Journal Article > ResearchAbstract Only
J Acquir Immune Defic Syndr; JAIDS. 1 March 2024; Volume 95 (Issue 3); 260-267.; DOI:10.1097/QAI.0000000000003341
van Heerden JK, Meintjes G, Barr D, Zhao Y, Griesel R, et al.
J Acquir Immune Defic Syndr; JAIDS. 1 March 2024; Volume 95 (Issue 3); 260-267.; DOI:10.1097/QAI.0000000000003341
Français
BACKGROUND
Tenofovir diphosphate (TFV-DP) concentration in dried blood spots is a marker of long-term adherence. We investigated the relationship between TFV-DP concentrations and virological outcomes in participants initiating tenofovir–lamivudine–dolutegravir (TLD) as first-line or second-line antiretroviral therapy.
SETTING
Three primary care clinics in Khayelitsha, Cape Town, South Africa.
METHODS
We conducted a post hoc analysis of 2 randomized controlled trials of participants initiating TLD. TFV-DP concentrations and viral loads were measured at 12, 24, and 48 weeks. Multivariable logistic regression was performed to assess the association with virological suppression (<50 copies/mL) per natural logarithm increase in TFV-DP concentration. Generalized estimating equations with logit link were used to assess associations with virological rebound. The Akaike Information Criterion and Quasi-likelihood Information Criteria were used to compare models built on continuous TFV-DP data to 4 previously defined concentration categories.
RESULTS
We included 294 participants in the analysis, 188 (64%) of whom initiated TLD as second-line therapy. Adjusted odds ratios (95% CIs) of virological suppression were 2.12 (1.23, 3.75), 3.11 (1.84, 5.65), and 4.69 (2.81, 8.68) per natural logarithm increase in TFV-DP concentration at weeks 12, 24, and 48, respectively. In participants with virological suppression at week 12, the adjusted odds ratio for remaining virologically suppressed was 3.63 (95% CI: 2.21 to 5.69) per natural logarithm increase in TFV-DP concentration. Models using continuous TFV-DP data had lower Akaike Information Criterion and Quasi-likelihood Information Criteria values than those using categorical data for predicting virological outcomes.
CONCLUSION
TFV-DP concentrations in dried blood spots exhibit a dose–response relationship with viral load. Analyzing TFV-DP concentrations as continuous variables rather than conventional categorization may be appropriate.
Tenofovir diphosphate (TFV-DP) concentration in dried blood spots is a marker of long-term adherence. We investigated the relationship between TFV-DP concentrations and virological outcomes in participants initiating tenofovir–lamivudine–dolutegravir (TLD) as first-line or second-line antiretroviral therapy.
SETTING
Three primary care clinics in Khayelitsha, Cape Town, South Africa.
METHODS
We conducted a post hoc analysis of 2 randomized controlled trials of participants initiating TLD. TFV-DP concentrations and viral loads were measured at 12, 24, and 48 weeks. Multivariable logistic regression was performed to assess the association with virological suppression (<50 copies/mL) per natural logarithm increase in TFV-DP concentration. Generalized estimating equations with logit link were used to assess associations with virological rebound. The Akaike Information Criterion and Quasi-likelihood Information Criteria were used to compare models built on continuous TFV-DP data to 4 previously defined concentration categories.
RESULTS
We included 294 participants in the analysis, 188 (64%) of whom initiated TLD as second-line therapy. Adjusted odds ratios (95% CIs) of virological suppression were 2.12 (1.23, 3.75), 3.11 (1.84, 5.65), and 4.69 (2.81, 8.68) per natural logarithm increase in TFV-DP concentration at weeks 12, 24, and 48, respectively. In participants with virological suppression at week 12, the adjusted odds ratio for remaining virologically suppressed was 3.63 (95% CI: 2.21 to 5.69) per natural logarithm increase in TFV-DP concentration. Models using continuous TFV-DP data had lower Akaike Information Criterion and Quasi-likelihood Information Criteria values than those using categorical data for predicting virological outcomes.
CONCLUSION
TFV-DP concentrations in dried blood spots exhibit a dose–response relationship with viral load. Analyzing TFV-DP concentrations as continuous variables rather than conventional categorization may be appropriate.
Journal Article > ResearchFull Text
Lancet Global Health. 1 June 2023; Volume 11 (Issue 6); e903-e916.; DOI:10.1016/S2214-109X(23)00135-3
Broger T, Koeppel L, Huerga H, Miller P, Gupta-Wright A, et al.
Lancet Global Health. 1 June 2023; Volume 11 (Issue 6); e903-e916.; DOI:10.1016/S2214-109X(23)00135-3
BACKGROUND
Sputum is the most widely used sample to diagnose active tuberculosis, but many people living with HIV are unable to produce sputum. Urine, in contrast, is readily available. We hypothesised that sample availability influences the diagnostic yield of various tuberculosis tests.
