Jennifer Cohn

Viral load monitoring as a tool to reinforce adherence: a systematic review.

Objective:Viral load monitoring has been proposed as a tool to reinforce adherence, but outcomes have never been systematically assessed. Design:A meta-analysis was conducted to systematically analyze the research on viral load monitoring as a tool to reinforce adherence. Viremic resuppression is defined here as a decrease in viral load beneath a particular threshold following viral load levels that have been elevated despite antiretroviral treatment. Methods:Six databases were searched for studies published up to November 2012, which reported the use of viral load monitoring as a tool to identify patients in need of adherence support. Three conference abstract sites were reviewed for studies reported in the last 2 years. Randomized and quasi-randomized trials and observational studies, were eligible. No language or geographical restrictions were applied. Results:Six retrospective and 2 prospective observational studies reported data from 8 countries: South Africa, the United States, Thailand, Mali, Burkina Faso, Swaziland, India, and France. Five studies reported on viremic resuppression, with a pooled estimate of 70.5% (95% confidence interval: 56.6% to 84.4%) resuppressed. The remaining 3 studies all reported declines in mean viral load. Delayed onset of routine viral load monitoring was associated with the emergence of drug resistance. Conclusions:The clear trend of resuppression, following viral load testing and adherence support, demonstrates the utility of viral load as a tool to identify patients in need of enhanced adherence support.

Sustainable HIV treatment in Africa through viral-load-informed differentiated care

There are inefficiencies in current approaches to monitoring patients on antiretroviral therapy in sub-Saharan Africa. Patients typically attend clinics every 1 to 3 months for clinical assessment. The clinic costs are comparable with the costs of the drugs themselves and CD4 counts are measured every 6 months, but patients are rarely switched to second-line therapies. To ensure sustainability of treatment programmes, a transition to more cost-effective delivery of antiretroviral therapy is needed. In contrast to the CD4 count, measurement of the level of HIV RNA in plasma (the viral load) provides a direct measure of the current treatment effect. Viral-load-informed differentiated care is a means of tailoring care so that those with suppressed viral load visit the clinic less frequently and attention is focussed on those with unsuppressed viral load to promote adherence and timely switching to a second-line regimen. The most feasible approach to measuring viral load in many countries is to collect dried blood spot samples for testing in regional laboratories; however, there have been concerns over the sensitivity and specificity of this approach to define treatment failure and the delay in returning results to the clinic. We use modelling to synthesize evidence and evaluate the cost-effectiveness of viral-load-informed differentiated care, accounting for limitations of dried blood sample testing. We find that viral-load-informed differentiated care using dried blood sample testing is cost-effective and is a recommended strategy for patient monitoring, although further empirical evidence as the approach is rolled out would be of value. We also explore the potential benefits of point-of-care viral load tests that may become available in the future.This article has not been written or reviewed by Nature editors. Nature accepts no responsibility for the accuracy of the information provided.

Scale-up of Routine Viral Load Testing in Resource-Poor Settings: Current and Future Implementation Challenges

Cost and complexity have hindered implementation to date of viral load testing in resource-limited settings. If rapid and timely scale-up is to become a reality, numerous factors will need to be addressed, including health and laboratory system strengthening, pricing, and multiple programmatic and funding challenges.

International cooperation to improve access to and sustain effectiveness of antimicrobials

Securing access to effective antimicrobials is one of the greatest challenges today. Until now, efforts to address this issue have been isolated and uncoordinated, with little focus on sustainable and international solutions. Global collective action is necessary to improve access to life-saving antimicrobials, conserving them, and ensuring continued innovation. Access, conservation, and innovation are beneficial when achieved independently, but much more effective and sustainable if implemented in concert within and across countries. WHO alone will not be able to drive these actions. It will require a multisector response (including the health, agriculture, and veterinary sectors), global coordination, and financing mechanisms with sufficient mandates, authority, resources, and power. Fortunately, securing access to effective antimicrobials has finally gained a place on the global political agenda, and we call on policy makers to develop, endorse, and finance new global institutional arrangements that can ensure robust implementation and bold collective action.

