Summary Testing and diagnosis of hepatitis C virus (HCV) infection is the gateway for access to both treatment and prevention services, and crucial for an effective hepatitis epidemic response. In ...contrast to HIV, a systematic approach to hepatitis C testing has been fragmented and limited to a few countries, and there remains a large burden of undiagnosed cases globally. Key challenges in the current hepatitis testing response, include lack of simple, reliable, and low cost diagnostic tests, laboratory capacity, and testing facilities; inadequate data to guide country-specific hepatitis testing approaches and who to test; stigmatization and social marginalization of some groups with or at risk of viral hepatitis; and lack of international or national guidelines on hepatitis testing for resource-limited settings. New tools to support the hepatitis global response include the 2016 Global Hepatitis Health Sector Strategy which include targets for testing and diagnosis, and World Health Organization (WHO) 2016 hepatitis testing guidelines for adults, adolescents, and children in low- and middle-income countries. The testing guidance complements recent published WHO guidance on the prevention, care and treatment of chronic hepatitis C and hepatitis B infection. These testing guidelines outline the public health approach to strengthening and expanding current testing practices for HCV and HBV and address what serological and virological assays to use, and who to test, as well as interventions to promote linkage to prevention and care after testing. They are intended for use across all age groups and populations. See boxes for key recommendations. Future directions and innovations in viral hepatitis testing include use of point-of-care assays for nucleic acid testing (NAT) and core antigen; validation of dried blood spots specimens with different commercial serological and NAT assays; multiplex and polyvalent platforms for integrated testing of HIV, HBV and HCV; and potential for self-testing.
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Integration of hepatitis B vaccination into national immunization programs has resulted in substantial reductions of hepatitis B virus (HBV) transmission in previously high endemic countries. The key ...strategy for control of the HBV epidemic is birth dose and infant vaccination. Additional measures include use of hepatitis B immunoglobulin (HBIG) and diagnosis of mothers at high risk of transmitting HBV and use of antiviral agents during pregnancy to decrease maternal DNA concentrations to undetectable concentrations. Despite the substantial decrease in HBV cases since vaccination introduction, implementation of birth dose vaccination in low-income and middle-income countries and vaccination of high-risk adults remain challenging.
The increased use of meta-analysis in systematic reviews of healthcare interventions has highlighted several types of bias that can arise during the completion of a randomised controlled trial. Study ...publication bias has been recognised as a potential threat to the validity of meta-analysis and can make the readily available evidence unreliable for decision making. Until recently, outcome reporting bias has received less attention.
We review and summarise the evidence from a series of cohort studies that have assessed study publication bias and outcome reporting bias in randomised controlled trials. Sixteen studies were eligible of which only two followed the cohort all the way through from protocol approval to information regarding publication of outcomes. Eleven of the studies investigated study publication bias and five investigated outcome reporting bias. Three studies have found that statistically significant outcomes had a higher odds of being fully reported compared to non-significant outcomes (range of odds ratios: 2.2 to 4.7). In comparing trial publications to protocols, we found that 40-62% of studies had at least one primary outcome that was changed, introduced, or omitted. We decided not to undertake meta-analysis due to the differences between studies.
Recent work provides direct empirical evidence for the existence of study publication bias and outcome reporting bias. There is strong evidence of an association between significant results and publication; studies that report positive or significant results are more likely to be published and outcomes that are statistically significant have higher odds of being fully reported. Publications have been found to be inconsistent with their protocols. Researchers need to be aware of the problems of both types of bias and efforts should be concentrated on improving the reporting of trials.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Cryptococcal immune reconstitution inflammatory syndrome (IRIS) may present as a clinical worsening or new presentation of cryptococcal disease after initiation of antiretroviral therapy ...(ART), and is thought to be caused by recovery of cryptococcus-specific immune responses. We have reviewed reports of cryptococcal IRIS and have developed a consensus case definition specifically for paradoxical crytopcoccal IRIS in patients with HIV-1 and known cryptococcal disease before ART, and a separate definition for incident cryptococcosis developed during ART (termed ART-associated cryptococcosis), for which a proportion of cases are likely to be unmasking cryptococcal IRIS. These structured case definitions are intended to aid design of future clinical, epidemiological, and immunopathological studies of cryptococcal IRIS, to standardise diagnostic criteria, and to facilitate comparisons between studies. As for definitions of tuberculosis-associated IRIS, definitions for cryptococcal IRIS should be regarded as preliminary until further insights into the immunopathology of IRIS permit their refinement.
