4. Diagnosis of LTBI

Prior to putting people on chemoprophylaxis for LTBI, active TB has to be first excluded by standard case finding methods. Latent tuberculosis infection (LTBI) is most often diagnosed by the tuberculin skin test (TST), and the Mantoux TST is the standard method of determining Mycobacterium tuberculosis infection. This test is performed by injecting 0.1 ml of tuberculin purified protein derivative (PPD) (equivalent to 1 TU of PPD RT 23 or 2.5 TU of PPD- S) into the inner surface of the forearm. In India, PPD-RT 23 with Tween 80 of strength 1 TU and 2 TU are standardized tuberculins available which is supplied by the Bacillus Calmette-Guérin (BCG) vaccine Laboratory, Guindy, Chennai. CDC recommended strength is 5 TU of PPD-S. The injection is given intradermally with a tuberculin syringe, with the needle bevel facing upward. The injection should produce a pale wheal 6–10 mm in diameter and the skin test reaction should be read between 48 and 72 hours after administration. The reaction should be measured in millimeters of the induration (palpable, raised, hardened area or swelling) across the forearm (perpendicular to the long axis) and not the erythema (redness).


Classification of positive TST results

In interpreting a positive TST, it is important to consider much more than only the size of the induration. Rather, the TST should be considered according to three dimensions: size of induration, pre-test probability of infection and risk of disease if the person were truly infected [14]. There are two important causes of false-positive results: nontuberculous mycobacterial (NTM) infection and prior BCG vaccination [15]. NTMs are not a clinically important cause of falsepositive TST results, except in populations with a high prevalence of NTM sensitization and a very low prevalence of TB infection [15]. The impact of BCG on TST specificity depends on when BCG is given and on how many doses are administered. If BCG is administered at birth or infancy and not repeated, then its impact on TST specificity is minimal and can be ignored while interpreting the results [15]. In contrast, if BCG is given after infancy (e.g., school entry) and/or given multiple times (i.e., booster shots), then TST specificity is compromised [15].

gamma + CD 8+ T cells [10–12]. Other mechanisms include suppression of cell-mediated responses of regulatory T cells (Tregs) and impairment of TNF-α- mediated apoptosis of Mtb-infected

Prior to putting people on chemoprophylaxis for LTBI, active TB has to be first excluded by standard case finding methods. Latent tuberculosis infection (LTBI) is most often diagnosed by the tuberculin skin test (TST), and the Mantoux TST is the standard method of determining Mycobacterium tuberculosis infection. This test is performed by injecting 0.1 ml of tuberculin purified protein derivative (PPD) (equivalent to 1 TU of PPD RT 23 or 2.5 TU of PPD- S) into the inner surface of the forearm. In India, PPD-RT 23 with Tween 80 of strength 1 TU and 2 TU are standardized tuberculins available which is supplied by the Bacillus Calmette-Guérin (BCG) vaccine Laboratory, Guindy, Chennai. CDC recommended strength is 5 TU of PPD-S. The injection is given intradermally with a tuberculin syringe, with the needle bevel facing upward. The injection should produce a pale wheal 6–10 mm in diameter and the skin test reaction should be read between 48 and 72 hours after administration. The reaction should be measured in millimeters of the induration (palpable, raised, hardened area or swelling) across

the forearm (perpendicular to the long axis) and not the erythema (redness).

≥5 mm ≥10 mm ≥15 mm

• Recent immigrants (<5 years) from highprevalence countries • Injection drug users • Residents and

gories

In interpreting a positive TST, it is important to consider much more than only the size of the induration. Rather, the TST should be considered according to three dimensions: size of induration, pre-test probability of infection and risk of disease if the person were truly infected [14].

employees of high-risk congregate settings • Mycobacteriology laboratory personnel • Persons with clinical conditions that place them at high risk • Children <4 years of age • Infants, children, and adolescents exposed to adults in high-risk cateAny person, including persons with no known risk factors for TB

cells [13].

