Epidemiology, pathogenesis, clinical presentation and management of TB in patients with HIV and diabetes

Caused by Mycobacterium tuberculosis,TBistheleading cause of death from an infectious disease. HIVand diabetes are recognised risk factors for progression of TB disease and both have a strong impact on the diagnosis and management of TB, threatening efforts to end TB globally. Here we provide the latest data on the complex interplay between these conditions. TB patients with HIV present systemic immune activation, increased HIV viral load, more severe clinical presentations and reduced success of TB therapy. Similarly, TB patients with diabetes are characterised by an exaggerated adaptive immunity, worsening of the clinical presentations and a higher risk for multidrug resistance and treatment failure. It is important to strengthen resources to prevent these comorbidities from occurring and to implement screening, early diagnosis and appropriate management strategies.

In 2021, an estimated 10.6 million people had TB worldwide, leading to 1.6 million deaths. TB is present in all countries and age groups: 6 million men, 3.4 million women and 1.2 million children. These figures are dramatic, given that TB is curable and preventable. TB is an ongoing pandemic, with increased new cases and deaths in recent years due to the reduction in TB services during the COVID-19 pandemic. 1 In infected patients, Mycobacterium tuberculosis (Mtb) replication is controlled through the immune response involving both innate (mostly at the beginning) and adaptive immunity, with important roles for CD4 and CD8 T-cells, although the correlates of protective immunity are not yet clear. 2 In people at risk of TB, the WHO recommends preventive therapy to reduce the risk of progression to TB disease. 3 The main five risk factors for progression to TB disease are undernourishment, HIV infection, alcohol use disorders, smoking (especially among men) and diabetes mellitus (DM). 3 In this review, we focus on the epidemiology, pathogenesis, clinical presentation, treatment and prevention of TB coinfection with HIV and with DM.

EPIDEMIOLOGY
Globally, there are an estimated 38.4 million people living with HIV (PLWH), and 537 million with DM, mostly type 2 DM. 4 In 2022, the global estimate of HIV-coinfected patients with TB was 710,000 (6.7% of all TB cases), and 187,000 deaths. 5 With a pooled DM prevalence of 15.3% in TB patients, 6 it is likely that at least 1.0-1.5 million people have combined TB-DM. However, numbers are likely to grow with a global doubling of DM prevalence over the next 30 years, the largest increase occurring in sub-Saharan Africa and Asia.
The risk of TB is much higher in PLWH than in those with DM, and strongly associated with the level of immunodeficiency ( Figure 1A and B; Table 1). Soon after HIV infection, the risk of TB disease increases 2-5-fold compared to non-HIV-infected individuals. With progression to HIV-induced severe immunodeficiency, the risk of TB is further increased at least 20-fold greater than in the general population. Antiretroviral therapy (ART) for HIV-1 does not fully restore the baseline level of risk. 22 It is unknown how many people suffer from a combination of TB, HIV and DM. To date, the highest HIV prevalence among TB patients is found in sub-Saharan Africa (SSA), exceeding 50% in parts of southern Africa; the highest reported prevalence rates of DM in TB patients is in India. However, SSA is witnessing the most rapid growth in DM worldwide, while HIV prevalence is rising in other countries, such as Russia, where DM is also common. DM is associated with an estimated 3.5-fold increased risk of TB, with the highest risks found in TB-endemic countries. 23 Glycaemic control is likely to be an important means of reducing the risk of TB. 24,25 PATHOGENESIS HIV-TB pathogenesis is complex, with increased levels of circulating immune complexes found in the early stages and associated with localised tissue necrosis that may lead to increased bacillary numbers. 26 The excessive type I interferon (IFN) signalling inhibits the immunoprotective effects of type II IFN on Mtb infection in macrophages co-infected with HIV-1, leading to inefficient containment of Mtb infection and disease reactivation. 27 HIV-TB coinfection is associated with systemic immune activation, 28 which precedes CD4 T-cell depletion. 29 Factors underlying increased susceptibility to TB are still largely unknown in the case of DM, but innate immunity in TB-DM may be underperforming, while adaptive immunity may be exaggerated, with a possible role for excess advanced glycation end products, oxidative stress and epigenetic or immunometabolic changes. 30 Clinical presentation Clinical presentation of TB in PLWH varies by CD4 T-cell count: if ,350/lL, lung lesions appear similar to those in the non-HIV-infected individuals, including presence of infiltrates in the upper lobe and cavity development. With lower CD4 T-cell counts (e.g., ,50/lL), extrapulmonary TB (with potential concomitant pulmonary TB) is more common, accounting for up to 40-80% of the manifestations. Patients may present with lymphadenitis, pleuritis, pericarditis, meningitis, central nervous system tuberculomas, or with disseminated disease manifestations. Radiological images may show atypical features, including lower lobe or middle lobe diseases, miliary infiltrates with lack of cavitations. Transient decrease in CD4 Tcell count and a 5-160-fold rise in HIV load have been demonstrated in TB disease; 31 this is associated with a more rapid progression of HIV disease. 15 TB-immune reconstitution inflammatory syndrome (TB-IRIS) is a paradoxical deteriorating or recurring of pre-existing TB lesions, or a development of new lesions in patients on effective anti-TB treatment. In non-HIV-infected patients, prevalence is 2-23%, whereas in PLWH a retrospective metaanalysis of 54 cohorts showed that the incidence of TB-IRIS in patients on ART treatment was 15.7%, with a mortality of 3.2%. 32 Risk factors for a paradoxical response in PLWH include disseminated disease, lymphopenia or CD4 T-lymphocyte count ,50/mm 3 and a marked increase in lymphocyte count or suppression of HIV-RNA replication with ART. The median time to onset of the paradoxical response is usually 2-4 weeks in PLWH on ART. However, clinicians should be aware that TB-IRIS could occur even later than 4 weeks after anti-TB treatment initiation. Unlike HIV, DM is not associated with extrapulmonary or disseminated TB; however, some studies have shown it is associated with more pulmonary cavities and a higher bacterial load, 16 Also, diabetic TB patients tend to be older and heavier than TB patients without DM.