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Appropriate second-line antiretroviral therapy for HIV infection is needed in resource-limited settings. In a comparison of three protease-inhibitor–based regimens in sub-Saharan Africa, the one that ...included nucleoside reverse-transcriptase inhibitors performed favorably.
The public health approach of the World Health Organization (WHO),
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together with large-scale donor funding, has enabled millions of adults and children in sub-Saharan Africa who are infected with the human immunodeficiency virus (HIV) to have access to lifesaving antiretroviral therapy.
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The key principle is the use of simplified, standardized approaches that are feasible on a large scale in resource-limited settings,
1
,
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including a first-line regimen of two nucleoside reverse-transcriptase inhibitors (NRTIs) plus one non-NRTI (NNRTI). In most settings, treatment is monitored clinically and with the use of CD4+ counts, with typically late detection of treatment failure, accompanied by substantial . . .
Diagnosis of viral hepatitis Easterbrook, Philippa J; Roberts, Teri; Sands, Anita ...
Current opinion in HIV & AIDS
12, Issue:
3
Journal Article
Open access
PURPOSE OF REVIEWChronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and HIV–HBV and HCV coinfection are major causes of chronic liver disease worldwide. Testing and diagnosis is ...the gateway for access to both treatment and prevention services, but there remains a large burden of undiagnosed infection globally. We review the global epidemiology, key challenges in the current hepatitis testing response, new tools to support the hepatitis global response (2016–2020 Global Hepatitis Health Sector strategy, and 2017 WHO guidelines on hepatitis testing) and future directions and innovations in hepatitis diagnostics.
RECENT FINDINGSKey challenges in the current hepatitis testing response include lack of quality-assured serological and low-cost virological in-vitro diagnostics, limited facilities for testing, inadequate data to guide country-specific hepatitis testing approaches, stigmatization of those with or at risk of viral hepatitis and lack of guidelines on hepatitis testing for resource-limited settings. The new Global Hepatitis Health Sector strategy sets out goals for elimination of viral hepatitis as a public health threat by 2030 and gives outcome targets for reductions in new infections and mortality, as well as service delivery targets that include testing, diagnosis and treatment. The 2017 WHO hepatitis testing guidelines for adults, adolescents and children in low-income and middle-income countries outline the public health approach to strengthen and expand current testing practices for viral hepatitis and addresses who to test (testing approaches), which serological and virological assays to use (testing strategies) as well as interventions to promote linkage to prevention and care.
SUMMARYFuture directions and innovations in hepatitis testing include strategies to improve access such as through use of existing facility and community-based testing opportunities for hepatitis testing, near-patient or point-of-care assays for virological markers (nucleic acid testing and HCV core antigen), dried blood spot specimens used with different serological and nucleic acid test assays, multiplex and multi-disease platforms to enable testing for multiple analytes/pathogens and potential self-testing for viral hepatitis.
Diagnosis of chronic hepatitis C virus (HCV) infection requires both a positive HCV antibody screen and confirmatory nucleic acid testing (NAT). Testing for hepatitis C virus core antigen (HCVcAg) is ...a potential alternative to NAT.
To evaluate the accuracy of diagnosis of active HCV infection among adults and children for 5 HCVcAg tests compared with NAT.
EMBASE, PubMed, Web of Science, Scopus, and Cochrane Database of Systematic Reviews from 1990 through 31 March 2016.
Case-control, cross-sectional, cohort, or randomized trials that compared any of 5 HCVcAg tests with an NAT reference standard.
2 independent reviewers extracted data and assessed quality using an adapted QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) tool.
44 studies evaluated 5 index tests. Studies for the Abbott ARCHITECT HCV Ag assay had the highest quality, whereas those for the Ortho HCV Ag enzyme-linked immunosorbent assay (ELISA) had the lowest quality. From bivariate analyses, the sensitivity and specificity of the assays were as follows: Abbott ARCHITECT, 93.4% (95% CI, 90.1% to 96.4%) and 98.8% (CI, 97.4% to 99.5%); Ortho ELISA, 93.2% (CI, 81.6% to 97.7%) and 99.2% (CI, 87.9% to 100%); and Hunan Jynda Bioengineering Group HCV Ag ELISA, 59.5% (CI, 46.0% to 71.7%) and 82.9% (CI, 58.6% to 94.3%). Insufficient data were available for a meta-analysis about the Fujirebio Lumipulse Ortho HCV Ag and Eiken Lumispot HCV Ag assays. In 3 quantitative studies using Abbott ARCHITECT, HCVcAg correlated closely with HCV RNA levels greater than 3000 IU/mL.
Insufficient data were available on covariates, such as HIV or hepatitis B virus status, for subgroup analyses. Few studies reported genotypes of isolates, and data for genotypes 4, 5, and 6 were scant. Most studies were conducted in high-resource settings and reference laboratories.
The HCVcAg assays with signal amplification have high sensitivity, high specificity, and good correlation with HCV RNA levels greater than 3000 IU/mL and have the potential to replace NAT in settings with high HCV prevalence.
National Institutes of Health.
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.
OBJECTIVES:The objective of this review was to update evidence on when to initiate antiretroviral therapy (ART) to inform revision of the 2013 WHO guidelines for ART in low and middle-income ...countries.
DESIGN:A systematic review and meta-analysis.
METHODS:We comprehensively searchescohorts. Outcomes were mortality, clinical progression, virologic failure, immunologic recover, and severe adverse events. We pooled data across studies and estimated summary effect sizes. We graded the quality of evidence from the literature for each outcome.
RESULTS:We identified 24 studies; 3 were RCTs. Studies found reduced risk of mortality 1 RCThazard ratio 0.77, 95% confidence interval (CI) 0.34–1.76; 13 cohortsrelative risk (RR) 0.66, 95% CI 0.55–0.79, progression to AIDS or death (2 RCTsRR 0.48, 95% CI 0.26–0.91; 9 cohortsRR 0.70, 95% CI 0.40–1.24) and diagnosis of a non-AIDS-defining illness (1 RCTRR 0.14, 95% CI 0.03–0.64; 1 cohortRR 0.47, 95% CI 0.23–0.98), and an increased risk of grade 3/4 laboratory abnormalities in patients initiating ART at at least 350 cells/μl (1 RCTRR 1.49, 95% CI 1.25–1.77). The quality of evidence was low or very low for clinical outcomes due to few events and imprecision, and high for adverse events.
CONCLUSIONS:Our findings contributed to the evidence base for the revised 2013 WHO guidelines on ART, which recommend initiating ART at CD4 T-cell counts of 350–500 cells/μl, but not above 500 cells/μl compared to initiating it later when CD4 T-cell counts fall below 350 cells/μl.
Background.There is no validated case definition for human immunodeficiency virus-associated immune reconstitution inflammatory syndrome (IRIS). We measured the level of agreement of 2 published case ...definitions (hereafter referred to as CD1 and CD2) with expert opinion in a prospective cohort of patients who were starting antiretroviral therapy in South Africa. Methods.A total of 498 adult patients were monitored for the first 6 months of antiretroviral therapy. All new or worsening clinical events were reviewed by ⩾2 investigators and classified on the basis of expert opinion, CD1, and CD2. Events were categorized according to whether they were paradoxical or unmasking in presentation. We measured positive, negative, and chance-corrected agreement (κ) with expert opinion for CD1 and CD2, and reviewed areas of disagreement. Results.A total of 620 clinical events were recorded, of which, on the basis of expert opinion, 144 (23.2%) were defined as probable IRIS and 112 (18.1%) were defined as possible IRIS. Of the 144 probable IRIS events, 93 (64.6%) were unmasking in presentation, 99 (68.8%) were associated with dermatological or orogenital disease, and 45 (31.3%) were associated with tuberculosis or major opportunistic infections. Of the 620 clinical events recorded, 41 (6.6%) were classified as IRIS on the basis of CD1, and 156 (25.2%) were classified as IRIS on the basis of CD2. Positive agreement between CD1 and expert opinion was low for both unmasking (17.2%; k=0.24) and paradoxical events (37.3%; k=0.43), mainly because 1 major criterion requires IRIS to be atypical and either an opportunistic infection or a tumor, although negative agreement was >98%. In contrast, CD2 had good positive agreement (>75% for most event types), with a κ value of 0.75 for paradoxical and 0.62 for unmasking. Conclusions.CD2 agreed well with expert opinion, with additional clinical events, such as arthropathy and inflammatory dermatoses, being classified as IRIS and added to CD2. We propose revised case definitions for both paradoxical and unmasking IRIS.
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