Induration size/Patient profile

4. Diagnosis of LTBI

172 Advances in HIV and AIDS Control

Classification of positive TST results

HIV-infected persons

ease

• A recent contact of a person with TB dis-

• Persons with fibrotic changes on chest radiograph consistent with prior TB • Patients with organ transplants • Persons who are immunosuppressed for other reasons (e.g., taking the equivalent of >15 mg/day of prednisone for 1 month or longer, taking TNF- alpha antagonists) Tuberculin skin tests are subject to variability when repeated tuberculin tests are given. Chance variation should result in differences of less than 6 mm (representing two standard deviations) in 95% of subjects. This supports the adoption of 6 mm as a criterion to distinguish increases in reaction size due to random variation alone from true biologic phenomena, which could be either conversion or boosting [16]. Boosting is best distinguished from conversion on clinical grounds. One can attribute an increase in reaction size to boosting when the increase in reaction is seen after an interval of 1–5 weeks during which there has been no possibility of exposure, such as pre-employment testing of a health care worker [16]. Conversion can be confidently stated to have occurred when a previously tuberculin-negative individual becomes tuberculin test positive after receiving BCG vaccination, or following significant exposure such as during an outbreak or as a result of close contact with a highly contagious index case [17, 18]. Among subjects vaccinated in infancy, and tested after an interval of 5 years or more, prevalence of initial tuberculin reactions is the same in vaccinated and unvaccinated reference populations but prevalence of boosting was 7% higher in vaccinated than unvaccinated [19].

The other method of detecting LTBI is based on IFNγ release assays (IGRA). These tests detect a set of Mtb genes that are present in Mtb complex but not present in BCG immunized or in a setting of NTM infection. In this test, the sera of patients is incubated with Mtb specific T lymphocytes. The T cells respond to Mtb-specific gene products by secretion of proinflammatory cytokines that are detected. Two IGRAs are commercially available today. QuantiFERON-Gold In Tube test (QFT; Germany) uses whole blood and is ELISA based. The T-SPOT.TB test (Oxford Immunotec, Abingdon, UK) uses peripheral blood mononucleated cell (PBMC) and ELISPOT technique. Both IGRAs incorporate the region of difference 1 (RD1) encoded 6 kDa early secretory antigenic target (ESAT-6) and 10 kDa culture filtrate protein (CFP10) antigens, whereas an additional single peptide from TB7.7, encoded in RD11, is added to the QFT [20]. The selections of antigens for these tests are critical. Natural immunity to M. tuberculosis is highly individual, multi-epitopic and multiantigenic, and more than 80 antigens are necessary to capture 80% of the MTB-specific T-cell response [21]. The currently used antigens ESAT-6, CFP10 and TB7.7 were selected for their high immunogenicity and specificity for M. tuberculosis infection, not for their predictive potential. ESAT-6 is considered among the most immunogenic proteins, but it has a drawback when used to detect LTBI. It is secreted through the entire spectrum of latency and also in active stages of the infection. Therefore, disease stage-specific diagnosis is impossible using ESAT-6 [22].

Various studies have evaluated the utility of IGRAs and TST. A study from Turkey published in 2007 seems relevant to countries like India as Turkey is also a country with high prevalence of TB and high BCG vaccination coverage [23]. The workers compared TST with QuantiFERON®-TB in three population groups: household contacts of smear-positive TB cases, community members who had been exposed to index smear-positive TB cases and healthcare workers dealing with TB cases or handling TB specimens. They did a Kappa analysis to look for agreement between the tests. They found that QuantiFERON®-TB values were higher in the first group of patients when compared to the other two groups. In case of TST, there was no difference among the three groups. Evaluation for agreement rates between the groups showed poor agreement in all three groups. The authors concluded that while Quantiferon Gold was more objective, practical and gave quantitative values, it was more expensive and required a wellequipped laboratory and thus did not have a programmatic role in detection of LTBI in a country will high TB prevalence and high BCG coverage [23].

of existing LTBI tests, LTBI screening should be reserved only for those who are at sufficiently high risk of progressing to disease. The recommendations for systematic testing for LTBI as per

