1. Lula 3d Multi2 Isoniazid D
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Main ResultsThis review assessed ten randomized clinical trials that assigned 7619 HIV patients to IPT or placebo. An overall 35% of TB risk reduction (RR = 0.65, 95% CI (0.51, 0.84)) was found in all participants, however, larger benefit of IPT was observed in Tuberculin Skin Test (TST) positive participants, with pooled relative risk reduction of 52% RR = 0.48; 95% CI (0.29, 0.82) and with a prediction interval ranging from 0.13 to 1.81. There was no statistically significant effect of IPT on TB occurrence in TST negative or unknown participants.

IPT also reduced the risk of HIV disease progression in all participants (RR = 0.69; 95% CI (0.48, 0.99)) despite no benefits observed in TST strata. All-cause mortality was not affected by IPT although participants who had 12 months of IPT tend to have a reduced risk (RR = 0.65; 95% CI(0.47, 0.90)).

IPT had an elevated, yet statistically non-significant, risk of adverse drug reaction RR = 1.20; 95% CI (1.20, 1.71). Only a single study assessed the effect of IPT in combination with ART in preventing TB and occurrence of multi-drug resistant tuberculosis. Search methods for the identification of studiesA comprehensive search of PubMed, Excerpta Medica dataBASE (EMBASE), the Cochrane Central Register of Controlled Trials (CENTRAL) and Cumulative Index of Nursing and Allied Health (CINAHL) was performed to identify all relevant studies in the English language available from the start of MEDLINE to September 11 th 2015.

Both text words in title, abstract and medical subject heading (MeSH) terms were used in varying combinations. The literature search strategy was adapted to suit each database. Moreover, the website of Health Internet Internetwork and Research Initiative (HINARI) and Google Scholar databases were checked for potential eligible studies. Domain, intervention, outcome and designHIV/AIDS (1)Isoniazid (2)Tuberculosis (3)Randomization (4)Search termsHuman immunodeficiency OR virus, OR HIV, OR Acquired immunodeficiency syndrome, OR AIDSIsoniazid, INH, OR Prevention, OR Preventive, OR Prophylaxis, OR ProphylacticTuberculosis OR TBRandomized OR RandomizationSearch fieldsMeSH AND Title/AbstractMeSH AND Title/AbstractMeSH AND Title/AbstractMeSH AND Title/AbstractFinal search(((#1) AND #2) AND #3) AND #4Date of search closure at September 11 th 2015. DeterminantThe primary determinant was IPT stratified by TST status. TST reactivity demonstrates a functional anti-mycobacterial response; a TST negative status can therefore indicate a lack of TB exposure, but also result from severe immune deficiency (anergy) with or without underlying latent TB. A TST positive status, therefore, demonstrates TB exposure as well as a preserved immune response.

The latter could affect the efficacy of IPT. Analyses were further stratified by dosage and duration of the IPT regimen. Statistical MethodsThe reviewed articles’ unit of analysis was the individual patient. All the randomization and intervention allocation was patient-based. Due to the underlying clinical heterogeneity of selected studies, a random-effects model was used to estimate the pooled effect of IPT, using the method of Hartung and Knapp.The between-study heterogeneity in treatment effect was assessed by the I squared (I 2) statistic and 95% prediction intervals (95% PI). The I 2 statistic indicates the extent of variability that cannot be explained by sampling error and ranges between 0 and 100%. Conversely, the prediction interval gives an indication of true treatment effect of IPT that can be expected when the intervention is applied to new studies; it thereby provides a sense of the heterogeneity in expected benefits.

Furthermore, subgroup analyses were performed and stratified by baseline TST status (positive, negative, and unknown) and dosing and duration of the regimen. MetaAnalyst and R version 3.2.1 were used for the data analysis. ADR: Adverse Drug Reaction; AFB: Acid fast bacilli; AIDS: Acquired immune deficiency Syndrome; ART: Antiretroviral Therapy; IGRA: Interferon Gamma Release Assay; IPT: Isoniazid Preventive Therapy; ITT: Intention To Treat; LTF: Lost To Follow-up; PP: Per Protocol; TB: Tuberculosis; TST: Tuberculin Skin Test; VB6: Vitamin B 6 (Pyridoxine)All studies randomized participants to IPT or placebo or no IPT intervention; however, the dosage and duration of IPT varied.