METHODS
In this systematic review and meta-analysis of individual participant data, we compared the diagnostic yield of point-of-care urine-based lipoarabinomannan tests with that of sputum-based nucleic acid amplification tests (NAATs) and sputum smear microscopy (SSM). We used microbiologically confirmed tuberculosis based on positive culture or NAAT from any body site as the denominator and accounted for sample provision. We searched PubMed, Web of Science, Embase, African Journals Online, and clinicaltrials.gov from database inception to Feb 24, 2022 for randomised controlled trials, cross-sectional studies, and cohort studies that assessed urine lipoarabinomannan point-of-care tests and sputum NAATs for active tuberculosis detection in participants irrespective of tuberculosis symptoms, HIV status, CD4 cell count, or study setting. We excluded studies in which recruitment was not consecutive, systematic, or random; provision of sputum or urine was an inclusion criterion; less than 30 participants were diagnosed with tuberculosis; early research assays without clearly defined cutoffs were tested; and humans were not studied. We extracted study-level data, and authors of eligible studies were invited to contribute deidentified individual participant data. The main outcomes were the tuberculosis diagnostic yields of urine lipoarabinomannan tests, sputum NAATs, and SSM. Diagnostic yields were predicted using Bayesian random-effects and mixed-effects meta-analyses. This study is registered with PROSPERO, CRD42021230337.
FINDINGS
We identified 844 records, from which 20 datasets and 10 202 participants (4561 [45%] male participants and 5641 [55%] female participants) were included in the meta-analysis. All studies assessed sputum Xpert (MTB/RIF or Ultra, Cepheid, Sunnyvale, CA, USA) and urine Alere Determine TB LAM (AlereLAM, Abbott, Chicago, IL, USA) in people living with HIV aged 15 years or older. Nearly all (9957 [98%] of 10 202) participants provided urine, and 82% (8360 of 10 202) provided sputum within 2 days. In studies that enrolled unselected inpatients irrespective of tuberculosis symptoms, only 54% (1084 of 1993) of participants provided sputum, whereas 99% (1966 of 1993) provided urine. Diagnostic yield was 41% (95% credible interval [CrI] 15-66) for AlereLAM, 61% (95% Crl 25-88) for Xpert, and 32% (95% Crl 10-55) for SSM. Heterogeneity existed across studies in the diagnostic yield, influenced by CD4 cell count, tuberculosis symptoms, and clinical setting. In predefined subgroup analyses, all tests had higher yields in symptomatic participants, and AlereLAM yield was higher in those with low CD4 counts and inpatients. AlereLAM and Xpert yields were similar among inpatients in studies enrolling unselected participants who were not assessed for tuberculosis symptoms (51% vs 47%). AlereLAM and Xpert together had a yield of 71% in unselected inpatients, supporting the implementation of combined testing strategies.
INTERPRETATION
AlereLAM, with its rapid turnaround time and simplicity, should be prioritised to inform tuberculosis therapy among inpatients who are HIV-positive, regardless of symptoms or CD4 cell count. The yield of sputum-based tuberculosis tests is undermined by people living with HIV who cannot produce sputum, whereas nearly all participants are able to provide urine. The strengths of this meta-analysis are its large size, the carefully harmonised denominator, and the use of Bayesian random-effects and mixed-effects models to predict yields; however, data were geographically restricted, clinically diagnosed tuberculosis was not considered in the denominator, and little information exists on strategies for obtaining sputum samples.
FUNDING
FIND, the Global Alliance for Diagnostics.
Sputum is the most widely used sample to diagnose active tuberculosis, but many people living with HIV are unable to produce sputum. Urine, in contrast, is readily available. We hypothesised that sample availability influences the diagnostic yield of various tuberculosis tests.
METHODS
In this systematic review and meta-analysis of individual participant data, we compared the diagnostic yield of point-of-care urine-based lipoarabinomannan tests with that of sputum-based nucleic acid amplification tests (NAATs) and sputum smear microscopy (SSM). We used microbiologically confirmed tuberculosis based on positive culture or NAAT from any body site as the denominator and accounted for sample provision. We searched PubMed, Web of Science, Embase, African Journals Online, and clinicaltrials.gov from database inception to Feb 24, 2022 for randomised controlled trials, cross-sectional studies, and cohort studies that assessed urine lipoarabinomannan point-of-care tests and sputum NAATs for active tuberculosis detection in participants irrespective of tuberculosis symptoms, HIV status, CD4 cell count, or study setting. We excluded studies in which recruitment was not consecutive, systematic, or random; provision of sputum or urine was an inclusion criterion; less than 30 participants were diagnosed with tuberculosis; early research assays without clearly defined cutoffs were tested; and humans were not studied. We extracted study-level data, and authors of eligible studies were invited to contribute deidentified individual participant data. The main outcomes were the tuberculosis diagnostic yields of urine lipoarabinomannan tests, sputum NAATs, and SSM. Diagnostic yields were predicted using Bayesian random-effects and mixed-effects meta-analyses. This study is registered with PROSPERO, CRD42021230337.
