Publications by authors named "Gary Maartens"

228 Publications

Standard versus double dose dolutegravir in patients with HIV-associated tuberculosis: a phase 2 non-comparative randomised controlled (RADIANT-TB) trial.

Wellcome Open Res 2021 11;6. Epub 2021 Jan 11.

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

Dolutegravir, a second-generation integrase strand transfer inhibitor (InSTI), is replacing efavirenz as first-line antiretroviral therapy (ART) in low middle-income countries (LMICs). Tuberculosis remains the leading cause of HIV-related morbidity and mortality in LMICs. Rifampicin is a key agent in the treatment of tuberculosis but induces genes involved in dolutegravir metabolism and efflux. The resulting drug-drug interaction (DDI) reduces the exposure of dolutegravir. However, this can be overcome by supplying a supplemental dose of 50 mg dolutegravir 12 hours after the standard daily dose, which is difficult to implement in LMICs. Four lines of evidence suggest that the supplemental dose may not be necessary: 1) a phase 2 study showed 10 mg of dolutegravir as effective as 50 mg; 2) the prolonged dissociative half-life of dolutegravir after binding to its receptor; 3) a DDI study reported dolutegravir trough concentrations were maintained above its minimum effective concentration when using 50 mg dolutegravir with rifampicin; and 4) virologic outcomes were similar between standard and double dose of raltegravir (a first-generation InSTI) in participants with HIV-associated tuberculosis treated with rifampicin. We hypothesise that virologic outcomes with standard dose dolutegravir-based ART will be acceptable in patients on rifampicin-based antituberculosis therapy. Here we outline the protocol for a phase 2, non-comparative, randomised, double-blind, placebo-controlled trial of standard versus double dose dolutegravir among adults living with HIV (ART naïve or first-line interrupted) on rifampicin-based antituberculosis therapy. A total of 108 participants will be enrolled from Khayelitsha in Cape Town, South Africa. Follow up will occur over 48 weeks. The primary objective is to assess proportion virological suppression at 24 weeks between groups analysed by modified intention to treat. Participant safety and the emergence of antiretroviral resistance mutations among those with virologic failure will be assessed throughout. ns: clinicaltrials.gov NCT03851588 (22/02/2019), SANCTR DOH-27-072020-8159 (03/07/2020).
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http://dx.doi.org/10.12688/wellcomeopenres.16473.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063551PMC
January 2021

Effectiveness and cardiac safety of bedaquiline-based therapy for drug-resistant tuberculosis: a prospective cohort study.

Clin Infect Dis 2021 Apr 21. Epub 2021 Apr 21.

Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, and Department of Medicine, University of Cape Town, Cape Town, South Africa.

Background: Bedaquiline improves treatment outcomes in patients with rifampin-resistant TB (RR-TB) but prolongs the QT-interval and carries a black-box warning by the U.S. Food and Drug Administration. The World Health Organization recommends that all patients with RR-TB receive a regimen containing bedaquiline, yet a phase 3 clinical trial demonstrating its cardiac safety has not been published.

Methods: We conducted an observational cohort study of RR-TB patients from 3 provinces in South Africa who received regimens containing bedaquiline. We performed rigorous cardiac monitoring, including electrocardiograms (ECGs) performed in triplicate at four time points during bedaquiline therapy. Participants were followed until the end of therapy or 24 months. Outcomes included final tuberculosis treatment outcome and QT-prolongation, defined as any QTcF>500 ms or an absolute change from baseline (△ QTcF) >60 ms.

Results: We enrolled 195 eligible participants, of whom 40% had extensively drug-resistant (XDR) TB. Most participants (97%) received concurrent clofazimine. 74% of participants were cured or successfully completed treatment, and outcomes did not differ by HIV status. QTcF continued to increase throughout bedaquiline therapy, with a mean increase of 23.7 (SD 22.7) ms from baseline to month 6. Four participants experienced a QTcF>500 ms and 19 experienced a △QTcF>60 ms. Older age was independently associated with QT-prolongation. QT-prolongation was neither more common nor severe in participants receiving concurrent lopinavir-ritonavir.

Conclusions: Severe QT-prolongation was uncommon and did not require permanent discontinuation of either bedaquiline or clofazimine. Close QT-monitoring may be advisable in older patients.
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http://dx.doi.org/10.1093/cid/ciab335DOI Listing
April 2021

The effect of Clofazimine Concentration on QT prolongation in patients treated for tuberculosis.

Antimicrob Agents Chemother 2021 Apr 19. Epub 2021 Apr 19.

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

Clofazimine is classified as a WHO group B drug for the treatment of rifampicin-resistant tuberculosis. QT prolongation, which is associated with fatal cardiac arrhythmias, is caused by several anti-tubercular drugs, including clofazimine, but there are no data quantifying the effect of clofazimine concentration on QT prolongation.To describe the effect of clofazimine exposure on QT prolongationFifteen adults drug-susceptible tuberculosis patients received clofazimine mono-therapy as 300 mg daily for three days followed by 100 mg daily in one arm of a 2-week, multi-arm early bactericidal activity trial in South Africa. Pre-treatment Fridericia-corrected QT (QTcF) (105 patients, 524 ECGs) and QTcF's from the clofazimine-monotherapy arm matched with clofazimine concentrations (199 ECGs) were interpreted with a nonlinear mixed-effects model.Clofazimine was associated with significant QT prolongation described by an E function. We predicted clofazimine exposures using 100-mg daily doses and two-weeks loading with 200 and 300 mg daily, respectively. The expected proportions of patients with QTcF change from baseline above 30 ms (ΔQTcF>30) were 2.52%, 11.6%, and 23.0% for 100, 200, and 300-mg daily doses, respectively. At steady state, the expected proportion with ΔQTcF>30 ms was 23.7% and for absolute QTcF>450 ms was 3.42% for all simulated regimens.The use of loading doses of 200 and 300 mg is not predicted to expose patients to increased risk of QT prolongation, compared to the current standard treatment, and is, therefore, an alternative option to achieve therapeutic concentrations faster.
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http://dx.doi.org/10.1128/AAC.02687-20DOI Listing
April 2021

Neuropsychiatric toxicity and cycloserine concentrations during treatment for multidrug-resistant tuberculosis.

