Outcomes

Anticipated absolute effects* (95% CI)

Relative effect

(95% CI)

Number of participants (studies)

Certainty of the evidence (GRADE)

Comments

Risk with 6‐month standard ATT

Risk with 4‐month moxifloxacin‐containing ATT

Relapse
Follow‐up: range 12 to 24 months

32 per 1000

82 more relapses per 1000
(44 more to 140 more)

RR 3.56
(2.37 to 5.37)

2265
(3 RCTs)

⊕⊕⊕⊝
MODERATE^a,b,c

Due to indirectness

The 4‐month regimen probably increases relapse compared to the 6‐month regimen

Death from any cause

Follow‐up: range 18 to 24 months

21 per 1000

2 more deaths per 1000
(7 fewer to 16 more)

RR 1.06
(0.65 to 1.75)

2760
(3 RCTs)

⊕⊕⊕⊝
MODERATE^a,c,d

Due to indirectness

The 4‐month regimen probably makes little or no difference in death from any cause compared to the 6‐month regimen

Treatment failure

16 per 1000

5 fewer treatment failures per 1000
(11 fewer to 8 more)

RR 0.71
(0.33 to 1.52)

2282
(3 RCTs)

⊕⊕⊕⊝
MODERATE^a,c,d

Due to indirectness

The 4‐month regimen probably results in little or no difference in treatment failure compared to the 6‐month regimen

Acquired drug resistance

7 per 1000

5 fewer with acquired drug resistance per 1000

(6 fewer to 2 more)

RR 0.33
(0.08 to 1.31)

2282

(3 RCTs)^e

⊕⊕⊝⊝
LOW^c,f,g

Due to indirectness and imprecision

The 4‐month regimen may be little or no different than the 6‐month regimen in the incidence of acquired drug resistance

Serious adverse events

Follow‐up: range 18 to 24 months

62 per 1000

2 fewer with serious adverse events per 1000
(16 fewer to 16 more)

RR 0.97
(0.74 to 1.27)

3548
(4 RCTs)^g

⊕⊕⊕⊝
MODERATE^a,c,d,h

Due to indirectness

The 4‐month regimen probably results in little or no difference in serious adverse events compared to the 6‐month regimen

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
ATT: anti‐tuberculosis treatment; CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio.

GRADE Working Group grades of evidence.
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^aNo serious risk of bias: although Jawahar 2013 was at high risk of allocation bias, exclusion of this trial from the sensitivity analysis did not change the direction of effect. Not downgraded.
^bNo serious inconsistency: although trial results indicated a moderate degree of heterogeneity (I² = 58%), the differences were between small and large effects favouring 6‐month ATT. Changing the model from fixed effect to random effects did not alter the direction of effect. Not downgraded.
^cDowngraded one level for serious indirectness: trials excluded children and adolescents, people with diabetes, and other physical comorbid conditions.
^dNo serious imprecision: the 95% CI for the risk ratio was wide but event rates were low and the sample size was large; the risk ratio and the 95% CI around absolute estimates did not indicate clinically appreciable differences with either regimen. Not downgraded.
^eNo serious imprecision: the 95% CI for the risk ratio was wide but event rates were low and the sample size was large; the 95% CI for the risk ratio (RR 0.5% fewer with the 4‐month regimen, 95% CI 1.1% fewer to 0.8% more) did not indicate that there were clinically important differences in proportions with treatment failure. Not downgraded.
^fDrug resistance was assessed using LJ solid media in one trial, MGIT liquid media in another trial, and either or both in the third trial.
^gSerious imprecision: events were few and the 95% CI for the pooled estimate was wide. In the largest study that also reported the most events, results were equivocal for acquired resistance and only possible resistance was reported. Downgraded one level.
^hThree trials provided data for all outcomes in this summary table (Gillespie 2014; Jawahar 2013; Jindani 2014); Velayutham 2014 provided data only for serious adverse events.

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with 6‐month standard ATT

Risk with gatifloxacin‐containing
4‐month ATT

Relapse
Follow‐up: 24 months

70 per 1000

77 more relapses per 1000
(32 more to 128 more)

RR 2.11
(1.56 to 2.84)

1633
(2 RCTs)

⊕⊕⊕⊝
MODERATE^a,b

Due to indirectness

The 4‐month regimen probably increases relapse compared to the 6‐month regimen

Death from any cause
Follow‐up: 24 months

29 per 1000

3 fewer deaths per 1000
(14 fewer to 16 more)

RR 0.90
(0.53 to 1.53)

1886
(2 RCTs)

⊕⊕⊕⊝
MODERATE^a,b,c

Due to indirectness

The 4‐month regimen probably makes little or no difference in death compared to the 6‐month regimen