FINDINGS
We identified 844 records, from which 20 datasets and 10 202 participants (4561 [45%] male participants and 5641 [55%] female participants) were included in the meta-analysis. All studies assessed sputum Xpert (MTB/RIF or Ultra, Cepheid, Sunnyvale, CA, USA) and urine Alere Determine TB LAM (AlereLAM, Abbott, Chicago, IL, USA) in people living with HIV aged 15 years or older. Nearly all (9957 [98%] of 10 202) participants provided urine, and 82% (8360 of 10 202) provided sputum within 2 days. In studies that enrolled unselected inpatients irrespective of tuberculosis symptoms, only 54% (1084 of 1993) of participants provided sputum, whereas 99% (1966 of 1993) provided urine. Diagnostic yield was 41% (95% credible interval [CrI] 15-66) for AlereLAM, 61% (95% Crl 25-88) for Xpert, and 32% (95% Crl 10-55) for SSM. Heterogeneity existed across studies in the diagnostic yield, influenced by CD4 cell count, tuberculosis symptoms, and clinical setting. In predefined subgroup analyses, all tests had higher yields in symptomatic participants, and AlereLAM yield was higher in those with low CD4 counts and inpatients. AlereLAM and Xpert yields were similar among inpatients in studies enrolling unselected participants who were not assessed for tuberculosis symptoms (51% vs 47%). AlereLAM and Xpert together had a yield of 71% in unselected inpatients, supporting the implementation of combined testing strategies.
INTERPRETATION
AlereLAM, with its rapid turnaround time and simplicity, should be prioritised to inform tuberculosis therapy among inpatients who are HIV-positive, regardless of symptoms or CD4 cell count. The yield of sputum-based tuberculosis tests is undermined by people living with HIV who cannot produce sputum, whereas nearly all participants are able to provide urine. The strengths of this meta-analysis are its large size, the carefully harmonised denominator, and the use of Bayesian random-effects and mixed-effects models to predict yields; however, data were geographically restricted, clinically diagnosed tuberculosis was not considered in the denominator, and little information exists on strategies for obtaining sputum samples.
FUNDING
FIND, the Global Alliance for Diagnostics.
Journal Article > ResearchFull Text
Lancet HIV. 22 May 2023; Volume S2352-3018 (Issue 23); 00081-4.; DOI:10.1016/S2352-3018(23)00081-4
Griesel R, Zhao Y, Simmons B, Omar Z, Wiesner L, et al.
Lancet HIV. 22 May 2023; Volume S2352-3018 (Issue 23); 00081-4.; DOI:10.1016/S2352-3018(23)00081-4
BACKGROUND
The drug-drug interaction between rifampicin and dolutegravir can be overcome by supplemental dolutegravir dosing, which is difficult to implement in high-burden settings. We aimed to test whether virological outcomes with standard-dose dolutegravir-based antiretroviral therapy (ART) are acceptable in people with HIV on rifampicin-based antituberculosis therapy.
METHODS
RADIANT-TB was a phase 2b, randomised, double-blind, non-comparative, placebo-controlled trial at a single site in Khayelitsha, Cape Town, South Africa. Participants were older than 18 years of age, with plasma HIV-1 RNA greater than 1000 copies per mL, CD4 count greater than 100 cells per μL, ART-naive or first-line ART interrupted, and on rifampicin-based antituberculosis therapy for less than 3 months. By use of permuted block (block size of 6) randomisation, participants were assigned (1:1) to receive either tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus supplemental 50 mg dolutegravir 12 h later or tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus matched placebo 12 h later. Participants received standard antituberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol for the first 2 months followed by isoniazid and rifampicin for 4 months). The primary outcome was the proportion of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 24 analysed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03851588.
FINDINGS
Between Nov 28, 2019, and July 23, 2021, 108 participants (38 female, median age 35 years [IQR 31-40]) were randomly assigned to supplemental dolutegravir (n=53) or placebo (n=55). Median baseline CD4 count was 188 cells per μL (IQR 145-316) and median HIV-1 RNA was 5·2 log10 copies per mL (4·6-5·7). At week 24, 43 (83%, 95% CI 70-92) of 52 participants in the supplemental dolutegravir arm and 44 (83%, 95% CI 70-92) of 53 participants in the placebo arm had virological suppression. No treatment-emergent dolutegravir resistance mutations were detected up to week 48 in the 19 participants with study-defined virological failure. Grade 3 and 4 adverse events were similarly distributed between the study arms. The most frequent grade 3 and 4 adverse events were weight loss (4/108 [4%]), insomnia (3/108 [3%]), and pneumonia (3/108 [3%]).
