tuberculosis treatment and drug regimens - cshl...

Tuberculosis Treatment and Drug Regimens

Giovanni Sotgiu1, Rosella Centis2, Lia D’ambrosio2, and Giovanni Battista Migliori2

1Clinical Epidemiology and Medical Statistics Unit, Department of Biomedical Sciences, Universityof Sassari, Research, Medical Education and Professional Development Unit, AOU Sassari 07100, Italy

2World Health Organization Collaborating Centre for Tuberculosis and Lung Diseases, FondazioneS. Maugeri, Care and Research Institute, Tradate 21049, Italy

Correspondence: [email protected]

Tuberculosis is an airborne infectious disease treated with combination therapeutic regi-mens. Adherence to long-term antituberculosis therapy is crucial for maintaining adequateblood drug level. The emergence and spread of drug-resistant Mycobacterium tuberculosisstrains are mainly favored by the inadequate medical management of the patients. Thetherapeutic approach for drug-resistant tuberculosis is cumbersome, because of the poor,expensive, less-effective, and toxic alternatives to the first-line drugs. New antituberculosisdrugs (bedaquiline and delamanid) have been recently approved by the health authorities,but they cannot represent the definitive solution to the clinical management of drug-resistanttuberculosis forms, particularly in intermediate economy settings where the prevalence ofdrug resistance is high (China, India, and former Soviet Union countries). New research anddevelopment activities are urgently needed. Public health policies are required to preservethe new and old therapeutic options.

Medical treatment of tuberculosis, togetherwith correct diagnosis, represents a cor-

nerstone in the management and control of tu-berculosis. It is relevant from a clinical and pub-lic health perspective, as tuberculosis is a seriouscontagious airborne disease.

Antibiotic treatment, reducing the bacterialload in the lungs, can be helpful to reduce theprobability of transmission, along with otherpublic health measures, such as isolation andcough etiquette.

The dramatic change of the epidemiologicalscenario during the last two decades, as a con-sequence of the increased incidence of the tu-berculosis/HIV (human immunodeficiency vi-rus) coinfection and of drug-resistant forms of

tuberculosis, however, significantly complicatedthe clinical and public health management ofthe patients and of their contacts.

Currently, clinicians and public health spe-cialists are facing daily problems related to theprescription of less effective and toxic second-line drugs, with frequent pharmacological in-teractions with antiretroviral drugs or medi-cines used to treat other comorbidities.

TUBERCULOSIS THERAPY: HISTORYAND RATIONALE

Tuberculosis is an ancient disease; nevertheless,effective drugs were not available for centuries.The preantibiotic therapy was initially repre-

Editors: Stefan H.E. Kaufmann, Eric J. Rubin, and Alimuddin Zumla

Additional Perspectives on Tuberculosis available at www.perspectivesinmedicine.org

Copyright # 2015 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a017822

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sented by isolation in sanatoria to reduce theprobability of Mycobacterium tuberculosis trans-mission to healthy contacts, with rest, adequatenutrition, and sunlight exposure; then, the sur-gical approach represented the gold standard,after Carlo Forlanini’s discovery of the benefi-cial effects of the artificially induced pneumo-thorax in 1927 (Rosenblatt 1973; Sakula 1983;Dheda and Migliori 2012).

Only after the discovery of the etiologicalagent by Robert Koch in 1882 and the identifi-cation of the antibacterial activity of penicillinby Alexander Fleming did new experimentalactivities focused on the evaluation of the effi-cacy of natural and chemical compounds inanimals start (Goldsworthy and McFarlane2002; Daniel 2006).

The first experimental evidence of the po-tential efficacy of new antituberculosis drugswas obtained in 1940 when a dapsone-deri-vative compound, known as promin, was ad-ministered to a sample of guinea pigs. However,that sulfonamide was never given to humans(Barry 1964; World Health Organization 2004;Migliori et al. 2011; Sotgiu et al. 2013).

