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Recent developments in treatment of latent tuberculosis infection

Recent developments in treatment of latent tuberculosis infection Review Article Indian J Med Res 133, March 2011, pp 257-266 Dick Menzies, Hamdan Al Jahdali & Badriah Al Otaibi Montreal Chest Institute, McGill University, Montreal, Quebec, Canada Received December 24, 2010 Latent tuberculosis infection (LTBI) can be detected with immune based tests such as the tuberculin skin test (TST) or interferon gamma release assays (IGRA). Therapy for those with positive tests can reduce the subsequent risk of re-activation and development of active TB. Current standard therapy is isoniazid (INH) which reduce the risk of active TB by as much as 90 per cent if taken daily for 9 months. However, this lengthy duration of therapy discourages patients, and the risk of serious adverse events such as hepatotoxicity, discourages both patients and providers. As a result completion of INH therapy is less than 50 per cent in many programmes. However, programmes that offer close follow up with supportive staff who emphasize patient education, have reported much better results. The problems with INH have stimulated development and evaluation of several shorter regimens. One alternative was two months daily rifampin and pyrazinamide; this regimen has been largely abandoned due to unacceptably high rates of hepatotoxicity and poor tolerability. The combination of INH and rifampin, taken for 3 or 4 months, has efficacy equivalent to 6 months INH albeit with somewhat increased hepatotoxicity. Four months rifampin has efficacy at least equivalent to 6 months INH but there are inadequate trial data on efficacy. The safety of this regimen has been demonstrated repeatedly. Most recently, a regimen of 3 months INH rifapentine taken once weekly under direct observation has been evaluated in a large scale trial. Results have not yet been published, but if this regimen is as effective as INH, this may be a very good alternative. However, close monitoring and surveillance is strongly suggested for the first few years after its introduction. Evidence from several randomized trials has shown that the benefits of LTBI therapy is only in individuals who are tuberculin skin test (TST) positive even among those with HIV infection. Hence, LTBI therapy should be given only to those with positive tests for LTBI. We conclude that LTBI therapy is considerably underutilized in many settings, particularly in low and middle income countries. Key words Latent tuberculosis - tuberculosis - tuberculosis infection - tuberculosis prevention - tuberculosis treatment develop active TB during their lifetime . More than Introduction 80 per cent of these will be contagious and transmit It has been estimated by the World Health TB infection to others, perpetuating the cycle of TB Organization (WHO) that more than one third of the and resulting in continued morbidity and mortality entire world’s population, or approximately 2 billion from TB for generations to come . The impact of persons are infected and can be considered carriers TB is even greater than these numbers may suggest, of TB. From this vast pool of persons with latent as 75 per cent of individuals with TB are within the TB infection (LTBI) approximately 200 million will economically productive age group of 15-54 yr , and 257 258 INDIAN J MED RES, MARCH 2011 TB disproportionately affects low and middle income However, INH treatment of LTBI is problematic countries, as 95 per cent of all cases and 99 per cent of for several reasons. The lengthy duration of treatment 2 6-8 all deaths occur in these countries . reduces patient compliance , while the potential occurrence of serious adverse events such as hepatitis, Two approaches can be taken to reduce the burden further discourages patients’ and providers’ acceptance of TB over the long term. One approach requires early 9,10 of this therapy . As a result there has been considerable and rapid diagnosis of all persons with active TB with interest and many evaluations of alternative shorter institution of effective therapy to render them non regimens. This work continues even today. contagious. This will reduce transmission, reducing the number of carriers, who will later develop active The objectives of the present article are to (i) TB. However, WHO has estimated that less than 50 review the evidence from systematic reviews and per cent of all cases globally are currently diagnosed recent trials of efficacy, completion, and adverse effects and treated . Since each person with undiagnosed and of several commonly used regimens for treatment of untreated active TB will survive an average of 2 yr, LTBI; (ii) review risk-benefit and other considerations it has been estimated that they will infect 20 others . for treatment of LTBI in high income, as well as An additional problem is that most patients in high low and middle income countries; and (iii) review incidence settings are diagnosed by direct smear the indications for tuberculin testing (or use of other microscopy of unconcentrated sputum specimens , methods of diagnosis of LTBI) prior to starting LTBI which only detects patients with advanced disease. treatment. Hence, significant transmission can occur prior to Regimens for treatment of LTBI diagnosis . 6 Months INH (6INH) An alternate approach is to detect persons while Numerous trials have evaluated different durations they still have LTBI and treat them to prevent the later development of disease. This approach dates back to of INH However, only one clinical trial has directly compared regimens of different durations of INH. the 1950s. Soon after isoniazid (INH) was introduced as an effective agent to treat disease, clinicians noted that The International Unit Against Tuberculosis (IUAT) trial, conducted in Eastern Europe, randomized INH monotherapy effectively prevented development of disease in children with primary TB . Following approximately 28,000 individuals with positive tuberculin skin tests (TST) and fibronodular changes on this clinical observation, more than 20 randomized trials, involving more than 100,000 participants, were chest X-ray . Approximately 7,000 participants each were randomized to placebo, 3, 6 or 12 months of INH conducted in more than a dozen countries . These studies demonstrated that INH taken for at least 6 (Table I). Compliance was assessed with monthly pill counts. Compared to participants who took placebo, months in persons with LTBI reduced subsequent TB incidence by 25 to 92 per cent. The differences in participants who completed 3 months INH had 31 per cent reduction in TB; this effect waned over the 5 years effectiveness found in different studies were largely explained by differences in treatment completion . of follow up. Participants who completed 6 months Table I. Summary of LTBI regimens in common use Regimen Efficacy Completion of therapy Serious adverse events (relative to placebo)# Type Rate 12 6,8,54 23,68 INH: 6 months 69% 50% Hepatitis 1 -5% 12,17 31,33,34,69 23,31,34,68 INH: 9-12 months 90 – 93% <50% Hepatitis 1 -5% 27,63 *27 27,68,70 RIF&PZA: 2 months Equal to 6 -12INH 6% > 6-12INH Hepatitis 3 -5% 30,36 **36 36,37 INH&RIF: 3-4 months Equal to 6INH 6% > 6-12INH Hepatitis† 1 – 5% ##30 ***31-34,71 31,34 RIF: 3-4 months 65% 22% > 9INH Rash 1- 2% 31,32,34 Hepatitis <1% Superscript numerals denote reference nos.; INH, isoniazid, 6 INH, 6 months isoniazid; 6-12 INH, 6-12 months INH; PZA, Pyrazinamide; RIF, Rifampins; Efficacy from placebo randomized trials. If trials were not placebo controlled then efficacy relative to INH is given; ## * Based on one placebo-controlled trial with 3 months rifampin (30); Average 6% (range: -5 to 19%) better completion than with 6-12INH; ** *** Average 6% (range: 3 to 