Maunank Shah

Diagnostic accuracy of a urine lipoarabinomannan test for tuberculosis in hospitalized patients in a high HIV prevalence setting

Background:Effective tuberculosis (TB) control in HIV-prevalent settings is hindered by absence of accurate, rapid TB diagnostic tests. We evaluated the accuracy of a urine lipoarabinomannan (LAM) test for TB diagnosis in South Africa. Methods:Hospitalized adults with signs and/or symptoms of active TB were enrolled. Sputum smear microscopy and mycobacterial culture, mycobacterial blood culture, and HIV testing were performed. A spot urine specimen was tested for LAM. Results:Four hundred ninety nine participants were enrolled; 422 (84.6%) were HIV infected. In microbiologically confirmed TB patients, the LAM test was positive in 114 of 193 [sensitivity 59%, (95% confidence interval: 52 to 66)], including 112 of 167 [67% (59 to 74)] who were HIV infected. Among individuals classified as “not TB”, the LAM test was negative in 117 of 122 [specificity 96% (91 to 99)], including 83 of 88 [94% (87 to 98)] who were HIV infected. In confirmed TB patients, the LAM test was more sensitive than sputum smear microscopy (42%, 82 of 193, P < 0.001) and detected 56% (62 of 111) of those who were sputum smear negative. HIV infection [adjusted odds ratio (AOR 13.4)], mycobacteremia (AOR 3.21), and positive sputum smear (AOR 2.42) were risk factors for a positive LAM test. Conclusions:The urine LAM test detected a subset of HIV-infected patients with severe TB in whom sputum smear microscopy had suboptimal sensitivity. The combination of urine LAM testing and sputum smear microscopy is attractive for use in settings with high HIV burden.

Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in HIV-positive adults.

