Predicting tuberculosis among people living with HIV on antiretroviral treatment in high TB burden settings

Tuberculosis (TB) remains a common opportunistic infection and a major cause of death among people living with HIV (PWH). The aim of this thesis is to evaluate biomarkers that can predict incident TB and to investigate the role of human cytomegalovirus (HCMV) infection in TB disease progression among PWH in high TB and HIV burden settings. The present thesis begins by showing the incidence of TB among PWH who are on long term antiretroviral therapy (ART) in Thailand. We analyzed data from the HIV cohort with the longest follow-up in Southeast Asia. Then, we provide new evidence that the monocyte to lymphocyte ratio (MLR), a simple biomarker that is available in routine HIV care, can be used to predict the occurrence of TB in PWH. We also validated the MLR in combination with the hemoglobin level to assess TB disease progression in a large international PWH cohort. This thesis also identified the role of the plasma kynurenine to tryptophan (K/T ratio) in predicting TB disease, diagnosis and monitoring treatment response. Lastly, we assessed the role of HCMV infection in the progression of TB disease among virally suppressed PWH. The results presented here might only apply to high TB and HIV burden settings. Nevertheless, the findings from this thesis have the potential to open up the use of biomarkers that are readily available in routine HIV care and may provide an opportunity to scale up preventive treatment, which has great potential to reduce TB morbidity and mortality in PWH

Predicting tuberculosis among people living with HIV on antiretroviral treatment in high TB burden settings

Tuberculosis (TB) remains a common opportunistic infection and a major cause of death among people living with HIV (PWH). The aim of this thesis is to evaluate biomarkers that can predict incident TB and to investigate the role of human cytomegalovirus (HCMV) infection in TB disease progression among PWH in high TB and HIV burden settings. The present thesis begins by showing the incidence of TB among PWH who are on long term antiretroviral therapy (ART) in Thailand. We analyzed data from the HIV cohort with the longest follow-up in Southeast Asia. Then, we provide new evidence that the monocyte to lymphocyte ratio (MLR), a simple biomarker that is available in routine HIV care, can be used to predict the occurrence of TB in PWH. We also validated the MLR in combination with the hemoglobin level to assess TB disease progression in a large international PWH cohort. This thesis also identified the role of the plasma kynurenine to tryptophan (K/T ratio) in predicting TB disease, diagnosis and monitoring treatment response. Lastly, we assessed the role of HCMV infection in the progression of TB disease among virally suppressed PWH. The results presented here might only apply to high TB and HIV burden settings. Nevertheless, the findings from this thesis have the potential to open up the use of biomarkers that are readily available in routine HIV care and may provide an opportunity to scale up preventive treatment, which has great potential to reduce TB morbidity and mortality in PWH

Risk-stratified treatment for drug-susceptible pulmonary tuberculosis

The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, 95%CI 0.54–0.77). The only other risk factors identified are markers of higher baseline disease severity, namely Xpert MTB/RIF cycle threshold and extent of disease on baseline chest radiography (Xpert: HR 1.43 for every 3-cycle-threshold decrease, 95%CI 1.07–1.91; extensive disease: HR 2.02, 95%CI 1.07–3.82). From these risk factors, we developed a simple risk stratification to classify disease phenotypes as easier-, moderately-harder, or harder-to-treat TB. Notably, high rifapentine exposures are not associated with any predefined adverse safety outcomes. Our results suggest that the easier-to-treat subgroup may be eligible for further treatment shortening while the harder-to-treat subgroup may need higher doses or longer treatment

Predicting tuberculosis among people living with HIV on antiretroviral treatment in high TB burden settings

Tuberculosis (TB) remains a common opportunistic infection and a major cause of death among people living with HIV (PWH). The aim of this thesis is to evaluate biomarkers that can predict incident TB and to investigate the role of human cytomegalovirus (HCMV) infection in TB disease progression among PWH in high TB and HIV burden settings. The present thesis begins by showing the incidence of TB among PWH who are on long term antiretroviral therapy (ART) in Thailand. We analyzed data from the HIV cohort with the longest follow-up in Southeast Asia. Then, we provide new evidence that the monocyte to lymphocyte ratio (MLR), a simple biomarker that is available in routine HIV care, can be used to predict the occurrence of TB in PWH. We also validated the MLR in combination with the hemoglobin level to assess TB disease progression in a large international PWH cohort. This thesis also identified the role of the plasma kynurenine to tryptophan (K/T ratio) in predicting TB disease, diagnosis and monitoring treatment response. Lastly, we assessed the role of HCMV infection in the progression of TB disease among virally suppressed PWH. The results presented here might only apply to high TB and HIV burden settings. Nevertheless, the findings from this thesis have the potential to open up the use of biomarkers that are readily available in routine HIV care and may provide an opportunity to scale up preventive treatment, which has great potential to reduce TB morbidity and mortality in PWH