12%) better completion than with 6–12INH; Average 22% (range: 18 to 27%) better completion than with 9INH; Hepatitis more frequent with INH&RIF than INH alone (37); Figures in parentheses denote Ref numbers MENZIES et al: UPDATE IN TREATMENT OF LATENT TB 259 INH had 69 per cent reduction of active TB, while Society (ATS) in 1971, the potential for adverse effects subjects who completed 12 months INH (12INH) had was considered minimal, and this treatment was strongly recommended for TST reactors of all ages . With the 93 per cent reduction in TB. The efficacy of 6INH and 12INH waned during the 5 yr of followup but always ensuing much greater use, serious hepatotoxicity causing 12 22 deaths was described . Subsequent surveillance studies remained significantly better than placebo . However, confirmed that hepatotoxicity was quite common in completion of the 12 month regimen was much less patients taking INH, and could be severe, with up to 1 than the 6 month regimen. per cent mortality in older patients . Subsequently INH Based on these results, and assuming that under 24,25 related mortality has declined over the last 30 yr – programme conditions completion of longer regimens presumably related to better selection of patients for would be equally poor, if not worse, many authoritative therapy and closer follow up. agencies have recommended 6INH as an acceptable 13,14 15 2 Months rifampin –pyrazinamide (2RZ) alternative to 12INH . Snider and colleagues estimated that 6INH would be more cost-effective Studies of latent TB infection in a mouse model than 12INH. This reflects the fact that the majority of revealed that 2 months of treatment with a combination costs of LTBI therapy is related to the initial screening, of rifampin and pyrazinamide (PZA) resulted in subsequent medical evaluation and start of therapy . complete clearance of TB bacilli - a bacteriologic However, it is important to remember that in patients effect comparable to that achieved with 6 months INH who take therapy properly, 12INH is significantly and in the same mouse model. Following publication of substantially more efficacious than 6INH. 26 these results in 1989 , several randomized trials were conducted to compare 6 to 12 months INH with 2RZ 9 Months INH (9INH) in HIv infected patients . These trials demonstrated Concerns regarding the relatively low efficacy of equivalent efficacy; however, since most compared 2Rz 6INH, and equally serious concerns regarding the poor to 6INH this would indicate that efficacy of 2Rz was completion of 12INH resulted in recommendations likely less than the ideal achieved with 9INH. Serious for 9 months INH by the American Thoracic Society adverse events were not more frequent with 2RZ than in 2000 . This recommendation was based almost with INH in these trials. However, completion of 2RZ entirely upon a re-analysis by Dr George Comstock was not significantly better than completion of 6INH in of data from several INH trials among Alaskan Inuit several of these trials, despite the shorter duration . In populations . This re-analysis demonstrated that retrospect, this may have been a harbinger of events to the optimal duration of INH was 9 months, with come. estimated efficacy of 90 per cent and no significant In 2000, based on these promising trial results, gain with extension to 12 months. Hence, 9INH was the American Thoracic Society recommended use of recommended as the standard of care by the American 2RZ . This was a strong recommendation for use in Thoracic Society in 2000 , and other authorities HIv infected persons, and a conditional (or weak) followed suit soon after . recommendation for non-HIv infected persons. Completion of 9INH under programme conditions Publication of these recommendations was quickly is poor. Many programmes report less than 50 per followed by rapid, enthusiastic and widespread use of cent completion although a few programmes report 2RZ. In turn this was quickly followed by reports of 18,19 much higher completion rates . These programmes serious hepatotoxicity and death . Subsequent trials in emphasize initial intensive patient education, with non HIv infected individuals revealed very high rates of subsequent close follow up, and patient support; they grade 3 to 4 hepatotoxicity, which sometimes occurred demonstrate that many patients can be motivated to at the end or even after completion of therapy . As a complete 9 months therapy. result recommendations were revised that 2RZ should be used with caution in HIV infected and extreme However, INH has the major disadvantage of caution in non HIv infected . potential serious adverse events. Of particular concern is hepatotoxicity, as this is difc fi ult to detect, and can Our current practice is to consider use of this regimen in HIv infected individuals in situations be fatal. Interestingly in the randomized trials conducted up to 1970 this problem had not been noted . Hence where close supervision and monitoring is possible and longer therapy LTBI regimens may be impractical. We when INH was recommended by the American Thoracic 260 INDIAN J MED RES, MARCH 2011 do not recommend this regimen in non-HIv infected A series of randomized trials , have demonstrated persons. that the efficacy of 3-4INH-RIF is equivalent to that of 6INH (4 studies) or 9INH (1 study) although 4 Months rifampin (4RIF) adverse events are significantly more frequent . This An overlooked finding in the same study of treatment latter finding is not that surprising, since the majority of latent LTBI in mice was that rifampin alone for 2 of hepatotoxic adverse events with INH occur in the 34,38 months was equally efficacious as 2Rz, or 2 months of first 2-3 months . Therefore adding INH to rifampin rifampin plus- INH . Complete bacteriologic clearing for 3 or 4 months will inevitably increase the risk of adverse events. However, the benefits of adding the had occurred in all TB infected mice by the end of two months mono-RIF therapy. Unfortunately, despite this INH to RIF are unclear. In theory, therapy with two agents will provide a margin of safety if the person has very promising evidence, only one randomized trial has evaluated a regimen of rifampin alone. In this trial, minimal active TB rather than true latent TB infection. There is no evidence of improved efficacy compared to older men living in Hong Kong, who had pulmonary RIF alone, and to justify LTBI therapy on the basis of silicosis with a positive TST were randomized to potential misdiagnosis of active TB as latent TB seems placebo, 6INH, 3 months INH plus Rifampin, or a fairly weak rationale for this regimen. 3 months Rifampin alone . During five years of follow up, 27 per cent of those randomized to placebo New regimens developed active TB, compared to 16, 13, and 10 per A trial comparing 9INH with 3 months of once cent for the three regimens respectively. The estimated weekly directly observed INH combined with effectiveness of 3 months rifampin was approximately rifapentine (3INH-RPT) has just been completed. 