Population groups Test Quality of recommendation

In the long term, highly predictive biomarkers need to be identified. This is an active area of research, and future generations of LTBI tests should overcome the limitations of current assays. A great endeavor is on to discover reliable, low-cost biomarkers. Gene signatures can distinguish between active and latent TB [32]. A lot of works have been done to identify differential expression of cytokines and chemokines in active TB and LTBI. It has been shown that plasma levels of the CXC chemokine IP-10 and soluble TNF receptor type 2 (sTNFr2) can significantly differentiate active TB from the LTBI group, irrespective of HIV status [33]. Another study showed that serum IL-2, IL-9, IL-13, IL-17, TNF-α, sCD40L and VEGF-A levels may be adjunctive biomarkers for differential diagnosis of active TB, LTBI, and NTM disease [34]. Assessment of serum sCD40L and Mtb antigen-specific IFN-γ, TNF-α, and IL-2 levels could also help predict successful anti-TB treatment in conjunction with Mtb clearance [31]. Achkar et al. looked at biomarkers to distinguish active TB and LTBI from no TB infection in HIV positive and negative populations [35]. They did so because inflammatory response and repair are both blunted in PLHA. They identified a set of biomarkers which reliably predict

Treatment of LTBI reduces the risk for active disease and hence various authorities have recommended treatment for this entity. Chemoprophylaxis for LTBI can prevent 60–90% of

IGRA/ TST

Latent Tuberculosis Infection: Patho-Biology and Treatment

http://dx.doi.org/10.5772/intechopen.76665

IGRA/ TST

Strong recommendation, low/ very low quality evidence

175

Conditional recommendation, low/very low quality evidence

WHO 2015 guidelines are as follows [31]:

haemotologic transplant and patients of silicosis

homeless persons and illicit drug users

5. Treatment of LTBI

Lipid metabolism APOC1

protein 6; PGLYRP2, peptidoglycan recognition protein 2.

Table 1. Newer biomarkers for diagnosis of active TB.

PLHA, child contacts of TB cases, patients being initiated on anti-TNF treatment, patients receiving dialysis, patients preparing for organ/

Prisoners, health-care workers, immigrants from high TB-burden countries,

active TB. The biomarkers identified are shown in Table 1 [32]:

Functional category HIV-Positive TB HIV-Negative TB Immune response CD14, SEPP1, SELL CD14, SEPP1, PGL YR P2

Other GP1BA CPN2, TAGLN2, IGFBP6

SEPP, selenoprotein P; SELL, selectin L; TNXB, tenascin XB; LUM, lumican; PEPD-peptidase D; QSOX1, quiescin sulfhydryl oxidase 1; COMP, cartilage oligomeric matrix protein; APOC1, apolipoprotein C-I; GP1 BA-glycoprotein 1 BA; VASN, vasorin; PFN 1, profilin1; CPN 2, chaperon 2; TAGLN2, transgelin 2; IGFBP 6, insulin-like growth factor binding

Tissue development & repair TNXB, LUM, PEPD, QSOX1, COMP PFN1, VASN

In a Japanese study, the specificity of IGRA was studied in healthy low-risk individuals with history of BCG vaccination [24]. It was seen that TST was positive (≥ 10 mm) in 64.6% (specificity 35.4%) while QuantiFERON®-TB test was positive in 1.9% (specificity 98.1%,) [24]. Similar results were obtained in another study done in Korea [25].In this study, 273 participants were included, 220 (95.7%) had received BCG vaccine. Participants were grouped according to their risk of infection: group 1, no identifiable risk of M. tuberculosis infection (n = 99); group 2, recent casual contacts (n = 72); group 3, recent close contacts (n = 48); group 4, bacteriologically or pathologically confirmed TB patients (n = 54). They studied the levels of agreement between the TST and the IFN-gamma assay and the likelihood of infection in the various groups and found out that the overall agreement between the TST and the IFN-gamma assay in healthy volunteers was a kappa value of 0.16. The odds of a positive test result per unit increase in exposure across the four groups increased by a factor of 5.31 (95% confidence interval [CI], 3.62–7.79) for the IFN-gamma assay and by a factor of 1.52 (95% CI, 1.20–1.91) for the TST (P < .001). In another study of 590 HIV-infected patients, QuantiFERON® -TB Gold test correlated with known risk factors for LTBI or past history of TB [26].