Hepatitis C Core Antigen Testing for Diagnosis of Hepatitis C Virus Infection: A Systematic Review and Meta-analysis

Background Diagnosis of chronic Hepatitis C Virus (HCV) infection requires both a positive HCV antibody screen and confirmatory nucleic acid test (NAT). HCV core antigen (HCVcAg) is a potential alternative to NAT.Approximately 130 to 150 million persons are infected with chronic hepatitis C virus (HCV), and approximately 75% of all cases occur in low- and middle-income countries (LMICs) (1, 2). Direct-acting antivirals allow safe and effective curative treatment, but treatment is the final step in a long cascade that requires screening, confirmation, notification of results, and linkage to care (3, 4). Diagnosis of HCV is a 2-step process that starts with screening for exposure with an assay that detects antibodies to HCV (anti-HCV), followed by nucleic acid testing (NAT) for persons with reactive anti-HCV to confirm active viremia. Among those who acquire a primary infection, 15% to 50% will spontaneously clear the virus within the first 2 to 6 months and remain positive for anti-HCV, although they are not actively infected and do not require treatment (5). The diagnostic process is designed to be cost-effective, with a low-cost screening test followed by targeted testing with the more expensive NAT. In LMICs, implementation of a complex algorithm is often not feasible and diagnostic capacity is low; as a result, fewer than 1% of patients are aware of their infection (6). In addition, a significant proportion of patients who test positive for anti-HCV do not receive diagnostic NAT and are lost to follow-up (7). The 2-step diagnostic process is a major bottleneck to the HCV cascade of care that needs to be addressed to achieve the ambitious elimination strategy proposed by the World Health Organization (WHO) (8). Testing for hepatitis C virus core antigen (HCVcAg) is a potential replacement for NAT. The HCVcAg forms the internal capsid, which is highly conserved and antigenic (9, 10). During viral assembly, nucleocapsid peptide 22 is released into the plasma (11) and can be detected earlier than antibodies and throughout the course of infection (12). The following 5 tests for HCVcAg detection are commercially available: Abbott ARCHITECT HCV Ag, which is an automated chemiluminescent microparticle immunoassay; Fujirebio Lumipulse Ortho HCV Ag and Eiken Lumispot HCV Ag, which are similar automated chemiluminescent enzyme immunoassays available in Japan and China; Hunan Jynda Bioengineering Group HCV Ag enzyme-linked immunosorbent assay (ELISA); and Ortho HCV Ag ELISA. Although all current HCVcAg tests require laboratory capacity, the development of a highly sensitive point-of-care (POC) platform is feasible and probably possible at a lower cost than NAT POC. Such a test has been defined as the highest-priority target product profile in a global stakeholder consultation process (13). As such, tests targeting HCVcAg could be attractive as a single-step diagnosis for chronic HCV infection in high-prevalence settings, which would streamline the HCV cascade of care and reduce loss to follow-up. This WHO-commissioned systematic review to inform forthcoming WHO guidelines on hepatitis testing evaluated the accuracy of diagnosis of active HCV infection among adults and children for 5 commercially available HCVcAg tests compared with NAT. Methods We performed a systematic review of HCV diagnostics literature, extracted data from selected studies, and conducted a bivariate meta-analysis of the test characteristics of HCVcAg as a diagnostic test for HCV infection. We used standard methods for systematic reviews and meta-analyses of diagnostic tests (1418), including preparation of an a priori protocol for the literature search, article selection, data extraction, quality assessment, and analysis (see Supplement). Supplement. Data Supplement Data Sources and Searches We searched EMBASE, PubMed, Scopus, Web of Science, and Cochrane Database of Systematic Reviews for citations related to HCVcAg screening and diagnosis published until 31 March 2016. We did not restrict the search by language, and terms were selected under the guidance of medical librarians. The search strategies included terms related to HCV, antigen, and nucleic acid amplification. See the Supplement for specific search strategies and the number of studies retrieved from each database. Two authors (J.M.F. and T.M.T.) independently assessed titles and abstracts identified by the literature search to select eligible studies. Citations identified by either reviewer were selected for full-text review. These same 2 authors then independently assessed the full-text articles using predefined inclusion and exclusion criteria. Discrepancies were resolved by discussion between the authors and, when needed, by the decision of a third author (C.M.D.). Study Selection Inclusion criteria were as follows: casecontrol, cross-sectional, cohort, or randomized trials; commercially available HCVcAg tests; commercially available NAT as the reference standard; whole blood, plasma, or serum specimens; and at least 10 independent clinically collected samples. Studies done using commercially prepared reference panel specimens, published in abstract form only, or presented as slides or posters were excluded. We included articles that reported results from populations with any distribution of patient age, from any country, and in any screening setting (for example, hospital- or