65 per cent; this was better than the other regimens Rifapentine is a rifamycin with half life that is 5 times although the differences between active regimens was longer than rifampin - allowing once weekly therapy. not significant, and all were significantly better than More than 8,000 participants were randomized. placebo . To date, there are no other published trial Completion of 3INH-RPT was 84 per cent, compared evaluating mono-RIF therapy. However, a large scale to 71 per cent completing 9INH. Efficacy and safety trial comparing the effectiveness and efficacy of 4RIF data are still being analyzed, but results are expected and 9INH is ongoing. soon. If these are acceptable, this may be an excellent Several studies have reported that completion alternative regimen. However, the requirements for rates with 4RIF are substantially and significantly directly observed preventive therapy may make this 31-34 better than with 9INH . In addition, rates of serious impractical in some settings. adverse events with 4RIF are very low, particularly 31 In addition, the experience with INH in 1970, and rates of hepatotoxicity . In a recently published the 2RZ regimen in 2000 should provide a cautionary randomized trial rates of grade 3 to 4 adverse events note for implementation of this new regimen. For were significantly lower with 4RIF than 9INH. Grade both of these regimens the potential for serious and 3-4 hepatotoxicity occurred in 4 per cent of patients even fatal adverse events was not detected in multiple taking 9INH compared to less than 1 per cent in those 34 randomized trials. The serious hepatotoxicity of both taking 4RIF . The earlier results in the Hong Kong regimens was only recognized after these had been silicosis trial suggest that 4RIF should have efficacy 30 recommended and implemented widely in routine of at least 65 per cent - equivalent to the documented practice. Rifapentine is a relatively new and untested efficacy of 6INH. drug. Hence this drug may cause unexpected adverse In summary, 4RIF appears to be well tolerated, has events that were not detected in the randomized trial. excellent completion and a very good safety record. Given the long half life of this drug the adverse events However, 4RIF cannot be recommended for routine may progress even after treatment is stopped, resulting use until the results of the efficacy trial are available. in more serious sequelae. Hence, introduction of this new regimen should be accompanied by careful 3 to 4 Months of INH and RIF (3-4INH-RIF) monitoring and evaluation of adverse events. The animal study described earlier suggested that Drug-resistant LTBI INH and RIF for 2 months was effective in the mouse model. Uncontrolled trials in paediatric populations Treatment of close contacts of drug resistant active have suggested that this regimen should be adequate . cases is difficult and yet is an increasingly common MENZIES et al: UPDATE IN TREATMENT OF LATENT TB 261 clinical problem. For contacts of INH resistant In high income settings, the costs are not index cases, INH will be ineffective , so 4RIF is as determinant of LTBI therapy as risk-benefit 13,14 recommended . Contacts of index cases with MDR considerations. After realization that serious adverse TB are recommended to receive 6 months of PZA and events and even deaths could occur with INH, several a quinolone . However, two observational studies investigators performed decision analyses to estimate have reported very high rates of toxicity and extremely the risks and benefits of INH therapy. As shown in Table 40,41 poor completion due to intolerance . In both series II, the majority of these studies examined the risks and no patients actually completed the proposed 6 month benefits of treatment with INH in healthy individuals course of therapy. Based on this and our own clinical with a positive tuberculin skin test but no other risk experience which was similar, our current practice factors. In these individuals the benefits of INH therapy is to give moxifloxacin or levofloxacin alone for 6 are low because the life-time risk of development months. The rationale for this monotherapy is the of active TB is low. Therefore, the benefits barely published evidence that moxifloxacin can replace INH exceeded the risks. And, because of slightly different in treatment of active TB . assumptions made by the different investigators, INH therapy was found to result in small net gains or losses Consideration for use in different settings of life expectancy. However, the absolute differences 44-48 Over the past 30-40 yr treatment of LTBI has been a in findings between these studies were very small . major priority for TB control programmes in many high Despite this, the authors concluded, often very strongly, income countries such as Canada, U.S.A., Australia or that 9INH was good, or was bad. These apparently Saudi Arabia. However, LTBI diagnosis and treatment contradictory findings resulted in greater confusion has been a low priority for TB control programmes in about benefits of, and indications for, treatment of LTBI. most low and middle income countries (LMIC). This These may have contributed to the chronic underuse of ree fl cts the cost and resources required for effective and LTBI treatment. Risk-benefit analyses of INH therapy in 49,50 19 safe treatment of LTBI, given the need for close follow HIv infected individuals or other high risk groups up and monitoring to detect serious adverse events and have estimated much greater, and consistent benefits. to encourage and monitor compliance with therapy. Until These analyses support current recommendations to an LTBI regimen is found that is perfectly safe and very test and treat LTBI only in individuals with high risk of 13,14 easy to take, these resource requirements will be present. reactivation to disease, if infected . Medication costs are low, but micro costing studies have There are many factors that increase the risk shown that medications account for less than 10 per of re-activation. In view of this complexity, a web 16,43 cent of total resources used . Nevertheless therapy based algorithm has been developed which may of individuals with LTBI and important risk factors for provide some assistance in estimating that risk . This reactivation such as HIv co-infection, or close contacts algorithm, (available at www.tstin3d.com) incorporates is warranted in all settings as this therapy provides information on age, TST or interferon gamma release significant individual benefits, and is much more cost- assay (IGRA) results, country of birth, ethnic origin effective. Table II. Risk benefit studies of INH for tuberculin reactors Study Year Age group Preferred Margin of benefit* (yr) (INH or Not) (days) Low risk reactors Rose et al 1986 10-80 INH 1- 16 Tsevat 1988 20-80 No INH 4-17 Colice 1990 30 INH 3-19 Jordan et al 1991 20-35 INH 3-19 50 No INH 2-33 Salpeter et al 1997 35-70 INH 3-5 High risk reactors (HIv infected) Jordan et al 1991 20-60 INH 285 Rose 1998 Adults INH 254 Margin: means gain or loss of life expected with INH treatment, relative to no treatment. Superscript numerals denote reference numbers 262 INDIAN J MED RES, MARCH 2011 and clinical risk factors including chest radiographic therapy because tuberculin testing is not commonly findings. This information is entered and the algorithm performed. In some LMIC the tuberculin material itself calculates the likelihood of true latent infection, as (i.e., the PPD) is not available. In addition, WHO has well as the annual and cumulative life time risk of recommended that LTBI therapy can be given without development of active TB. performing a TST . One important consideration for any programme This question has been addressed in several for screening and treatment for LTBI is its potential randomized trials and in one systematic review. In public health impact. This is of particular interest in these trials INH therapy was compared to placebo in LMIC given the resource implications of initiating such HIv infected patients who had initial TST, but were a programme. As seen in Table III, several studies have randomized to active therapy or placebo regardless of described the impact of LTBI screening and treatment 59-64 TST results . There is convincing evidence, (Table 16,43,52,57 programmes in many different settings . In all IV) that a positive TST predicts benefit from INH these studies, the public health impact was very low. This therapy. INH therapy is of minimal and non-significant is because patients did not participate in initial screening benefit in HIV infected persons who are initially