Monocyte-to-lymphocyte ratio as a predictor of TB among people living with HIV

BACKGROUND: Diagnostic tools to identify incipient or subclinical TB stages will be helpful for preventive intervention. A simple biomarker to predict TB may be the monocytes to lymphocytes ratio (ML ratio) in peripheral blood.METHODS: We assessed the relationship between multiple time-updated ML ratio measurements and incidence of TB in people living with HIV (PLWH) after antiretroviral therapy (ART) was initiated. The ML ratio was updated at least every 6 months. TB incidence with corresponding 95% confidence intervals stratified according to time-updated ML ratio was calculated using ML ratio in quartiles.RESULTS: A total of 1305 PLWH were included in the analyses: 46 had incident TB and 1259 remained TB-free. The TB incidence rate was 10.3 (95% CI 7.1–14.9) cases/1000 patient-years (PYR) among participants with ML ratio ≥0.25 compared with 1.1/1000 PYR (95% CI 0.4–2.9) among those with ML ratio &lt;0.15. At cut-point 0.23, the ML ratio provided a diagnostic area under the receiver operating characteristics curve (AROC) of 0.849 (95% CI 0.784–0.914) and a sensitivity of 85% and specificity of 71%.CONCLUSION: Increased ML ratio was predictive of incident TB among PLWH on or after ART. The ML ratio can be a simple tool to stratify the risk of TB in PLWH.</jats:p

Monocyte-to-lymphocyte ratio as a predictor of TB among people living with HIV

B A C K G R O U N D: Diagnostic tools to identify incipient or subclinical TB stages will be helpful for preventive intervention. A simple biomarker to predict TB may be the monocytes to lymphocytes ratio (ML ratio) in peripheral blood. M E T H O D S: We assessed the relationship between multiple time-updated ML ratio measurements and incidence of TB in people living with HIV (PLWH) after antiretroviral therapy (ART) was initiated. The ML ratio was updated at least every 6 months. TB incidence with corresponding 95% confidence intervals stratified according to time-updated ML ratio was calculated using ML ratio in quartiles. R E S U L T S: A total of 1305 PLWH were included in the analyses: 46 had incident TB and 1259 remained TB-free. The TB incidence rate was 10.3 (95% CI 7.1–14.9) cases/1000 patient-years (PYR) among participants with ML ratio ≥0.25 compared with 1.1/1000 PYR (95% CI 0.4–2.9) among those with ML ratio,0.15. At cut-point 0.23, the ML ratio provided a diagnostic area under the receiver operating characteristics curve (AROC) of 0.849 (95% CI 0.784–0.914) and a sensitivity of 85% and specificity of 71%. C O N C L U S I O N: Increased ML ratio was predictive of incident TB among PLWH on or after ART. The ML ratio can be a simple tool to stratify the risk of TB in PLWH

Incidence and factors associated with active tuberculosis among people living with HIV after long-term antiretroviral therapy in Thailand: a competing risk model

