

3.47

3.74

3.09

2.81

4.56

3.04

0.66

2.71

1.77

2.00

1.30

4.20

1.36

1.68

3.89

0.34

4.56

3.44

0.37

3.15

3.29

0.86

2.47

1.69

0.31

2.36

2.201.91

1.40

0.34

3.87

0.31

0.68

0.53

0.78

0.37

1.03

0.60

1.61

Weight

1.99

1.91

3.89

3.91

1.94

3.24

1.09

%

2.10 (1.76, 2.51)

1.37 (0.38, 4.90)

2.86 (1.08, 7.62)

1.30 (0.81, 2.07)

1.95 (1.32, 2.88)

1.98 (1.11, 3.51)

2.73 (1.42, 5.27)

0.93 (0.87, 1.00)

2.31 (1.28, 4.16)

0.36 (0.05, 2.70)

0.70 (0.35, 1.40)

1.35 (0.48, 3.82)

5.40 (2.12, 13.81)

1.77 (0.48, 6.56)

1.87 (1.45, 2.40)

7.44 (2.09, 26.51)

5.37 (1.81, 15.91)

1.46 (1.03, 2.08)

16.35 (0.89, 301.66)

1.55 (1.46, 1.66)

1.41 (0.87, 2.27)

1.83 (0.11, 30.19)

1.22 (0.70, 2.13)

9.61 (5.72, 16.15)

3.55 (0.64, 19.72)

1.70 (0.79, 3.65)

3.83 (1.30, 11.27)

5.13 (0.24, 108.62)

5.32 (2.39, 11.85)

2.56 (1.08, 6.03)1.96 (0.74, 5.20)

2.53 (0.73, 8.77)

0.14 (0.01, 2.49)

1.50 (1.05, 2.15)

29.22 (1.39, 613.44)

5.06 (0.70, 36.39)

0.95 (0.10, 9.26)

6.33 (1.03, 38.98)

1.35 (0.08, 21.92)

1.43 (0.31, 6.67)

16.93 (2.02, 141.78)

3.45 (1.13, 10.56)

Odds ratio (95% CI)

6.13 (2.39, 15.70)

3.62 (1.36, 9.62)

1.15 (0.81, 1.63)

2.27 (1.61, 3.20)

2.65 (1.01, 6.94)

1.65 (0.97, 2.80)

1.67 (0.38, 7.31)

100.00

1.36

1.91

3.47

3.74

3.09

2.81

4.56

3.04

0.66

2.71

1.77

2.00

1.30

4.20

1.36

1.68

3.89

0.34

4.56

3.44

0.37

3.15

3.29

0.86

2.47

1.69

0.31

2.36

2.201.91

1.40

0.34

3.87

0.31

0.68

0.53

0.78

0.37

1.03

0.60

1.61

Weight

1.99

1.91

3.89

3.91

1.94

3.24

1.09

%

1.2 .5 1 2.11 3 5 10 15 20

48estudios

ORcombinado:2.1(1.8-2.5)

Huangfu P,Ugarte-GilC,GolubJ,PearsonF,CritchleyJ.2017

AsociaciónentreDMyrecaídasenpacientecontratamientoTB

NOTE: Weights are from random effects analysis

Overall (I-squared = 60.7%, p = 0.006)

Study

Mboussa, 2003

Wada, 2000

Bashar, 2001

Singla, 2006

De Oliveira, 2000

Pérez-Navarro, 2011

Jiménez-Corona, 2013

Zhang, 2009

Maâlej, 2009

Lee, 2014

Country

Congo

Japan

United States

Saudi Arabia

Brazil

Mexico

Mexico

China

Tunisia

Taiwan

n/N

6/32

TB-DM

7/61

10/50

2/130

6/11

./.

26/308

33/165

4/55

102/170

n/N

9/100

TB-nonDM

4/284

4/105

3/367

50/150

./.

48/711

9/170

1/82

198/430

2.35 (1.56, 3.54)

ratio (95% CI)

2.33 (0.76, 7.16)

Odds

9.07 (2.57, 32.07)

6.31 (1.87, 21.30)

1.90 (0.31, 11.47)

2.40 (0.70, 8.25)

1.20 (0.79, 1.82)

1.27 (0.77, 2.09)

4.47 (2.07, 9.68)

6.35 (0.69, 58.44)

1.76 (1.23, 2.52)

100.00

Weight

8.15

%

7.00

7.35

4.15

7.21

17.20

16.00

12.00

2.93

18.02

2.35 (1.56, 3.54)

ratio (95% CI)

2.33 (0.76, 7.16)

Odds

9.07 (2.57, 32.07)

6.31 (1.87, 21.30)

1.90 (0.31, 11.47)

2.40 (0.70, 8.25)

1.20 (0.79, 1.82)

1.27 (0.77, 2.09)