or failed to come for reading of tuberculin results, or TST negative. Based on the systematic review of the did not report for medical evaluation of positive tests. earlier trials in HIv infected INH provides 60 per cent In addition physicians were non-compliant with protection against disease in TST positive, but only 16 recommendations to prescribe treatment, and then per cent benefit in TST negative persons . patients refused to start LTBI therapy, or they were non-compliant if they did start. As a result, in all these A trial just completed in Botswana confirmed studies fewer than 40 per cent of patients who could these findings. In this trial HIV infected patients were have benefited from LTBI therapy actually did so; in randomized to 6 or 36 months of INH. In those who some studies as few as 10 per cent with presumed LTBI were initially TST positive, 36 months INH resulted derived any benefit. If LTBI screening and treatment is in 92 per cent reduction in TB disease relative to being considered, then a great deal of attention must those who received only 6 months INH. However, be paid to ensure that every stage of the programme is participants who were initially TST negative had only well organized, in order to enhance the public health a 14 per cent reduction in TB disease with 36 months benefit of this approach. INH, compared to 6INH - a reduction that was not statistically significant . Is testing for latent TB infection required before latent TB treatment? To date, no trials have addressed this question in IGRA positive and IGRA negative individuals. A A common clinical question is whether a TST or an recent systematic review found that the risk of disease IGRA is needed prior to giving LTBI therapy. This is in IGRA positive close contacts was similar to the rate particularly important in LMIC that are initiating LTBI Table III. True impact of large scale screening programmes Country Total TST positive Medically Started INH Completed INH evaluated screened (N) (N) (N) Of all positive Of all screened (N) with TST (N) TST (%) (%) Canada 19,001 4,292 814 452 11 2 USA 4,840 2,039 1,528 853 716 35 15 Canada 720 162 142 56 52 13 7 Canada 33,146 7,668 2,600 1589 21 5 16* Canada 3,300 1,598 647 347 251 31 18 USA 66,767 12,901 9,018 5746 37 9 Canada 7,669 782 525 293 140 13 2 57 * Uganda 9,862 5227 579 520 322 6 3 In some studies the number of studies of TST positive is calculated based upon the expected number of TST positive in the original populations screened, because individuals did not accept TST or did not return for reading. Superscript numerals denote reference numbers MENZIES et al: UPDATE IN TREATMENT OF LATENT TB 263 of disease in close contacts who are TST positive . Table IV. Protection of INH against development of active TB in IT was also found that the relative risk of disease HIv infected individuals who were TST positive or TST Negative (from placebo controlled trials) in IGRA positive compared to IGRA negative was similar to the relative risk of disease in TST positive Studies Year Country Risk reduction compared to placebo vs. TST negative. From this one can infer that benefit of INH will be found only in those who are initially Among TST Among TST positive negative IGRA positive. However, this extrapolation needs to persons % persons be confirmed by evidence from studies specifically (range) addressing this issue. Pape et al 1993 Haiti 76 (0-94) 30 (0-85) In summary, LTBI treatment is beneficial only in Whalen et al 1997 Uganda 70 (32-87) 26 (0-70) patients with a positive test for LTBI. It is important Hawken et al 1997 Kenya 40 (0 - 77) 0 (0 - 45) to remember that these studies were all conducted 62 Mwinga et al 1998 Zambia 72 (0-93) 18 (0 - 70) in settings with high TB incidence, and therefore 65 Pooled 2010 All 60 ( 35-76) 16 (0 - 40) 38 ** presumed high levels of TB exposure and transmission. Samandari et al 2009 Botswana 90 (N/A) 14 (N/A) In addition, all study populations were HIv infected – Pooled risk reduction from systematic review and meta-analysis 63 64 ** and most had no access to anti-retroviral therapy. Hence of the above 4 studies plus Gordin et al and Garcia et al ; The we can assume they were very likely to have been Botswana trial compared rate of reduction with 36 months INH vs. 6 months INH in HIv infected persons who were initially TST immune suppressed. Therefore, these results should be positive or TST negative, Hence the placebo control was given considered highly relevant in low and middle income from month 7 to 36; both groups received INH for the first 6 countries - TST negative persons should be given months. Superscript numerals denote reference numbers LTBI treatment only in exceptional circumstances. The one exception is in the situation of recent exposure. Table V. Comparison of treatment of hypertension vs. treatment Following TB exposure and primary infection cell- of latent TB mediated immunity will develop only after several Latent TB infection Hypertension weeks. In close contacts who are initially TST • Asymptomatic condition • Asymptomatic condition • v ery serious complications • v ery serious complications negative it is recommended that a second TST should – Death – Death, be performed eight weeks after the end of exposure. – Major disability – Major disability By this time all tuberculin conversions would have – AND transmission occurred . In individuals at very high risk of rapidly • Treatment is for years • Treatment is max 9 developing active disease, such as very young children months (under 5), or HIv infected it is prudent to give INH – Expensive medications – Cheap medications – Potential serious – Potential serious side while awaiting the results of the second TST. side effects effects Conclusion: Why is there a debate about treating – Requires close monitoring – Requires close LTBI? and follow up monitoring and follow up Despite clear evidence of benefits of LTBI therapy • WHY the debate about • BUT – no debate about Treating in persons with a positive TST and increased risk of re- Treating?? activation, treatment of LTBI remains controversial. The reasons for the controversy may be the history of As summarized (Table v ) there are many parallels repeated cycles of enthusiastic recommendations of between treatment of LTBI and treatment of hypertension. new regimens, followed by imprudent application of Hypertension is also an asymptomatic condition with therapy, followed by disastrous adverse events (INH serious complications that can cause substantial morbidity in 1971 and 2RZ in 2000). The controversy is further and mortality, yet these can be successfully prevented fuelled by studies documenting poor performance with medication. In contrast to LTBI treatment, these of programmes, leading many to conclude that medications must be taken for many years, and many the therapy is sub-optimal, rather than concluding are quite expensive. Treatment of hypertension is also that the programmes were suboptimal. Apparently associated with unpleasant side effects. 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The Cochrane environmental measures in reducing potentially infectious Library 1. 2010. bioaerosols during sputum induction. Infect Control Hosp Epidemiol 2003; 24 : 483-9. 66. Rangaka MX, Wilkinson KA, Glynn JR, Ling D, Mwansa J, Menzies D, et al. Predictive value of interferon release assays 70. Jasmer RM, Saukkonen JJ, Blumberg HM, Daley CL, for incident active tuberculoasis: A systematic review. PLos Bernardo J, v ittinghoff E, et al. Short-course rifampin and one in Press 2010. pyrazinamide compared with isoniazid for latent tuberculosis 67. Menzies D. Interpretation of repeated tuberculin tests. infection: a multicenter clinical trial. Ann Intern Med 2002; Boosting, conversion, and reversion. Am J respir Crit Care 137 : 640-7. Med 1999; 159 : 15-21. 71. Haley CA, Stephan S, Vossel LF, Sherfy E.A., Laserson KF, 68. Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Kainer MA. Successful use of rifampicin for Hispanic foreign- Nolan CM, et al. An official ATS statement: hepatotoxicity of born patients with latent tuberculosis infection. Int J Tuberc antituberculosis therapy. Am J respir Crit Care Med 2006; Lung Dis 2008: 12 : 160-7. 174 : 935-52. reprint requests : Dr Dick Menzies, 3650 St. Urbain Rm k1.24, Montreal, Quebec, H2X 2P4, Canada e-mail: dick.menzies@mcgill.ca http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Indian Journal of Medical Research Pubmed Central