Diagnosis
For the initial pulmonary TB diagnosis, especially in PLWH, a molecular test such as GeneXpert (Cepheid, Sunnyvale, CA, USA) should be used. Microbial diagnosis of HIV-associated TB may be difficult at a late stage of HIV disease due to the (possibly) low number of bacilli detected using standard procedures, and the fact that extrapulmonary TB is more common. 33 Mycobacterial blood cultures and urine lipoarabinomannan have shown considerable sensitivity in patients with advanced HIV. 14 In contrast, these tests lack sensitivity in diabetic TB patients and diagnostic approaches are similar to those for patients without DM.
Some studies have suggested a relation between HIV and drug resistance, possibly as a result of nosocomial transmission of drug-resistant strains, but this was not found in a systematic review. 34 In contrast, two systematic reviews have shown that DM is associated with an almost two-fold higher prevalence of multidrug-resistant TB (MDR-TB), both for primary as well as acquired resistance. One study using whole-genome sequencing has confirmed these findings and shown that mutations associated with resistance to other drugs may also be more common. 35 Treatment TB treatment is similar for both TB-HIV and TB-DM. Although some guidelines have suggested a need for prolonged TB therapy, this is not supported by evidence. TB treatment success rates remain lower among PLWH (77% globally in 2021) than in non-HIV-infected subjects (86% globally in 2021), although the WHO has registered steady improvements over time. 8 Providing TB treatment and ART to PLWH with TB, is estimated to have averted 74 million deaths between 2000 and 2021. 8 In PLWH, TB therapy is a major challenge complicated by the optimal timing of ART, drug-drug interactions, overlapping toxicities, IRIS, conditions that may affect treatment adherence and MDR-TB emergence. For drug-susceptible TB, daily administration of isoniazid (INH), rifampicin (RIF), ethambutol, pyrazinamide (PZA) for 2 months is recommended, followed by 4 months of INH and RIF. 36 A 4-month regimen comprising rifapentine/INH/PZA/moxifloxacin has been shown to be non-inferior to the standard therapy; 8 however, the trial included only 8% of HIV-infected patients, limiting the comparison of regimens in this population. 37 ART should be started regardless of CD4 T-cell count within 2 weeks of initiating TB therapy, especially in patients with CD4 ,50/mm 3 . 36 In these patients, early ART initiation significantly reduces TB mortality. 38 ART should be delayed for at least 4 weeks in PLWH with TB meningitis, so that the risk of severe neurological TB-IRIS may be treated with adjunctive glucocorticoids. 39 For all forms of drugresistant TB, the appropriate regimen should be selected on the basis of resistance tests. Recent developments for the treatment of these forms of TB are given in Table 2. 40 Unless there are drug-drug interaction issues with ART, these regimens can be used regardless of HIV status. A TB-IRIS therapy regimen comprising prednisone treatment during the first 4 weeks after the initiation of ART for HIV infection resulted in a lower incidence of TB-IRIS than placebo, without evidence of an increased risk of severe infections or cancers. 39,41 In TB-DM, TB treatment is similar but therapy failure, disease recurrence, toxicity or dangerous drug interactions are more common. 42,43 Drug toxicity Drug toxicity is a major challenge due to the shared toxicity of ART with anti-TB drugs. Drug-induced liver injury is the most serious adverse event linked to antiretrovirals and some anti-TB drugs such as PZA, RIF and INH. 36 If drug-induced liver injury is suspected, all potential hepatotoxic drugs should be stopped and administered again when liver function tests have improved. 44 Cutaneous drug reactions have been reported with thiacetazone, and with nevirapine and abacavir within ART. Severity may range from transient erythematous rash to lifethreatening Steven-Johnson syndrome. 44 Neuropsychiatric side effects are mainly found with dolutegravir and efavirenz. Among anti-TB drugs, INH, cycloserine and terizidone may cause psychosis and suicidal ideation. 44 Prolongation of the QT interval is associated with several TB drugs (fluoroquinolones, bedaquiline [BDQ], clofazimine), and require close electrocardiogram monitoring during treatment. 44 In TB-DM patients who are on average 10-15 years older than TB-only patients, liver fibrosis, diabetic nephropathy and concomitant drug treatment may lead to more drug toxicity and side effects.