INTERPRETATION
Our findings suggest that twice-daily dolutegravir might be unnecessary in people with HIV-associated tuberculosis.
The drug-drug interaction between rifampicin and dolutegravir can be overcome by supplemental dolutegravir dosing, which is difficult to implement in high-burden settings. We aimed to test whether virological outcomes with standard-dose dolutegravir-based antiretroviral therapy (ART) are acceptable in people with HIV on rifampicin-based antituberculosis therapy.
METHODS
RADIANT-TB was a phase 2b, randomised, double-blind, non-comparative, placebo-controlled trial at a single site in Khayelitsha, Cape Town, South Africa. Participants were older than 18 years of age, with plasma HIV-1 RNA greater than 1000 copies per mL, CD4 count greater than 100 cells per μL, ART-naive or first-line ART interrupted, and on rifampicin-based antituberculosis therapy for less than 3 months. By use of permuted block (block size of 6) randomisation, participants were assigned (1:1) to receive either tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus supplemental 50 mg dolutegravir 12 h later or tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus matched placebo 12 h later. Participants received standard antituberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol for the first 2 months followed by isoniazid and rifampicin for 4 months). The primary outcome was the proportion of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 24 analysed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03851588.
FINDINGS
Between Nov 28, 2019, and July 23, 2021, 108 participants (38 female, median age 35 years [IQR 31-40]) were randomly assigned to supplemental dolutegravir (n=53) or placebo (n=55). Median baseline CD4 count was 188 cells per μL (IQR 145-316) and median HIV-1 RNA was 5·2 log10 copies per mL (4·6-5·7). At week 24, 43 (83%, 95% CI 70-92) of 52 participants in the supplemental dolutegravir arm and 44 (83%, 95% CI 70-92) of 53 participants in the placebo arm had virological suppression. No treatment-emergent dolutegravir resistance mutations were detected up to week 48 in the 19 participants with study-defined virological failure. Grade 3 and 4 adverse events were similarly distributed between the study arms. The most frequent grade 3 and 4 adverse events were weight loss (4/108 [4%]), insomnia (3/108 [3%]), and pneumonia (3/108 [3%]).
INTERPRETATION
Our findings suggest that twice-daily dolutegravir might be unnecessary in people with HIV-associated tuberculosis.
Journal Article > ResearchAbstract Only
J. Infect.. 16 May 2022; Volume S0163-4453 (Issue 22); 00292-4.; DOI:10.1016/j.jinf.2022.05.010
Dhana A, Hamada Y, Kengne AP, Kerkhoff AD, Broger T, et al.
J. Infect.. 16 May 2022; Volume S0163-4453 (Issue 22); 00292-4.; DOI:10.1016/j.jinf.2022.05.010
BACKGROUND
WHO recommends urine lateral-flow lipoarabinomannan (LF-LAM) testing with AlereLAM in HIV-positive inpatients only if screening criteria are met. We assessed the performance of WHO screening criteria and alternative screening tests/strategies to guide LF-LAM testing and compared diagnostic accuracy of the WHO AlereLAM algorithm (WHO screening criteria → AlereLAM) with AlereLAM and FujiLAM (a novel LF-LAM test).
METHODS
We searched MEDLINE, Embase, and Cochrane Library from Jan 1, 2011 to March 1, 2020 for studies among adult/adolescent HIV-positive inpatients regardless of tuberculosis signs and symptoms. The reference standards were 1) AlereLAM or FujiLAM for screening tests/strategies and 2) culture or Xpert for AlereLAM/FujiLAM. We determined proportion of inpatients eligible for AlereLAM using WHO screening criteria; assessed accuracy of WHO criteria and alternative screening tests/strategies to guide LF-LAM testing; compared accuracy of WHO AlereLAM algorithm with AlereLAM/FujiLAM in all; and determined diagnostic yield of AlereLAM, FujiLAM, and Xpert MTB/RIF (Xpert). We estimated pooled proportions with a random-effects model, assessed diagnostic accuracy using random-effects bivariate models, and assessed diagnostic yield descriptively.
FINDINGS
We obtained data from all 5 identified studies (n=3,504). The pooled proportion of inpatients eligible for AlereLAM using WHO criteria was 93% (95%CI 91, 95). Among screening tests/strategies to guide LF-LAM testing, WHO criteria, C-reactive protein (≥5 mg/L), and CD4 count (<200 cells/μL) had high sensitivities but low specificities; cough (≥2 weeks), haemoglobin (<8 g/dL), body mass index (<18.5 kg/m2), lymphadenopathy, and WHO-defined danger signs had higher specificities but suboptimal sensitivities. AlereLAM in all had the same sensitivity (62%) and specificity (88%) as WHO AlereLAM algorithm. Sensitivity of FujiLAM and AlereLAM was 69% and 48%, while specificity was 48% and 96%, respectively. Diagnostic yield of sputum Xpert was 29-41%, AlereLAM was 39-76%, and urine Xpert was 35-62%. In one study, FujiLAM diagnosed 80% of tuberculosis cases (vs 39% for AlereLAM), and sputum Xpert combined with AlereLAM, urine Xpert, or FujiLAM diagnosed 69%, 81%, and 92% of all cases, respectively.