A different destiny awaited streptomycin, anatural substance isolated from Streptomycesgriseus, which proved its efficacy in animalsand then in humans. In 1944, Schatz and Waks-man stated that the drug could be prescribed forthe treatment of tuberculosis as a consequenceof its bactericidal activity. In 1946, the UnitedKingdom Medical Research Council Tuberculo-sis Unit showed its short-term 6-mo efficacy interms of mortality reduction (i.e., from 27%to 7%). However, after 5 yr, no differences werefound between those exposed and not exposedto streptomycin as aconsequence of the acquiredantibiotic resistance (Table 1) (Schatz et al. 1944;Hinshaw and Feldman 1945; Wassersug 1946;Fox et al. 1954, 1999; World Health Organiza-tion 2004).

Four years later, the discovery of streptomy-cin, a new synthetic drug, called para-aminosal-icylic acid (PAS), was presented as an alternativedrug for the treatment of tuberculosis.

Following the poor results of the mono-therapy, in 1952, the first regimen based on thecombination of streptomycin, PAS, and isonia-

zid was proposed. Sir John Crofton with the“Edinburgh method,” characterized by the pre-scription of at least two drugs, showed the effi-cacy of the combination therapy (Crofton 1960,1969, 2006; Fox et al. 1999; World Health Orga-nization 2004; Migliori et al. 2011; Sotgiu et al.2013).

In 1954, pyrazinamide was discovered, butat the prescribed dosages, the rate of hepatictoxicity was significantly high. Ethambutoland rifampicin were introduced in 1961 and1963, respectively. The duration of therapy var-ied from 1 to 2 yr. In 1970, trials on regimensincluding rifampicin showed good results witha therapy of 9 mo, whereas in 1974, the inclu-sion of rifampicin and pyrazinamide at low dos-ages demonstrated the efficacy of a 6-mo treat-

Table 1. Antituberculosis drugs

Drug Mean daily dosage

Isoniazid 5 mg/kgRifampicin 10 mg/kgEthambutol 15–25 mg/kgPyrazinamide 30–40 mg/kgStreptomycin 15–20 mg/kgAmikacin 15–20 mg/kgKanamycin 15–20 mg/kgCapreomycin 15–20 mg/kgOfloxacin 800 mgCiprofloxacin 1000 mgGatifloxacin 400 mgMoxifloxacin 400 mgLevofloxacin 1000 mgEthionamide 15–20 mg/kgProthionamide 15–20 mg/kgCycloserine 500–1000 mgPara-aminosalicylic

acid150 mg/kg

Linezolid 600 mgClofazimine 200–300 mgAmoxicillin/

clavulanate875/125 mg BID or

500/125 mg TIDClarithromycin 1000 mgTerizidone 600–900 mgThiacetazone 150 mgThioridazine 75 mgBedaquiline 400 mg (for 2 wk)

200 mg TIW (for 22 wk)Delamanid 200 mg

BID, twice a day; TID, thrice a day; TIW, thrice a week.

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ment (East African/British Medical ResearchCouncil 1974; Sensi 1983; Fox et al. 1999; Mi-gliori et al. 2011; Sotgiu et al. 2013).

The Madras study started in India in 1956.It showed the efficacy of the ambulatory treat-ment and the crucial role of the directly ob-served treatment for the improvement of thepatient’s adherence (Table 2) (Dawson et al.1966; Migliori et al. 2011; Sotgiu et al. 2013).

On the basis of the microbiological charac-teristics of M. tuberculosis (i.e., slow growth anddormancy of some of the bacilli belonging to thebacterial population), numerous scientific con-tributions showed the efficacy of a long-termand multidrug therapeutic approach to obtaina bacteriological eradication in pulmonary andextrapulmonary sites.