Recent developments in treatment of latent tuberculosis infection

The Indian Journal of Medical Research , Volume 133 (3) – Mar 1, 2011

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Review Article Indian J Med Res 133, March 2011, pp 257-266 Dick Menzies, Hamdan Al Jahdali & Badriah Al Otaibi Montreal Chest Institute, McGill University, Montreal, Quebec, Canada Received December 24, 2010 Latent tuberculosis infection (LTBI) can be detected with immune based tests such as the tuberculin skin test (TST) or interferon gamma release assays (IGRA). Therapy for those with positive tests can reduce the subsequent risk of re-activation and development of active TB. Current standard therapy is isoniazid (INH) which reduce the risk of active TB by as much as 90 per cent if taken daily for 9 months. However, this lengthy duration of therapy discourages patients, and the risk of serious adverse events such as hepatotoxicity, discourages both patients and providers. As a result completion of INH therapy is less than 50 per cent in many programmes. However, programmes that offer close follow up with supportive staff who emphasize patient education, have reported much better results. The problems with INH have stimulated development and evaluation of several shorter regimens. One alternative was two months daily rifampin and pyrazinamide; this regimen has been largely abandoned due to unacceptably high rates of hepatotoxicity and poor tolerability. The combination of INH and rifampin, taken for 3 or 4 months, has efficacy equivalent to 6 months INH albeit with somewhat increased hepatotoxicity. Four months rifampin has efficacy at least equivalent to 6 months INH but there are inadequate trial data on efficacy. The safety of this regimen has been demonstrated repeatedly. Most recently, a regimen of 3 months INH rifapentine taken once weekly under direct observation has been evaluated in a large scale trial. Results have not yet been published, but if this regimen is as effective as INH, this may be a very good alternative. However, close monitoring and surveillance is strongly suggested for the first few years after its introduction. Evidence from several randomized trials has shown that the benefits of LTBI therapy is only in individuals who are tuberculin skin test (TST) positive even among those with HIV infection. Hence, LTBI therapy should be given only to those with positive tests for LTBI. We conclude that LTBI therapy is considerably underutilized in many settings, particularly in low and middle income countries. Key words Latent tuberculosis - tuberculosis - tuberculosis infection - tuberculosis prevention - tuberculosis treatment develop active TB during their lifetime . More than Introduction 80 per cent of these will be contagious and transmit It has been estimated by the World Health TB infection to others, perpetuating the cycle of TB Organization (WHO) that more than one third of the and resulting in continued morbidity and mortality entire world’s population, or approximately 2 billion from TB for generations to come . The impact of persons are infected and can be considered carriers TB is even greater than these numbers may suggest, of TB. From this vast pool of persons with latent as 75 per cent of individuals with TB are within the TB infection (LTBI) approximately 200 million will economically productive age group of 15-54 yr , and 257 258 INDIAN J MED RES, MARCH 2011 TB disproportionately affects low and middle income However, INH treatment of LTBI is problematic countries, as 95 per cent of all cases and 99 per cent of for several reasons. The lengthy duration of treatment 2 6-8 all deaths occur in these countries . reduces patient compliance , while the potential occurrence of serious adverse events such as hepatitis, Two approaches can be taken to reduce the burden further discourages patients’ and providers’ acceptance of TB over the long term. One approach requires early 9,10 of this therapy . As a result there has been considerable and rapid diagnosis of all persons with active TB with interest and many evaluations of alternative shorter institution of effective therapy to render them non regimens. This work continues even today. contagious. This will reduce transmission, reducing the number of carriers, who will later develop active The objectives of the present article are to (i) TB. However, WHO has estimated that less than 50 review the evidence from systematic reviews and per cent of all cases globally are currently diagnosed recent trials of efficacy, completion, and adverse effects and treated . Since each person with undiagnosed and of several commonly used regimens for treatment of untreated active TB will survive an average of 2 yr, LTBI; (ii) review risk-benefit and other considerations it has been estimated that they will infect 20 others . for treatment of LTBI in high income, as well as An additional problem is that most patients in high low and middle income countries; and (iii) review incidence settings are diagnosed by direct smear the indications for tuberculin testing (or use of other microscopy of unconcentrated sputum specimens , methods of diagnosis of LTBI) prior to starting LTBI which only detects patients with advanced disease. treatment. Hence, significant transmission can occur prior to Regimens for treatment of LTBI diagnosis . 6 Months INH (6INH) An alternate approach is to detect persons while Numerous trials have evaluated different durations they still have LTBI and treat them to prevent the later development of disease. This approach dates back to of INH However, only one clinical trial has directly compared regimens of different durations of INH. the 1950s. Soon after isoniazid (INH) was introduced as an effective agent to treat disease, clinicians noted that The International Unit Against Tuberculosis (IUAT) trial, conducted in Eastern Europe, randomized INH monotherapy effectively prevented development of disease in children with primary TB . Following approximately 28,000 individuals with positive tuberculin skin tests (TST) and fibronodular changes on this clinical observation, more than 20 randomized trials, involving more than 100,000 participants, were chest X-ray . Approximately 7,000 participants each were randomized to placebo, 3, 6 or 12 months of INH conducted in more than a dozen countries . These studies demonstrated that INH taken for at least 6 (Table I). Compliance was assessed with monthly pill counts. Compared to participants who took placebo, months in persons with LTBI reduced subsequent TB incidence by 25 to 92 per cent. The differences in participants who completed 3 months INH had 31 per cent reduction in TB; this effect waned over the 5 years effectiveness found in different studies were largely explained by differences in treatment completion . of follow up. Participants who completed 6 months Table I. Summary of LTBI regimens in common use Regimen Efficacy Completion of therapy Serious adverse events (relative to placebo)# Type Rate 12 6,8,54 23,68 INH: 6 months 69% 50% Hepatitis 1 -5% 12,17 31,33,34,69 23,31,34,68 INH: 9-12 months 90 – 93% <50% Hepatitis 1 -5% 27,63 *27 27,68,70 RIF&PZA: 