Pharmacokinetics of Single-Dose Versus Double-Dose Dolutegravir After Switching From a Failing Efavirenz-Based Regimen.

BACKGROUND: Dolutegravir exposure is reduced after switching from efavirenz, which could select for dolutegravir resistance if switching occurs during virologic failure. METHODS: We measured serial dolutegravir trough concentrations after switching from efavirenz in a clinical trial, which randomized some participants to a supplemental dolutegravir dose or placebo for the first 14 days. Changes in dolutegravir trough concentrations between days 3, 7, 14, and 28 were evaluated. The primary outcome was the geometric mean ratio of dolutegravir trough concentrations on day 7 versus day 28. RESULTS: Twenty-four participants received double-dose dolutegravir (50 mg twice daily) and 11 standard dose for the first 14 days. Baseline characteristics were 77% female, median age 36 years, CD4 cell count 254 cells/mm3, and HIV-1 RNA 4.0 log10 copies/mL. The geometric mean ratio (90% CI) of dolutegravir trough concentrations on day 7 versus day 28 was 0.637 (0.485 to 0.837) in the standard-dose group and 1.654 (1.404 to 1.948) in the double-dose group. There was a prolonged induction effect at day 28 in participants with efavirenz slow metaboliser genotypes. One participant in the double-dose group had a dolutegravir trough concentration below the protein-binding adjusted concentration needed to inhibit 90% of HIV-1 (PA-IC90) at day 3. CONCLUSIONS: No participants on standard-dose dolutegravir had dolutegravir trough concentrations below the PA-IC90. Slow efavirenz metaboliser genotypes had higher baseline efavirenz concentrations and more pronounced and longer period of induction postswitch. These findings suggest that a 14-day lead-in supplemental dolutegravir dose may not be necessary when switching from a failing efavirenz-based first-line regimen.

Relationship Between Tenofovir Diphosphate Concentrations in Dried Blood Spots and Virological Outcomes After Initiating Tenofovir-Lamivudine-Dolutegravir as First-Line or Second-Line Antiretroviral Therapy.

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.

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

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. FUNDING: Wellcome Trust.

Initial Supplementary Dose of Dolutegravir in Second-Line Antiretroviral Therapy: A Noncomparative, Double-Blind, Randomized Placebo-Controlled Trial.

BACKGROUND: Dolutegravir concentrations are reduced by efavirenz induction effect necessitating twice-daily dolutegravir dosing when coadministered. Efavirenz induction persists for several weeks after stopping, which could potentially select for dolutegravir resistance if switching occurred with unsuppressed human immunodeficiency virus type 1 (HIV-1) RNA levels and standard dolutegravir dosing. We evaluated the need for a lead-in supplementary dolutegravir dose in adults failing first-line tenofovir-emtricitabine-efavirenz (TEE). METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2 trial in Khayelitsha, South Africa. Eligible patients had virologic failure (2 consecutive HIV-1 RNA ≥1000 copies/mL) on first-line TEE. Participants were randomly assigned (1:1) to switch to tenofovir-lamivudine-dolutegravir (TLD) with a supplementary 50 mg dolutegravir dose or placebo taken 12 hours later for 14 days. Primary outcome was proportion with HIV-1 RNA <50 copies/mL at week 24. This study was not powered to compare arms. RESULTS: One hundred thirty participants were randomized (65 to each arm). Median baseline HIV-1 RNA was 4.0 log10 copies/mL and 76% had baseline resistance to both tenofovir and lamivudine. One participant died and 2 were lost to follow-up. At week 24, 55 of 64 (86% [95% confidence interval {CI}: 75%-93%]) in the supplementary dolutegravir arm and 53 of 65 (82% [95% CI: 70%-90%]) in the placebo arm had HIV-1 RNA <50 copies/mL. Grade 3 or 4 adverse events were similar in frequency between arms. None of 6 participants (3 in each arm) eligible for resistance testing by 24 weeks developed dolutegravir resistance. CONCLUSIONS: Our findings do not support the need for initial dolutegravir dose adjustment in patients switching to TLD who failed first-line TEE. CLINICAL TRIALS REGISTRATION: NCT03991013.

Recycling Tenofovir in Second-line Antiretroviral Treatment With Dolutegravir: Outcomes and Viral Load Trajectories to 72 weeks.

BACKGROUND: Recycling tenofovir and lamivudine/emtricitabine with dolutegravir (TLD) after failure of non-nucleoside transcriptase inhibitor first-line antiretroviral therapy is more tolerable and scalable than dolutegravir plus optimized nucleoside reverse transcriptase inhibitors. Studies have demonstrated TLD's efficacy as second line, but long-term follow-up is limited. METHODS: ARTIST is a single arm, prospective, interventional study conducted in Khayelitsha, South Africa, which switched 62 adults with 2 viral loads >1000 copies/mL from tenofovir, lamivudine/emtricitabine, and an non-nucleoside transcriptase inhibitor to TLD. We report efficacy to 72 weeks and, in a post hoc analysis, evaluated viral load trajectories of individuals with viremic episodes. RESULTS: Virologic suppression was 86% [95% confidence interval (CI) 74 to 93], 74% (95% CI: 61 to 84), and 75% (95% CI: 63 to 86) <50 copies/mL and 95%, 84%, and 77% <400 copies/mL at week 24, 48, and 72, respectively, with 89% (50/56) resistant (Stanford score ≥15) to tenofovir and/or lamivudine preswitch. No participants developed integrase-inhibitor resistance. Of the 20 participants not suppressed at week 24 and/or 48, 2 developed virologic failure, 1 switched regimen (adverse event), 2 were lost to follow-up, 1 missed the visit, 1 transferred out, 9 resuppressed <50 copies/mL with enhanced adherence counseling, and 4 remained viremic (3 with <200 copies/mL) at week 72. CONCLUSIONS: Recycling NRTIs with dolutegravir was effective for most participants to 72 weeks. Most with viremia did not develop virologic failure and subsequently suppressed with enhanced adherence counseling or continued to have low-level viremia. No integrase-inhibitor resistance was detected despite low-level viremia in a minority of participants.

Pharmacokinetic and pharmacogenetic associations with dolutegravir neuropsychiatric adverse events in an African population.

BACKGROUND: Dolutegravir has been associated with neuropsychiatric adverse events (NPAEs), but relationships between dolutegravir concentrations and NPAEs are unclear. OBJECTIVES: To determine in an African population whether a concentration-response relationship exists between dolutegravir and treatment-emergent NPAEs, and whether selected loss-of-function polymorphisms in genes encoding UDP-glucuronosyltransferase-1A1 (the major metabolizing enzyme for dolutegravir) and organic cation transporter-2 (involved in neurotransmitter transport and inhibited by dolutegravir) are associated with NPAEs. METHODS: Antiretroviral therapy-naive participants randomized to dolutegravir-based therapy in the ADVANCE study were enrolled into a pharmacokinetic sub-study. Primary outcome was change in mental health screening [modified mini screen (MMS)] and sleep quality from baseline to weeks 4, 12 and 24. Dolutegravir exposure was estimated using a population pharmacokinetic model. Polymorphisms analysed were UGT1A1 rs887829 and SLC22A2 rs316019. RESULTS: Data from 464 participants were available for pharmacokinetic analyses and 301 for genetic analyses. By multivariable linear regression, higher dolutegravir exposure was associated with worsening sleep quality only at week 12 [coefficient  = -0.854 (95% CI -1.703 to -0.005), P = 0.049], but with improved MMS score at weeks 12 and 24 [coefficient = -1.255 (95% CI -2.250 to -0.261), P = 0.013 and coefficient = -1.199 (95% CI -2.030 to -0.368), P = 0.005, respectively]. The UGT1A1 and SLC22A2 polymorphisms were not associated with change in MMS score or sleep quality. CONCLUSIONS: Only at week 12 did we find evidence of a relationship between dolutegravir exposure and worsening sleep quality. However, higher dolutegravir exposure was associated with improved MMS scores, suggesting a possible beneficial effect.

Concentration-response relationships of dolutegravir and efavirenz with weight change after starting antiretroviral therapy.

Dolutegravir is associated with more weight gain than efavirenz in people starting antiretroviral therapy (ART). We investigated the concentration-response relationships of efavirenz and dolutegravir with weight gain. We determined concentration-response relationships of dolutegravir and efavirenz (both combined with tenofovir disoproxil fumarate and emtricitabine) with changes in weight and fat distribution, derived from dual-energy x-ray absorptiometry scans, in a nested study of ART-naïve participants from a randomised controlled trial. Pharmacokinetic parameters used in analyses were efavirenz mid-dosing interval concentrations and estimated dolutegravir area under the concentration-time curve using a population pharmacokinetic model developed in the study population. Study outcomes were percentage changes from baseline to week 48 in weight, and visceral and subcutaneous adipose tissue mass. Pharmacokinetic data were available for 158 and 233 participants in the efavirenz arm and dolutegravir arms respectively; 57.0% were women. On multivariable linear regression there were independent negative associations between efavirenz concentrations and changes in both weight (P < .001) and subcutaneous adipose tissue mass (P = .002). Estimated dolutegravir area under the concentration-time curve up to 24 hours was not associated with change in weight (P = .109) but was negatively associated with change in visceral adipose tissue mass (P = .025). We found an independent negative concentration-response relationship between efavirenz concentrations and weight change in ART-naïve participants. Dolutegravir concentrations were not independently associated with weight change. These findings suggest that weight gain differences between efavirenz and dolutegravir are driven by efavirenz toxicity impairing weight gain rather than by off-target effects of dolutegravir causing weight gain.

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

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. Trial registrations: clinicaltrials.gov NCT03851588 (22/02/2019), SANCTR DOH-27-072020-8159 (03/07/2020).

Virologic efficacy of tenofovir, lamivudine and dolutegravir as second-line antiretroviral therapy in adults failing a tenofovir-based first-line regimen.

OBJECTIVE: Recycling tenofovir and lamivudine/emtricitabine (XTC) with dolutegravir would provide a more tolerable, affordable, and scalable second-line regimen than dolutegravir with an optimized nucleoside reverse transcriptase inhibitor (NRTI) backbone. We evaluated efficacy of tenofovir/lamivudine/dolutegravir (TLD) in patients failing first-line tenofovir/XTC/efavirenz or nevirapine. DESIGN: Single arm, prospective, interventional study. SETTING: Two primary care clinics in Khayelitsha, South Africa. PARTICIPANTS: Sixty adult patients with two viral loads greater than 1000 copies/ml. INTERVENTION: Participants were switched to TLD with additional dolutegravir (50 mg) for 2 weeks to overcome efavirenz induction. PRIMARY OUTCOME: Proportion achieving viral load less than 50 copies/ml at week 24 using the FDA snapshot algorithm. RESULTS: Baseline median CD4+ cell count was 248 cells/µl, viral load 10 580 copies/ml and 48 of 54 (89%) had resistance (Stanford score ≥15) to one or both of tenofovir and XTC. No participants were lost to follow-up. At week 24, 51 of 60 [85%, 95% confidence interval (CI) 73-93%] were virologically suppressed, six had viral load 50-100 copies/ml, one had viral load 100-1000 copies/ml, one no viral load in window, and one switched because of tenofovir-related adverse event. No integrase mutations were detected in the one participant meeting criteria for resistance testing. Virological suppression was achieved by 29 of 35 (83%, 95% CI 66-93%) with resistance to tenofovir and XTC, 11 of 13 (85%, 95% CI 55-98%) with resistance to XTC, and six of six (100%, 95% CI 54-100%) with resistance to neither. CONCLUSION: A high proportion of adults switching to second-line TLD achieved virologic suppression despite substantial baseline NRTI resistance and most not suppressed had low-level viraemia (≤100 copies/ml). This suggests recycling tenofovir and XTC with dolutegravir could provide an effective second-line option.

AntiRetroviral Therapy In Second-line: investigating Tenofovir-lamivudine-dolutegravir (ARTIST): protocol for a randomised controlled trial.

Background: Dolutegravir has superior efficacy and tolerability than lopinavir-ritonavir in second-line antiretroviral therapy after failure of a first-line non-nucleoside reverse transcriptase inhibitors-based regimen, when dolutegravir is accompanied by at least one fully active nucleoside reverse transcriptase inhibitor (NRTI). Resistance testing to select NRTIs is not feasible in low- and middle-income countries due to cost and limited laboratory capacity. Evidence suggests that recycling tenofovir plus lamivudine or emtricitabine backbone with dolutegravir could provide an effective second-line option. This study aims to determine the virologic efficacy of tenofovir-lamivudine-dolutegravir (TLD) with and without a lead-in supplementary dose of dolutegravir (to counteract the inducing effect of efavirenz) in patients failing a first-line regimen of tenofovir-emtricitabine-efavirenz (TEE). Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled, Phase II trial, comparing TLD fixed dose combination daily with a lead-in supplementary 50 mg dolutegravir dose versus matching placebo taken 12 hours later for the first 14 days, in patients failing a first-line TEE regimen. The trial will be set in two primary care clinics in Khayelitsha; a large, peri-urban informal settlement in Cape Town, South Africa. We will enrol 130 participants, with follow-up to 48 weeks. The primary endpoint is proportion achieving viral load <50 copies/mL at week 24 using a modified intention-to-treat analysis and the U.S. Food and Drug Administration snapshot algorithm. Secondary endpoints include virologic suppression at weeks 12 and 48, time to suppression, emergence of dolutegravir and new NRTI resistance mutations, safety, and tolerability. Discussion: Impaired viral fitness due to NRTI resistance mutations and dolutegravir's high barrier to resistance provide rationale for switching patients from a failing TEE regimen to TLD; however, clinical evidence regarding virologic efficacy is lacking. This study provides estimates of such a strategy's early virologic efficacy with and without a supplementary dolutegravir dosing. Registration: ClinicalTrials.gov NCT03991013 (19/06/2019).

CYP2B6 Genotype and Weight Gain Differences Between Dolutegravir and Efavirenz.

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.

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

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 (p = 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 (p < 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.

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

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 38­52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63­87), increasing to 89% (80­94) 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 2·05­3·08) but not after 30 days (1·25, 0·84­2·49). 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 1·16­8·84). 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

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.

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.

Etiology of Pulmonary Infections in Human Immunodeficiency Virus-infected Inpatients Using Sputum Multiplex Real-time Polymerase Chain Reaction.

BACKGROUND: There are limited data on the etiology of respiratory infections in human immunodeficiency virus (HIV)-infected patients in resource-limited settings. METHODS: We performed quantitative multiplex real-time polymerase chain reaction (PCR) for Pneumocystis jirovecii and common bacterial and viral respiratory pathogens on sputum samples (spontaneous or induced) from a prospective cohort study of HIV-infected inpatients with World Health Organization danger signs and cough. Mycobacterial culture was done on 2 sputum samples, blood cultures, and relevant extrapulmonary samples. RESULTS: We enrolled 284 participants from 2 secondary-level hospitals in Cape Town, South Africa: median CD4 count was 97 cells/µL, 64% were women, and 38% were on antiretroviral therapy. One hundred forty-eight had culture-positive tuberculosis, 100 had community-acquired pneumonia (CAP), 26 had P. jirovecii pneumonia (PJP), and 64 had other diagnoses. Probable bacterial infection (>105 copies/mL) was detected in 133 participants; the prevalence was highest in those with CAP (52%). Haemophilus influenzae and Streptococcus pneumoniae were the commonest bacterial pathogens detected; atypical bacteria were uncommon. Viruses were detected in 203 participants; the prevalence was highest in those with PJP (85%). Human metapneumovirus was the commonest virus detected. Multiple coinfections were commonly detected. CONCLUSIONS: Sputum multiplex PCR could become a useful diagnostic tool for bacterial respiratory infections in HIV-infected inpatients, but its value is limited as quantitative cutoffs have only been established for a few bacterial pathogens and validation has not been done in this patient population. We found a high prevalence of respiratory viruses, but it is unclear whether these viruses were causing infection as there are no accepted quantitative PCR cutoffs for diagnosing respiratory viral infections.

Abdominal ultrasound for diagnosing abdominal tuberculosis or disseminated tuberculosis with abdominal involvement in HIV-positive individuals.