Drug interactions
Important agents in TB therapy with high sterilising activity, rifamycins are responsible for several drug interactions as they induce cytocrome P450 enzyme-3A4 and uridine disphosphate glucoronosyltrasferase-1A1 and are P-glycoprotein transporters. 44 The most significant RIF drug-drug interactions with ART are shown in Table 3. 45,46 RIF substantially lowers levels of most oral drugs, but not metformin, 47 which likely improves TB treatment outcomes. Insulin is often advocated as first choice in TB-DM as it is not metabolised, but it may be inaccessible or hard to use in low-resource settings. Limited data are available on interactions between ART and drugs for RIF-resistant TB. BDQ is a CYP3A4 substrate, thus drugs that inhibit this enzyme (such as ritonavirboosted PIs), may lead to an increase in BDQ concentration, increasing its toxicity as QT-prolongation. In contrast, nevirapine and rilpivirine do not appear to have a significant effect on BDQ exposure. For delamanid and linezolid, interactions with ART are considered unlikely. 48 Prevention and control Prevention of HIV-associated TB now largely relies on TB disease screening and TB preventive therapy (TPT). 28 These measures contribute to reducing the risk of TB reactivation in PLWH with TB infection (TBI). 49 Current tests for TBI have a lower sensitivity in people with advanced HIV, 20 and according to the WHO, all HIV-infected individuals should receive TPT irrespective of the TBI test result. 3 However, the yield of TBI screening and TPT in low TB-endemic settings is currently unknown, and some guidelines in Western countries now advocate a more risk-stratified approach. There are several regimes for TPT, including a 1-month regimen of combined daily rifapentine and INH that proved effective in HIVinfected people. 28 Current guidelines do not recommend TPT for DM patients, but one study in Indonesia has shown a high incidence among them and a positive interferongamma release assay result; 50 the first randomised clinical trial examining the effect and safety of TPT among diabetics has started in Uganda and Tanzania (Clinical Trial Registration NCT04600167). 51 Other proposed measures to control TB-HIV and TB-DM include a more effective vaccine than bacille Calmette-Guérin, which mainly protects against childhood TB, along with better control of both HIV and DM.

CONCLUSION
Both HIV infection and DM have a strong impact on the clinical presentation, diagnosis and management of TB. It is vital that we strengthen our efforts to