INTERPRETATION
WHO criteria and alternative screening tests/strategies have limited utility in guiding LF-LAM testing, suggesting that AlereLAM testing in all HIV-positive medical inpatients be implemented. Routine FujiLAM may improve tuberculosis diagnosis.
WHO recommends urine lateral-flow lipoarabinomannan (LF-LAM) testing with AlereLAM in HIV-positive inpatients only if screening criteria are met. We assessed the performance of WHO screening criteria and alternative screening tests/strategies to guide LF-LAM testing and compared diagnostic accuracy of the WHO AlereLAM algorithm (WHO screening criteria → AlereLAM) with AlereLAM and FujiLAM (a novel LF-LAM test).
METHODS
We searched MEDLINE, Embase, and Cochrane Library from Jan 1, 2011 to March 1, 2020 for studies among adult/adolescent HIV-positive inpatients regardless of tuberculosis signs and symptoms. The reference standards were 1) AlereLAM or FujiLAM for screening tests/strategies and 2) culture or Xpert for AlereLAM/FujiLAM. We determined proportion of inpatients eligible for AlereLAM using WHO screening criteria; assessed accuracy of WHO criteria and alternative screening tests/strategies to guide LF-LAM testing; compared accuracy of WHO AlereLAM algorithm with AlereLAM/FujiLAM in all; and determined diagnostic yield of AlereLAM, FujiLAM, and Xpert MTB/RIF (Xpert). We estimated pooled proportions with a random-effects model, assessed diagnostic accuracy using random-effects bivariate models, and assessed diagnostic yield descriptively.
FINDINGS
We obtained data from all 5 identified studies (n=3,504). The pooled proportion of inpatients eligible for AlereLAM using WHO criteria was 93% (95%CI 91, 95). Among screening tests/strategies to guide LF-LAM testing, WHO criteria, C-reactive protein (≥5 mg/L), and CD4 count (<200 cells/μL) had high sensitivities but low specificities; cough (≥2 weeks), haemoglobin (<8 g/dL), body mass index (<18.5 kg/m2), lymphadenopathy, and WHO-defined danger signs had higher specificities but suboptimal sensitivities. AlereLAM in all had the same sensitivity (62%) and specificity (88%) as WHO AlereLAM algorithm. Sensitivity of FujiLAM and AlereLAM was 69% and 48%, while specificity was 48% and 96%, respectively. Diagnostic yield of sputum Xpert was 29-41%, AlereLAM was 39-76%, and urine Xpert was 35-62%. In one study, FujiLAM diagnosed 80% of tuberculosis cases (vs 39% for AlereLAM), and sputum Xpert combined with AlereLAM, urine Xpert, or FujiLAM diagnosed 69%, 81%, and 92% of all cases, respectively.
INTERPRETATION
WHO criteria and alternative screening tests/strategies have limited utility in guiding LF-LAM testing, suggesting that AlereLAM testing in all HIV-positive medical inpatients be implemented. Routine FujiLAM may improve tuberculosis diagnosis.
Journal Article > ResearchFull Text
Lancet Infect Dis. 2 May 2022; Online ahead of print; DOI:10.1016/S1473-3099(21)00811-2
Ndjeka N, Campbell JR, Meintjes GA, Maartens G, Schaaf HS, et al.
Lancet Infect Dis. 2 May 2022; Online ahead of print; DOI:10.1016/S1473-3099(21)00811-2
BACKGROUND
There is a need for short and safe all-oral treatment of rifampicin-resistant tuberculosis. We compared outcomes up to 24 months after treatment initiation for patients with rifampicin-resistant tuberculosis in South Africa treated with a short, all-oral bedaquiline-containing regimen (bedaquiline group), or a short, injectable-containing regimen (injectable group).
METHODS
Patients with rifampicin-resistant tuberculosis, aged 18 years or older, eligible for a short regimen starting treatment between Jan 1 and Dec 31, 2017, with a bedaquiline-containing or WHO recommended injectable containing treatment regimen of 9–12 months, registered in the drug-resistant tuberculosis database (EDRWeb), and with known age, sex, HIV status, and national identification number were eligible for study inclusion; patients receiving linezolid, carbapenems, terizidone or cycloserine, delamanid, or para-aminosalicylic acid were excluded. Bedaquiline was given at a dose of 400 mg once daily for two weeks followed by 200 mg three times a week for 22 weeks. To compare regimens, patients were exactly matched on HIV and ART status, previous tuberculosis treatment history, and baseline acid-fast bacilli smear and culture result, while propensity score matched on age, sex, province of treatment, and isoniazid-susceptibility status. We did binomial linear regression to estimate adjusted risk differences (aRD) and 95% CIs for 24-month outcomes, which included: treatment success (ie, cure or treatment completion without evidence of recurrence) versus all other outcomes, survival versus death, disease free survival versus survival with treatment failure or recurrence, and loss to follow-up versus all other outcomes.