Background Rapid detection of tuberculosis (TB) among people living with human immunodeficiency virus (HIV) is a global health priority. HIV‐associated TB may have different clinical presentations and is challenging to diagnose. Conventional sputum tests have reduced sensitivity in HIV‐positive individuals, who have higher rates of extrapulmonary TB compared with HIV‐negative individuals. The lateral flow urine lipoarabinomannan assay (LF‐LAM) is a new, commercially available point‐of‐care test that detects lipoarabinomannan (LAM), a lipopolysaccharide present in mycobacterial cell walls, in people with active TB disease. Objectives To assess the accuracy of LF‐LAM for the diagnosis of active TB disease in HIV‐positive adults who have signs and symptoms suggestive of TB (TB diagnosis). To assess the accuracy of LF‐LAM as a screening test for active TB disease in HIV‐positive adults irrespective of signs and symptoms suggestive of TB (TB screening). Search methods We searched the following databases without language restriction on 5 February 2015: the Cochrane Infectious Diseases Group Specialized Register; MEDLINE (PubMed,1966); EMBASE (OVID, from 1980); Science Citation Index Expanded (SCI‐EXPANDED, from 1900), Conference Proceedings Citation Index‐Science (CPCI‐S, from 1900), and BIOSIS Previews (from 1926) (all three using the Web of Science platform; MEDION; LILACS (BIREME, from 1982); SCOPUS (from 1995); the metaRegister of Controlled Trials (mRCT); the search portal of the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP); and ProQuest Dissertations & Theses A&l (from 1861). Selection criteria Eligible study types included randomized controlled trials, cross‐sectional studies, and cohort studies that determined LF‐LAM accuracy for TB against a microbiological reference standard (culture or nucleic acid amplification test from any body site). A higher quality reference standard was one in which two or more specimen types were evaluated for TB, and a lower quality reference standard was one in which only one specimen type was evaluated for TB. Participants were HIV‐positive people aged 15 years and older. Data collection and analysis Two review authors independently extracted data from each included study using a standardized form. We appraised the quality of studies using the Quality Assessment of Diagnostic Accuracy Studies‐2 (QUADAS‐2) tool. We evaluated the test at two different cut‐offs: (grade 1 or 2, based on the reference card scale of five intensity bands). Most analyses used grade 2, the manufacturers currently recommended cut‐off for positivity. We carried out meta‐analyses to estimate pooled sensitivity and specificity using a bivariate random‐effects model and estimated the models using a Bayesian approach. We determined accuracy of LF‐LAM combined with sputum microscopy or Xpert® MTB/RIF. In addition, we explored the influence of CD4 count on the accuracy estimates. We assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Main results We included 12 studies: six studies evaluated LF‐LAM for TB diagnosis and six studies evaluated the test for TB screening. All studies were cross‐sectional or cohort studies. Studies for TB diagnosis were largely conducted among inpatients (median CD4 range 71 to 210 cells per µL) and studies for TB screening were largely conducted among outpatients (median CD4 range 127 to 437 cells per µL). All studies were conducted in low‐ or middle‐income countries. Only two studies for TB diagnosis (33%) and one study for TB screening (17%) used a higher quality reference standard. LF‐LAM for TB diagnosis (grade 2 cut‐off): meta‐analyses showed median pooled sensitivity and specificity (95% credible interval (CrI)) of 45% (29% to 63%) and 92% (80% to 97%), (five studies, 2313 participants, 35% with TB, low quality evidence). The pooled sensitivity of a combination of LF‐LAM and sputum microscopy (either test positive) was 59% (47% to 70%), which represented a 19% (4% to 36%) increase over sputum microscopy alone, while the pooled specificity was 92% (73% to 97%), which represented a 6% (1% to 24%) decrease from sputum microscopy alone (four studies, 1876 participants, 38% with TB). The pooled sensitivity of a combination of LF‐LAM and sputum Xpert® MTB/RIF (either test positive) was 75% (61% to 87%) and represented a 13% (1% to 37%) increase over Xpert® MTB/RIF alone. The pooled specificity was 93% (81% to 97%) and represented a 4% (1% to 16%) decrease from Xpert® MTB/RIF alone (three studies, 909 participants, 36% with TB). Pooled sensitivity and specificity of LF‐LAM were 56% (41% to 70%) and 90% (81% to 95%) in participants with a CD4 count of less than or equal to 100 cells per µL (five studies, 859 participants, 47% with TB) versus 26% (16% to 46%) and 92% (78% to 97%) in participants with a CD4 count greater than 100 cells per µL (five studies, 1410 participants, 30% with TB). LF‐LAM for TB screening (grade 2 cut‐off): for individual studies, sensitivity estimates (95% CrI) were 44% (30% to 58%), 28% (16% to 42%), and 0% (0% to 71%) and corresponding specificity estimates were 95% (92% to 97%), 94% (90% to 97%), and 95% (92% to 97%) (three studies, 1055 participants, 11% with TB, very low quality evidence). There were limited data for additional analyses. The main limitations of the review were the use of a lower quality reference standard in most included studies, and the small number of studies and participants included in the analyses. The results should, therefore, be interpreted with caution. Authors conclusions We found that LF‐LAM has low sensitivity to detect TB in adults living with HIV whether the test is used for diagnosis or screening. For TB diagnosis, the combination of LF‐LAM with sputum microscopy suggests an increase in sensitivity for TB compared to either test alone, but with a decrease in specificity. In HIV‐positive individuals with low CD4 counts who are seriously ill, LF‐LAM may help with the diagnosis of TB.

The Impact of Pre-Exposure Prophylaxis Among Men Who Have Sex With Men: An Individual-Based Model