Both TST and IGRAs are acceptable but imperfect LTBI tests, with advantages and disadvantages [27]. In some situations, neither test is appropriate (e.g., active TB diagnosis in adults) and in some situations, both the tests may be necessary to detect M. tuberculosis infection (e.g., immunocompromised populations), and there are situations where one test may be preferable to another. For example, IGRAs may be preferable to the TST in populations where BCG is given after infancy or given multiple times. In contrast, TST may be preferable to the IGRAs for serial testing of health care workers. Both TST and IGRAs have reproducibility challenges, and dichotomous cut-offs are inadequate for interpretation [27]. The ability of tuberculin skin tests and IGRAs to identify persons at highest risk of progressing to active tuberculosis is poor. Neither test reliably predicts future disease among persons with positive tests nor do strongly positive tests mean a higher risk. In one meta-analysis, the pooled positive predictive value for progression to active tuberculosis was 2.7% (95% confidence interval [CI], 2.3–3.2) for IGRAs and 1.5% (95% CI, 1.2–1.7) for the tuberculin skin test [28]. A meta-analysis of only longitudinal studies of IGRAs, with a median follow-up of 4 years, showed a moderate association between positive tests and subsequent tuberculosis (unadjusted incidence ratio, 2.10 [95% CI, 1.42–3.08]) [29]. The other limitations of these tests are inability to distinguish reactivation from reinfection, reduced accuracy in immunocompromised patients, and inability to discriminate the various stages within the spectrum of LTBI [30]. To maximize the positive predictive value of existing LTBI tests, LTBI screening should be reserved only for those who are at sufficiently high risk of progressing to disease. The recommendations for systematic testing for LTBI as per WHO 2015 guidelines are as follows [31]:


In the long term, highly predictive biomarkers need to be identified. This is an active area of research, and future generations of LTBI tests should overcome the limitations of current assays. A great endeavor is on to discover reliable, low-cost biomarkers. Gene signatures can distinguish between active and latent TB [32]. A lot of works have been done to identify differential expression of cytokines and chemokines in active TB and LTBI. It has been shown that plasma levels of the CXC chemokine IP-10 and soluble TNF receptor type 2 (sTNFr2) can significantly differentiate active TB from the LTBI group, irrespective of HIV status [33]. Another study showed that serum IL-2, IL-9, IL-13, IL-17, TNF-α, sCD40L and VEGF-A levels may be adjunctive biomarkers for differential diagnosis of active TB, LTBI, and NTM disease [34]. Assessment of serum sCD40L and Mtb antigen-specific IFN-γ, TNF-α, and IL-2 levels could also help predict successful anti-TB treatment in conjunction with Mtb clearance [31]. Achkar et al. looked at biomarkers to distinguish active TB and LTBI from no TB infection in HIV positive and negative populations [35]. They did so because inflammatory response and repair are both blunted in PLHA. They identified a set of biomarkers which reliably predict active TB. The biomarkers identified are shown in Table 1 [32]:


SEPP, selenoprotein P; SELL, selectin L; TNXB, tenascin XB; LUM, lumican; PEPD-peptidase D; QSOX1, quiescin sulfhydryl oxidase 1; COMP, cartilage oligomeric matrix protein; APOC1, apolipoprotein C-I; GP1 BA-glycoprotein 1 BA; VASN, vasorin; PFN 1, profilin1; CPN 2, chaperon 2; TAGLN2, transgelin 2; IGFBP 6, insulin-like growth factor binding protein 6; PGLYRP2, peptidoglycan recognition protein 2.

#### 5. Treatment of LTBI

and high BCG vaccination coverage [23]. The workers compared TST with QuantiFERON®-TB in three population groups: household contacts of smear-positive TB cases, community members who had been exposed to index smear-positive TB cases and healthcare workers dealing with TB cases or handling TB specimens. They did a Kappa analysis to look for agreement between the tests. They found that QuantiFERON®-TB values were higher in the first group of patients when compared to the other two groups. In case of TST, there was no difference among the three groups. Evaluation for agreement rates between the groups showed poor agreement in all three groups. The authors concluded that while Quantiferon Gold was more objective, practical and gave quantitative values, it was more expensive and required a wellequipped laboratory and thus did not have a programmatic role in detection of LTBI in a