Other factors can contribute to the success-ful outcome of the antituberculosis therapy, in-cluding the chemical features of the infectionsite. An adequate combination of effectivedrugs can reduce the probability of failure, re-lapse, and selection of resistant strains. Toachieve those clinical and public health out-comes, it is necessary to prescribe antitubercu-losis drugs with an adequate dosage, for a spe-cific time of exposure, and whose efficacy hasbeen proved in in vitro tests (i.e., drug-suscept-ibility testing). In particular, to avoid the emer-

gence of resistant strains, it is necessary to pre-scribe at least two effective drugs.

Duration of drug exposure is different ac-cording to the susceptibility of the isolatedstrains. In general, two different steps in thetreatment of tuberculosis can be recognized—initial (or bactericidal) phase and continuation(or sterilizing) phase. During the first step oftreatment, mycobacteria with a high replicationrate are killed, and, consequently, with the his-tological pulmonary restoration and the reduc-tion of the inflammation process, symptomsand clinical signs resolve (clinical recovery).From a public health perspective, this phase iscrucial because the treated patient becomesnoninfectious and the probability of selectionof drug-resistant strains decreases (it is directlycorrelated to the fast-growing bacteria). Thecontinuation phase is oriented to the elimina-tion of semidormant bacteria, whose size is sig-nificantly reduced if compared with that at thebeginning of the antituberculosis therapy; thisquantitative feature, related to the low replica-tion rate, is associated with a low probability ofemergence of drug-resistant mycobacteria. Incases of drug-susceptible tuberculosis, two po-tent medicines are sufficient (e.g., isoniazid andrifampicin) in this phase. On the other hand,the regimen prescribed during the initial phaseis more complex: two bactericidal drugs (isoni-azid with streptomycin or rifampicin), etham-butol to inhibit monoresistant strains and toreduce the mycobacterial burden, and pyrazina-mide, whose action is mainly focused to thesemidormant mycobacteria. The intensivephase has a duration of 4 mo, whereas the ster-ilizing phase has a duration of 2 mo.

On this basis, the choice of the antitu-berculosis drugs in the different phases is notrandom but is based on the epidemiology (e.g.,resistance rate in a specific setting, probability ofhaving been infected by a contact with drug-resistant tuberculosis) and on the specificity ofaction of the antituberculosis drugs. The anti-tuberculosis drug armamentarium is character-ized by molecules with two main differentmechanisms of action—bactericidal effect andsterilizing effect. The first one is crucial in theintensive phase and allows a relevant reduction

Table 2. Historical steps of the antituberculosistreatment

Year Historical step

1940 Use of promin in guinea pigs1944–1946 Discovery of streptomycin1948 Discovery of para-aminosalicylic acid1952 Streptomycin þ para-aminosalicylic

acid þ isoniazid1954 Discovery of pyrazinamide1956 Madras study1961 Discovery of ethambutol1963 Discovery of rifampicin1970 9-mo rifampicin-containing regimens1974 6-mo rifampicin- and pyrazinamide-

containing regimens2012 Food and Drug Administration

approval of bedaquiline2013 Approval of delamanid by European

Regulatory authorities

Tuberculosis Therapy

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of the bacterial load; the indirect consequenceof this activity is the reduction of the probabili-ty of selecting drug-resistant strains. The mostimportant drugs prescribed for that aim areisoniazid, pyrazinamide, rifampicin, and strep-tomycin. The sterilizing activity is relevant inthe initial phase and in the continuationphase, but primarily in the continuation phasebecause it is oriented to kill mycobacteria in adormancy state. Antituberculosis drugs deemedhelpful in this phase are pyrazinamide andrifampicin.

These general principles are accepted world-wide, and the standardized regimens recom-mended by the World Health Organization inits guidelines have their roots in this biologicalrationale (World Health Organization 2004;Migliori et al. 2011; Sotgiu et al. 2013).