Objectives: Preexposure prophylaxis (PrEP) is recommended for preventing HIV infection among individuals at high risk, including men who have sex with men (MSM). Although its individual-level efficacy is proven, questions remain regarding population-level impact of PrEP implementation. Design: We developed an agent-based simulation of HIV transmission among MSM, accounting for demographics, sexual contact network, HIV disease stage, and use of antiretroviral therapy. We use this framework to compare PrEP delivery strategies in terms of impact on HIV incidence and prevalence. Results: The projected reduction in HIV incidence achievable with PrEP reflects both population-level coverage and individual-level adherence (as a proportion of days protected against HIV transmission). For example, provision of PrEP to 40% of HIV-negative MSM reporting more than one sexual partner in the last 12 months, taken with sufficient adherence to provide protection on 40% of days, can reduce HIV incidence by 9.5% (95% uncertainty range: 8%–11%) within 5 years. However, if this could be increased to 80% coverage on 80% of days (eg, through mass campaigns with a long-acting injectable formulation), a 43% (42%–44%) reduction in HIV incidence could be achieved. Delivering PrEP to MSM at high risk for HIV acquisition can augment population-level impact up to 1.8-fold. Conclusions: If highly ambitious targets for coverage and adherence can be achieved, PrEP can substantially reduce HIV incidence in the short-term. Although the reduction in HIV incidence largely reflects the proportion of person-years protected, the efficiency of PrEP delivery can be enhanced by targeting high-risk populations.OBJECTIVESnPre-exposure prophylaxis (PrEP) is recommended for preventing HIV infection among individuals at high risk, including men who have sex with men (MSM). Although its individual-level efficacy is proven, questions remain regarding population-level impact of PrEP implementation.nnnDESIGNnWe developed an agent-based simulation of HIV transmission among MSM, accounting for demographics, sexual contact network, HIV disease stage and use of antiretroviral therapy. We use this framework to compare PrEP delivery strategies in terms of impact on HIV incidence and prevalence.nnnRESULTSnThe projected reduction in HIV incidence achievable with PrEP reflects both population-level coverage and individual-level adherence (as a proportion of days protected against HIV transmission). For example, provision of PrEP to 40% of HIV-negative MSM reporting more than one sexual partner in the last 12 months, taken with sufficient adherence to provide protection on 40% of days, can reduce HIV incidence by 9.5% (95% uncertainty range: 8-11%) within five years. However, if this could be increased to 80% coverage on 80% of days (e.g., through mass campaigns with a long-acting injectable formulation), a 43% (42-44%) reduction in HIV incidence could be achieved. Delivering PrEP to MSM at high risk for HIV acquisition can augment population-level impact up to 1.8-fold.nnnCONCLUSIONSnIf highly ambitious targets for coverage and adherence can be achieved, PrEP can substantially reduce HIV incidence in the short-term. While the reduction in HIV incidence largely reflects the proportion of person-years protected, the efficiency of PrEP delivery can be enhanced by targeting high-risk populations.

Cost-effectiveness of rapid susceptibility testing against second-line drugs for tuberculosis

BACKGROUNDnDrug susceptibility testing (DST) against second-line tuberculosis drugs (SLDs) is essential for improving outcomes among multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) cases.nnnOBJECTIVEnTo evaluate the potential cost-effectiveness of rapid DST for SLDs.nnnDESIGNnWe constructed a decision analysis model of Xpert MTB/RIF-based TB diagnosis in East and South-East Asia to compare culture-based DST vs. a hypothetical rapid SLD DST system for specimens resistant to rifampin. Our primary outcomes were the effectiveness and incremental cost-effectiveness of a rapid SLD DST assay relative to culture-based DST.nnnRESULTSnFor rapid SLD DST to be more effective than culture-based DST, treating individuals with pre-XDR/XDR-TB with a standardized MDR-TB regimen while awaiting culture-based DST must incur at least 30% excess XDR-TB mortality (100% = treatment with first-line drugs); rapid SLD DST should attain an aggregate sensitivity and specificity for all pre-XDR/XDR mutations of 88% and 96%, respectively. The unit cost of the rapid SLD DST assay must approach that of culture to achieve common thresholds for cost-effectiveness in low-income countries.nnnCONCLUSIONnRapid SLD DST has the potential to be cost-effective, but must meet stringent criteria for accuracy and costs, and requires that standardized second-line treatment for pre-XDR/XDR-TB incur substantial excess mortality before the return of culture results.

Epidemiological impact of achieving UNAIDS 90-90-90 targets for HIV care in India: a modelling study

Objective Recent UNAIDS ‘90-90-90’ targets propose that to end the HIV epidemic by 2030, 90% of persons living with HIV (PLWH) worldwide should know their diagnosis, 90% of diagnosed PLWH should be on antiretroviral therapy (ART) and 90% of PLWH on ART should be virally suppressed by 2020. We sought to quantify the epidemiological impact of achieving these targets in India. Methods We constructed a dynamic-transmission model of the Indian HIV epidemic to project HIV infections and AIDS-related deaths that would occur in India over 15u2005years. We considered several scenarios: continuation of current care engagement (with early ART initiation), achieving 90-90-90 targets on time and delaying achievement by 5 or 10u2005years. Results In the base case, assuming continuation of current care engagement, we project 794u2005000 (95% uncertainty range (UR) 571u2005000–1u2005104u2005000) HIV infections and 689u2005000 (95% UR 468u2005000–976u2005000) AIDS-related deaths in India over 15u2005years. In this scenario, nearly half of PLWH diagnosed would fail to achieve viral suppression by 2030. With achievement of 90-90-90 targets, India could avert 392u2005000 (95% UR 248u2005000–559u2005000) transmissions (48% reduction) and 414u2005000 (95% UR 260u2005000–598u2005000) AIDS-related deaths (59% reduction) compared to the base-case scenario. Furthermore, fewer than 20u2005000 (95% UR 12u2005000–30u2005000) HIV infections would occur in 2030. Delaying achievement of targets resulted in a similar reduction in HIV incidence by 2030 but at the cost of excess overall infections and mortality. Conclusions India can halve the epidemiological burden of HIV over 15u2005years with achievement of the UNAIDS 90-90-90 targets. Reaching the targets on time will require comprehensive healthcare strengthening, especially in early diagnosis and treatment, expanded access to second-line and third-line ART and long-term retention in care.

