Philippa Easterbrook

Prevalence and burden of HCV co-infection in people living with HIV: a global systematic review and meta-analysis

BACKGROUND At global level, there are 37 million people infected with HIV and 115 million people with antibodies to hepatitis C virus (HCV). Little is known about the extent of HIV-HCV co-infection. We sought to characterise the epidemiology and burden of HCV co-infection in people living with HIV. METHODS In this systematic review and meta-analysis we searched MEDLINE, Embase, CINAHL+, POPLINE, Africa-wide Information, Global Health, Web of Science, and the Cochrane Library and WHO databases for studies measuring prevalence of HCV and HIV, published between Jan 1, 2002, and Jan 28, 2015. We included studies in HIV population samples of more than 50 individuals and recruited patients based on HIV infection status or other behavioural characteristics. We excluded editorials or reviews containing no primary data, samples of HCV or HIV-HCV co-infected individuals, or samples relying on self-reported infection status. We also excluded samples drawn from populations with other comorbidities or undergoing interventions that put them at increased risk of co-infection. Populations were categorised according to HIV exposure, with the regional burden of co-infection being derived by applying co-infection prevalence estimates to published numbers of HIV-infected individuals. We did a meta-analysis to estimate the odds of HCV in HIV-infected individuals compared with their HIV-negative counterparts. FINDINGS From 31 767 citations identified, 783 studies met the inclusion criteria, resulting in 902 estimates of the prevalence of HIV-HCV co-infection. In HIV-infected individuals, HIV-HCV co-infection was 2·4% (IQR 0·8-5·8) within general population samples, 4·0% (1·2-8·4) within pregnant or heterosexually exposed samples, 6·4% (3·2-10·0) in men who have sex with men (MSM), and 82·4% (55·2-88·5) in people who inject drugs (PWID). Odds of HCV infection were six times higher in people living with HIV (5·8, 95% CI 4·5-7·4) than their HIV-negative counterparts. Worldwide, there are approximately 2 278 400 HIV-HCV co-infections (IQR 1 271 300-4 417 000) of which 1 362 700 (847 700-1 381 800) are in PWID, equalling an overall co-infection prevalence in HIV-infected individuals of 6·2% (3·4-11·9). INTERPRETATION We noted a consistently higher HCV prevalence in HIV-infected individuals than HIV-negative individuals  across all risk groups and regions, but especially in PWID. This study highlights the importance of routine HCV testing in all HIV-infected individuals, but especially in PWID. There is also a need to improve country-level surveillance of HCV prevalence across different population groups in all regions. FUNDING WHO.

Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries

Cryptococcal meningitis is the leading cause of adult meningitis in sub-Saharan Africa, and contributes up to 20% of AIDS-related mortality in low-income and middle-income countries every year. Antifungal treatment for cryptococcal meningitis relies on three old, off-patent antifungal drugs: amphotericin B deoxycholate, flucytosine, and fluconazole. Widely accepted treatment guidelines recommend amphotericin B and flucytosine as first-line induction treatment for cryptococcal meningitis. However, flucytosine is unavailable in Africa and most of Asia, and safe amphotericin B administration requires patient hospitalisation and careful laboratory monitoring to identify and treat common side-effects. Therefore, fluconazole monotherapy is widely used in low-income and middle-income countries for induction therapy, but treatment is associated with significantly increased rates of mortality. We review the antifungal drugs used to treat cryptococcal meningitis with respect to clinical effectiveness and access issues specific to low-income and middle-income countries. Each drug poses unique access challenges: amphotericin B through cost, toxic effects, and insufficiently coordinated distribution; flucytosine through cost and scarcity of registration; and fluconazole through challenges in maintenance of local stocks--eg, sustainability of donations or insufficient generic supplies. We advocate ten steps that need to be taken to improve access to safe and effective antifungal therapy for cryptococcal meningitis.

Predicting treatment failure in adults and children on antiretroviral therapy: a systematic review of the performance characteristics of the 2010 WHO immunologic and clinical criteria for virologic failure.