4.47 (2.07, 9.68)

6.35 (0.69, 58.44)

1.76 (1.23, 2.52)

100.00

Weight

8.15

%

7.00

7.35

4.15

7.21

17.20

16.00

12.00

2.93

18.02

1.5 1 2.35 5 10 15

HuangfuP,Ugarte-GilC,GolubJ,PearsonF,CritchleyJ.2017

ORcombinado:2.4(1.6-3.5)

Estudio TANDEM– Lima

• 600pacientesconTBenrolados,47had DM• à prevalencia7.8%(95%CI:5.9%-10.3%)

• 31/47 condiagnósticopreviodeDMy16/47eranNuevosdiagnósticos

…próximapublicación2017(2337pacientesen4países)

43

CaracterísticasTB-DM:TANDEMLima

• Medianaedad(RIQ):52.0(47.0-58.5)años

• MedianaIMC(RIQ):24.7(21.8-28.4)

• MedianaHbA1c%(RIQ):10.6(9.0-13.3)

• Másdel55%delospacientesteníanmenosde5añosdediagnósticodeDM

• HistoriafamiliardeDM:40.4%RIQ:Rango interquartilHbA1c:Hemoglobina glicosilada

HbA1cen cohorte TANDEM- Perú

HbA1c:pre-dxDMvsDMnuevo

Pre-dxDM DMnuevo valorP

Mediana HbA1c(RIQ) 10.9(9.7-13.5) 8.5(6.8-11.3) 0.02

*Mann-Whitney(median)andChi2 (#participants)

Ugarte-GilC,etal.2017

RIQ:Rango interquartilHbA1c:Hemoglobina glicosilada

Hiperglicemia noDM:TANDEM- Lima

• Prevalencia general• 39.7% (95%CI: 35.8% -43.6%)

• Prevalencia en mayores de 35 años• 27.3% (95%CI: 21.8%-33.7%)

44

The Journal of Infectious Diseases

M A J O R A R T I C L E

Transient Hyperglycemia in Patients With Tuberculosis inTanzania: Implications for Diabetes Screening AlgorithmsNoémie Boillat-Blanco,1,5,6,7 Kaushik L. Ramaiya,2,3 Maliwasa Mganga,4 Lilian T. Minja,1 Pascal Bovet,8 Christian Schindler,5,6 Arnold Von Eckardstein,9

Sebastien Gagneux,5,6 Claudia Daubenberger,5,6 Klaus Reither,1,5,6 and Nicole Probst-Hensch5,6

1Ifakara Health Institute, 2Shree Hindu Mandal Hospital, 3Muhimbili University of Health Sciences, and 4Kinondoni Municipal Council, National Tuberculosis Program, Dar es Salaam, United Republic ofTanzania; 5Swiss Tropical and Public Health Institute, and 6Department of Sciences, University of Basel, 7Infectious Diseases Service, and 8Institute of Social and Preventive Medicine, LausanneUniversity Hospital, and 9Institute of Clinical Chemistry, University of Zurich, University Hospital of Zurich, Switzerland

Background. Diabetes mellitus (DM) increases tuberculosis risk while tuberculosis, as an infectious disease, leads to hypergly-cemia. We compared hyperglycemia screening strategies in controls and patients with tuberculosis in Dar es Salaam, Tanzania.

Methods. Consecutive adults with tuberculosis and sex- and age-matched volunteers were included in a case-control study be-tween July 2012 and June 2014. All underwent DM screening tests (fasting capillary glucose [FCG] level, 2-hour CG [2-hCG] level,and glycated hemoglobin A1c [HbA1c] level) at enrollment, and cases were tested again after receipt of tuberculosis treatment. As-sociation of tuberculosis and its outcome with hyperglycemia was assessed using logistic regression analysis adjusted for sex, age,body mass index, human immunodeficiency virus infection status, and socioeconomic status. Patients with tuberculosis and newlydiagnosed DM were not treated for hyperglycemia.

Results. At enrollment, DM prevalence was significantly higher among patients with tuberculosis (n = 539; FCG level > 7 mmol/L, 4.5% of patients, 2-hCG level > 11 mmol/L, 6.8%; and HbA1c level > 6.5%, 9.3%), compared with controls (n = 496; 1.2%, 3.1%,and 2.2%, respectively). The association between hyperglycemia and tuberculosis disappeared after tuberculosis treatment (adjustedodds ratio [aOR] for the FCG level: 9.6 [95% confidence interval {CI}, 3.7–24.7] at enrollment vs 2.4 [95% CI, .7–8.7] at follow-up;aOR for the 2-hCG level: 6.6 [95% CI, 4.0–11.1] vs 1.6 [95% CI, .8–2.9]; and aOR for the HbA1c level, 4.2 [95% CI, 2.9–6.0] vs 1.4[95% CI, .9–2.0]). Hyperglycemia, based on the FCG level, at enrollment was associated with tuberculosis treatment failure or death(aOR, 3.3; 95% CI, 1.2–9.3).