In a Japanese study, the specificity of IGRA was studied in healthy low-risk individuals with history of BCG vaccination [24]. It was seen that TST was positive (≥ 10 mm) in 64.6% (specificity 35.4%) while QuantiFERON®-TB test was positive in 1.9% (specificity 98.1%,) [24]. Similar results were obtained in another study done in Korea [25].In this study, 273 participants were included, 220 (95.7%) had received BCG vaccine. Participants were grouped according to their risk of infection: group 1, no identifiable risk of M. tuberculosis infection (n = 99); group 2, recent casual contacts (n = 72); group 3, recent close contacts (n = 48); group 4, bacteriologically or pathologically confirmed TB patients (n = 54). They studied the levels of agreement between the TST and the IFN-gamma assay and the likelihood of infection in the various groups and found out that the overall agreement between the TST and the IFN-gamma assay in healthy volunteers was a kappa value of 0.16. The odds of a positive test result per unit increase in exposure across the four groups increased by a factor of 5.31 (95% confidence interval [CI], 3.62–7.79) for the IFN-gamma assay and by a factor of 1.52 (95% CI, 1.20–1.91) for the TST (P < .001). In another study of 590 HIV-infected patients, QuantiFERON® -TB Gold test

Both TST and IGRAs are acceptable but imperfect LTBI tests, with advantages and disadvantages [27]. In some situations, neither test is appropriate (e.g., active TB diagnosis in adults) and in some situations, both the tests may be necessary to detect M. tuberculosis infection (e.g., immunocompromised populations), and there are situations where one test may be preferable to another. For example, IGRAs may be preferable to the TST in populations where BCG is given after infancy or given multiple times. In contrast, TST may be preferable to the IGRAs for serial testing of health care workers. Both TST and IGRAs have reproducibility challenges, and dichotomous cut-offs are inadequate for interpretation [27]. The ability of tuberculin skin tests and IGRAs to identify persons at highest risk of progressing to active tuberculosis is poor. Neither test reliably predicts future disease among persons with positive tests nor do strongly positive tests mean a higher risk. In one meta-analysis, the pooled positive predictive value for progression to active tuberculosis was 2.7% (95% confidence interval [CI], 2.3–3.2) for IGRAs and 1.5% (95% CI, 1.2–1.7) for the tuberculin skin test [28]. A meta-analysis of only longitudinal studies of IGRAs, with a median follow-up of 4 years, showed a moderate association between positive tests and subsequent tuberculosis (unadjusted incidence ratio, 2.10 [95% CI, 1.42–3.08]) [29]. The other limitations of these tests are inability to distinguish reactivation from reinfection, reduced accuracy in immunocompromised patients, and inability to discriminate the various stages within the spectrum of LTBI [30]. To maximize the positive predictive value

country will high TB prevalence and high BCG coverage [23].

174 Advances in HIV and AIDS Control

correlated with known risk factors for LTBI or past history of TB [26].

Treatment of LTBI reduces the risk for active disease and hence various authorities have recommended treatment for this entity. Chemoprophylaxis for LTBI can prevent 60–90% of reactivation TB [36]. But chemoprophylaxis cannot be considered as a universal approach due to the inherent toxicity of all TB drugs. However, in vulnerable populations, the benefits far outweigh the risks [33].

The International Union against Tuberculosis (IUAT) trial, conducted in Eastern Europe, randomized approximately 28,000 individuals with positive tuberculin skin tests (TST) and fibronodular changes on chest X-ray [37]. Approximately 7000 participants each were randomized to placebo, 3, 6 or 12 months of INH. Compared to participants who took placebo, participants who completed 3 months INH had 31% reduction in TB; those who completed 6 months INH (6INH) 69% reduction and the subjects who completed 12 months INH (12INH) had 93% reduction in TB. The efficacy of 6INH and 12INH waned during 5 years of follow-up but remained significantly better than the placebo. It is to be noted that fewer people completed 12 INH regimens as compared to 6INH [34].