BACKGROUND: Accurate diagnosis of tuberculosis in people living with HIV is difficult. HIV-positive individuals have higher rates of extrapulmonary tuberculosis and the diagnosis of tuberculosis is often limited to imaging results. Ultrasound is such an imaging test that is widely used as a diagnostic tool (including point-of-care) in people suspected of having abdominal tuberculosis or disseminated tuberculosis with abdominal involvement. OBJECTIVES: To determine the diagnostic accuracy of abdominal ultrasound for detecting abdominal tuberculosis or disseminated tuberculosis with abdominal involvement in HIV-positive individuals.To investigate potential sources of heterogeneity in test accuracy, including clinical setting, ultrasound training level, and type of reference standard. SEARCH METHODS: We searched for publications in any language up to 4 April 2019 in the following databases: MEDLINE, Embase, BIOSIS, Science Citation Index Expanded (SCI-EXPANDED), Social Sciences Citation Index (SSCI), Conference Proceedings Citation Index- Science (CPCI-S), and also ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform to identify ongoing trials. SELECTION CRITERIA: We included cross-sectional, cohort, and diagnostic case-control studies (prospective and retrospective) that compared the result of the index test (abdominal ultrasound) with one of the reference standards. We only included studies that allowed for extraction of numbers of true positives (TPs), true negatives (TNs), false positives (FPs), and false negatives (FNs). Participants were HIV-positive individuals aged 15 years and older. A higher-quality reference standard was the bacteriological confirmation of Mycobacterium tuberculosis from any clinical specimen, and a lower-quality reference standard was a clinical diagnosis of tuberculosis without microbiological confirmation. We excluded genitourinary tuberculosis. DATA COLLECTION AND ANALYSIS: For each study, two review authors independently extracted data using a standardized form. We assessed the quality of studies using a tailored Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. We used the bivariate model to estimate pooled sensitivity and specificity. When studies were few we simplified the bivariate model to separate univariate random-effects logistic regression models for sensitivity and specificity. We explored the influence of the type of reference standard on the accuracy estimates by conducting separate analyses for each type of reference standard. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 11 studies. The risks of bias and concern about applicability were often high or unclear in all domains. We included six studies in the main analyses of any abnormal finding on abdominal ultrasound; five studies reported only individual lesions.The six studies of any abnormal finding were cross-sectional or cohort studies. Five of these (83%) were conducted in low- or middle-income countries, and one in a high-income country. The proportion of participants on antiretroviral therapy was none (1 study), fewer then 50% (4 studies), more than 50% (1 study), and not reported (5 studies). The first main analysis, studies using a higher-quality reference standard (bacteriological confirmation), had a pooled sensitivity of 63% (95% confidence interval (CI) 43% to 79%; 5 studies, 368 participants; very low-certainty evidence) and a pooled specificity of 68% (95% CI 42% to 87%; 5 studies, 511 participants; very low-certainty evidence). If the results were to be applied to a hypothetical cohort of 1000 people with HIV where 200 (20%) have tuberculosis then:- About 382 individuals would have an ultrasound result indicating tuberculosis; of these, 256 (67%) would be incorrectly classified as having tuberculosis (false positives).- Of the 618 individuals with a result indicating that tuberculosis is not present, 74 (12%) would be incorrectly classified as not having tuberculosis (false negatives).In the second main analysis involving studies using a lower-quality reference standard (clinical diagnosis), the pooled sensitivity was 68% (95% CI 45% to 85%; 4 studies, 195 participants; very low-certainty evidence) and the pooled specificity was 73% (95% CI 41% to 91%; 4 studies, 202 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: In HIV-positive individuals thought to have abdominal tuberculosis or disseminated tuberculosis with abdominal involvement, abdominal ultrasound appears to have 63% sensitivity and 68% specificity when tuberculosis was bacteriologically confirmed. These estimates are based on data that is limited, varied, and low-certainty.The low sensitivity of abdominal ultrasound means clinicians should not use a negative test result to rule out the disease, but rather consider the result in combination with other diagnostic strategies (including clinical signs, chest x-ray, lateral flow urine lipoarabinomannan assay (LF-LAM), and Xpert MTB/RIF). Research incorporating the test into tuberculosis diagnostic algorithms will help in delineating more precisely its value in diagnosing abdominal tuberculosis or disseminated tuberculosis with abdominal involvement.