Conclusions. Transient hyperglycemia is frequent during tuberculosis, and DM needs confirmation after tuberculosis treatment.Performance of DM screening at tuberculosis diagnosis gives the opportunity to detect patients at risk of adverse outcome.

Keywords. tuberculosis; diabetes mellitus; stress-induced hyperglycemia; transient hyperglycemia; sub-Saharan Africa.

Interest in the comorbidity between tuberculosis and diabetesmellitus (DM) has reemerged due to the global increase ofDM and its potential impact on tuberculosis control. DM dou-bles or triples the incidence of active tuberculosis and increasesthe risk of tuberculosis treatment failure and death [1–3]. Aframework was developed to guide national programs in theirresponse to DM and tuberculosis [4]. The prevalence of DMamong patients with tuberculosis differs between countries(16%–45%). Sub-Saharan Africa has the highest rate of undiag-nosed DM, is expecting the sharpest increase in DM by 2035,has a high tuberculosis burden, and has the highest rate of tu-berculosis and human immunodeficiency virus (HIV) coinfection

[5, 6]. Two studies in Tanzania and Uganda confirmed the cross-sectional tuberculosis-DM association in the presence of high HIVprevalence [7, 8]. Unexpectedly, HIV seamed to protect againstDM. The impact of HIV infection on the tuberculosis-DM associ-ation needs further investigations, as HIV increases metabolic riskbut can also lower body mass index [9].

When and how best diagnose DM in the presence of infec-tions is challenging. As an infectious disease, tuberculosis in-creases insulin resistance and stress-induced hyperglycemia,which may lead to overdiagnosis of DM during the acutephase of tuberculosis [10]. Screening of DM is based on bloodglucose criteria and, lately, on the use of glycated hemoglobinA1c (HbA1c), with its advantage of not requiring fasting andexhibiting fewer day-to-day variations during periods of stressand illness, owing to its half-life of 120 days [11–13]. Fewsmall studies have examined the longitudinal course of glycemiaduring tuberculosis treatment, but none were conducted on theAfrican continent or compared the performance of differentDM screening tests over time within the same study population[14–17]. We therefore examined the association of tuberculosisand its outcome with the presence and persistence of hypergly-cemia in Tanzania, using 3 different DM screening tests.

Received 23 September 2015; accepted 19 November 2015; published online 25 November2015.

Presented in part: 9th European Congress on Tropical Medicine and International Health,Basel, Switzerland, 6–10 September 2015; 46th Union World Conference on Lung Health,Cape Toen, South Africa, 2–6 December 2015.

Correspondence: N. Boillat-Blanco, Infectious Diseases Service, Lausanne University Hospi-tal, Rue du Bugnon 46, 1011 Lausanne, Switzerland ([email protected]).

The Journal of Infectious Diseases® 2016;213:1163–72© The Author 2015. Published by Oxford University Press for the Infectious Diseases Societyof America. All rights reserved. For permissions, e-mail [email protected]: 10.1093/infdis/jiv568

Transient Hyperglycemia and Tuberculosis • JID 2016:213 (1 April) • 1163

at Walaeus Library LU

MC

on May 18, 2016

http://jid.oxfordjournals.org/D

ownloaded from

LahiperglicemiatransitoriaparecefrecuenteenpacientesconTB

Global Tuberculosis Report. WHO 2016

TB-MDRyDM

52

Características TB-MDR no DM(n=1871)

TB-MDR DM(n=128) p-value

Mediana Edad (RIQ) 26 (22-34) 52 (44-59) < 0.05

Edad > 35 años (%) 460 (24.6%) 114 (89.1%) <0.05

Mediana IMC (RIQ) (n=1652) 21.6 (19.5-23.9) 23.0 (10.7-27.1) <0.05

IMC ³ 25kg/m2 (%) (n=1652) 283 (18.3%) 35 (34.7%) <0.05

Mediana glucosa mg/dl (RIQ) (n=1934) 85 (76-94) 155.9 (115.4-

236) <0.05

Glucosa ³ 200 mg/dl (%) (n=1934) 13 (0.7%) 41 (33.1%) <0.05

Pacientes TB-MDRyDM

57Ugarte-GilC,etal.2017

Sobrevidaalmes36deiniciadotratamientoMDR:mayoresde35años

Log-rank test p-value <0.01

60

0.00

0.25

0.50

0.75

1.00

Cum

ulat

ive

surv

ival

0 10 20 30 40Time (months)

Diabetes Mellitus = No Diabetes Mellitus = Yes

Ugarte-GilC,etal.2017

Factores asociados a mortalidad en pacientesTB-MDR (n=1564)

Factores HR crudo(95% CI)