Concerns regarding the relatively low efficacy of 6INH, and equally serious concerns regarding the poor completion of 12INH resulted in recommendations for 9 months INH by the American Thoracic Society in 2000 [38]. The optimal duration of INH was recommended as 9 months, with estimated efficacy of 90% and no significant gain with extension to 12 months [35].

Directly observed once-weekly regimen of isoniazid and rifapentine is recommended as an option equal to the standard INH 9-month daily regimen for treating LTBI. The regimen may be used in otherwise healthy HIV-infected persons, 12 years of age and older, who are not on antiretroviral medications. It may also be considered for children aged 2–11 years if comple-

Rifapentine (wt band): 10.0–14.0 kg = 300 mg; 14.1–

25.0 kg = 450 mg; 25.1–32.0 kg = 600 mg; 32.1–49.9 kg = 750 mg; ≥50.0 kg = 900 mg

Rifampicin: Adults & children - 10 mg/kg isoniazid-300 mg

Regimen Dose isoniazid Dose rifapentine or rifampicin Maximum dose

isoniazid - 300 mg

177

Latent Tuberculosis Infection: Patho-Biology and Treatment

http://dx.doi.org/10.5772/intechopen.76665

isoniazid - 900 mg Rifapentine - 900 mg

Rifampicin - 600 mg

Rifampicin - 600 mg

The regimen using 4 months of rifampicin can be considered for persons who cannot tolerate INH or who have been exposed to INH-resistant TB. It should also not be used to treat HIV-

The National Aids Control Organization guidelines for LTBI in PLHA published in 2016

• Adults and adolescents living with HIV should be screened for TB with a clinical algorithm and those who do not report any one of the symptoms of current cough, fever, weight loss or night sweats are unlikely to have active TB and should be offered Isoniazid

• Children living with HIV (more than 12 months of age) who do not report poor weight gain, fever, current cough or history of contact with a TB case, are unlikely to have active

• Additional investigations will help in ruling out active TB (X-ray chest and tuberculin skin

• The treatment recommended in adult and adolescent is Isoniazid 300 mg + Pyridoxine 50 mg (Vitamin B6) per day for 6 months and for children above 12 months is Isoniazid

Treatment of close contacts of drug-resistant active TB cases is difficult and yet is an increasingly common clinical problem. For contacts of INH-resistant index cases, INH will be ineffec-

10 mg/kg + Pyridoxine 25 mg (Vitamin B6) per day for 6 months.

6. Chemoprophylaxis after contact with MDR-TB

infected persons taking some combinations of ART especially protease inhibitors.

tion of 9 months of INH is unlikely and hazard of TB disease is great.

recommends the following strategy [8]

6 m or 9 m isoniazid

isoniazid + rifampicin

3 or 4 m rifampicin alone daily

3 m rifapentine + isoniazid weekly

Adults = 5 mg/kg Children = 10 mg/kg

Adults & children isoniazid - 15 mg/kg

Adults & children 10 mg/kg

Isoniazid: Adults - 5 mg/kg Children - 10 mg/kg

daily

3 or 4 m

daily

Preventive Therapy (IPT).

TB and should be offered IPT.

test) but are not mandatory.

tive, so 4RIF is recommended [47, 48].

In another trial, in Hong Kong, people who had pulmonary silicosis with a positive TST were randomized to placebo, 6INH, 3 m INH + Rifampin, or 3 m Rifampin alone [39]. During 5 years of follow-up, 27% of those randomized to placebo arm developed active TB, compared to 16, 13, and 10% for the three regimens respectively [36]. The estimated effectiveness of 3-months rifampin was approximately 65%; this was better than the other regimens although the differences between active regimens were not significant, and all were significantly better than placebo [36].

A series of randomized trials have demonstrated that the efficacy of 3-4INH + RIF to be equivalent to that of 6INH (four studies) or 9INH (one study) although adverse events are significantly more frequent [40, 41].