community-based). Although we were primarily interested in test performance among persons at risk for HCV and with known infection, we also included studies using specimens from healthy blood donors. Because the performance characteristics of NAT are very similar when HCV RNA levels are greater than 50 IU/mL, we accepted any of the following NAT techniques as the reference standard: polymerase chain reaction, branched-chain DNA, or transcription-mediated amplification. Tests were classified as either qualitative or quantitative. Data Extraction and Quality Assessment Two authors (J.M.F. and T.M.T.) independently assessed all studies for inclusion and extracted data on study methods, characteristics, and test accuracy using a standardized extraction form (Supplement). Foreign-language studies were translated and extracted by native speakers using the same form. We crosschecked data points for 25% of the included studies. Disagreements between reviewers were resolved by discussion or by a third reviewer (C.M.D.). When elements for extraction were missing, we contacted the authors to request further data. We also requested individual specimen data to allow for a quantitative assessment of HCVcAg against HCV RNA. Studies without extractable sensitivity and specificity data were excluded if no further information was acquired after 3 attempts to contact the study authors. Methodological quality of the included studies was assessed using a validated QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) tool (19). Details of the QUADAS-2 questions and interpretation are reported in the Supplement. Data Synthesis and Analysis We defined HCVcAg sensitivity as the proportion of samples with a positive NAT result that was also positive for HCVcAg. We defined HCVcAg specificity as the proportion of samples with a negative NAT result that was also negative for HCVcAg. Sensitivity and specificity were the primary outcome measures. Positive and negative likelihood ratios were calculated when pooled sensitivity and specificity data were available from meta-analysis. Indeterminate test results accounted for fewer than 1% for all index tests and were excluded from further analyses. We constructed forest plots for each HCVcAg index test to visually assess heterogeneity by examining the CIs of individual studies. We then used summary plots to examine the width of the prediction region, with a wider prediction region suggesting more heterogeneity. When at least 4 studies with limited heterogeneity were available, we used a bivariate random-effects model and carried out meta-analyses using the metandi command in STATA, version 14 (StataCorp) (20, 21). When at least 4 studies provided sensitivity data only, we did a univariate random-effects meta-analysis on the sensitivities to use all available data. Results from the univariate analyses (including all studies) were compared with the pooled estimates from the bivariate analyses where possible. Descriptive analyses were done for index tests with fewer than 4 studies and when substantial heterogeneity was evident from inspection of the forest and summary plots. When quantitative data were available, a locally weighted regression smoother was used to visually assess the linearity of quantitative HCVcAg (measured in fmol/L) to HCV RNA (measured in IU/mL) (22). We identified outliers and recorded descriptive statistics of these points. Quantitative data were insufficient to assess any test other than Abbott ARCHITECT. We assessed for publication bias when more than 10 studies were available for an index test. We generated funnel plots displaying the log diagnostic odds ratio versus the SE for each study (18). We also did the trim-and-fill statistical assessment in STATA using the metatrim command (23). Unpublished data were not included. All statistical analyses were done using STATA and R, version 3.2.5 (R Foundation for Statistical Computing). Role of the Funding Source This systematic review was supported by the National Institutes of Health, which had no direct involvement in the study design, collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Study Selection and Characteristics The systematic review identified 8508 citations, from which we reviewed 299 full-text articles and identified 44 that met the a prioridefined inclusion criteria (Appendix Figure 1). Of the included studies, 44 used the 5 HCVcAg assays; 1 of these studies directly compared 3 antigen tests. Four studies were translated from Mandarin (2427), 1 from German (28), and 2 from Japanese (29, 30). Characteristics for each study are presented in Table 1. Table 1. Characteristics of Included Studies Grouped Alphabetically, by Index Test Type Appendix Fig

Disparity in market prices for hepatitis C virus direct-acting drugs

www.thelancet.com/lancetgh Vol 3 November 2015 e676 gross national income (figure). In high-income countries, the price per bottle of sofosbuvir ranged from

Bartonella infection in immunocompromised hosts: immunology of vascular infection and vasoproliferation.

14 000 (Spain) to

Dried blood spot in the genotyping, quantification and storage of HCV RNA: a systematic literature review

20 590 (Switzerland). Prices for daclatasvir ranged from

Using global health initiatives to strengthen health systems: a civil society perspective.

1128 (South Korea) to

Translational research for tuberculosis elimination: priorities, challenges, and actions

14 899 (Germany); those of simeprevir from