HR* ajustado(95%CI) valor p

DM 2.6 (1.7-4.0) 2.6 (1.4-4.7) <0.05

Edad >35 (%) 2.3 (1.7-3.1) 2.5 (1.7-3.6) <0.05

IMC ³ 25kg/m2 (%) 0.2 (0.1-0.5) 0.2 (0.1-0.4) <0.05

VIH 4.4 (2.7-7.2) 4.7 (2.8-7.9) <0.05

*Ajustado por género, estar en prisión, tratameinto previo de TB, BK positivo al inicio, glucosa encima de200mg/dlHR: Hazard Ratio

59Ugarte-GilC,etal.2017

SituaciónTB-DM:Lima2015-2016

• 15254casosdeEnero2015-Diciembre2016mayoresde18años:– 1081(7.1%)teniaDM– 2769(18.2%)noteniapruebaparadescartarDM

• ComparemosconVIH– 769(5.0%)teniaVIH– 1576(10.3%)noteniaprueba

Fuente:SIGTB

SituaciónTB-DM:Lima2015-2016

• BateríacompletadeAnálisis– NoDM:80.1%– DM:75.6%

• BateríaparcialdeAnálisis– NoDM:7.1%– DM:10.7%

• Norealizada– NoDM:0.4%– DM:1.2

Fuente:SIGTB

57.2% 84.7% 89.3% 84.6% 69.7% 62.8% 73.6%

18.8%

13.6% 10.7%

11.5%

10.6%

13.2%

10.2% 24.0%

1.8% 0.0% 3.9%

19.7% 24.1%

16.2%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

AteII Magdalena Lurin ManuelBarreto LosOlivos Collique Rimac

Microredesconmásde10%decasosTB-DM

NoDM DM PruebanoRealizadaFuente:SIGTB

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

18-34años 35-44años 45-54años 55-64años 65+años

77.8% 76.0% 69.3%

61.9% 70.9%

2.6% 8.1% 14.1%

20.9% 13.5%

19.6% 15.9% 16.6% 17.2% 15.6%

Porcen

tajede

casosd

eTB

DistribucióndecasosTB-DMporedad– 2015/2016

NoDM DM PruebanorealizadaFuente:SIGTB

PreguntaspendientesenTB-DM• ¿ValelapenaimplementarHbA1cencentrosdesalud?Aparentemente:saleestudioTANDEMesteaño

• ¿QuébarrerassepresentanenelcuidadodepacientesTB-DMenLima?

Estacorriendoelestudiodecascadadecuidado,encolaboraciónconlaDPCTB- resultadosafinales2017

• ¿CuáleselmejortratamientoparaDMenpacientesTB-DM?

Aunnoexisteevidenciacualesmejor:insulinaometformina

Amit Singhal et al., Sci Transl Med 2014;6:263ra159

Efecto delametformina en pacientesTB-DM

Amit Singhal et al., Sci Transl Med 2014;6:263ra159

Reducción en incidencia deTBlatente enpacientes TB-DMtratados conmetformina

Conclusiones

• TB-DMesmáscomúndeloqueparece

• Estafuertementeasociadoalaedad,IMCyconpeoresresultadosaltratamiento

• ElmanejodelpacienteTB-DMescomplejoymultidisciplinario➡ paraevitarrecaídas

Financiamiento• EstapresentaciónserealizaconelapoyodeWorld Diabetes

Foundation (grant WDF15-224)

• Losresultadospresentadoshansidoapoyadosporlossiguientesfondos:

• TANDEMapoyadoporEuropean Union’s Seventh FrameworkProgramme (FP7/2007–2013)bajoelGrant AgreementNumber 305279.

• InternationalClinical,Operational,andHealth Services Research andTrainingAward Networkfor AIDS/TBResearchTraining(National Institutes ofHealth Grant 1U2RTW007368-01A1Fogarty InternationalCenter,Lima,Peru)

• National Institutes ofHealth Officeofthe Director,Fogarty InternationalCenter,OfficeofAIDSResearch,National CancerCenter,National Heart,Blood,andLung Institute,andthe National Institutes ofHealth OfficeofResearch for Women’sHealth through the Fogarty GlobalHealth Fellows Program Consortium comprised ofthe University ofNorthCarolina,JohnHopkins,Morehouse andTulane(1R25TW009340-01)andthe AmericanRecovery andReinvestment Act

• Program for Advanced Research Capacities for AIDSinPeru (PARACAS)atUniversidadPeruanaCayetanoHeredia(D43TW00976301)from Fogarty InternationalCenteratthe U.S.National Institute ofHealth (NIH)

• World DiabetesFoundation (grant WDF15-224)

Losinvitamos!

co-morbilidadtb-dm: ¿tormentaperfecta? · multidrug-resistant (mdr) tuberculosis (tb) has emerged...

Documents