Abdominal Ultrasound for the Diagnosis of Tuberculosis Among Human Immunodeficiency Virus-Positive Inpatients With World Health Organization Danger Signs.

BACKGROUND: Studies of the value of abdominal ultrasound for diagnosing human immunodeficiency virus (HIV)-associated tuberculosis have major limitations. METHODS: We conducted a prospective study of HIV-positive inpatients with cough and World Health Organization danger signs. The reference standard was positive Mycobacterium tuberculosis culture from any site. Participants had at least 2 sputa and 1 blood specimen sent for mycobacterial cultures. Standardized data capture sheets were used for ultrasound reports. A blinded radiologist interpreted chest radiographs, categorized as "likely", "possible", and "unlikely" for HIV-associated tuberculosis. RESULTS: We enrolled 377 participants: 249 women, median age 35 years, 201 with tuberculosis, and median CD4 count 75 cells/µL. The following abdominal ultrasound findings independently predicted tuberculosis: lymph node long-axis ≥10 mm (adjusted odds ratio [aOR], 4.76; 95% confidence interval [CI], 2.41-9.38), splenic hypoechoic lesions (aOR, 3.45; 95% CI, 1.91-6.24), and abdominal/pleural/pericardial effusions (aOR, 1.95; 95% CI, 1.16-3.29). Presence of ≥1 of these 3 features had a sensitivity of 76.4% (95% CI, 69.8-82.3), a specificity of 68.6% (95% CI, 61.1-75.4), and a c-statistic of 0.784 (95% CI, 0.739-0.830). The sensitivity and specificity of chest radiograph assessed as likely tuberculosis was 55.2% (95% CI, 47.2-62.9) and 83.9% (95% CI, 77.0-89.4), respectively. CONCLUSIONS: Three features of tuberculosis on abdominal ultrasound independently predicted tuberculosis with moderate diagnostic performance in seriously ill HIV-positive inpatients. Abdominal ultrasound was more sensitive but less specific than chest radiograph for diagnosing tuberculosis in this patient population.

Development of a clinical prediction rule to diagnose Pneumocystis jirovecii pneumonia in the World Health Organization's algorithm for seriously ill HIV-infected patients.

BACKGROUND: The World Health Organization (WHO) algorithm for the diagnosis of tuberculosis in seriously ill HIV-infected patients recommends that treatment for Pneumocystis jirovecii pneumonia (PJP) should be considered without giving clear guidance on selecting patients for empiric PJP therapy. PJP is a common cause of hospitalisation in HIV-infected patients in resource-poor settings where diagnostic facilities are limited. METHODS: We developed clinical prediction rules for PJP in a prospective cohort of HIV-infected inpatients with WHO danger signs and cough of any duration. The reference standard for PJP was > 1000 copies/mL of P. jirovecii DNA on real-time sputum polymerase chain reaction (PCR). Four potentially predictive variables were selected for regression models: dyspnoea, chest X-ray, haemoglobin and oxygen saturation. Respiratory rate was explored as a replacement for oxygen saturation as pulse oximetry is not always available in resource-poor settings. RESULTS: We enrolled 500 participants. After imputation for missing values, there were 56 PJP outcome events. Dyspnoea was not independently associated with PJP. Oxygen saturation and respiratory rate were inversely correlated. Two clinical prediction rules were developed: chest X-ray possible/likely PJP, haemoglobin ≥ 9 g/dL and either oxygen saturation < 94% or respiratory rate. The area under the receiver operating characteristic curve of the clinical prediction rule models was 0.761 (95% CI 0.683-0.840) for the respiratory rate model and 0.797 (95% CI 0.725-0.868) for the oxygen saturation model. Both models had zero probability for PJP for scores of zero, and positive likelihood ratios exceeded 10 for high scores. CONCLUSION: We developed simple clinical prediction rules for PJP, which, if externally validated, could assist decision-making in the WHO seriously ill algorithm.