Tuberculosis among people living with and without HIV in lower-income countries: Transmission, Resistance, Mortality.

Zürcher, Kathrin (2021). Tuberculosis among people living with and without HIV in lower-income countries: Transmission, Resistance, Mortality. (Unpublished). (Dissertation, University of Bern, Faculty of Medicine, the Faculty of Science and the Vetsuisse Faculty)

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Tuberculosis (TB), an airborne disease caused by the bacterium Mycobacterium tuberculosis (Mtb), is one of the most deadly infectious diseases, with an estimated 10 million newly diagnosed TB cases and 1.4 million deaths per year worldwide. The HIV pandemic and the emergence of drug-resistant Mtb strains are the main challenges to TB control, especially in low-and middle-income countries. HIV infection induces immunodeficiency and is a decisive risk factor for TB. With the significant scale-up of antiretroviral therapy (ART) for people living with HIV (PLHIV), their prognosis has improved and reduced TB incidence in this population. Nevertheless, the risk of TB in PLHIV on ART remains higher than in people without HIV. In addition, the diagnosis of TB in PLHIV is more challenging due to the reduced occurrence of lung cavitation and lower bacterial load in the sputum compared to HIV-negative people. The rising number of drug-resistant TB is another threat to the control of TB. To prevent drug-resistant TB, strategies such as surveillance, access to comprehensive drug susceptibility testing (DST), rapid treatment initiation and treatment completion with an appropriate regimen are still lacking in many low-and middle-income countries.

In this thesis, I explore different aspects of the epidemiology of TB, especially drug-resistant TB in PLHIV and HIV-negative people seeking care in low-and middle-income countries. I will focus on Mtb transmission, the management of TB in adults (age ≥16 years) from diagnosis to treatment and clinical outcomes, and the evolution of drug-resistant Mtb and the clinical consequences.

In chapter 1, I provide an introduction to TB. I describe the global burden of TB, the pathogen and the course of infection, the genetic diversity of TB, the diagnosis of TB including DST and the treatment of pan-susceptible and drug-resistant TB. In addition, I describe the current challenges to the control of TB.

Chapter 3 and chapter 4 focus on the transmission of Mtb at a primary care clinic in South Africa using a novel approach. Paper 1 is the study protocol, which describes the range of collected patient and environmental-associated data in detail. In paper 2, I showed that the risk of Mtb transmission increased with the presence of young adults and higher room humidity at the primary care clinic. During a clinic visit of one hour, the risk of infection was between 3-5% and increased to 9-29% for patients with monthly visits.

Chapter 5 and chapter 6 focus on the management of TB in adult PLHIV at ART clinics in low-and middle-income countries. In paper 3, I analysed clinical data of 2,695 adult PLHIV who developed TB, of whom 1,930 (72%) had pulmonary TB, and 765 (28%) had extra-pulmonary TB. I demonstrated the difficulties in obtaining bacteriological confirmation in PLHIV who also had pulmonary TB or extra-pulmonary TB (52% and 42%). I found no association between the increased mortality in PLHIV and the type of TB they developed (extra-pulmonary or pulmonary). I showed that bacteriological confirmation was associated with reduced mortality in PLHIV who had pulmonary TB or extra-pulmonary TB than PLHIV with a negative diagnostic result. Paper 4 used site-level data to study the integration of multidrug-resistant TB (MDR-TB) services at 29 ART clinics. I show that 14 (48%) ART clinics reported full MDR-TB services on-site, nine (31%) reported partial integration, and six (21%) had access to off-site MDR-TB services only. I demonstrated that the 22 clinics with on-site molecular DST could identify drug resistance to first-line drugs but rarely to second-line drugs. In addition, I showed that ART clinics with full integration of MDR-TB services were more likely to prescribe individualised MDR-TB treatment compared to off-site services.

Chapters 7 to 10 focus on the evolution of drug-resistant Mtb and clinical consequences. In paper 5 and 6, I examined mortality in adult PLHIV and HIV-negative adults who developed TB in seven low-and middle-income countries. I compared mortality by DST results done locally that were discordant or concordant with the results from the reference laboratory using culture-based phenotypic DST or WGS. In both studies, the degree of drug resistance, discordant DST results potentially leading to under-treatment and discordant DST results, which resulted in under-treatment according to WHO guidelines, led to increased mortality, especially among those with drug-resistant TB. Further, I demonstrate that DST for second-line drugs was rarely available locally. Paper 7 showed that mutation with low-fitness in rpoB variants is more likely in PLHIV who also had rifampicin-resistant TB than in HIV-negative people who had rifampicin-resistant TB. Finally, paper 8 demonstrated that drug resistance to delamanid occurred in people with TB who were drug naïve to delamanid.

In this thesis, I provide insights into different aspects of the epidemiology of TB, from Mtb transmission, management of TB, and drug resistance to death, but also identify the gaps in our current knowledge. I show that new approaches can be used to study Mtb transmission. I demonstrate the challenges of diagnosing PLHIV and pulmonary or extra-pulmonary TB at ART clinics in low-and middle-income countries. In addition, I show that DST to second-line drugs is limited in many low-and middle-income countries, and there is a need for more rapid and comprehensive DST testing to ensure appropriate treatment. My survey on integrated MDR-TB services also showed that 48% of ART clinics had full integrated MDR-TB services. I showed that low-fitness mutations in rpob are more likely in PLHIV who have rifampicin-resistant TB than in HIV-negative people who had rifampicin-resistant TB and that drug resistance can occur in people natïve to delamanid. In conclusion, to control TB, we need to strengthen the access and use of point-of-care diagnostic tests to diagnose TB disease and DST for first- and second-line anti-TB drugs and access to second-line anti-TB drugs in low-and middle-income countries. In addition, we need to improve surveillance of drug-resistant TB and better treatment options to ensure the completion of the treatment.

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