2 months Equal to 6 -12INH 6% > 6-12INH Hepatitis 3 -5% 30,36 **36 36,37 INH&RIF: 3-4 months Equal to 6INH 6% > 6-12INH Hepatitis† 1 – 5% ##30 ***31-34,71 31,34 RIF: 3-4 months 65% 22% > 9INH Rash 1- 2% 31,32,34 Hepatitis <1% Superscript numerals denote reference nos.; INH, isoniazid, 6 INH, 6 months isoniazid; 6-12 INH, 6-12 months INH; PZA, Pyrazinamide; RIF, Rifampins; Efficacy from placebo randomized trials. If trials were not placebo controlled then efficacy relative to INH is given; ## * Based on one placebo-controlled trial with 3 months rifampin (30); Average 6% (range: -5 to 19%) better completion than with 6-12INH; ** *** Average 6% (range: 3 to 12%) better completion than with 6–12INH; Average 22% (range: 18 to 27%) better completion than with 9INH; Hepatitis more frequent with INH&RIF than INH alone (37); Figures in parentheses denote Ref numbers MENZIES et al: UPDATE IN TREATMENT OF LATENT TB 259 INH had 69 per cent reduction of active TB, while Society (ATS) in 1971, the potential for adverse effects subjects who completed 12 months INH (12INH) had was considered minimal, and this treatment was strongly recommended for TST reactors of all ages . With the 93 per cent reduction in TB. The efficacy of 6INH and 12INH waned during the 5 yr of followup but always ensuing much greater use, serious hepatotoxicity causing 12 22 deaths was described . Subsequent surveillance studies remained significantly better than placebo . However, confirmed that hepatotoxicity was quite common in completion of the 12 month regimen was much less patients taking INH, and could be severe, with up to 1 than the 6 month regimen. per cent mortality in older patients . Subsequently INH Based on these results, and assuming that under 24,25 related mortality has declined over the last 30 yr – programme conditions completion of longer regimens presumably related to better selection of patients for would be equally poor, if not worse, many authoritative therapy and closer follow up. agencies have recommended 6INH as an acceptable 13,14 15 2 Months rifampin –pyrazinamide (2RZ) alternative to 12INH . Snider and colleagues estimated that 6INH would be more cost-effective Studies of latent TB infection in a mouse model than 12INH. This reflects the fact that the majority of revealed that 2 months of treatment with a combination costs of LTBI therapy is related to the initial screening, of rifampin and pyrazinamide (PZA) resulted in subsequent medical evaluation and start of therapy . complete clearance of TB bacilli - a bacteriologic However, it is important to remember that in patients effect comparable to that achieved with 6 months INH who take therapy properly, 12INH is significantly and in the same mouse model. Following publication of substantially more efficacious than 6INH. 26 these results in 1989 , several randomized trials were conducted to compare 6 to 12 months INH with 2RZ 9 Months INH (9INH) in HIv infected patients . These trials demonstrated Concerns regarding the relatively low efficacy of equivalent efficacy; however, since most compared 2Rz 6INH, and equally serious concerns regarding the poor to 6INH this would indicate that efficacy of 2Rz was completion of 12INH resulted in recommendations likely less than the ideal achieved with 9INH. Serious for 9 months INH by the American Thoracic Society adverse events were not more frequent with 2RZ than in 2000 . This recommendation was based almost with INH in these trials. However, completion of 2RZ entirely upon a re-analysis by Dr George Comstock was not significantly better than completion of 6INH in of data from several INH trials among Alaskan Inuit several of these trials, despite the shorter duration . In populations . This re-analysis demonstrated that retrospect, this may have been a harbinger of events to the optimal duration of INH was 9 months, with come. estimated efficacy of 90 per cent and no significant In 2000, based on these promising trial results, gain with extension to 12 months. Hence, 9INH was the American Thoracic Society recommended use of recommended as the standard of care by the American 2RZ . This was a strong recommendation for use in Thoracic Society in 2000 , and other authorities HIv infected persons, and a conditional (or weak) followed suit soon after . recommendation for non-HIv infected persons. Completion of 9INH under programme conditions Publication of these recommendations was quickly is poor. Many programmes report less than 50 per followed by rapid, enthusiastic and widespread use of cent completion although a few programmes report 2RZ. In turn this was quickly followed by reports of 18,19 much higher completion rates . These programmes serious hepatotoxicity and death . Subsequent trials in emphasize initial intensive patient education, with non HIv infected individuals revealed very high rates of subsequent close follow up, and patient support; they grade 3 to 4 hepatotoxicity, which sometimes occurred demonstrate that many patients can be motivated to at the end or even after completion of therapy . As a complete 9 months therapy. result recommendations were revised that 2RZ should be used with caution in HIV infected and extreme However, INH has the major disadvantage of caution in non HIv infected . potential serious adverse events. Of particular concern is hepatotoxicity, as this is difc fi ult to detect, and can Our current practice is to consider use of this regimen in HIv infected individuals in situations be fatal. Interestingly in the randomized trials conducted up to 1970 this problem had not been noted . Hence where close supervision and monitoring is possible and longer therapy LTBI regimens may be impractical. We when INH was recommended by the American Thoracic 260 INDIAN J MED RES, MARCH 2011 do not recommend this regimen in non-HIv infected A series of randomized trials , have demonstrated persons. that the efficacy of 3-4INH-RIF is equivalent to that of 6INH (4 studies) or 9INH (1 study) although 4 Months rifampin (4RIF) adverse events are significantly more frequent . This An overlooked finding in the same study of treatment latter finding is not that surprising, since the majority of latent LTBI in mice was that rifampin alone for 2 of hepatotoxic adverse events with INH occur in the 34,38 months was equally efficacious as 2Rz, or 2 months of first 2-3 months . Therefore adding INH to rifampin rifampin plus- INH . Complete bacteriologic clearing for 3 or 4 months will inevitably increase the risk of adverse events. However, the benefits of adding the had occurred in all TB infected mice by the end of two months mono-RIF therapy. Unfortunately, despite this INH to RIF are unclear. In theory, therapy with two agents will provide a margin of safety if the person has very promising evidence, only one randomized trial has evaluated a regimen of rifampin alone. In this trial, minimal active TB rather than true latent TB infection. There is no evidence of improved efficacy compared to older men living in Hong Kong, who had pulmonary RIF alone, and to justify LTBI therapy on the basis of silicosis with a positive TST were randomized to potential misdiagnosis of active TB as latent TB seems placebo, 6INH, 3 months INH plus Rifampin, or a fairly weak rationale for this regimen. 3 months Rifampin alone . During five years of follow up, 27 per cent of those randomized to placebo New regimens developed active TB, compared to 16, 13, and 10 per A trial comparing 9INH with 3 months of once cent for the three regimens respectively. The estimated weekly directly observed INH combined with effectiveness of 3 months rifampin was approximately rifapentine (3INH-RPT) has just been completed. 