The World Health Organization classifiedantituberculosis drugs into five classes follow-ing several criteria, among them their efficacyand their chemical characteristics. The drugsusually prescribed for the drug-susceptible tu-berculosis are included in the first class, where-as the drugs with unclear efficacy are includedin the fifth class. In particular, the followingdrugs are integrated in the first class: ethambu-tol, isoniazid, pyrazinamide, and rifampicin.The second class includes amikacin, capreomy-cin, kanamycin, and streptomycin; old- andnew-generation fluoroquinolones are includedin the third class. The antituberculosis drugsin the fourth class are cycloserine, ethionamide,para-aminosalicylic acid, prothionamide, teri-zidone, and thioacetazone. The fifth class en-compasses amoxicillin/clavulanate, clarithro-mycin, clofazimine, imipenem, and linezolid(World Health Organization 2010).

TREATMENT OF DRUG-SUSCEPTIBLETUBERCULOSIS (WORLD HEALTHORGANIZATION 2010)

Individuals diagnosed with a pulmonary formof tuberculosis, not exposed to antituberculo-sis drugs for .1 mo (i.e., “new cases” of tuber-culosis), have to be treated for 6 mo. Duringthe 2-mo intensive phase, patients shouldbe administered a combined regimen includ-

ing ethambutol, isoniazid, pyrazinamide, andrifampicin. Only isoniazid and rifampicinare prescribed during the 4-mo continuationphase.

Patients should take drugs daily to obtain aclinical and a microbiological cure; however,during the second phase of treatment, thriceper week is allowed, but, in that case, adherenceis crucial to avoid reduction of the drugs’ bloodlevel and, consequently, the risk of emergence ofdrugs’ resistances.

As mentioned above, a higher efficacy ofantituberculosis regimens longer than 6 mofor individuals both with and without HIV in-fection was not shown; a different scenario hasbeen found in the treatment of the latent tuber-culosis infection, in which the duration of thetreatment is longer in HIV-infected patients.

Microbiological monitoring of the efficacyof the prescribed regimen is mandatory; spu-tum smear and culture conversion should beevaluated, particularly at the end of the inten-sive and continuation phases of treatment.

Previously treated cases (i.e., previouscourse of antituberculosis drugs for .1 mo)should be managed differently. To prescribean effective regimen tailored on the phenotypicprofile of the mycobacterial isolates, a rapid andconventional drug-susceptibility testing is re-quired before the initiation of therapy. It is cru-cial to monitor the potential adverse events toavoid the interruption of the prescribed therapy(Table 3).

The World Health Organization recom-mends the prescription of an empiric regimenfor those who are identified as relapsers or de-faulters, in case of a low multidrug resistanceprevalence—ethambutol, isoniazid, pyrazina-mide, rifampicin, and streptomycin in the in-tensive phase, followed by ethambutol, isonia-zid, pyrazinamide, and rifampicin for 30 d; thelast 5-mo phase is characterized by ethambutol,isoniazid, and rifampicin, for a total duration of8 mo (Table 4).

It was clearly shown that the 6-mo regimenis practically 100% effective; after a follow-upperiod of 2 yr, the relapse rate can range from0% to 7%. Intermittent regimens proved a sim-ilar efficacy, with a slightly higher relapse rate at

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2 and 5 yr and a lower proportion of adverseevents (World Health Organization 2004).

Extrapulmonary tuberculosis is a pauciba-cillary disease, and therapeutic regimens are the

same as those prescribed for the pulmonaryforms. Severe extrapulmonary disease, charac-terized by the neurological, abdominal, bilateralpleural, pericardial, bone, or joint or systemicinvolvement, needs four drugs in the intensivephase and sometimes a treatment duration of9 mo (e.g., in case of neurological involvement).In case of relevant inflammation, the prescrip-tion of steroids is recommended. However, theprognosis strictly depends on the precocity ofthe administration of the antituberculosis drugs(World Health Organization 2004).

