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The cursed duet today: Tuberculosis and HIV-coinfection

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Summary

The tuberculosis (TB) and HIV syndemic continues to rage and are a major public health concern worldwide. This deadly association raises complexity and represent a significant barrier towards TB elimination. TB continues to be the leading cause of death amongst HIV-infected people. This paper reports the challenges that lay ahead and outlines some of the current and future strategies that may be able to address this co-epidemic efficiently. Improved diagnostics, cheaper and more effective drugs, shorter treatment regimens for both drug-sensitive and drug-resistant TB are discussed. Also, special topics on drug interactions, TB-IRIS and TB relapse are also described. Notwithstanding the defeats and meagre investments, diagnosis and management of the two diseases have seen significant and unexpected improvements of late. On the HIV side, expansion of ART coverage, development of new updated guidelines aimed at the universal treatment of those infected, and the increasing availability of newer, more efficacious and less toxic drugs are an essential element to controlling the two epidemics. On the TB side, diagnosis of MDR-TB is becoming easier and faster thanks to the new PCR-based technologies, new anti-TB drugs active against both sensitive and resistant strains (i.e. bedaquiline and delamanid) have been developed and a few more are in the pipeline, new regimens (cheaper, shorter and/or more effective) have been introduced (such as the “Bangladesh regimen”) or are being tested for MDR-TB and drug-sensitive-TB. However, still more resources will be required to implement an integrated approach, install new diagnostic tests, and develop simpler and shorter treatment regimens.

Introduction

The World health organisation (WHO) reported major advances in the treatment of tuberculosis (TB) disease, with a 47% reduction in mortality between 1990 and 2015. The incidence of TB had fallen by 1.4% every year since 2000, but due to better reporting had risen to an incidence of 10.4 million cases in 2015, 11% of whom had human immunodeficiency virus (HIV) infection. Following the geographical distribution of the two epidemics, TB/HIV cases are mainly concentrated in Sub-Saharan Africa and former-Soviet Union countries (table I) [1].

TB is the most prevalent opportunistic disease among people living with HIV (PLHIV), and the most common presenting illness in newly HIV diagnosed patients. Approximately 400,000 HIV-infected persons died of TB in 2015 [1], which accounted for nearly one-third of all mortality in this high-risk population. Among the 36.7 million individuals who were estimated to be HIV-infected in 2015, one in four is estimated to have latent TB infection (LTBI) [2]; HIV+ individuals are 26-fold more likely to develop active TB disease than HIV-individuals [1]. As many as 1.17 million new TB incident cases occurred among PLHIV in 2015, a third of whom were started on antiretroviral therapy (ART).

Increased TB risk is observable as early as HIV seroconversion and further exacerbates as CD4+ T cell counts decrease. Therefore, HIV+ individuals have a much higher probability of progressing to active TB disease, although they are not necessarily more infectious to others. These are some of the reasons behind WHO recommendation that all patients with a diagnosis of TB should be offered HIV testing [1].

The management of HIV and TB co-infections is challenging and usually associated with less favourable treatment outcomes. The emergence and spread of drug resistance among Mycobacterium tuberculosis (MTB) strains constitute an even greater threat for an already problematic epidemic, for both clinical and public health reasons. In South Africa where HIV testing and drug susceptibility testing (DST) capacity for MTB is robust, 40–80% of patients with multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) are HIV-infected [3], [4]. Other more localised epidemiological “hot-spots” exist in the Russian Federation and Eastern Europe, often in association with injection drug use [5]. In a Latvian cohort of 5200 TB patients, the risk of developing drug-resistant TB was two-fold in HIV-infected individuals [6].

Higher rates of extrapulmonary disease and smear-negative pulmonary disease in HIV-infected subjects limit diagnosis based on sputum examination. Delay in TB diagnosis contributes to poor treatment outcomes amongst HIV-infected patients. The effort to have a culture-based diagnosis of TB is imperative, and aspiration of lymph node, pleural fluid, as well as blood and urine culture for mycobacteria, have been of additive yield in diagnosing XDR-TB in some HIV-infected cohorts [7].

Once TB is diagnosed in HIV-infected patients, the international consensus favours ART naïve patients to begin ART within 2 weeks since anti-TB treatment initiation if CD4 < 50 cells/mm3 or if there is significantly advanced disease, and between 2 to 8 weeks if a better immunological profile is observed [8]. Significant challenges exist for the treatment of MDR/XDR-TB in the HIV co-infected population regarding the availability of new drugs and drug-drug interactions (DDIs).

Section snippets

Screening and diagnosis

The choice of a diagnostic tool for TB depends on the purpose of testing (detecting LTBI, active TB disease or drug resistance), as well as on the clinical conditions of the patient and the local resources available.

LTBI treatment

Isoniazid monotherapy has a protective effect on reactivation of LTBI. In a study by Golub et al. [68], the protective effect in HIV-infected individuals lasted for 2 to 4 years in endemic countries and more than 19 years in countries with low incidences [68], [69].

BHIVA guidelines recommend treating LTBI in HIV+ patients with daily isoniazid (H) with pyridoxine as the preferred method for 6 months or, an alternative, combination of rifampicin (R) and H for 3 months. NICE, however, recommends

HIV-TB special topics

The management of HIV-TB is complicated by several factors; firstly, DDIs between TB drugs and ART makes it difficult to design safe and effective regimens, which can cause severe adverse effects, such as hepatotoxicity and neurotoxicity. Secondly, in restoring immunity, ART can trigger the immune reconstitution inflammatory syndrome (IRIS), whereby the host inflammatory response to MTB infection is disproportionate and worsens the patient's status. Last but not least, TB in HIV is more likely

Expert commentary and conclusions

TB and HIV co-infections continue to be major public health concerns worldwide. Their deadly association have slowed down the TB incidence decline over the last two decades, representing a significant barrier towards TB elimination. At the same time, TB is still responsible for almost one-third of deaths among HIV-infected people.

Still many challenges lay ahead before being able to address this co-epidemic efficiently. Such problems cover all areas of TB control, such as diagnosis, drugs

Funding statements

none.

Disclosure of interest

the authors declare that they have no competing interest.

Acknowledgements

none.

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