Int J Infect Dis 2021 Apr 5;105:688-694. Epub 2021 Mar 5.

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa. Electronic address:

Background: Cycloserine, or its structural analogue terizidone, has been associated with neuropsychiatric toxicity (psychosis, depression, and neuropathy). Prospective clinical data on the incidence of and risk factors for neuropsychiatric toxicity in TB patients treated with cycloserine are limited.

Methods: A prospective evaluation of neuropsychiatric toxicity was performed using validated screening tools in patients with multidrug-resistant tuberculosis treated with terizidone. Cox proportional hazard modelling was performed to explore the effects of clinical variables and measures of cycloserine pharmacokinetics in plasma.

Results: A total 144 participants were recruited: 86 were male and 58 were female; their median age was 35.7 years and 91 (63%) were HIV-infected. Fifty-five (38%) participants developed at least one neuropsychiatric event (30 cases per 100 person-months): 50 (35%) neuropathy, 14 (10%) depression, and 11 (8%) psychosis. Neuropathy was independently associated with cycloserine clearance ((adjusted hazard ratio 0.34 (aHR), P = 0.03)) and high-dose pyridoxine (200 mg vs 150 mg daily, aHR: 2.79, P = 0.01).

Conclusions: A high incidence of early neuropsychiatric toxicity was observed in this cohort of patients treated with terizidone. Cycloserine clearance and higher doses of pyridoxine are associated with incident or worsening peripheral neuropathy.
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http://dx.doi.org/10.1016/j.ijid.2021.03.001DOI Listing
April 2021

Genetic Associations with Weight Gain among South Africans who Initiated Dolutegravir- and Tenofovir-containing Regimens.

J Acquir Immune Defic Syndr 2021 Feb 17. Epub 2021 Feb 17.

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA Ezintsha, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA Department of Internal Medicine, Meharry Medical College, Nashville, Tennessee, USA Joint senior authors.

Background: Excessive weight gain affects some HIV-positive individuals prescribed dolutegravir- containing regimens. Mechanisms underlying such weight gain are unknown.

Setting: Data and DNA from antiretroviral therapy-naïve participants who were randomized to initiate dolutegravir with emtricitabine plus either tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF) in the ADVANCE study (NCT03122262) were used to characterize associations between human genetic polymorphisms and magnitude of weight gain.

Methods: Associations with percent weight gain from baseline to week 48 were assessed using multivariable linear regression models. Primary analyses a priori considered 59 polymorphisms and 10 genes of potential relevance to dolutegravir, TAF or TDF pharmacokinetics. We also explored genome-wide associations.

Results: Among the 314 (92%) of 340 dolutegravir recipients who were successfully genotyped, 160 (47%) and 154 (45%) were randomized to TAF/emtricitabine and TDF/emtricitabine, respectively. In target gene analyses, the lowest P-values for the dolutegravir and tenofovir groups were ABCG2 rs4148149 (P = 7.0x10-4) and ABCC10 rs67861980 (P = 1.0x10-2), respectively, which were not significant after correction for multiple testing. In genome-wide analyses the lowest P-values for dolutegravir, was rs7590091 in TMEM163 (P = 3.7x10-8), rs17137701 in LOC105379130 (P = 6.4x10- 8) for TAF, and rs76771105 in LOC105371716 (P = 9.7x10-8) for TDF.

Conclusion: Among South African participants in a randomized clinical trial of dolutegravir plus either TAF/emtricitabine or TDF/emtricitabine, we identified several potential genetic associations with weight gain. Only TMEM163 rs7590091 withstood correction for multiple testing. These associations warrant replication in other cohorts.
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http://dx.doi.org/10.1097/QAI.0000000000002661DOI Listing
February 2021

QT effects of bedaquiline, delamanid, or both in patients with rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled trial.

Lancet Infect Dis 2021 Feb 12. Epub 2021 Feb 12.

Division of Clinical Pharmacology, Department of Medicine, Cape Town, South Africa.

Background: Bedaquiline and delamanid are the first drugs of new classes registered for tuberculosis treatment in 40 years. Each can prolong the QTc interval, with maximum effects occurring weeks after drug initiation. The cardiac safety and microbiological activity of these drugs when co-administered are not well-established. Our aim was to characterise the effects of bedaquiline, delamanid, or both on the QTc interval, longitudinally over 6 months of multidrug treatment, among patients with multidrug-resistant or rifampicin-resistant tuberculosis taking multidrug background therapy.

Methods: ACTG A5343 is a phase 2, open-label, randomised, controlled trial in which adults with multidrug-resistant or rifampicin-resistant tuberculosis receiving multidrug background treatment were randomly assigned 1:1:1 by centrally, computer-generated randomisation, by means of permuted blocks to receive bedaquiline, delamanid, or both for 24 weeks. Participants were enrolled at TASK in Cape Town and the South African Tuberculosis Vaccine Initiative in Worcester, both in South Africa, and Hospital Maria Auxiliadora in Peru. Individuals with QTc greater than 450 ms were excluded. HIV-positive participants received dolutegravir-based antiretroviral therapy. Clofazimine was disallowed, and levofloxacin replaced moxifloxacin. ECG in triplicate and sputum cultures were done fortnightly. The primary endpoint was mean QTcF change from baseline (averaged over weeks 8-24); cumulative culture conversation at week 8-24 was an exploratory endpoint. Analyses included all participants who initiated study tuberculosis treatment (modified intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT02583048 and is ongoing.

Findings: Between Aug 26, 2016 and July 13, 2018, of 174 screened, 84 participants (28 in each treatment group, and 31 in total with HIV) were enrolled. Two participants did not initiate study treatment (one in the delamanid group withdrew consent and one in the bedaquiline plus delamanid group) did not meet the eligibility criterion). Mean change in QTc from baseline was 12·3 ms (95% CI 7·8-16·7; bedaquiline), 8·6 ms (4·0-13·1; delamanid), and 20·7 ms (16·1-25·3) (bedaquiline plus delamanid). There were no grade 3 or 4 adverse QTc prolongation events and no deaths during study treatment. Cumulative culture conversion by week 8 was 21 (88%) of 24 (95% CI 71-97; bedaquiline), 20 (83%) of 24 (65-95; delamanid), and 19 (95%) of 20 (79-100; bedaquiline plus delamanid) and was 92% (77-99) for bedaquiline, 91% (76-99), for delamanid, and 95% (79-100) for bedaquiline plus delamanid at 24 weeks.