Treatment failure

25 per 1000

1 less treatment failure per 1000
(12 fewer to 18 more)

RR 0.93
(0.51 to 1.70)

1657
(2 RCTs)

⊕⊕⊝⊝
MODERATE^a,b,c

Due to indirectness

The 4‐month regimen probably makes little or no difference in treatment failure compared to the 6‐month regimen

Acquired drug resistance

12 per 1000

9 fewer with acquired drug resistance per 1000

(12 fewer to 49 more)

RR 0.24

(0.01 to 5.01)

301

(1 RCT)^d

⊕⊝⊝⊝
VERY LOW^b,e,f

Due to indirectness, risk of bias, and imprecision

We do not know if acquired drug resistance is any different in the 4‐month and the 6‐month regimens

Serious adverse events

24 per 1000

0 fewer serious adverse events per 1000
(10 fewer to 18 more)

RR 1.02
(0.58 to 1.77)

1993
(2 RCTs)

⊕⊕⊕⊝
MODERATE^a,b,c

Due to indirectness

The 4‐month regimen probably results in little or no difference in serious adverse events compared to the 6‐month regimen

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
ATT: anti‐tuberculosis treatment; CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio.

GRADE Working Group grades of evidence.

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^aNo serious risk of bias: although Jawahar 2013 was assigned high risk of bias for allocation concealment, removal of this trial from the sensitivity analysis did not significantly alter the direction, magnitude, or precision of the effect estimate. Not downgraded.
^bDowngraded one level for serious indirectness: trials excluded children and adolescents and people with diabetes mellitus and other comorbid physical conditions and those with alcohol abuse.
^cNo serious imprecision: the 95% CI of the risk ratio was wide, but events were few and the sample size was reasonably large; the 95% CI for the absolute estimates did not indicate clinically appreciable benefits for either regimen. Not downgraded.
^dOne trial provided data on acquired drug resistance (Jawahar 2013). Merle 2014 reported only drug susceptibility at baseline.
^eDowngraded one level for serious risk of bias: allocation concealment was compromised and there were baseline imbalances in proportions with drug resistance at baseline in the sole trial for this outcome (Jawahar 2013).
^fDowngraded two levels for very serious imprecision: the data for acquired resistance come from only one trial with 301 participants, and this trial did not evaluate resistance to gatifloxacin.

Findings

Interpretation

Equity – Which of the PROGRESS groups examined

The trials included in this review were conducted in a mix of low- and middle-income countries (Kenya, South Africa, Tanzania, Zambia, China, India, Malaysia, Thailand, Mexico, Botswana, Zimbabwe, Benin, Guinea, Senegal, and south India). There is a greater prevalence of tuberculosis in said countries relative to those of high-income.

TB is widespread in low- and middle-income countries and shortened treatment regimens may improve treatment adherence and thus decrease prevalence in these endemic areas. The study provides evidence demonstrating that four-month treatment regimens are inferior to standard six‐month regimens in preventing relapse (although there is probably little or no difference in serious side effects or cure). The included studies were deemed low or moderate quality and thus further trials are needed.  

No other PROGRESS-plus groups were

examined in the review

This review did not analyze the effect of shorter treatment regimens across additional PROGRESS groups. Several factors, such as residence, occupation, education, socioeconomic status, etc., must be taken into consideration when developing treatment programs, as they have an impact on treatment adherence.

Equity Applicability

The review summarized trials addressing treatment of HIV+ populations.

It did not discuss the effects on children, pregnant women, or those with comorbid conditions.

The impact of shortened treatment regimens may differ in marginalized populations, reducing the certainty in the effect of estimates. Further trials testing treatments in these groups are therefore needed.

This review also did not include people with many comorbid conditions, such as previous TB and those with diabetes. Future research could examine the effectiveness of shortened treatment regiments for patients with such co-morbidities. However, it may be argued that relapse with the four-month regimens would likely not be less in populations with serious comorbidities than was reported in the trials in this review.

Cost-equity

No studies contributed economic data

Patients in low- and middle-income countries may not be able to afford TB treatment due to economic hardship through illness and loss of work. As TB treatment duration

increases, it can be expected that the cost of the regimen will increase as well. Thus, shortened treatment regimens may offer a more affordable alternative for patients in such countries. Further economic analyses are needed to develop an understanding of the most cost-effective and efficient treatment regimen.

Community Preferences

Community preferences regarding the length of regimens were not discussed. However, given that shorter regimens require less time and money, they are likely to be favoured over lengthier treatments. Research is needed to develop a regimen with novel drug combinations, given for less than six months, that is proven to be as safe and effective as the currently recommended six-month regimen.