65 per cent; this was better than the other regimens Rifapentine is a rifamycin with half life that is 5 times although the differences between active regimens was longer than rifampin - allowing once weekly therapy. not significant, and all were significantly better than More than 8,000 participants were randomized. placebo . To date, there are no other published trial Completion of 3INH-RPT was 84 per cent, compared evaluating mono-RIF therapy. However, a large scale to 71 per cent completing 9INH. Efficacy and safety trial comparing the effectiveness and efficacy of 4RIF data are still being analyzed, but results are expected and 9INH is ongoing. soon. If these are acceptable, this may be an excellent Several studies have reported that completion alternative regimen. However, the requirements for rates with 4RIF are substantially and significantly directly observed preventive therapy may make this 31-34 better than with 9INH . In addition, rates of serious impractical in some settings. adverse events with 4RIF are very low, particularly 31 In addition, the experience with INH in 1970, and rates of hepatotoxicity . In a recently published the 2RZ regimen in 2000 should provide a cautionary randomized trial rates of grade 3 to 4 adverse events note for implementation of this new regimen. For were significantly lower with 4RIF than 9INH. Grade both of these regimens the potential for serious and 3-4 hepatotoxicity occurred in 4 per cent of patients even fatal adverse events was not detected in multiple taking 9INH compared to less than 1 per cent in those 34 randomized trials. The serious hepatotoxicity of both taking 4RIF . The earlier results in the Hong Kong regimens was only recognized after these had been silicosis trial suggest that 4RIF should have efficacy 30 recommended and implemented widely in routine of at least 65 per cent - equivalent to the documented practice. Rifapentine is a relatively new and untested efficacy of 6INH. drug. Hence this drug may cause unexpected adverse In summary, 4RIF appears to be well tolerated, has events that were not detected in the randomized trial. excellent completion and a very good safety record. Given the long half life of this drug the adverse events However, 4RIF cannot be recommended for routine may progress even after treatment is stopped, resulting use until the results of the efficacy trial are available. in more serious sequelae. Hence, introduction of this new regimen should be accompanied by careful 3 to 4 Months of INH and RIF (3-4INH-RIF) monitoring and evaluation of adverse events. The animal study described earlier suggested that Drug-resistant LTBI INH and RIF for 2 months was effective in the mouse model. Uncontrolled trials in paediatric populations Treatment of close contacts of drug resistant active have suggested that this regimen should be adequate . cases is difficult and yet is an increasingly common MENZIES et al: UPDATE IN TREATMENT OF LATENT TB 261 clinical problem. For contacts of INH resistant In high income settings, the costs are not index cases, INH will be ineffective , so 4RIF is as determinant of LTBI therapy as risk-benefit 13,14 recommended . Contacts of index cases with MDR considerations. After realization that serious adverse TB are recommended to receive 6 months of PZA and events and even deaths could occur with INH, several a quinolone . However, two observational studies investigators performed decision analyses to estimate have reported very high rates of toxicity and extremely the risks and benefits of INH therapy. As shown in Table 40,41 poor completion due to intolerance . In both series II, the majority of these studies examined the risks and no patients actually completed the proposed 6 month benefits of treatment with INH in healthy individuals course of therapy. Based on this and our own clinical with a positive tuberculin skin test but no other risk experience which was similar, our current practice factors. In these individuals the benefits of INH therapy is to give moxifloxacin or levofloxacin alone for 6 are low because the life-time risk of development months. The rationale for this monotherapy is the of active TB is low. Therefore, the benefits barely published evidence that moxifloxacin can replace INH exceeded the risks. And, because of slightly different in treatment of active TB . assumptions made by the different investigators, INH therapy was found to result in small net gains or losses Consideration for use in different settings of life expectancy. However, the absolute differences 44-48 Over the past 30-40 yr treatment of LTBI has been a in findings between these studies were very small . major priority for TB control programmes in many high Despite this, the authors concluded, often very strongly, income countries such as Canada, U.S.A., Australia or that 9INH was good, or was bad. These apparently Saudi Arabia. However, LTBI diagnosis and treatment contradictory findings resulted in greater confusion has been a low priority for TB control programmes in about benefits of, and indications for, treatment of LTBI. most low and middle income countries (LMIC). This These may have contributed to the chronic underuse of ree fl cts the cost and resources required for effective and LTBI treatment. Risk-benefit analyses of INH therapy in 49,50 19 safe treatment of LTBI, given the need for close follow HIv infected individuals or other high risk groups up and monitoring to detect serious adverse events and have estimated much greater, and consistent benefits. to encourage and monitor compliance with therapy. Until These analyses support current recommendations to an LTBI regimen is found that is perfectly safe and very test and treat LTBI only in individuals with high risk of 13,14 easy to take, these resource requirements will be present. reactivation to disease, if infected . Medication costs are low, but micro costing studies have There are many factors that increase the risk shown that medications account for less than 10 per of re-activation. In view of this complexity, a web 16,43 cent of total resources used . Nevertheless therapy based algorithm has been developed which may of individuals with LTBI and important risk factors for provide some assistance in estimating that risk . This reactivation such as HIv co-infection, or close contacts algorithm, (available at www.tstin3d.com) incorporates is warranted in all settings as this therapy provides information on age, TST or interferon gamma release significant individual benefits, and is much more cost- assay (IGRA) results, country of birth, ethnic origin effective. Table II. Risk benefit studies of INH for tuberculin reactors Study Year Age group Preferred Margin of benefit* (yr) (INH or Not) (days) Low risk reactors Rose et al 1986 10-80 INH 1- 16 Tsevat 1988 20-80 No INH 4-17 Colice 1990 30 INH 3-19 Jordan et al 1991 20-35 INH 3-19 50 No INH 2-33 Salpeter et al 1997 35-70 INH 3-5 High risk reactors (HIv infected) Jordan et al 1991 20-60 INH 285 Rose 1998 Adults INH 254 Margin: means gain or loss of life expected with INH treatment, relative to no treatment. Superscript numerals denote reference numbers 262 INDIAN J MED RES, MARCH 2011 and clinical risk factors including chest radiographic therapy because tuberculin testing is not commonly findings. This information is entered and the algorithm performed. In some LMIC the tuberculin material itself calculates the likelihood of true latent infection, as (i.e., the PPD) is not available. In addition, WHO has well as the annual and cumulative life time risk of recommended that LTBI therapy can be given without development of active TB. performing a TST . One important consideration for any programme This question has been addressed in several for screening and treatment for LTBI is its potential randomized trials and in one systematic review. In public health impact. This is of particular interest in these trials INH therapy was compared to