FINDINGS
Overall, 1387 (14%) of 10152 patients with rifampicin-resistant tuberculosis treated during 2017 met inclusion criteria; 688 in the bedaquiline group and 699 in the injectable group. Four patients (1%) had treatment failure or recurrence, 44 (6%) were lost to follow-up, and 162 (24%) died in the bedaquiline group, compared with 17 (2%), 87 (12%), and 199 (28%), respectively, in the injectable group. In adjusted analyses, treatment success was 14% (95% CI 8–20) higher in the bedaquiline group than in the injectable group (70% vs 57%); loss to follow-up was 4% (1–8) lower in the bedaquiline group (6% vs 12%); and disease-free survival was 2% (0–5) higher in the bedaquiline group (99% vs 97%). The bedaquiline group had 8% (4–11) lower risk of mortality during treatment (17·0% vs 22·4%), but there was no difference in mortality post-treatment.
INTERPRETATION
Patients in the bedaquiline group experienced significantly higher rates of treatment success at 24 months. This finding supports the use of short bedaquiline-containing regimens in eligible patients.
FUNDING
WHO Global TB Programme.
There is a need for short and safe all-oral treatment of rifampicin-resistant tuberculosis. We compared outcomes up to 24 months after treatment initiation for patients with rifampicin-resistant tuberculosis in South Africa treated with a short, all-oral bedaquiline-containing regimen (bedaquiline group), or a short, injectable-containing regimen (injectable group).
METHODS
Patients with rifampicin-resistant tuberculosis, aged 18 years or older, eligible for a short regimen starting treatment between Jan 1 and Dec 31, 2017, with a bedaquiline-containing or WHO recommended injectable containing treatment regimen of 9–12 months, registered in the drug-resistant tuberculosis database (EDRWeb), and with known age, sex, HIV status, and national identification number were eligible for study inclusion; patients receiving linezolid, carbapenems, terizidone or cycloserine, delamanid, or para-aminosalicylic acid were excluded. Bedaquiline was given at a dose of 400 mg once daily for two weeks followed by 200 mg three times a week for 22 weeks. To compare regimens, patients were exactly matched on HIV and ART status, previous tuberculosis treatment history, and baseline acid-fast bacilli smear and culture result, while propensity score matched on age, sex, province of treatment, and isoniazid-susceptibility status. We did binomial linear regression to estimate adjusted risk differences (aRD) and 95% CIs for 24-month outcomes, which included: treatment success (ie, cure or treatment completion without evidence of recurrence) versus all other outcomes, survival versus death, disease free survival versus survival with treatment failure or recurrence, and loss to follow-up versus all other outcomes.
FINDINGS
Overall, 1387 (14%) of 10152 patients with rifampicin-resistant tuberculosis treated during 2017 met inclusion criteria; 688 in the bedaquiline group and 699 in the injectable group. Four patients (1%) had treatment failure or recurrence, 44 (6%) were lost to follow-up, and 162 (24%) died in the bedaquiline group, compared with 17 (2%), 87 (12%), and 199 (28%), respectively, in the injectable group. In adjusted analyses, treatment success was 14% (95% CI 8–20) higher in the bedaquiline group than in the injectable group (70% vs 57%); loss to follow-up was 4% (1–8) lower in the bedaquiline group (6% vs 12%); and disease-free survival was 2% (0–5) higher in the bedaquiline group (99% vs 97%). The bedaquiline group had 8% (4–11) lower risk of mortality during treatment (17·0% vs 22·4%), but there was no difference in mortality post-treatment.
INTERPRETATION
Patients in the bedaquiline group experienced significantly higher rates of treatment success at 24 months. This finding supports the use of short bedaquiline-containing regimens in eligible patients.
FUNDING
WHO Global TB Programme.
Journal Article > ResearchFull Text
JAMA. 6 August 2008; Volume 300 (Issue 5); 530-539.; DOI:10.1001/jama.300.5.530
Boulle A, van Cutsem G, Cohen K, Hilderbrand K, Mathee S, et al.
JAMA. 6 August 2008; Volume 300 (Issue 5); 530-539.; DOI:10.1001/jama.300.5.530
CONTEXT
Rifampicin-based antitubercular therapy reduces the plasma concentrations of nevirapine and efavirenz. The virological consequences of these interactions are not well described.
OBJECTIVE
To assess the effectiveness and tolerability of concomitant efavirenz- or nevirapine-based combination antiretroviral therapy and rifampicin-based antitubercular therapy.
