Preventing TB in HIV-infected people !

naïve cells, however, persistent impairments of specific CD4 T cell populations can be observed despite long-term ART (Walker et al., 2013). A 1.7-fold increased risk of TB was observed early after ART initiation in persons with CD4 T cell counts less than 100 cells/µl (Lawn et al., 2009). The authors attribute the high levels of TB during the early phases of ART treatment to the unmasking of subclinical TB in these patients.

morbidity and mortality through early diagnosis and treatment, 2) TB transmission via shortening of infectious period and, 3) exclude TB to allow preventive treatment (Corbett and MacPherson 2013). In a South African study passive case finding identified only 33% of HIV-infected persons with smear positive TB (Wood et al.

2007), strengthening the need to implement active and intensified case finding approaches in communities.

ART reduces the risk of active TB disease in HIV-infected persons, albeit in a time dependent manner (Lawn et al., 2011). The incidence of TB disease can be more than halved if ART is started within five years of HIV seroconversion (Harries et al.

2010). Mathematical modelling of HIV-associated TB in sub-Saharan African countries estimates a reduction in incidence rates by 66%, 95% and 98% if ART is started within five years, two years or one year of HIV seroconversion, respectively, by 2050 (Williams et al. 2010). Scale up of ART can thus result in an estimated reduction in TB incidence of up to 25% over a five-year period and up to 50% over a 20-year period, according to a modelling approach (Chindelevitch et al. 2015). In agreement with this, a risk reduction of up to 70% (range: 54% to 92%) was observed in observational ART cohort studies in low burden and high burden countries (Lawn et al., 2010; Lawn, et al., 2009).

Preventive TB therapy has been shown to reduce the risk of active TB disease by 36% to 64% in a review of more than 5,000 HIV-infected persons from 13 trials (Volmink and Woldehanna 2004). A systematic review of 12 randomized controlled trials of HIV-infected individuals showed that a six to twelve month course of daily INH therapy can reduce TB incidence up to 32% (Akolo et al. 2010). Mass

administration of IPT protects individuals against TB disease but has no effect on TB incidence in the community in a high incidence setting (Churchyard et al. 2014;

Vynnycky et al. 2015). In a Zambian study a two-fold decrease in TB incidence was observed in HIV-infected persons who received six months of IPT, relative to those who received placebo (Mwinga et al. 1998). However, this protective effect of IPT was lost during a seven-year follow-up of participants from the same study (Quigley et al. 2001), with a higher TB incidence rate of 4.0 per 100 py observed in the IPT group relative to an incident rate of 2.1 per 100 py in the placebo group. Durability of protection by six months of IPT is short-lived as a limited benefit has been observed as early as 12 months after commencement of therapy (Johnson et al. 2001). No significant effect of six months of IPT daily was observed on both TB incidence and prevalence after TB therapy in a massive trial of gold miners (Churchyard et al.

2014). These studies suggest that there is limited duration of benefit after six months IPT in HIV-infected persons.

This has led to other randomised trials examining the durability of protection against TB offered by IPT and the effect of increasing IPT duration in HIV-infected persons.

Extending IPT to 36 months reduced TB incidence by 43% in a study in Botswana, but protection was sustained only in TST-positive individuals who completed therapy (Samandari et al. 2015, 2011). In India, six-month treatment of daily IPT and ethambuthol was equivalent to a 36-month regimen of daily IPT only in preventing active TB (Swaminathan et al. 2012). Extending therapy to six years did not provide any additional benefits in preventing active TB when compared to six months of daily therapy in a South African cohort (Martinson et al. 2011). A meta-analysis of the three studies mentioned above detected a 38% reduction in risk of developing active

TB with 36 months IPT compared to six months of IPT (Boon et al., 2016). This suggests that long-term IPT is required to provide adequate protection against TB disease in HIV-infected persons. The lack of durable protection after completion of six months of INH was attributed to repeated exposure to Mtb, or high force of re- infection, seen in TB endemic settings (Havlir et al., 2008). However, a recent clinical trial demonstrated that a shortened treatment regimen consisting of once weekly high-dose rifapentine and isoniazid for three months was as effective as and non- inferior to nine months of daily INH (Sterling et al. 2016). Treatment completion rates were higher in the shorter rifapentine arm compared to the isoniazid only arm, suggesting better adherence in the three-month study arm. Protection against active TB was observed to last up to three years after a three-month prophylaxis of rifampicin containing drugs (Johnson et al. 2001). In addition to preventing active TB disease, IPT can prevent TB-associated mortality in HIV-infected persons up to 37%

(Badje et al. 2017; Durovni et al. 2013). These studies suggest that shortening preventive therapy can prevent TB in HIV-infected persons and increases adherence, thereby reducing the risk of active TB in HIV-infected persons.

Daily IPT given in combination with ART for six months offers durable protection against TB, which lasted up to seven years after IPT initiation in a Brazilian study (Golub et al., 2007; Golub et al., 2015). Another study in both urban and rural settings in South Africa demonstrated TB risk reduction of 89% TB due to the combined effect of IPT and ART (Golub et al., 2009). In a South African township (informal residence), 12 months of IPT reduced TB incidence independent of ART by 37% (Rangaka et al. 2014). These studies suggest that combining IPT and ART will be more effective in preventing TB in HIV-infected persons. Thus, combining TB and

HIV care in a clinical setting is likely to effectively reduce the burden of active TB in HIV-infected persons.

The above-mentioned studies suggest that IPT should be given for extended periods in HIV-infected persons to prevent progression to active TB disease, as is recommended (World Health Organization 2011). In addition to poor adherence to treatment, as mentioned above, long-term IPT increases the risk of hepatotoxicity.

Adherence may be increased if only those persons at risk are identified, provided counselling, and provided long-term directly observed therapy to decrease risk of progression to disease. In addition, such individuals should be further investigated for subclinical TB disease and if found to be sputum positive for Mtb, provided with TB treatment. Thus, markers to identify HIV-infected persons at greatest risk of progression to TB disease would enhance early case detection and customising length of preventive therapy or full treatment for TB disease.