TREATMENT OF DRUG-RESISTANTTUBERCULOSIS

The clinical and public health management ofdrug-resistant tuberculosis is complicated. Thetherapeutic approach, as well as the prognosis,is significantly associated with the resistancepattern (Falzon et al. 2011; World Health Orga-nization 2011b).

It has been clearly shown that the multidrugresistance (i.e., the resistance in vitro to at leastisoniazid and rifampicin) could represent arelevant clinical issue because of the pooresttherapeutic armamentarium. The so-called sec-ond- and third-line antituberculosis drugs areless efficacious, more toxic, and more expensivethan the first-line drugs.

It is straightforward that the adequate treat-ment of drug-resistant tuberculosis can preventthe emergence of new serious drug-resistantforms, which could have a worst prognosis andless alternative therapeutic options.

Furthermore, another relevant feature of anadequate and early treatment is the low proba-bility of transmission of drug-resistant myco-bacterial strains in a specific setting, such as ahospital or a community.

Nevertheless, to obtain a clinical and a mi-crobiological cure, it is mandatory to treat in-dividuals for a long period because of the les-ser effectiveness of the second- and third-linedrugs. The prolonged exposure to medicines,characterized by a poor safety and tolerabilityprofile, reduces the adherence of the patient.This pathogenetic step could be crucial for the

Table 3. Main adverse events of the antituberculosisdrugs

Drug Adverse event

IsoniazidLinezolid

Peripheral neuropathy

BedaquilineIsoniazidPara-aminosalicylic

acidPyrazinamideRifampicin

Liver dysfunction

AmikacinAmoxicillin/

clavulanateFluoroquinolonesIsoniazid kanamycinRifampicinStreptomycinThiacetazone

Skin rash

BedaquilinePyrazinamideThiacetazone

Arthromyalgia

AmikacinCapreomycinKanamycinStreptomycin

Renal dysfunction


Vestibular and auditorydysfunction

Amoxicillin/clavulanate

BedaquilineClarithromycinClofazimineEthionamideFluoroquinolonesLinezolidProthionamidePara-aminosalicylic

acidTerizidoneThiacetazone

Gastrointestinal disorders

CycloserineFluoroquinolonesTerizidone

Psychosis



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emergence of new drug-resistant mycobacterialstrains and their spread in the community.

One of the most important points in themanagement of the drug-resistant strains isthe prescription of an efficacious drug regimen,which should be based on the results of thedrug-susceptibility testing. The current avail-ability of rapid molecular tests, which can assessthe resistances of mycobacterial strains to iso-niazid and rifampicin, can allow the admini-stration of an early tailored antituberculosisregimen. In particular, the World Health Orga-nizationrecentlyapprovedanautomatednucleicacid amplification test to diagnose tuberculo-sis disease and to assess mycobacterial resistanceto rifampicin (Xpert MTB/RIF System). Therapid identification of a multidrug-resistantcase can allow an immediate prescription of anempiric and specific antituberculosis drug regi-men. This molecular method might avoid theadministration of an inappropriate treatmentand, consequently, indirectly favor the clinicalrecovery of patients and the reduction of theirinfectiousness (World Health Organization2011a).

The World Health Organization suggeststhe prescription of at least four active drugs dur-ing the intensive phase. In particular, the back-bone of the administered regimen should in-clude pyrazinamide, one of the injectablesecond-line drugs (amikacin, capreomycin, orkanamycin), a new-generation fluoroquino-lone, ethionamide (or prothionamide), and cy-closerine (or PAS). Other drugs should be pre-scribed in case of resistances to one or more ofthe backbone drugs. The duration of the firstphase of the treatment should depend on theculture conversion, but it should last at least 8mo, whereas the duration of the second phaseshould be longer than 20 mo.

The World Health Organization guidelinesissued in 2011 (WHO 2011b) showed significantdifferences if compared with those issued in2008; in particular, the suggested duration ofthe intensive phase is longer (i.e., 8 vs. 6 mo),as well as the total duration of therapy (i.e., atleast 20 mo). If feasible, pyrazinamide shouldbe added up to a backbone regimen of foursecond-line antituberculosis drugs, in which

ethionamide and new-generation fluoroquino-lones are the preferred medicines. Furthermore,monthly monitoring of the culture conversion isrelevant to assess the efficacy of the prescribedtherapy (World Health Organization 2008).

New therapeutic options have been pro-posed in recent years for the management ofthe drug-resistant mycobacterial strains, includ-ing new molecules and drugs prescribed forother diseases.

Several drugs, approved for infectious dis-eases other than tuberculosis, showed in vitroand in vivo antimycobacterial activity; amongthem, imipenem-cilastatin, linezolid, and mer-openem-clavulanate have had a relevant role inindividuals with drug-resistant tuberculosis inthe last few years. The new molecules recentlyapproved or in the last clinical trial phases arebedaquiline (a new diarylquinoline, previous-ly called TMC 207), delamanid (previouslycalled OPC-67683), sutezolid (PNU 100480),and PA-824.

Bedaquiline and delamanid have recentlyreceived a marketing approval. Bedaquiline-containing regimens increase by 12 times theprobability of culture conversion in multi-drug-resistant tuberculosis cases and preventthe emergence of further resistances to the drugsincluded in the backbone regimens. It reducesthe time to culture conversion in the first 6 moof exposure (hazard ratio: 2.3). The safety andtolerability profile is good if compared withother antituberculosis drugs (i.e., acne, bilateralhearing impairment, extremity and noncardiacchest pain). However, the frequency of nauseawas significantly higher during some clinicaltrials if compared with that in the control group(Diacon et al. 2009, 2012a,b, 2013; Willyard2012; Mahajan 2013; World Health Organiza-tion 2013b).

Delamanid-containing regimens showed ashort- and long-term efficacy in terms of cul-ture conversion. The positive microbiologicalfeatures are associated with the relevant im-provement of a strong epidemiological indica-tor-like mortality; the proportion of individualswho died after a �6-mo exposure to delamanidwas 1% versus 8% in those not exposed orwith a short-term exposure. The percentage



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of individuals who culture-converted at 2 mowas about 45% versus nearly 30% in the con-trol group. The most important adverse eventthat occurred in patients exposed to this novelnitroimidazole was QT prolongation, althoughnot associated to relevant cardiac events (Di-acon et al. 2011; Gler et al. 2012; Skripconokaet al. 2013).

Other new promising drugs are currentlybeing tested in the phase II and III clinical trials.In particular, sutezolid, belonging to the samechemical familyof linezolid, showed its ability inthe reduction of the colony forming units (Shawand Barbachyn 2011; Wallis et al. 2012). Theearly bactericidal activity showed by PA-824, anew nitroimidazo-oxazine, was superior to thatof bedaquiline in the first clinical trials (Diaconet al. 2012a,b; Migliori and Sotgiu 2012).

Antibiotics licensed for bacterial infectionsother than tuberculosis proved their efficacy inthe treatment of the multidrug-resistant andextensively drug-resistant tuberculosis cases.

Linezolid is efficacious but is characterizedby several hematological side effects (anemiaand/or leucopenia and/or thrombocytopenia),peripheral nervous system problems, and gastro-intestinal toxicity. However, it has been provedthat the therapeutic monitoring of its blood lev-els (TDM) can allow a dosage adjustment, fol-lowed by the reduction of the probability ofoccurrence of adverse events. Several pharmaco-kinetic studies showed that a 600-mg dosage hasthe best cost/benefit ratio. TDM was helpful inunderstanding the best dosage to be adminis-tered to patients on the basis of the blood drugconcentration. It was clear that a daily dosageof 1200 mg is toxic if compared with a 600-mgdosage. On the other hand, a 300-mg daily dos-age is less efficacious (Migliori et al. 2009; Sotgiuet al. 2009, 2012; Alffenaar et al. 2010; Koh et al.2012; Srivastava et al. 2013).