For adults, the recommended duration of treatment is at least 6, and preferably 9, months. Children younger than 18 years and persons with HIV infection should be treated for 9 months [42]. In HIV TB setting, IPT has been shown to slow the progression to active disease. A Cochrane systematic review of 12 trials, published in 2010 among 8578 patients showed that IPT reduced the risk of active TB by 64% among TST positive HIV-infected participants [43]. WHO has recommended that in resource-limited countries and other middle-income countries, people living with HIV and children below 5 years of age who are household or close contacts of people with TB and who, after an appropriate clinical evaluation, are found not to have active TB but have LTBI should be treated. WHO has recommended the following regimens for the treatment of LTBI which are similar to current CDC guidelines [26, 44–46].

The 9-month regimen with isoniazid is preferred because it is more efficacious. However, treatment of LTBI for 6 months rather than 9 months may be more cost-effective and result in greater adherence by patients.


reactivation TB [36]. But chemoprophylaxis cannot be considered as a universal approach due to the inherent toxicity of all TB drugs. However, in vulnerable populations, the benefits far

The International Union against Tuberculosis (IUAT) trial, conducted in Eastern Europe, randomized approximately 28,000 individuals with positive tuberculin skin tests (TST) and fibronodular changes on chest X-ray [37]. Approximately 7000 participants each were randomized to placebo, 3, 6 or 12 months of INH. Compared to participants who took placebo, participants who completed 3 months INH had 31% reduction in TB; those who completed 6 months INH (6INH) 69% reduction and the subjects who completed 12 months INH (12INH) had 93% reduction in TB. The efficacy of 6INH and 12INH waned during 5 years of follow-up but remained significantly better than the placebo. It is to be noted that fewer people com-

Concerns regarding the relatively low efficacy of 6INH, and equally serious concerns regarding the poor completion of 12INH resulted in recommendations for 9 months INH by the American Thoracic Society in 2000 [38]. The optimal duration of INH was recommended as 9 months, with estimated efficacy of 90% and no significant gain with extension to 12 months

In another trial, in Hong Kong, people who had pulmonary silicosis with a positive TST were randomized to placebo, 6INH, 3 m INH + Rifampin, or 3 m Rifampin alone [39]. During 5 years of follow-up, 27% of those randomized to placebo arm developed active TB, compared to 16, 13, and 10% for the three regimens respectively [36]. The estimated effectiveness of 3-months rifampin was approximately 65%; this was better than the other regimens although the differences between active regimens were not significant, and all were significantly better than

A series of randomized trials have demonstrated that the efficacy of 3-4INH + RIF to be equivalent to that of 6INH (four studies) or 9INH (one study) although adverse events are

For adults, the recommended duration of treatment is at least 6, and preferably 9, months. Children younger than 18 years and persons with HIV infection should be treated for 9 months [42]. In HIV TB setting, IPT has been shown to slow the progression to active disease. A Cochrane systematic review of 12 trials, published in 2010 among 8578 patients showed that IPT reduced the risk of active TB by 64% among TST positive HIV-infected participants [43]. WHO has recommended that in resource-limited countries and other middle-income countries, people living with HIV and children below 5 years of age who are household or close contacts of people with TB and who, after an appropriate clinical evaluation, are found not to have active TB but have LTBI should be treated. WHO has recommended the following regimens for the treatment of LTBI which are similar to current CDC guidelines

The 9-month regimen with isoniazid is preferred because it is more efficacious. However, treatment of LTBI for 6 months rather than 9 months may be more cost-effective and result in

outweigh the risks [33].

176 Advances in HIV and AIDS Control

[35].

placebo [36].

[26, 44–46].

greater adherence by patients.

significantly more frequent [40, 41].

pleted 12 INH regimens as compared to 6INH [34].

Directly observed once-weekly regimen of isoniazid and rifapentine is recommended as an option equal to the standard INH 9-month daily regimen for treating LTBI. The regimen may be used in otherwise healthy HIV-infected persons, 12 years of age and older, who are not on antiretroviral medications. It may also be considered for children aged 2–11 years if completion of 9 months of INH is unlikely and hazard of TB disease is great.

The regimen using 4 months of rifampicin can be considered for persons who cannot tolerate INH or who have been exposed to INH-resistant TB. It should also not be used to treat HIVinfected persons taking some combinations of ART especially protease inhibitors.

The National Aids Control Organization guidelines for LTBI in PLHA published in 2016 recommends the following strategy [8]