DESIGN, SETTING, AND PARTICIPANTS
Cohort analysis of prospectively collected routine clinical data in a community-based South African antiretroviral treatment program. Antiretroviral treatment-naive adults enrolled between May 2001 and June 2006 were included in the analysis, and were followed up until the end of 2006.
INTERVENTIONS
Patients starting antiretroviral therapy with or without concurrent antitubercular therapy received either efavirenz or nevirapine at standard doses. Patients developing tuberculosis while taking antiretroviral therapy that included nevirapine were either changed to efavirenz or continued taking nevirapine.
MAIN OUTCOME MEASURES
Viral load of 400 copies/mL or more after 6, 12, and 18 months of antiretroviral therapy; time to the first viral load of 400 copies/mL or more; time to confirmed virological failure (2 consecutive values > or = 5000 copies/mL); time to death; and time to treatment-limiting toxicity were assessed.
RESULTS
The analysis included 2035 individuals who started antiretroviral therapy with efavirenz (1074 with concurrent tuberculosis) and 1935 with nevirapine (209 with concurrent tuberculosis). There were no differences in time to death or substitution of either antiretroviral drug for toxicity with and without concurrent tuberculosis. Patients starting nevirapine with concurrent tuberculosis were at a higher risk of elevated viral load most notably at 6 months (16.3%; 95% confidence interval [CI], 10.6%-23.5%) than those without tuberculosis (8.3%; 95% CI, 6.7%-10.0%; adjusted odds ratio [OR], 2.1; 95% CI, 1.2-3.4; and in the combined estimate, adjusted OR, 1.7; 95% CI, 1.2-2.6). In the time-to-event analysis of confirmed virological failure (2 consecutive values of > or = 5000 copies/mL), patients starting nevirapine with concurrent tuberculosis developed virological failure sooner (adjusted hazard ratio [HR] 2.2; 95% CI, 1.3-3.7). There were no differences between patients starting efavirenz with and without concurrent tuberculosis (adjusted OR, 1.1; 95% CI, 0.8-1.5 [combined estimate] and adjusted HR, 1.1; 95% CI, 0.6-2.0, respectively). There was no difference in time to virological rebound in patients free of tuberculosis and those developing tuberculosis during follow-up while taking nevirapine (adjusted HR, 1.0; 95% CI, 0.5-2.0) or efavirenz (adjusted HR, 0.8; 95% CI, 0.4-1.7).
CONCLUSION
In this cohort study, virological outcomes were inferior when nevirapine-based antiretroviral therapy was commenced while taking antitubercular treatment (vs without concurrent tuberculosis) but comparable when starting efavirenz-based antiretroviral therapy (vs without concurrent tuberculosis) or when tuberculosis developed while taking established nevirapine- or efavirenz-based therapies.
Rifampicin-based antitubercular therapy reduces the plasma concentrations of nevirapine and efavirenz. The virological consequences of these interactions are not well described.
OBJECTIVE
To assess the effectiveness and tolerability of concomitant efavirenz- or nevirapine-based combination antiretroviral therapy and rifampicin-based antitubercular therapy.
DESIGN, SETTING, AND PARTICIPANTS
Cohort analysis of prospectively collected routine clinical data in a community-based South African antiretroviral treatment program. Antiretroviral treatment-naive adults enrolled between May 2001 and June 2006 were included in the analysis, and were followed up until the end of 2006.
INTERVENTIONS
Patients starting antiretroviral therapy with or without concurrent antitubercular therapy received either efavirenz or nevirapine at standard doses. Patients developing tuberculosis while taking antiretroviral therapy that included nevirapine were either changed to efavirenz or continued taking nevirapine.
MAIN OUTCOME MEASURES
Viral load of 400 copies/mL or more after 6, 12, and 18 months of antiretroviral therapy; time to the first viral load of 400 copies/mL or more; time to confirmed virological failure (2 consecutive values > or = 5000 copies/mL); time to death; and time to treatment-limiting toxicity were assessed.
RESULTS
The analysis included 2035 individuals who started antiretroviral therapy with efavirenz (1074 with concurrent tuberculosis) and 1935 with nevirapine (209 with concurrent tuberculosis). There were no differences in time to death or substitution of either antiretroviral drug for toxicity with and without concurrent tuberculosis. Patients starting nevirapine with concurrent tuberculosis were at a higher risk of elevated viral load most notably at 6 months (16.3%; 95% confidence interval [CI], 10.6%-23.5%) than those without tuberculosis (8.3%; 95% CI, 6.7%-10.0%; adjusted odds ratio [OR], 2.1; 95% CI, 1.2-3.4; and in the combined estimate, adjusted OR, 1.7; 95% CI, 1.2-2.6). In the time-to-event analysis of confirmed virological failure (2 consecutive values of > or = 5000 copies/mL), patients starting nevirapine with concurrent tuberculosis developed virological failure sooner (adjusted hazard ratio [HR] 2.2; 95% CI, 1.3-3.7). There were no differences between patients starting efavirenz with and without concurrent tuberculosis (adjusted OR, 1.1; 95% CI, 0.8-1.5 [combined estimate] and adjusted HR, 1.1; 95% CI, 0.6-2.0, respectively). There was no difference in time to virological rebound in patients free of tuberculosis and those developing tuberculosis during follow-up while taking nevirapine (adjusted HR, 1.0; 95% CI, 0.5-2.0) or efavirenz (adjusted HR, 0.8; 95% CI, 0.4-1.7).