The total duration of the IPT treatment course ranged from 6 to 12 months with subsequent follow up of 12–44 months. Most of the included studies (n = 7) assessed 300mg of IPT daily for a duration of six months (n = 4) or twelve months (n = 3). A Zambian study assessed 900 mg of IPT twice weekly for 12 months and another South African study assessed 15mg/kg of IPT twice weekly. Six studies assessed the effect of Isoniazid alone in comparison to placebo or no intervention whereas two studies assessed the effect of Isoniazid alone compared to combinations of Rifampicin and Pyrazinamide with placebo or no intervention. The recent TEMPRANO study compared IPT treatment effect to no IPT in the setting of deferred ART or early ART.With the exception of two studies, the included studies assessed the TST status at baseline. Four studies included both TST positive and negative individuals while three studies solely considered TST negatives. The Ugandan study separately investigated the effect of IPT in TST positive and anergic patients.

In most African countries ART was widely introduced in 2004 and five studies conducted before this period lack information regarding ART use. Five studies used a block randomization, two studies used computer generated randomization and the remaining two studies used unclear randomization methods. Methodological quality assessmentThe qualitative assessment on data completion, randomization, treatment concealment and outcome blinding did not reveal major methodological flaws across studies. In some studies, exclusion of possible pre-existing TB disease by ascertainment of clinical symptoms and signs at baseline may have missed few cases of pre-existing TB. Ascertainment of the outcome of TB was active and mostly based on AFB test confirmed by culture positivity of sputum or biopsy.

Most of the included studies used family-reported all-cause mortality. There was no indication of selective reporting. StudiesFitzgerald 2001Gordin 1997Hawken 1997Mohammed 2007Mwinga 1998Pape 1993Rangaka 2014Rivero 2003TEMPRANO 2015Whalen 1997Optimal exclusion of TB patients at enrolment??Random sequence generationAllocation concealment-+?-+Placebo control-+Blinding of participants, personnel, and outcome assessors (TB, ADR, and AIDS)?+?-+?-+Completion of IPT course with adequate adherence?-Lost to follow up describedBoth primary and secondary outcomes were reported.

Assessment of heterogeneityAmong the included studies, there was substantial clinical and methodological variability, complicating interpretation of study findings. The clinical heterogeneity emanates in part from baseline variations of subjects such as TST status variation. In addition, the IPT intervention differed in terms of dose, duration, provision of IPT with other preventive therapies, adherence levels achieved and subsequent follow-up. Other methodological variation across studies was mostly related to differences in randomization techniques, outcome ascertainment and analysis methods. Finally, eight studies were conducted in low income and high TB burden countries; however, the other two studies were conducted in a high income country with lower levels of endemicity.

Given these differences, it is recommended to allow for the between-study heterogeneity in treatment effect and to adopt random effects models., Despite the presence of clinical heterogeneity between the included studies, an acceptable degree of statistical heterogeneity was found for the analysis including all relevant studies. A somewhat larger statistical heterogeneity was observed in the subset of studies where IPT effect on all-cause mortality was assessed in TST positive participants (I 2 = 54.7%) and IPT effect on HIV disease progression (I 2 = 59.4%). Prediction intervals were determined to indicate an anticipated variation in effect estimates. Overall populationIPT showed significantly reduced relative risk (RR) of TB (RR = 0.65 with 95% CI: 0.51, 0.84), substantial heterogeneity was however present in this effect (95% PI: 0.37, 1.17) Similar results were found for the effect of IPT toward confirmed TB (RR = 0.69, 95% CI: 0.48, 0.99) with a prediction interval (95%) of 0.38 to 1.24).

IPT tended to reduce the risk of all-cause mortality yet statistically non-significant RR = 0.90(95% CI (0.79, 1.02) and 95% PI (0.71, 1.13)). The effect of IPT was almost null on risk of HIV disease progression RR = 0.99; 95% CI (0.73, 1.34) and wide 95% PI (0.31, 3.18). Exposure categoryNumber of studiesSample sizePooled RR. (95% CI)95% PIOverall estimate1076190.65 (0.51, 0.84)(0.37, 1.17)TSTPositive517030.48 (0.29, 0.82)(0.13, 1.81)Negative931400.79 (0.58, 1.08)(0.54, 1.16)Unknown427760.68 (0.42, 1.10)(0.11, 4.23)ARTTreated222260.67(0.47, 0.96)Not estimable.Not treated842340.73 (0.53, 1.02)(0.33, 1.60)IPT dose300mg868190.62 (0.47, 0.82)(0.34, 1.12)900mg28000.89 (0.36, 2.18)Not estimable.IPT duration6 months658370.61 (0.45, 0.82)(0.30, 1.22)12 months417820.79 (0.45, 1.37)(0.11, 5.73). Exposure categoryNumber of studiesSample sizePooled RR. (95% CI)95% PIOverall estimates1076570.90 (0.79, 1.02)(0.71, 1.13)TSTPositive413110.67 (0.34, 1.35)(0.04, 10.10)Negative724281.02 (0.90, 1.15)(0.86, 1.20)Unknown324000.74 (0.52, 1.05)(0.08, 7.19)ARTTreated222260.77 (0.46, 1.28)Not estimable.Not treated842720.92 (0.81, 1.05)(0.72, 1.18)IPT dose300mg868190.91 (0.80, 1.03)(0.73, 1.13)900mg28380.81 (0.46, 1.40)Not estimable.IPT duration6 months658550.95 (0.85, 1.07)(0.81, 1.12)12 months418020.65 (0.47, 0.90)(0.32, 1.32). TST positiveIn TST positive participants, five studies including a total of 1703 participants demonstrated an effect of IPT on all types of TB (probable to confirmed) with a pooled RR of 0.48; (95%CI 0.29–0.82) and 95% PI ranging from 0.13 to 1.81.

Only one study reported the results for confirmed TB RR = 0.13; 95% CI (0.01, 2.32). Four studies, including 1311 participants, reported the effect of IPT on all-cause mortality with pooled RR of 0.67; 95% CI (0.34, 1.35) with a wide prediction interval of (0.04, 10.10). Data about the effect of IPT on HIV disease progression was could be derived from one study only (RR = 0.36; 95% CI (0.15, 0.85)).

TST negativeNine studies reported data for TST negative (n = 3140) participants. The pooled relative risk for IPT on all types of TB was 0.79 (95% CI: 0.58, 1.08) with a prediction interval of (0.54, 1.16). For confirmed TB only, data was obtained from three studies including 1021 participants. The pooled RR was 0.77 (95% CI: 0.36, 1.64).

All-cause mortality was determined from seven studies with 2428 participants. The pooled RR of IPT on all cause-mortality was 1.02 (95% CI: 0.90, 1.15) with a prediction interval of (95% PI: 0.86, 1.1.20). Three studies with 809 participants could deliver data about HIV disease progression, RR = 1.00; 95% CI (0.88, 1.15) with a prediction interval of from 0.42 to 2.40. TST unknownIn participants with an unknown TST status, the pooled relative risk of IPT on all types of TB was 0.68; 95% CI (0.42, 1.10) with a very wide prediction interval of (95% PI: 0.11, 4.23).

Based on two studies with 930 participants, the pooled RR of IPT on confirmed TB was 0.82; 95% CI (0.47, 1.43). Similarly, the other three studies had data on all-cause mortality and the pooled RR was 0.74; 95% CI (0.52, 1.05). One study with 2056 participants found an elevated risk of HIV disease progression yet statistically non-significant RR = 1.38; 95% CI (0.79, 2.40). ART treatmentIPT-ART combination treatment could be estimated from two studies with 2226 participants. IPT reduced risk of all-types of TB in participants treated with ART RR = 0.67 (95% CI 0.47, 0.96). The pooled effect from studies (n = 8) which did not include participants on ART was not statistically significant RR = 0.73; 95% CI (0.53, 1.02) and 95% PI (0.33, 1.60).

In the same studies, the pooled effect of IPT on all-cause mortality for participants on ART was 0.77; 95% CI (0.46, 1.28) and 0.92; 95% CI (0.81, 1.05) for those not on ART. (Tables, & ). IPT dose and durationThe 300 mg IPT daily dose had higher benefit than 900mg twice weekly dose in reducing all-types of TB risk, pooled RR = 0.62; 95% CI(0.47, 0.82) and 0.89; 95% (0.36, 2.18) respectively.

There were no differences in the pooled effect of different IPT doses on risk of all-cause mortality. Concerning the duration of IPT, 6 months therapy reduced all-types of TB RR = 0.61; 95% CI (0.45, 0.82).

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The same protective effect of 12 months IPT course observed toward all-types of TB risk reduction yet the pooled estimate was not statistically significant RR = 0.79; 95% CI (0.45, 1.37) with a wide 95% PI (0.11, 5.73). (Tables, & )For adverse drug reactions participants were not stratified by TST status. All studies included data about the overall number of ADR (5068 participants).

Nevertheless, two studies did not have withdrawal from the follow up due to ADR. The pooled RR of IPT compared to placebo for the development of severed ADR was 1.32; 95% CI (0.89, 1.96) with prediction interval of (0.46, 3.75). For the included studies, there appeared a positive association between the dosage of IPT and the risk of adverse drug reaction. The 900mg IPT dose showed higher risks of ADR RR = 3.98; 95% CI (1.13, 13.97) in comparison to 300mg daily dose RR = 1.06; 95% CI (0.79, 1.41).The details of the forest plots are annexed and additional effect estimates extracted from included studies are also annexed.Adherence to the IPT (or placebo) regimen could be assessed from seven studies. The studies reported similarity of TB incidence in adherent and non-adherent participants although the proportion of non-adherence varied from study to study. None of these studies described reasons for non-adherence or predictors of non-adherence.

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DiscussionIPT has been one of the four main strategies of TB prevention in both HIV positive and negative patients since the introduction of Isoniazid. 41,42,43 The clinical trials included in this review demonstrated that IPT was generally efficacious to prevent TB disease. Nevertheless, the width of calculated prediction intervals indicates that IPT may not be a beneficial strategy in all populations. Further research is needed to explore sources of this heterogeneity. Despite an effect on development of TB disease, a limited reduction in all-cause mortality was found; Some of the studies may have been under-powered to detect an effect on mortality or limited follow-up time precluded assessment of a long term effect.

From the subgroup analysis, it appears that the six-month 300 mg daily IPT regimen reduced the risk of TB with the lowest number of adverse events.The results of this meta-analysis confirm that a positive TST is a very strong indicator for the potential benefit of IPT also in countries with high burden of TB. 41,44 Patients with a positive TST experienced a relative risk of TB disease of RR = 0.48; 95% CI (0.29, 0.82) compared to untreated patients or treated with placebo. For subjects with negative TST reactions, there was a moderate, but not statistically significant, protective effect (RR = 0.79; 95% CI (0.58, 1.08) compared to untreated patients. This is in agreement with previous reports. 31,44 As TST reactivity also demonstrates a functional anti-mycobacterial response, a TST negative status can indicate either a lack of TB exposure, or result from severe immune deficiency with or without underlying latent TB. A TST positive status hence indicates a preserved immune response and this could affect the efficacy of IPT.

45ART contributes to the prevention of TB in HIV positive patients by maintaining the patient’s immune system. Only two of the included studies (Rangaka et. And TEMPRANO) assessed the combined effect of ART and IPT on TB, all-cause mortality, or HIV disease progression and found that ART decreased the risk of all-types of TB and increased the risk of ADR.