Meropenem-clavulanate and cotrimoxazoleshowed their efficacy in some observationalstudies. The former favored sputum smear andculture conversion in .80% of the multidrug-resistant tuberculosis cases (88% and 84%,respectively, in a case-control study) and wasassociated with an optimal safety profile (DeLorenzo et al. 2013). The latter was evaluated

in vitro and in a few cases, and its efficacy needsto be proved in experimental, controlled studies(Forgacs et al. 2009; Huang et al. 2012; Vilchezeand Jacobs 2012). New experimental clinicaltrials are needed to assess the clinical profile ofthe new therapeutic options (Grosset et al. 2012;Pontali et al. 2013).

The management of individuals with mul-tidrug-resistant tuberculosis and HIV infec-tion requires the involvement of tuberculosis/HIV specialists. Anti-HIV drugs should be pre-scribed within 8 mo from the first admini-stration of the antituberculosis drugs. The pillburden is relevant and the adherence of the pa-tients can be significantly affected; furthermore,the toxicity linked to the pharmacological in-teractions can contribute to reduce the compli-ance of the patients. In particular, the severity ofthe hepatic, gastrointestinal, hematological, re-nal, and central and peripheral nervous systemtoxicity could interrupt the treatment (Table 5).

A recent systematic review, enrolling 217 pa-tients, whose CD4 cell counts were ,200 mLin the majority of cases, showed that individu-als exposed to antiretrovirals were more likelyto survive (hazard ratio of 0.38) and have a lon-ger median time to death (i.e., 37 mo vs. 11 moamong those not exposed to antiretrovirals).Furthermore, the prescription of antiretroviraldrugs was associated with a higher probabilityof cure (hazard ratio, 3.4). It was proved that thelevel of immunodeficiency and the mycobac-terial resistance pattern do not influence theabove-mentioned risks (Arentz et al. 2012).

The concomitant prescription of anti-HIVand antituberculosis drugs does not depend onthe severity of the immunodeficiency and thenon the CD4 cell counts.

ADHERENCE TO ANTITUBERCULOSISTHERAPY

The efficacy of the combination regimens de-scribed above will determine, in addition tobacteriological conversion, a subjective im-provement of the patient’s clinical conditions.The latter feature may anticipate the microbio-logical conversion and could be paradoxicallydangerous from an individual and a public

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health perspective; patients feeling better mightdecide to interrupt their treatment.

Several approaches have been proposed toincrease patient’s adherence. One of the mostimportant is the so-called DOT (i.e., directlyobserved therapy). The patient takes the pre-scribed therapy in the presence of a health-care worker (physician or nurse), a social work-er, or another person involved in agreementwith the local tuberculosis program. The direct

observation avoids all the problems associatedwith self-administration, including compli-ance with the dosages and time of administra-tion affecting the pharmacokinetic curve ofthe drugs. In addition, DOT allows rapid man-agement of adverse events related to the drugintake.

Another important tool to enhance adher-ence is represented by the fixed-dose combina-tion of the antituberculosis drugs. They were

Table 5. Main adverse events of the antituberculosis drugs and of the antiretrovirals

Antituberculosis drugs Antiretroviral drugs Adverse event

IsoniazidLinezolid

DidanosineStavudine

Peripheral neuropathy

BedaquilineIsoniazidPara-aminosalicylic acidPyrazinamideRifampicin

EfavirenzEtravirineMaravirocNevirapineRitonavir/protease

inhibitors

Liver dysfunction

AmikacinAmoxicillin/clavulanateFluoroquinolonesIsoniazid kanamycinRifampicinStreptomycinThiacetazone

AbacavirEfavirenzEtravirineNevirapine

Skin rash

BedaquilinePyrazinamideThiacetazone

- Arthromyalgia


IndinavirTenofovir

Renal dysfuction


- Vestibular and auditory dysfunction

Amoxicillin/clavulanateBedaquiline clarithromycinClofazimineEthionamide fluoroquinolones

linezolidProthionamidePara-aminosalicylic acidTerizidoneThiacetazone

DidanosineProtease inhibitorsStavudineZidovudine

Gastrointestinal disorders

Cycloserine fluoroquinolones terizidone Efavirenz Psychosis

Data modified from Arentz et al. 2012.