Interpretation: Combining bedaquiline and delamanid has a modest, no more than additive, effect on the QTc interval, and initial microbiology data are encouraging. This study provides supportive evidence for use of these agents together in patients with multidrug-resistant or rifampicin-resistant tuberculosis with normal baseline QTc values.

Funding: Division of AIDS, National Institutes of Health.
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http://dx.doi.org/10.1016/S1473-3099(20)30770-2DOI Listing
February 2021

Adult medical emergency unit presentations due to adverse drug reactions in a setting of high HIV prevalence.

Afr J Emerg Med 2021 Mar 30;11(1):46-52. Epub 2020 Nov 30.

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

Introduction: South Africa has the world's largest antiretroviral treatment programme, which may contribute to the adverse drug reaction (ADR) burden. We aimed to determine the proportion of adult non-trauma emergency unit (EU) presentations attributable to ADRs and to characterise ADR-related EU presentations, stratified according to HIV status, to determine the contribution of drugs used in management of HIV and its complications to ADR-related EU presentations, and identify factors associated with ADR-related EU presentation.

Methods: We conducted a retrospective folder review on a random 1.7% sample of presentations over a 12-month period in 2014/2015 to the EUs of two hospitals in Cape Town, South Africa. We identified potential ADRs with the help of a trigger tool. A multidisciplinary panel assessed potential ADRs for causality, severity, and preventability.

Results: We included 1010 EU presentations and assessed 80/1010 (7.9%) as ADR-related, including 20/239 (8.4%) presentations among HIV-positive attendees. Among HIV-positive EU attendees with ADRs 17/20 (85%) were admitted, versus 22/60 (37%) of HIV-negative/unknown EU attendees. Only 5/21 (24%) ADRs in HIV-positive EU attendees were preventable, versus 24/63 (38%) in HIV-negative/unknown EU attendees. On multivariate analysis, only increasing drug count was associated with ADR-related EU presentation (adjusted odds ratio 1.10 per additional drug, 95% confidence interval 1.03 to 1.18), adjusted for age, sex, HIV status, comorbidity, and hospital.

Conclusions: ADRs caused a significant proportion of EU presentations, similar to findings from other resource-limited settings. The spectrum of ADR manifestations in our EUs reflects South Africa's colliding epidemics of infectious and non-communicable diseases. ADRs among HIV-positive EU attendees were more severe and less likely to be preventable.
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http://dx.doi.org/10.1016/j.afjem.2020.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787921PMC
March 2021

Diagnostic Accuracy of the INSHI Consensus Case Definition for the Diagnosis of Paradoxical Tuberculosis-IRIS.

J Acquir Immune Defic Syndr 2021 04;86(5):587-592

Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.

Background: The diagnosis of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) relies on characteristic clinical features synthesized as the International Network for the Study of HIV-associated IRIS (INSHI) case definition. There is no confirmatory laboratory test.

Setting: Site B HIV-TB clinic in Khayelitsha, Cape Town, South Africa.

Methods: Using data of participants with HIV-associated tuberculosis starting antiretroviral treatment from a prospective trial evaluating prednisone for TB-IRIS prevention, we applied latent class analysis to model a gold standard for TB-IRIS. The model-predicted probability of TB-IRIS for each participant was used to assess the performance of the INSHI case definition and compare its diagnostic accuracy with several adapted case definitions.

Results: Data for this analysis were complete for 217 participants; 41% developed TB-IRIS. Our latent class model included the following parameters: respiratory symptoms; night sweats; INSHI major criteria 1, 2, and 4; maximum C-reactive protein >90 mg/L; maximum heart rate >120/min; maximum temperature >37.7°C; and preantiretroviral therapy CD4 count <50 cells/µL. The model estimated a TB-IRIS incidence of 43% and had optimal goodness of fit (χ2 = 337, P = 1.0). The INSHI case definition displayed a sensitivity of 0.77 and a specificity of 0.86. Replacing all the minor INSHI criteria with objectives measures (C-reactive protein elevation, fever, and/or tachycardia) resulted in a definition with better diagnostic accuracy, with a sensitivity of 0.89 and a specificity of 0.88.

Conclusion: The INSHI case definition identifies TB-IRIS with reasonable accuracy. Amending the case definition by replacing INSHI minor criteria with objective variables improved sensitivity without loss of specificity.
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http://dx.doi.org/10.1097/QAI.0000000000002606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938911PMC
April 2021

Isoniazid preventive therapy plus antiretroviral therapy for the prevention of tuberculosis: a systematic review and meta-analysis of individual participant data.

Lancet HIV 2021 01;8(1):e8-e15

Department of Global Health, University of Washington, Seattle, WA, USA; Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, USA.

Background: Isoniazid preventive therapy prevents active tuberculosis in people with HIV, but previous studies have found no evidence of benefit in people with HIV who had a negative tuberculin skin test, and a non-significant effect on mortality. We aimed to estimate the effect of isoniazid preventive therapy given with antiretroviral therapy (ART) for the prevention of tuberculosis and death among people with HIV across population subgroups.

Methods: We searched PubMed, Embase, the Cochrane database, and conference abstracts from database inception to Jan 15, 2019, to identify potentially eligible randomised trials. Eligible studies were trials that enrolled HIV-positive adults (age ≥15 years) taking ART who were randomly assigned to either daily isoniazid preventive therapy plus ART or ART alone and followed up longitudinally for outcomes of incident tuberculosis and mortality. We approached all authors of included trials and requested individual participant data: coprimary outcomes were relative risk of incident tuberculosis and all-cause mortality. We did a single-stage meta-analysis of individual participant data using stratified Cox-proportional hazards models. We did prespecified subgroup analyses by sex, CD4 cell count, and evidence of immune sensitisation to tuberculosis (indicated by tuberculin skin test or interferon-γ release assays [IGRAs]). We also assessed the relative risk of liver injury in an additional prespecified analysis. This study is registered with PROSPERO, CRD42019121400.

Findings: Of 838 records, we included three trials with data for 2611 participants and 8584·8 person-years of follow-up for the outcome of incident tuberculosis, and a subset of 2362 participants with 8631·6 person-years of follow-up for the coprimary outcome of all-cause mortality. Risk for tuberculosis was lower in participants given isoniazid preventive therapy and ART than participants given ART alone (hazard ratio [HR] 0·68, 95% CI 0·49-0·95, p=0·02). Risk of all-cause mortality was lower in participants given isoniazid preventive therapy and ART than participants given ART alone, but this difference was non-significant (HR 0·69, 95% CI 0·43-1·10, p=0·12). Participants with baseline CD4 counts of less than 500 cells per μL had increased risk of tuberculosis, but there was no significant difference in the benefit of isoniazid preventive therapy with ART by sex, baseline CD4 count, or results of tuberculin skin test or IGRAs. 65 (2·5%) of 2611 participants had raised alanine aminotransferase, but data were insufficient to calculate an HR.

Interpretation: Isoniazid preventive therapy with ART prevents tuberculosis across demographic and HIV-specific and tuberculosis-specific subgroups, which supports efforts to further increase use of isoniazid preventive therapy with ART broadly among people living with HIV.

Funding: National Institutes of Health and National Institute of Allergy and Infectious Diseases.
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http://dx.doi.org/10.1016/S2352-3018(20)30299-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875572PMC
January 2021

Reply to author.

Clin Infect Dis 2020 Nov 4. Epub 2020 Nov 4.

University of Cape Town, Cape Town, SOUTH AFRICA.

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http://dx.doi.org/10.1093/cid/ciaa1687DOI Listing
November 2020

Dolutegravir with emtricitabine and tenofovir alafenamide or tenofovir disoproxil fumarate versus efavirenz, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection (ADVANCE): week 96 results from a randomised, phase 3, non-inferiority trial.

Lancet HIV 2020 10;7(10):e666-e676

Department of Translational Medicine, Liverpool University, Liverpool, UK.

Background: ADVANCE compared the efficacy and safety of two antiretroviral first-line combinations (dolutegravir combined with emtricitabine and either tenofovir disoproxil fumarate or tenofovir alafenamide), with a third regimen (efavirenz combined with emtricitabine and tenofovir disoproxil fumarate) previously recommended by WHO. Here, we report the 96-week data for the study.

Methods: This randomised, open-label, non-inferiority phase 3 trial, was done at two research sites in Johannesburg, South Africa, after participant recruitment from 11 public health clinics also in Johannesburg. Eligible participants were aged 12 years or older with HIV-1 infection, who weighed at least 40 kg, had no antiretroviral exposure in the previous 6 months, with a creatinine clearance of more than 60 mL/min (>80 mL per min in individuals aged <19 years), and a plasma HIV-1 RNA concentration of 500 copies per mL or higher. Individuals who were pregnant or had tuberculosis were excluded. Participants were randomly assigned (1:1:1) by study staff using a computerised randomisation system. Randomisation was stratified by age (12 and <19 years and ≥19 years). Participants were randomly assigned to once-daily oral fixed-dose combination tenofovir alafenamide 25 mg and emtricitabine 200 mg, and once-daily oral dolutegravir 50 mg; once-daily oral fixed-dose combination tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg, and once-daily oral dolutegravir 50 mg; or once-daily oral fixed-dose combination of tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg, and efavirenz 600 mg. The primary efficacy endpoint was the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at week 48, which has been reported previously. Here, we report the key secondary efficacy endpoint of the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at the week 96 visit, assessed in all participants who received at least one dose of any study drug, with a prespecified non-inferiority margin of -10%. Safety data, including clinical, dual-energy X-ray absorptiometry and laboratory data, are also reported. This study was registered with ClinicalTrials.gov, NCT03122262.

Findings: Between Jan 17, 2017, and May 14, 2018, we screened 1453 individuals, of whom 1053 were enrolled: 351 participants were randomly assigned to the tenofovir alafenamide, emtricitabine, and dolutegravir group, 351 to the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 351 to the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group. All participants received at least one dose of study medication and were included in the primary analysis. At week 96, 276 (79%) of 351 participants in the tenofovir alafenamide, emtricitabine, and dolutegravir group, 275 (78%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 258 (74%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group had achieved a plasma HIV-1 RNA concentration of less than 50 copies per mL. Non-inferiority was established in all three comparisons. The proportion of patients with protocol-defined virological failure at week 96 was low in all treatment groups. Participants in the tenofovir alafenamide, emtricitabine, and dolutegravir group had fewer changes in bone density than the two other treatment groups. Mean weight gain was substantial (7·1 kg [SD 7·4] in the tenofovir alafenamide, emtricitabine, and dolutegravir group; 4·3 kg [6·7] in the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 2·3 kg [7·0] in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group), and was greater among women than men. Ten (3%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group discontinued due to treatment-related adverse events, of which liver dysfunction (n=4) and rash (n=4) were most common.

Interpretation: Medium-term and long-term metabolic and clinical consequences of the considerable increase in bodyweight observed in participants given these antiretroviral regimens and the trajectory of this weight gain over time, especially among women, require further study.

Funding: USAID, Unitaid, South African Medical Research Council, ViiV Healthcare.
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http://dx.doi.org/10.1016/S2352-3018(20)30241-1DOI Listing
October 2020

CheXaid: deep learning assistance for physician diagnosis of tuberculosis using chest x-rays in patients with HIV.

NPJ Digit Med 2020 9;3:115. Epub 2020 Sep 9.

Stanford University AIMI Center, Stanford, CA USA.

Tuberculosis (TB) is the leading cause of preventable death in HIV-positive patients, and yet often remains undiagnosed and untreated. Chest x-ray is often used to assist in diagnosis, yet this presents additional challenges due to atypical radiographic presentation and radiologist shortages in regions where co-infection is most common. We developed a deep learning algorithm to diagnose TB using clinical information and chest x-ray images from 677 HIV-positive patients with suspected TB from two hospitals in South Africa. We then sought to determine whether the algorithm could assist clinicians in the diagnosis of TB in HIV-positive patients as a web-based diagnostic assistant. Use of the algorithm resulted in a modest but statistically significant improvement in clinician accuracy ( = 0.002), increasing the mean clinician accuracy from 0.60 (95% CI 0.57, 0.63) without assistance to 0.65 (95% CI 0.60, 0.70) with assistance. However, the accuracy of assisted clinicians was significantly lower ( < 0.001) than that of the stand-alone algorithm, which had an accuracy of 0.79 (95% CI 0.77, 0.82) on the same unseen test cases. These results suggest that deep learning assistance may improve clinician accuracy in TB diagnosis using chest x-rays, which would be valuable in settings with a high burden of HIV/TB co-infection. Moreover, the high accuracy of the stand-alone algorithm suggests a potential value particularly in settings with a scarcity of radiological expertise.
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http://dx.doi.org/10.1038/s41746-020-00322-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481246PMC
September 2020

CYP2B6 Genotype and Weight Gain Differences Between Dolutegravir and Efavirenz.

Clin Infect Dis 2020 Sep 22. Epub 2020 Sep 22.

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

Background: Dolutegravir is associated with more weight gain than efavirenz. Loss-of-function polymorphisms in CYP2B6 result in higher efavirenz concentrations, which we hypothesized would impair weight gain among people living with human immunodeficiency virus (HIV; PLWH) starting efavirenz-based antiretroviral therapy (ART).

Methods: We studied ART-naive participants from the ADVANCE study randomized to the efavirenz /emtricitabine/tenofovir disoproxil fumarate (TDF) and dolutegravir/emtricitabine/TDF arms. We compared changes in weight and regional fat on DXA from baseline to week 48 between CYP2B6 metabolizer genotypes in the efavirenz arm, and with the dolutegravir arm.

Results: There were 342 participants in the dolutegravir arm and 168 in the efavirenz arm who consented to genotyping. Baseline characteristics were similar. Weight gain was greater in women than men. In the efavirenz arm CYP2B6 metaboliser genotype was associated with weight gain (P = .009), with extensive metabolizers gaining the most weight, and with changes in regional fat in women, but not in men. Weight gain was similar in CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm (P = .836). The following variables were independently associated with weight gain in all participants: baseline CD4 count, baseline human immunodeficiency virus type 1 (HIV-1) RNA, and CYP2B6 metaboliser genotype.

Conclusions: CYP2B6 metaboliser genotype was associated with weight gain in PLWH starting efavirenz-based ART. Weight gain was similar between CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm, suggesting that impaired weight gain among CYP2B6 slow or intermediate metabolizers could explain the increased weight gain on dolutegravir compared with efavirenz observed in ADVANCE and other studies.
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http://dx.doi.org/10.1093/cid/ciaa1073DOI Listing
September 2020

Diagnosing lymphoma in the shadow of an epidemic: lessons learned from the diagnostic challenges posed by the dual tuberculosis and HIV epidemics.

Leuk Lymphoma 2020 12 13;61(14):3417-3421. Epub 2020 Sep 13.

Division of Clinical Haematology, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa.

Infectious disease epidemics may overshadow and exacerbate existing challenges in diagnosing lymphoma. We describe pragmatic strategies we have implemented to overcome diagnostic obstacles caused by the local tuberculosis (TB) and HIV epidemics in South Africa, which may serve as a guide to minimize diagnostic delay during the COVID-19 pandemic. We report on the diagnostic utility of a rapid-access lymph node core-biopsy clinic, where lymph node biopsies are taken from outpatients at their first visit. Analysis of tissue biopsies ( = 110) revealed the three most common conditions diagnosed were TB adenitis (34%), lymphoma (29%), and disseminated malignancy (20%). A first-attempt core-biopsy was able to diagnose lymphoma in 27/32 (84%) of cases. Compared with a historical cohort, the (time from first health visit to diagnostic biopsy) for patients with lymphoma was significantly shorter, 13.5 vs 48 days ( = 0.002).
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http://dx.doi.org/10.1080/10428194.2020.1815016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880867PMC
December 2020

Risk factors for COVID-19 death in a population cohort study from the Western Cape Province, South Africa.

Clin Infect Dis 2020 Aug 29. Epub 2020 Aug 29.

Health Programmes Directorate, Western Cape Government: Health.

Background: Risk factors for COVID-19 death in sub-Saharan Africa and the effects of HIV and tuberculosis on COVID-19 outcomes are unknown.

Methods: We conducted a population cohort study using linked data from adults attending public sector health facilities in the Western Cape, South Africa. We used Cox-proportional hazards models adjusted for age, sex, location and comorbidities to examine the association between HIV, tuberculosis and COVID-19 death from 1 March-9 June 2020 among (i) public sector "active patients" (≥1 visit in the 3 years before March 2020), (ii) laboratory-diagnosed COVID-19 cases and (iii) hospitalized COVID-19 cases. We calculated the standardized mortality ratio (SMR) for COVID-19 comparing HIV positive vs. negative adults using modelled population estimates.

Results: Among 3,460,932 patients (16% HIV positive), 22,308 were diagnosed with COVID-19, of whom 625 died. COVID-19 death was associated with male sex, increasing age, diabetes, hypertension and chronic kidney disease. HIV was associated with COVID-19 mortality (adjusted hazard ratio [aHR] 2.14; 95% confidence interval [CI] 1.70-2.70), with similar risks across strata of viral load and immunosuppression. Current and previous tuberculosis were associated with COVID-19 death (aHR [95%CI] 2.70 [1.81-4.04] and 1.51 [1.18-1.93] respectively). The SMR for COVID-19 death associated with HIV was 2.39 (95%CI 1.96-2.86); population attributable fraction 8.5% (95%CI 6.1-11.1).

Conclusion: While our findings may over-estimate HIV- and tuberculosis-associated COVID-19 mortality risks due to residual confounding, both HIV and current tuberculosis were independently associated with increased COVID-19 mortality. The associations between age, sex and other comorbidities and COVID-19 mortality were similar to other settings.
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http://dx.doi.org/10.1093/cid/ciaa1198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499501PMC
August 2020

A Randomized Controlled Trial of Intravenous N-acetylcysteine in the Management of Anti-tuberculosis Drug-Induced Liver Injury.

Clin Infect Dis 2020 Aug 26. Epub 2020 Aug 26.

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

Background: Liver injury is a common complication of first-line anti-tuberculosis therapy. N-acetylcysteine (NAC) is widely used in patients with paracetamol toxicity with limited evidence of benefit in liver injury due to other causes.

Methods: We conducted a randomized, double-blind, placebo-controlled trial to assess whether intravenous NAC hastens liver recovery in hospitalized adult patients with anti-tuberculosis drug induced liver injury (AT-DILI). The primary endpoint was the time for serum alanine aminotransferase (ALT) to fall below 100 U/L. Secondary endpoints included length of hospital stay, in-hospital mortality and adverse events.

Results: Fifty-three participants were randomized to NAC and 49 to placebo. Mean age was 38 (SD±10) years, 58 (57%) were female and 89 (87%) were HIV-positive. Median serum ALT and total bilirubin at presentation were 462 U/L (IQR 266-790) and 56 μmol/L (IQR 25-100) respectively. Median time to ALT&100 U/L was 7.5 days (IQR 6 -11) in the NAC arm and 8 days (IQR 5 -13) in the placebo arm. Median time to hospital discharge was shorter in the NAC arm (9 days; IQR 6-15) than in the placebo arm (18 days; IQR 10-25), hazard ratio 1.73 (95% CI 1.13-2.65). Mortality was 14% overall and did not differ by study arm. The study infusion was stopped early due to an adverse reaction in 5 participants receiving NAC [nausea and vomiting (3), anaphylaxis (1), pain at drip site (1)].

Conclusion: NAC did not shorten time to ALT&100 U/L in participants with AT-DILI, but significantly reduced length of hospital stay. NAC should be considered in management of AT-DILI.
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http://dx.doi.org/10.1093/cid/ciaa1255DOI Listing
August 2020

Case report: Emergence of dolutegravir resistance in a patient on second-line antiretroviral therapy.

South Afr J HIV Med 2020 2;21(1):1062. Epub 2020 Jul 2.

Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

Introduction: The integrase strand transfer inhibitor dolutegravir (DTG) has a high genetic barrier to resistance. Only rare cases of resistance to DTG have been reported when it is used as a component of antiretroviral therapy regimens in treatment-experienced patients unless there was prior use of a first-generation integrase inhibitor.

Patient Presentation: A 38-year-old woman diagnosed with tuberculosis was switched to a second-line antiretroviral regimen of zidovudine, lamivudine and dolutegravir 50 mg 12-hourly together with rifampicin-based TB treatment. Based on treatment history and a previous resistance test there was resistance to lamivudine but full susceptibility to zidovudine. The patient did not suppress her viral load on this regimen and later admitted to only taking dolutegravir 50 mg in the morning because of insomnia.

Management And Outcome: A second resistance test was performed which showed intermediate level of resistance to dolutegravir. Her regimen was changed to tenofovir, emtricitabine and ritonavir-boosted atazanavir with rifabutin replacing rifampicin for the remainder of her TB treatment. She achieved viral suppression on this regimen.

Conclusion: To our knowledge this is the first case report from South Africa of emergent dolutegravir resistance in a treatment-experienced, integrase inhibitor-naïve patient. Factors that may have contributed to resistance emergence in this patient were that there was only one fully active nucleoside reverse transcriptase inhibitor in the regimen and lower exposure to dolutegravir because of the reduced dosing frequency while on rifampicin.
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http://dx.doi.org/10.4102/sajhivmed.v21i1.1062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433307PMC
July 2020

Population Pharmacokinetics of Cycloserine and Pharmacokinetic/Pharmacodynamic Target Attainment in Multidrug-Resistant Tuberculosis Patients Dosed with Terizidone.

Antimicrob Agents Chemother 2020 10 20;64(11). Epub 2020 Oct 20.

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa

Cycloserine is a WHO group B drug for the treatment of multidrug-resistant tuberculosis (TB). Pharmacokinetic/pharmacodynamic data for cycloserine when dosed as terizidone are sparse. The aim of this analysis was to describe the population pharmacokinetics of cycloserine when administered as terizidone and predict the doses of terizidone attaining cycloserine exposures associated with efficacy. The plasma cycloserine level was measured 2 to 6 weeks after treatment initiation in patients hospitalized for second-line tuberculosis treatment. The pretreatment MICs of cycloserine were determined for the clinical isolates. We enrolled 132 participants with rifampicin-resistant TB; 79 were HIV positive. The median pretreatment MIC was 16 mg/liter. A one-compartment disposition model with two clearance pathways, nonrenal (0.35 liters/h) and renal (0.43 liters/h), described cycloserine pharmacokinetics well. Nonrenal clearance and the volume of distribution were allometrically scaled using fat-free mass. Smoking increased nonrenal clearance by 41%. Simulations showed that with daily doses of terizidone (750 mg and 1,000 mg for patients weighing ≤45 kg and >45 kg, respectively), the probability of maintaining the plasma cycloserine concentration above the MIC for more than 30% of the dosing interval (30% ) (which is associated with a 1.0-log-CFU/ml kill ) exceeded 90% at MIC values of ≤16 mg/liter, but the proportion of patients achieving 100% (which is associated with the prevention of resistance) was more than 90% only at MICs of ≤8 mg/liter. Based on a target derived , the WHO-recommended doses of terizidone are effective for cycloserine MICs of ≤8 mg/liter, and higher doses are required to prevent the development of resistance.
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http://dx.doi.org/10.1128/AAC.01381-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577169PMC
October 2020

Clofazimine pharmacokinetics in patients with TB: dosing implications.

J Antimicrob Chemother 2020 11;75(11):3269-3277

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

Background: Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization.

Objectives: To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients.

Patients And Methods: Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L.

Results: We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10 500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant.

Conclusions: Clofazimine was widely distributed with a long elimination half-life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.
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http://dx.doi.org/10.1093/jac/dkaa310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566350PMC
November 2020

Responding to SARS-CoV-2 in South Africa: what can we learn from drug-resistant tuberculosis?

Eur Respir J 2020 07 23;56(1). Epub 2020 Jul 23.

Dept of Medicine and Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa.

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http://dx.doi.org/10.1183/13993003.01369-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7257618PMC
July 2020

Mycobacterium tuberculosis bloodstream infection prevalence, diagnosis, and mortality risk in seriously ill adults with HIV: a systematic review and meta-analysis of individual patient data.

Lancet Infect Dis 2020 06 13;20(6):742-752. Epub 2020 Mar 13.

Johns Hopkins University Centre for TB Research, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Background: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI.

Methods: We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022.

Findings: We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per μL (the median for the cohort) was 45% (95% CI 38-52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63-87), increasing to 89% (80-94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05-3·08) but not after 30 days (1·25, 0·84-2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16-8·84).

Interpretation: In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients.

Funding: This study was supported by Wellcome fellowships 109105Z/15/A and 105165/Z/14/A.
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http://dx.doi.org/10.1016/S1473-3099(19)30695-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254058PMC
June 2020

'Covering the tail' after stopping efavirenz-based antiretroviral therapy.

Authors:
Gary Maartens

South Afr J HIV Med 2020 27;21(1):1036. Epub 2020 Jan 27.

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

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http://dx.doi.org/10.4102/sajhivmed.v21i1.1036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059239PMC
January 2020

Correction to: Diagnostic accuracy of the Xpert MTB/Rif Ultra for tuberculosis adenitis.

BMC Infect Dis 2020 03 2;20(1):187. Epub 2020 Mar 2.

Division of Haematology, Department of Medicine, University of Cape Town, Anzio Rd, Observatory, Cape Town, 7925, South Africa.

After publication of the original article [1], we were notified that there is a mistake in the article note.
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http://dx.doi.org/10.1186/s12879-020-4917-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050142PMC
March 2020

A Clinical Prediction Score Including Trial of Antibiotics and C-Reactive Protein to Improve the Diagnosis of Tuberculosis in Ambulatory People With HIV.

Open Forum Infect Dis 2020 Feb 6;7(2):ofz543. Epub 2020 Jan 6.

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

Background: The use of a "trial of antibiotics" as empiric therapy for bacterial pneumonia as a diagnostic tool for tuberculosis in people with HIV (PWH) was removed from World Health Organization (WHO) recommendations in 2007, based on expert opinion. Current guidelines recommend antibiotics only after 2 Xpert MTB/RIF tests (if available), chest x-ray, and clinical assessment have suggested that tuberculosis is unlikely. Despite this, a "trial of antibiotics" remains common in algorithms in low-resource settings, but its value is uncertain. C-reactive protein (CRP), which has been proposed as a "rule-out" test for tuberculosis, may be an objective marker of response to antibiotics.

Methods: We performed a passive case-finding cohort study of adult PWH with a positive WHO symptom screen. All participants received antibiotics at first visit according to the local protocol and were reviewed to ascertain clinical response. Point-of-care CRP was measured at both visits. All patients had sputum tested with Xpert MTB/RIF Ultra (Ultra), and the reference standard was based on 2 sputum mycobacterial cultures. We explored multivariable prediction models (MPM) for tuberculosis based on 1 or 2 visits.

Results: Seventy-five of 207 patients (36%) had confirmed tuberculosis. Clinical response to antibiotics after 2 days was a good predictor of disease. An MPM based on 2 visits, without CRP, had acceptable discrimination (c-statistic, 0.75) and calibration (goodness-of-fit  = .07). Addition of CRP after antibiotics improved the model moderately (c-statistic, 0.78). CRP at first visit was not an independent predictor of tuberculosis.

Conclusions: In adult PWH seeking care for symptoms suggestive of tuberculosis, lack of response to antibiotics is a strong predictor of disease and is likely to be useful, particularly when access to Ultra is limited. CRP adds value when measured after antibiotics but is of limited value at first visit.
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http://dx.doi.org/10.1093/ofid/ofz543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000838PMC
February 2020

Increased Mortality With Delayed and Missed Switch to Second-Line Antiretroviral Therapy in South Africa.

J Acquir Immune Defic Syndr 2020 05;84(1):107-113

Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.

Background: After failure of first-line antiretroviral therapy (ART) in the public sector, delayed or missed second-line ART switch is linked with poor outcomes in patients with advanced HIV.

Setting: We investigated delayed or missed second-line ART switch after confirmed virologic failure in the largest private sector HIV cohort in Africa.

Methods: We included HIV-infected adults with confirmed virologic failure after 6 months of nonnucleoside reverse-transcriptase inhibitor-based ART. We estimated the effect of timing of switch on the hazard of death using inverse probability of treatment weighting of marginal structural models. We adjusted for time-dependent confounding of CD4 count, viral load, and visit frequency.

Results: Five thousand seven hundred forty-eight patients (53% female) with confirmed virologic failure met inclusion criteria; the median age was 40 [interquartile range (IQR): 35-47], advanced HIV was present in 48% and the prior duration of nonnucleoside reverse-transcriptase inhibitor-based ART was 1083 days (IQR: 665-1770). Median time to confirmation of virologic failure and to second-line switch was 196 (IQR: 136-316) and 220 days (IQR: 65-542), respectively. Switching to second-line ART after confirmed failure compared with remaining on first-line ART reduced risk of subsequent death [adjusted hazard ratio: 0.47 (95% confidence interval: 0.36 to 0.63)]. Compared with patients who experienced delayed switch, those switched immediately had a lower risk of death, regardless of CD4 cell count.

Conclusions: Delayed or missed switch to second-line ART after confirmed first-line ART failure is common in the South African private sector and associated with mortality. Novel interventions to minimize switch delay should be tested and not limited to those with advanced disease at treatment failure.
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http://dx.doi.org/10.1097/QAI.0000000000002313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269121PMC
May 2020

Pharmacokinetic profile and safety of adjusted doses of darunavir/ritonavir with rifampicin in people living with HIV.

J Antimicrob Chemother 2020 04;75(4):1019-1025

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

Background: Darunavir/ritonavir is better tolerated than lopinavir/ritonavir and has a higher genetic barrier to resistance. Co-administration with rifampicin has been contraindicated as a significant reduction in darunavir exposure is expected. This is a barrier to darunavir/ritonavir use where TB is endemic.

Objectives: To evaluate the safety and pharmacokinetic profile of adjusted doses of darunavir/ritonavir with rifampicin.

Methods: Virally suppressed participants on second-line lopinavir/ritonavir-based ART were switched to darunavir/ritonavir 800/100 mg q24h. In sequence: rifampicin was added; the dose of ritonavir was escalated; and darunavir was increased (darunavir/ritonavir 1600/200 mg q24h and 800/100 mg q12h were given in randomized sequence with rifampicin). Darunavir plasma concentrations were measured on the seventh/last day of each treatment period. To prevent viral rebound, dolutegravir (50 mg q12h) was added during rifampicin administration and for 1 week thereafter. Clinical events, ALT and bilirubin were monitored every 2-3 days during rifampicin administration.

Results: A total of 17/28 participants started study treatment. Six (35.3%) were withdrawn for symptomatic hepatitis with severe ALT elevations, developing after 9-11 days of rifampicin and 2-4 days of ritonavir 200 mg. The study was stopped prematurely due to this high rate of hepatotoxicity. Only four participants completed the study. All hepatotoxicity resolved on withdrawal of study treatment. All participants were successfully re-established on their lopinavir/ritonavir-based regimen. After doubling the darunavir/ritonavir doses on rifampicin, darunavir pre-dose concentrations approached those on standard doses without rifampicin for q12h doses, but not for q24h doses.

Conclusions: Adjusted doses of darunavir/ritonavir with rifampicin had unacceptable risk of hepatotoxicity. Darunavir trough concentrations were markedly reduced with the daily adjusted dose.
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http://dx.doi.org/10.1093/jac/dkz522DOI Listing
April 2020

Correlation of Linezolid Hair Concentrations with Plasma Exposure in Patients with Drug-Resistant Tuberculosis.

Antimicrob Agents Chemother 2020 02 21;64(3). Epub 2020 Feb 21.

Division of Pulmonary and Critical Care Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, University of California, San Francisco, California, USA.

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http://dx.doi.org/10.1128/AAC.02145-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038252PMC
February 2020

Diagnostic accuracy of the Xpert MTB/Rif Ultra for tuberculosis adenitis.

BMC Infect Dis 2020 Jan 13;20(1):33. Epub 2020 Jan 13.

Division of Haematology, Department of Medicine, University of Cape Town, Anzio Rd, Observatory, Cape Town, 7925, South Africa.

Background: The WHO recently recommended the new Xpert MTB/RIF Ultra assay (Ultra) instead of the Xpert MTB/RIF assay because Ultra has improved sensitivity. We report the diagnostic accuracy of Ultra for tuberculous adenitis in a tuberculosis and HIV endemic setting.

Methods: We obtained fine-needle aspirates (FNA) and lymph node tissue by core-needle biopsy in adult patients with peripheral lymphadenopathy of >20 mm. Ultra and mycobacterial culture were performed on FNA and tissue specimens, with histological examination of tissue specimens. We assessed the diagnostic accuracy of Ultra against a composite reference standard of 'definite tuberculosis' (microbiological criteria) or 'probable tuberculosis' (histological and clinical criteria).

Results: We prospectively evaluated 99 participants of whom 50 were HIV positive: 21 had 'definite tuberculosis', 15 'probable tuberculosis' and 63 did not have tuberculosis (of whom 38% had lymphoma and 19% disseminated malignancy). Using the composite reference standard the Ultra sensitivity on FNA was 70% (95% CI 51-85; 21 of 30), and on tissue was 67% (45-84; 16/24) these were far superior to the detection of acid-fast bacilli on an FNA (26%; 7/27); AFB on tissue (33%; 8/24); or tissue culture (39%; 9/23). The detection of granulomas on histology had high senstivity (83%) but the lowest specficity. When compared with culture the Ultra on FNA had a sensitvity of 78% (40-97; 7/9) and tissue 90% (55-100; 9/10).

Conclusions: Ultra performed on FNA or tissue of a lymph node had good sensitivity and high specificity. Ultra had a higher yield than culture and has the advantage of being a rapid test. Ultra on FNA would be an appropriate initial investigation for lymphadenopathy in tuberculosis endemic areas followed by a core biopsy for histopathology with a repeat Ultra on tissue if granulomas are present.
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http://dx.doi.org/10.1186/s12879-019-4749-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958753PMC
January 2020

Early antituberculosis drug exposure in hospitalized patients with human immunodeficiency virus-associated tuberculosis.

Br J Clin Pharmacol 2020 05 17;86(5):966-978. Epub 2020 Feb 17.

Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, South Africa.

Aims: Patients hospitalized at the time of human immunodeficiency virus-associated tuberculosis (HIV-TB) diagnosis have high early mortality. We hypothesized that compared to outpatients, there would be lower anti-TB drug exposure in hospitalized HIV-TB patients, and amongst hospitalized patients exposure would be lower in patients who die or have high lactate (a sepsis marker).

Methods: We performed pharmacokinetic sampling in hospitalized HIV-TB patients and outpatients. Plasma rifampicin, isoniazid and pyrazinamide concentrations were measured in samples collected predose and at 1, 2.5, 4, 6 and 8 hours on the third day of standard anti-TB therapy. Twelve-week mortality was ascertained for inpatients. Noncompartmental pharmacokinetic analysis was performed.

Results: Pharmacokinetic data were collected in 59 hospitalized HIV-TB patients and 48 outpatients. Inpatient 12-week mortality was 11/59 (19%). Rifampicin, isoniazid and pyrazinamide exposure was similar between hospitalized and outpatients (maximum concentration [C ]: 7.4 vs 8.3 μg mL , P = .223; 3.6 vs 3.5 μg mL , P = .569; 50.1 vs 46.8 μg mL , P = .081; area under the concentration-time curve from 0 to 8 hours: 41.0 vs 43.8 mg h L , P = 0.290; 13.5 vs 12.4 mg h L , P = .630; 316.5 vs 292.2 mg h L , P = .164, respectively) and not lower in inpatients who died. Rifampicin and isoniazid C were below recommended ranges in 61% and 39% of inpatients and 44% and 35% of outpatients. Rifampicin exposure was higher in patients with lactate >2.2 mmol L .

Conclusion: Mortality in hospitalized HIV-TB patients was high. Early anti-TB drug exposure was similar to outpatients and not lower in inpatients who died. Rifampicin and isoniazid C were suboptimal in 61% and 39% of inpatients and rifampicin exposure was higher in patients with high lactate. Treatment strategies need to be optimized to improve survival.
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http://dx.doi.org/10.1111/bcp.14207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163385PMC
May 2020