Objective:We systematically reviewed the performance of 2010 WHO immunologic and clinical criteria for predicting virologic failure in HIV-infected patients on antiretroviral therapy (ART). Design:Systematic review. Methods:We used Cochrane Collaboration methods. We calculated unweighted sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of immunologic and clinical criteria for predicting virologic failure. Results:We identified 18 studies. Sixteen assessed immunologic criteria in adults; 12 defined virologic failure as a plasma viral load of more than 50 to more than 1000 copies/ml in adults, three as viral load at least 5000 copies/ml, and two as viral load more than 10 000 copies/ml; the sensitivity ranged from 16.8 to 54.9%, specificity from 82.9 to 95.5%, PPV from 15.0 to 38.8%, and NPV from 90.9 to 98.6%. Seven studies assessed clinical criteria to predict viral load of more than 50 to more than 1000 copies/ml; the sensitivity was 11.0%, specificity 90.5%, PPV 44.9%, and NPV 90.2%. Seven studies assessed clinical or immunologic criteria defining virologic failure as viral load of more than 50 to more than1000 copies/ml; their sensitivity was 26.6%, specificity 85.9%, PPV 49.4%, and NPV 91.1%. Four studies assessed immunologic criteria in children; three defined virologic failure as viral load at least 5000 copies/ml and one as viral load at least 400 copies/ml. The sensitivity ranged from 4.5 to 6.3%, specificity from 97.7 to 99.3%, PPV from 20.0 to 54.9%, and NPV from 85.5 to 91.8%. Conclusion:The 2010 WHO clinical and immunologic criteria are insensitive and have low PPV for predicting virologic failure. These data support the strong recommendation 2013 treatment guidelines that viral load testing be used to monitor for, diagnose, and confirm ART failure.

The next generation of the World Health Organization's global antiretroviral guidance

The 2013 World Health Organization’s (WHO) Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection provide more than 50 new recommendations across the continuum of HIV care, including recommendations on HIV testing, using antiretroviral drugs for prevention, linking individuals to HIV care and treatment services, initiating and maintaining antiretroviral therapy (ART) and monitoring treatment. Guidance is provided across all age groups and populations of adults, pregnant and breastfeeding women, adolescents and key populations. The guidelines are based on a public health approach to expanding the use of ARV drugs for HIV treatment and prevention, with a particular focus on resource‐limited settings.

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

Potential impact of task-shifting on costs of antiretroviral therapy and physician supply in Uganda.

BackgroundLower-income countries face severe health worker shortages. Recent evidence suggests that this problem can be mitigated by task-shifting--delegation of aspects of health care to less specialized health workers. We estimated the potential impact of task-shifting on costs of antiretroviral therapy (ART) and physician supply in Uganda. The study was performed at the Infectious Diseases Institute (IDI) clinic, a large urban HIV clinic.MethodsWe built an aggregate cost-minimization model from societal and Ministry of Health (MOH) perspectives. We compared physician-intensive follow-up (PF), the standard of care, with two methods of task-shifting: nurse-intensive follow-up (NF) and pharmacy-worker intensive follow-up (PWF). We estimated personnel and patient time use using a time-motion survey. We obtained unit costs from IDI and the literature. We estimated physician personnel impact by calculating full time equivalent (FTE) physicians saved. We made national projections for Uganda.ResultsAnnual mean costs of follow-up per patient were

Early initiation of antiretroviral therapy in HIV-infected adults and adolescents: a systematic review

59.88 (societal) and

Adoption of national recommendations related to use of antiretroviral therapy before and shortly following the launch of the 2013 WHO consolidated guidelines.

31.68 (medical) for PF,

Challenges and priorities in the management of HIV/HBV and HIV/HCV coinfection in resource-limited settings.

44.58 (societal) and

Epidemiology of Hepatitis B Virus Infection and Impact of Vaccination on Disease

24.58 (medical) for NF and