CONCLUSION
In this cohort study, virological outcomes were inferior when nevirapine-based antiretroviral therapy was commenced while taking antitubercular treatment (vs without concurrent tuberculosis) but comparable when starting efavirenz-based antiretroviral therapy (vs without concurrent tuberculosis) or when tuberculosis developed while taking established nevirapine- or efavirenz-based therapies.
Journal Article > ResearchFull Text
Am J Respir Crit Care Med. 7 December 2007; Volume 175 (Issue 5); DOI:10.1164/rccm.200610-1439OC
Rangaka MX, Wilkinson KA, Seldon R, van Cutsem G, Meintjes GA, et al.
Am J Respir Crit Care Med. 7 December 2007; Volume 175 (Issue 5); DOI:10.1164/rccm.200610-1439OC
RATIONALE: Two forms of the IFN-gamma release assay (IFNGRA) to detect tuberculosis infection are available, but neither has been evaluated in comparable HIV-infected and uninfected persons in a high tuberculosis incidence environment. OBJECTIVE: To compare the ability of the T-SPOT.TB (Oxford Immunotec, Abingdon, UK), QuantiFERON-TB Gold (Cellestis, Melbourne, Australia), and Mantoux tests to identify latent tuberculosis in HIV-infected and uninfected persons. METHODS: A cross-sectional study of 160 healthy adults without active tuberculosis attending a voluntary counseling and testing center for HIV infection in Khayelitsha, a deprived urban South African community with an HIV antenatal seroprevalence of 33% and a tuberculosis incidence of 1,612 per 100,000. MEASUREMENTS AND MAIN RESULTS: One hundred and sixty (74 HIV(+) and 86 HIV(-)) persons were enrolled. A lower proportion of Mantoux results was positive in HIV-infected subjects compared with HIV-uninfected subjects (p < 0.01). By contrast, the proportion of positive IFNGRAs was not significantly different in HIV-infected persons for the T-SPOT.TB test (52 vs. 59%; p = 0.41) or the QuantiFERON-TB Gold test (43 and 46%; p = 0.89). Fair agreement between the Mantoux test (5- and 10-mm cutoffs) and the IFNGRA was seen in HIV-infected people (kappa = 0.52-0.6). By contrast, poor agreement between the Mantoux and QuantiFERON-TB Gold tests was observed in the HIV-uninfected group (kappa = 0.07-0.30, depending on the Mantoux cutoff). The pattern was similar for T-SPOT.TB (kappa = 0.18-0.24). Interpretation: IFNGRA sensitivity appears relatively unimpaired by moderately advanced HIV infection. However, agreement between the tests and with the Mantoux test varied from poor to fair. This highlights the need for prospective studies to determine which test may predict the subsequent risk of tuberculosis.
Journal Article > ResearchFull Text
J Int AIDS Soc. 10 April 2017 (Issue 1)
de Waal R, Cohen K, Fox MP, Stinson K, Maartens G, et al.
J Int AIDS Soc. 10 April 2017 (Issue 1)
Tenofovir has been associated with decline in kidney function, but in patients with low baseline kidney function, improvements over time have been reported. Additionally, the magnitude and trajectory of estimated glomerular filtration rate (eGFR) changes may differ according to how eGFR is calculated. We described changes in eGFR over time, and the incidence of, and risk factors for, kidney toxicity, in a South African cohort.
Journal Article > ResearchFull Text
Lancet. 14 May 2014 (Issue 9944); DOI:10.1016/S0140-6736(14)60162-8
Rangaka MX, Wilkinson RJ, Boulle AM, Glynn JR, Fielding K, et al.
Lancet. 14 May 2014 (Issue 9944); DOI:10.1016/S0140-6736(14)60162-8
Antiretroviral therapy reduces the risk of tuberculosis, but tuberculosis is more common in people with HIV than in people without HIV. We aimed to assess the effect of isoniazid preventive therapy on the risk of tuberculosis in people infected with HIV-1 concurrently receiving antiretroviral therapy.
Journal Article > ResearchFull Text
Lancet Respir Med. 15 March 2017 (Issue 4)
Dheda K, Gumbo T, Maartens G, Dooley KE, McNerney R, et al.
Lancet Respir Med. 15 March 2017 (Issue 4)
Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms-including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions-are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues.