Antiretroviral Therapy and Tuberculosis: What's the Connection and What's the Way Forward?

Abstract

The articles by Nicholas et al1 and Petit et al2 in this issue of the Journal of Acquired Immune Deficiency Syndromes report on the incidence of tuberculosis (TB) before and after the initiation of highly active antiretroviral therapy in high and low-TB-prevalence settings. The TB incidence rate reported by Nicholas et al1 was high (13 per 100 person-years) during the first 3 months of antiretroviral therapy (ART) in a multicountry African cohort. Petit et al also found high TB incidence (4 per 1000 person-years) during the first 6 months of ART in a low-TB-prevalence setting cohort in the United States. Multiple studies in countries with a high TB burden have consistently documented high rates of TB during the very early months of ART.3-8 This high TB incidence during the early phase of ART is, at least in part, the result of unmasking of subclinical TB during the initial rapid restoration of immune response.9,10 However, suboptimal TB case finding due to the use of poorly sensitive TB screening and diagnostic tools before the initiation of ART is also a contributory factor for this reported high TB incidence. Nicholas et al used respiratory symptoms lasting for a duration of ≥2 weeks as the sole screening criterion to identify TB suspects. This TB screening approach has been shown to have a low sensitivity and likely to miss a large proportion of prevalent cases at the time of ART initiation.11,12 Many of the cases identified as incident TB cases during the first 3 months of ART could have been identified before the initiation of ART with the use of a more sensitive TB-screening tool. The World Health Organization (WHO) recommends that people living with HIV (PLHIV) in resource-constrained settings should be actively screened for TB using an evidence-based symptom screening tool (any one of current cough, fever, night sweats, or weight loss) and that the identified TB suspect should be further evaluated.13 In addition to using a less sensitive TB-screening tool, Nicholas et al used sputum smear microscopy and chest radiography for the diagnosis of TB. These diagnostic tests have a low sensitivity to detect culture-positive TB among HIV-infected individuals and might have missed some prevalent TB cases at the initiation of ART.14 A study in South Africa found that when using routine liquid culture to identify persons with active TB before initiating ART, the TB incidence rates after the initiation of ART were 2-fold lower than previously reported and that the rates during the first 3 months of ART were comparable with the rates during months 4-12.15 This study by Lawn et al suggests that approximately half of incident TB cases during the first 3 months of ART under routine program conditions might have been diagnosed before the initiation of ART by using sensitive screening methods and diagnostic tests such as sputum TB culture. Although there are international efforts to scale up culture-based TB diagnosis, the availability of qualified laboratory facilities that can reliably perform this test remains limited.16,17 Moreover, despite the high sensitivity, automated liquid culture takes a median of >3 weeks to yield a positive result, delaying the diagnosis of TB and thereby limits the value of culture results for clinical management. The new fully automated polymerase chain reaction-based Xpert MTB/RIF assay developed using GeneXpert technology (Cepheid, Sunnyvale, CA) can be used at the district level or even closer to the point of care and can provide TB diagnosis and identify rifampin resistance in <2 hours. This assay has been recently endorsed by the WHO as the first diagnostic test for TB suspects among PLHIV and offers great potential to revolutionize TB diagnosis among this high-risk population.18,19 A low CD4 count was the main risk factor for the development of TB during ART identified in both the articles and highlights the need for the initiation of ART at higher CD4 counts to reduce TB risk. The recently revised WHO guidelines on ART for HIV infection among adults and adolescents recommend the initiation of ART at CD4 count <350 cells per cubic millimeter.20 Although the early initiation of ART in accordance with these new WHO ART guidelines would likely reduce the incidence of TB, the current debate revolves around even earlier initiation of ART to achieve the maximum TB-preventive benefit of ART.21,22 A recent HIV prevention randomised clinical trial (HPTN 052) initiating early ART among serodiscordant couples reported a statistically significant reduction in the risk of extrapulmonary TB (P = 0.0013) among the HIV-infected partner who was starter on ART at a CD4 count of 350-550 cells per cubic millimeter.23 A study from South Africa suggested that minimizing the time spent at CD4 count <500 cells per cubic millimeter as a result of early HIV diagnosis and initiation of ART at higher CD4 counts was necessary to reduce the long-term burden of TB among PLHIV.10 A mathematical modeling study suggests that widespread implementation of ART early in the course of HIV infection using an “HIV test and treat” strategy may have a major impact on controlling HIV-associated TB at a population level.24,25 Nicholas et al found an 88% reduction of TB incidence between the first 3 months of ART and the period after the first year of treatment (13 per 100 vs. 1.5 per 100 person-years.) Similarly, Petit et al also found a dramatic reduction in TB risk between the first 6 months of ART and the period after the first 6 months (4 per 1000 vs. 0.7 per 1000 person-years). A meta-analysis of multiple observational cohort studies in countries with both high and low TB incidence rates reported TB risk reduction of 54-92% during the first few years of ART compared with PLHIV not on ART.26-31 Despite the dramatic reduction in TB risk among PLHIV on long-term ART, this risk remains several times higher than that observed among persons without HIV infection living in the same communities.4,8,10,32 A 5-year follow-up study from South Africa suggested that ART reduced the TB rates from 12.5 per 100 person-years in the first year after the initiation of ART to 2.2 per 100 person-years in the fifth year; however, this later rate was still 3 times higher than that among HIV-seronegative adults in the same community.10 Even among patients who achieved CD4 cell counts >500 cells per cubic millimeter, the TB risk stayed 2 times higher than the background rate. These findings highlight the fact that for long-term reduction of TB among PLHIV on ART, other adjunctive strategies such as isoniazid preventive therapy (IPT) should be implemented along with ART. Several studies have demonstrated the additive benefit of ART and IPT.33-35 A randomized controlled trial conducted in Botswana suggested that tuberculin skin test-positive PLHIV on ART benefited the most from IPT.36 The recent WHO guidelines for intensified TB case finding and IPT for PLHIV in resource-constrained settings recommend that once active TB has been determined to be unlikely (through the application of the same evidence-based symptom screening tool described above), PLHIV should be started on IPT for a minimum of 6 months.13 For longer term protection from IPT, the Guidelines recommend 36 months as a surrogate for life-long IPT. The feasibility and cost effectiveness of life-long IPT, however, needs to be evaluated in programmatic settings. TB continues to be a major cause of preventable illness and death among PLHIV. Widespread testing for HIV infection and early initiation of ART would substantially reduce the incidence of TB among PLHIV on ART. In addition, aggressive promotion of routine TB symptom screening especially during the early months of ART, use of better diagnostic tools, and implementation of IPT in HIV service settings are needed to effectively control this scourge among PLHIV.