Economic challenges associated with tuberculosis diagnostic development

Tuberculosis remains a global health crisis in part due to underdiagnosis. Technological innovations are needed to improve diagnostic test accuracy and reduce the reliance on expensive laboratory infrastructure. However, there are significant economic challenges impeding the development and implementation of new diagnostics. The aim of this piece is to examine the current state of TB diagnostics, outline the unmet needs for new tests, and detail the economic challenges associated with development of new tests from the perspective of developers, policy makers and implementers.

Advancing Patient-Centered Care in Tuberculosis Management: A Mixed-Methods Appraisal of Video Directly Observed Therapy

Abstract Background Directly observed therapy (DOT) remains an integral component of treatment support and adherence monitoring in tuberculosis care. In-person DOT is resource intensive and often burdensome for patients. Video DOT (vDOT) has been proposed as an alternative to increase treatment flexibility and better meet patient-specific needs. Methods We conducted a pragmatic, prospective pilot implementation of vDOT at 3 TB clinics in Maryland. A mixed-methods approach was implemented to assess (1) effectiveness, (2) acceptability, and (3) cost. Medication adherence on vDOT was compared with that of in-person DOT. Interviews and surveys were conducted with patients and providers before and after implementation, with framework analysis utilized to extract salient themes. Last, a cost analysis assessed the economic impacts of vDOT implementation across heterogeneous clinic structures. Results Medication adherence on vDOT was comparable to that of in-person DOT (94% vs 98%, P = .17), with a higher percentage of total treatment doses (inclusive of weekend/holiday self-administration) ultimately observed during the vDOT period (72% vs 66%, P = .03). Video DOT was well received by staff and patients alike, who cited increased treatment flexibility, convenience, and patient privacy. Our cost analysis estimated a savings with vDOT of

Infectious Diseases (ID) Learning Unit: How Rapidly to Evaluate for Active Tuberculosis Disease in Low-Prevalence Settings

1391 per patient for a standard 6-month treatment course. Conclusions Video DOT is an acceptable and important option for measurement of TB treatment adherence and may allow a higher proportion of prescribed treatment doses to be observed, compared with in-person DOT. Video DOT may be cost-saving and should be considered as a component of individualized, patient-centered case management plans.

Projecting the impact of implementing pre-exposure prophylaxis for HIV among men who have sex with men in Baltimore city

With declining tuberculosis (TB) incidence in low-prevalence settings, many clinicians are likely unaware that the approach to diagnosing active TB is evolving with newer technologies. Rapid molecular assays are commercially available, and more are likely to enter the market in the coming years. These tests, such as the Xpert MTB/RIF, which can detect TB and drug-resistance in 2 hours, are increasingly used in settings with higher TB prevalence; however, uptake has been slower in low-prevalence settings. Newer algorithms incorporating rapid TB diagnostics have the ability to alter current clinical and infection control practice patterns. In this learning unit, we review current and newly available tests for the detection of active TB disease and their usage in low-prevalence settings.

Urine lateral flow lipoarabinomannan assay for diagnosing active tuberculosis in adults living with HIV

Men who have sex with men (MSM) experience over half of new HIV infections annually in Baltimore city. Oral pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) are likely to play central roles in reducing the risk of HIV transmission. However, the likely combined impact of these interventions remains uncertain. We propose an individual-based simulation approach to project the population-level impact of implementing PrEP for high-risk MSM in Baltimore, with different levels of coverage and adherence. The primary outcome is the HIV incidence over five years. We project non-linear relationships between program coverage, individual-level adherence, and population-level impact. The impact of PrEP increases with time but is not sustained if PrEP provision ceases. Expansion of ART coverage can augment the impact of PrEP on HIV incidence over the next decade.