placebo in LMIC given the resource implications of initiating such HIv infected patients who had initial TST, but were a programme. As seen in Table III, several studies have randomized to active therapy or placebo regardless of described the impact of LTBI screening and treatment 59-64 TST results . There is convincing evidence, (Table 16,43,52,57 programmes in many different settings . In all IV) that a positive TST predicts benefit from INH these studies, the public health impact was very low. This therapy. INH therapy is of minimal and non-significant is because patients did not participate in initial screening benefit in HIV infected persons who are initially or failed to come for reading of tuberculin results, or TST negative. Based on the systematic review of the did not report for medical evaluation of positive tests. earlier trials in HIv infected INH provides 60 per cent In addition physicians were non-compliant with protection against disease in TST positive, but only 16 recommendations to prescribe treatment, and then per cent benefit in TST negative persons . patients refused to start LTBI therapy, or they were non-compliant if they did start. As a result, in all these A trial just completed in Botswana confirmed studies fewer than 40 per cent of patients who could these findings. In this trial HIV infected patients were have benefited from LTBI therapy actually did so; in randomized to 6 or 36 months of INH. In those who some studies as few as 10 per cent with presumed LTBI were initially TST positive, 36 months INH resulted derived any benefit. If LTBI screening and treatment is in 92 per cent reduction in TB disease relative to being considered, then a great deal of attention must those who received only 6 months INH. However, be paid to ensure that every stage of the programme is participants who were initially TST negative had only well organized, in order to enhance the public health a 14 per cent reduction in TB disease with 36 months benefit of this approach. INH, compared to 6INH - a reduction that was not statistically significant . Is testing for latent TB infection required before latent TB treatment? To date, no trials have addressed this question in IGRA positive and IGRA negative individuals. A A common clinical question is whether a TST or an recent systematic review found that the risk of disease IGRA is needed prior to giving LTBI therapy. This is in IGRA positive close contacts was similar to the rate particularly important in LMIC that are initiating LTBI Table III. True impact of large scale screening programmes Country Total TST positive Medically Started INH Completed INH evaluated screened (N) (N) (N) Of all positive Of all screened (N) with TST (N) TST (%) (%) Canada 19,001 4,292 814 452 11 2 USA 4,840 2,039 1,528 853 716 35 15 Canada 720 162 142 56 52 13 7 Canada 33,146 7,668 2,600 1589 21 5 16* Canada 3,300 1,598 647 347 251 31 18 USA 66,767 12,901 9,018 5746 37 9 Canada 7,669 782 525 293 140 13 2 57 * Uganda 9,862 5227 579 520 322 6 3 In some studies the number of studies of TST positive is calculated based upon the expected number of TST positive in the original populations screened, because individuals did not accept TST or did not return for reading. Superscript numerals denote reference numbers MENZIES et al: UPDATE IN TREATMENT OF LATENT TB 263 of disease in close contacts who are TST positive . Table IV. Protection of INH against development of active TB in IT was also found that the relative risk of disease HIv infected individuals who were TST positive or TST Negative (from placebo controlled trials) in IGRA positive compared to IGRA negative was similar to the relative risk of disease in TST positive Studies Year Country Risk reduction compared to placebo vs. TST negative. From this one can infer that benefit of INH will be found only in those who are initially Among TST Among TST positive negative IGRA positive. However, this extrapolation needs to persons % persons be confirmed by evidence from studies specifically (range) addressing this issue. Pape et al 1993 Haiti 76 (0-94) 30 (0-85) In summary, LTBI treatment is beneficial only in Whalen et al 1997 Uganda 70 (32-87) 26 (0-70) patients with a positive test for LTBI. It is important Hawken et al 1997 Kenya 40 (0 - 77) 0 (0 - 45) to remember that these studies were all conducted 62 Mwinga et al 1998 Zambia 72 (0-93) 18 (0 - 70) in settings with high TB incidence, and therefore 65 Pooled 2010 All 60 ( 35-76) 16 (0 - 40) 38 ** presumed high levels of TB exposure and transmission. Samandari et al 2009 Botswana 90 (N/A) 14 (N/A) In addition, all study populations were HIv infected – Pooled risk reduction from systematic review and meta-analysis 63 64 ** and most had no access to anti-retroviral therapy. Hence of the above 4 studies plus Gordin et al and Garcia et al ; The we can assume they were very likely to have been Botswana trial compared rate of reduction with 36 months INH vs. 6 months INH in HIv infected persons who were initially TST immune suppressed. Therefore, these results should be positive or TST negative, Hence the placebo control was given considered highly relevant in low and middle income from month 7 to 36; both groups received INH for the first 6 countries - TST negative persons should be given months. Superscript numerals denote reference numbers LTBI treatment only in exceptional circumstances. The one exception is in the situation of recent exposure. Table V. Comparison of treatment of hypertension vs. treatment Following TB exposure and primary infection cell- of latent TB mediated immunity will develop only after several Latent TB infection Hypertension weeks. In close contacts who are initially TST • Asymptomatic condition • Asymptomatic condition • v ery serious complications • v ery serious complications negative it is recommended that a second TST should – Death – Death, be performed eight weeks after the end of exposure. – Major disability – Major disability By this time all tuberculin conversions would have – AND transmission occurred . In individuals at very high risk of rapidly • Treatment is for years • Treatment is max 9 developing active disease, such as very young children months (under 5), or HIv infected it is prudent to give INH – Expensive medications – Cheap medications – Potential serious – Potential serious side while awaiting the results of the second TST. side effects effects Conclusion: Why is there a debate about treating – Requires close monitoring – Requires close LTBI? and follow up monitoring and follow up Despite clear evidence of benefits of LTBI therapy • WHY the debate about • BUT – no debate about Treating in persons with a positive TST and increased risk of re- Treating?? activation, treatment of LTBI remains controversial. The reasons for the controversy may be the history of As summarized (Table v ) there are many parallels repeated cycles of enthusiastic recommendations of between treatment of LTBI and treatment of hypertension. new regimens, followed by imprudent application of Hypertension is also an asymptomatic condition with therapy, followed by disastrous adverse events (INH serious complications that can cause substantial morbidity in 1971 and 2RZ in 2000). The controversy is further and mortality, yet these can be successfully prevented fuelled by studies documenting poor performance with medication. In contrast to LTBI treatment, these of programmes, leading many to conclude that medications must be taken for many years, and many the therapy is sub-optimal, rather than concluding are quite expensive. Treatment of hypertension is also that the programmes were suboptimal. Apparently associated with unpleasant side effects. 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Published: Mar 1, 2011

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