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introduced in clinical practice at the end of the1980s, and several advantages were immediatelyrecognized: easy management for the nationaltuberculosis program and for health staff notfully familiar with antituberculosis drugs andreduced probability of emergence of drug re-sistances because of the improved patient’sadherence. The main disadvantages, intrinsi-cally related to the fixed dose, are the risk of anonadequate blood level (rare, and limited topatients characterized by a poor intestinal ab-sorption or by a rapid metabolism) and the dif-ficulty in attributing an adverse event to a spe-cific drug.

Another strategic therapeutic approach toimprove adherence is represented by the inter-mittent regimens, whose efficacy was shown in1964 in Chennai, India. Antituberculosis drugsare administered at intervals of .1 d. The re-lapse rate is 8% after a follow-up of 2 yr (WorldHealth Organization 2004).

An important role to increase adherence canbe played by incentives and enablers (money,food, incentives for transportation, etc.), par-ticularly in resource-limited countries. Poor pa-tients living in rural areas can lose their job andtheir daily salary because of the medical visitsin far urban settings. National tuberculosis pro-grams should identify the geographical areasor the social groups where these nonmedicalinterventions could be crucial in improving ad-herence (Tuberculosis Coalition for TechnicalAssistance 2009).

Last but not least, when health education isadequately provided by health services to thepatients and their families, adherence tends toimprove.

CONCLUDING REMARKS

The current therapeutic management of drug-susceptible and drug-resistant strains needs tobe further improved. The available regimens arecharacterized by a relevant pill burden, long du-ration, variable efficacy, safety, and tolerability.The overall treatment success rate is below therecommended World Health Organization pro-portion of 85%, and, consequently, the drugresistance level increases.

The World Health Organization estimatesthat a suboptimal proportion of multidrug-re-sistant cases is presently diagnosed and treated.In 2010, 48% of the detected multidrug-re-sistant tuberculosis cases were successfully treat-ed. Only 34 countries obtained a treatment suc-cess rate �75% (World Health Organization2013a). Even in tuberculosis reference centers,the proportion of treatment success in multi-drug-resistant cases does not exceed 50%.

Although the adherence, efficacy, safety, andtolerability profile of the newly available drugs(delamanid and bedaquiline, in particular) ap-pear to be promising, we cannot predict, as oftoday, their long-term efficacy and the afford-ability of their use in resource-limited settings.Further research efforts are necessary to identifythe potentialities of the new drugs and to un-derstand better how to use them in combina-tion regimens.

These new regimens are ideally able to treattuberculosis sustained by both drug-susceptibleand drug-resistant strains without interferingwith antiretroviral drugs, thus allowing a moreeffective approach against HIV-infected cases.

The new approach adopted to test differentdrug combinations in parallel can improve thecurrent situation, giving new insights in a short-er period of time.

New research and development activitiesare requested, along with a preservation of thecurrent therapeutic options. Training and edu-cational activities focused on the rationale useof the antituberculosis drugs are necessary toavoid the dramatic increase of the drug-resistantforms.

National and local public health programsshould issue guidance, based on the local epi-demiology, to prevent inappropriate manage-ment of the new and old antibiotics, as to ensurethat all cases of tuberculosis diagnosed and cor-rectly treated, complete their treatment. Therisk is to loose the new drugs in much less thanthe time necessary to develop them.

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