© 2022, The Author(s).Background: Antiretroviral therapy (ART) is known to reduce tuberculosis (TB) incidence among people living with HIV (PLWH). However, studies describing the impact of long-term ART and CD4 count recovery on TB incidence remain scarce due to limited follow up in previous studies. We evaluated TB incidence in a long-term cohort of PLWH on ART in Thailand. Methods: We conducted an analysis of PLWH aged ≥ 18 years who started ART between 1996 and December 2020. Participants were followed up every 6 months for routine HIV care. TB risk factors, body mass index (BMI), physical examination and full differential blood counts were evaluated at each clinic visit, and CD4 cell counts and HIV RNA every 12 months. Participants diagnosed with TB > 3 months after starting ART were classified as incident cases. Time to event models with death as a competing risk, were used to derive the TB cumulative incidence function (CIF) after ART initiation, and assess time-updated factors associated with incident TB using a six month lag. Results: A total of 2,636 PLWH contributing 24,229 person years (PY) of follow-up on ART were analysed. Median age was 32.0 (IQR 27.4–37.6) years; 67.5% were male. Median CD4 cell count at ART initiation was 264 (IQR 167–379) cells/mm3 and median follow-up duration was 7.6 (IQR 1.9–15.7) years. During follow-up, 113 PLWH developed TB. The probability of incident TB was 0.7%, 1.7%, 3.3% and 4.3%, at 1, 2, 5 and 7 years after ART initiation, respectively. TB CIF was highest among participants with CD4 < 50 cells/mm3. The overall crude incidence of TB was 4.66 (95% CI 3.87–5.60) per 1000 PY. Low CD4 count, BMI < 18 kg/m2, and substance use in the previous six months were significantly associated with incident TB. Incidence declined with time on suppressive ART, but remained higher than the Thai general population 7 years after ART initiation (2.2 vs 1.5/1000 PY, respectively). Conclusion: Despite a marked reduction in TB incidence following ART, ongoing TB risk remains high among PLWH, despite long-term suppressive ART. Those with low CD4 cell counts, who are underweight, or currently having substance abuse should be carefully monitored

Monocyte-to-lymphocyte ratio as a predictor of TB among people living with HIV

B A C K G R O U N D: Diagnostic tools to identify incipient or subclinical TB stages will be helpful for preventive intervention. A simple biomarker to predict TB may be the monocytes to lymphocytes ratio (ML ratio) in peripheral blood. M E T H O D S: We assessed the relationship between multiple time-updated ML ratio measurements and incidence of TB in people living with HIV (PLWH) after antiretroviral therapy (ART) was initiated. The ML ratio was updated at least every 6 months. TB incidence with corresponding 95% confidence intervals stratified according to time-updated ML ratio was calculated using ML ratio in quartiles. R E S U L T S: A total of 1305 PLWH were included in the analyses: 46 had incident TB and 1259 remained TB-free. The TB incidence rate was 10.3 (95% CI 7.1–14.9) cases/1000 patient-years (PYR) among participants with ML ratio ≥0.25 compared with 1.1/1000 PYR (95% CI 0.4–2.9) among those with ML ratio,0.15. At cut-point 0.23, the ML ratio provided a diagnostic area under the receiver operating characteristics curve (AROC) of 0.849 (95% CI 0.784–0.914) and a sensitivity of 85% and specificity of 71%. C O N C L U S I O N: Increased ML ratio was predictive of incident TB among PLWH on or after ART. The ML ratio can be a simple tool to stratify the risk of TB in PLWH

Efficacy and safety of a once-daily single-tablet regimen of tenofovir, lamivudine, and efavirenz assessed at 144 weeks among antiretroviral-naive and experienced HIV-1-infected Thai adults

OBJECTIVE: To assess the efficacy and safety of a new single-tablet regimen (STR) of tenofovir disoproxil fumarate (TDF) 300mg, lamivudine (3TC) 300mg, and efavirenz (EFV) 600mg in HIV-infected Thai patients. METHODS: This was a prospective study performed for 144 weeks among 51 treatment-naive patients and 49 experienced patients on separate tablets of TDF, 3TC, and EFV with HIV RNA<50 copies/ml. CD4, HIV RNA, liver and renal function, and lipid profiles were assessed at baseline, weeks 12, 24, and 48, and then every 24 weeks. RESULTS: The median baseline CD4 cell count was 512 cells/mul for treatment-experienced patients and 230 cells/mul for treatment-naive patients. Median baseline log10 HIV-1 RNA for treatment-naive subjects was 4.9 copies/ml. From the intention-to-treat (ITT) analysis, the proportion of subjects with HIV RNA <50 copies/ml at week 48, 96, and 144 was 95%, 94%, and 94%, respectively, for antiretroviral-experienced patients and 88%, 90%, and 80%, respectively, for antiretroviral-naive patients. One virological failure at week 12 had primary drug resistance of K70R, T69D, V75L. Three serious adverse events occurred (tension headache, infective endocarditis, and cervical dysplasia) and another three discontinued the study drug due to EFV intolerance. CONCLUSIONS: This generic STR TDF/3TC/EFV is effective and well-tolerated. These findings lend support to the use of this generic STR as first-line antiretroviral therapy in resource-limited settings