Determining the lower limit of detection required for HCV viral load assay for test of cure following direct-acting antiviral-based treatment regimens: Evidence from a global data set.

Achieving global elimination of hepatitis C virus requires a substantial scale-up of testing. Point-of-care HCV viral load assays are available as an alternative to laboratory-based assays to promote access in hard to reach or marginalized populations. The diagnostic performance and lower limit of detection are important attributes of these new assays for both diagnosis and test of cure. Therefore, our objective was to determine an acceptable LLoD for detectable HCV viraemia as a test for cure, 12 weeks post-treatment (SVR12). We assembled a global data set of patients with detectable viraemia at SVR12 from observational databases from 9 countries (Egypt, the United States, United Kingdom, Georgia, Ukraine, Myanmar, Cambodia, Pakistan, Mozambique) and two pharmaceutical-sponsored clinical trial registries. We examined the distribution of HCV viral load at SVR12 and presented the 90th, 95th, 97th and 99th percentiles. We used logistic regression to assess characteristics associated with low-level virological treatment failure (defined as <1000 IU/mL). There were 5973 cases of detectable viraemia at SVR12 from the combined data set. Median detectable HCV RNA at SVR12 was 287,986 IU/mL. The level of detection for the 95th percentile was 227 IU/mL (95% CI 170-276). Females and those with minimal fibrosis were more likely to experience low-level viraemia at SVR12 compared to men (adjusted odds ratio AOR = 1.60 95% confidence interval [CI] 1.30-1.97 and those with cirrhosis (AOR = 1.49 95% CI 1.15-1.93). In conclusion, an assay with a level of detection of 1000 IU/mL or greater may miss a proportion of those with low-level treatment failure.

Deriving the optimal limit of detection for an HCV point-of-care test for viraemic infection: Analysis of a global dataset.

BACKGROUND & AIMS: Affordable point-of-care tests for hepatitis C (HCV) viraemia are needed to improve access to treatment in low- and middle-income countries. Our aims were to determine the target limit of detection (LOD) necessary to diagnose the majority of people with HCV eligible for treatment, and identify characteristics associated with low-level viraemia (LLV) (defined as the lowest 3% of the distribution of HCV RNA) to understand those at risk of being misdiagnosed. METHODS: We established a multi-country cross-sectional dataset of first available quantitative HCV RNA measurements linked to demographic and clinical data. We excluded individuals on HCV treatment. We analysed the distribution of HCV RNA and determined critical thresholds for detection of HCV viraemia. We then performed logistic regression to evaluate factors associated with LLV, and derived relative sensitivities for significant covariates. RESULTS: The dataset included 66,640 individuals with HCV viraemia from across the world. The LOD for the 95th and 99th percentiles were 3,311 IU/ml and 214 IU/ml. The LOD for the 97th percentile was 1,318 IU/ml (95% CI 1,298.4-1,322.3). Factors associated with LLV, defined as HCV RNA <1,318 IU/ml, were younger age 18-30 vs. 51-64 years (odds ratios [OR] 2.56; 95% CI 2.19-2.99), female vs. male sex (OR 1.32; 95% CI 1.18-1.49), and advanced fibrosis stage F4 vs. F0-1 (OR 1.44; 95% CI 1.21-1.69). Only the younger age group had a decreased relative sensitivity below 95%, at 93.3%. CONCLUSIONS: In this global dataset, a test with an LOD of 1,318 IU/ml would identify 97% of viraemic HCV infections among almost all populations. This LOD will help guide manufacturers in the development of affordable point-of-care diagnostics to expand HCV testing and linkage to care in low- and middle-income countries. LAY SUMMARY: We created and analysed a dataset from 12 countries with 66,640 participants with chronic hepatitis C virus infection. We determined that about 97% of those with viraemic infection had 1,300 IU/ml or more of circulating virus at the time of diagnosis. While current diagnostic tests can detect as little as 12 IU/ml of virus, our findings suggest that increasing the level of detection closer to 1,300 IU/ml would maintain good test accuracy and will likely enable development of more affordable portable tests for use in low- and middle-income countries.

Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial.

BACKGROUND: Cross-resistance after first-line antiretroviral therapy (ART) failure is expected to impair activity of nucleoside reverse-transcriptase inhibitors (NRTIs) in second-line therapy for patients with HIV, but evidence for the effect of cross-resistance on virological outcomes is limited. We aimed to assess the association between the activity, predicted by resistance testing, of the NRTIs used in second-line therapy and treatment outcomes for patients infected with HIV. METHODS: We did an observational analysis of additional data from a published open-label, randomised trial of second-line ART (EARNEST) in sub-Saharan Africa. 1277 adults or adolescents infected with HIV in whom first-line ART had failed (assessed by WHO criteria with virological confirmation) were randomly assigned to a boosted protease inhibitor (standardised to ritonavir-boosted lopinavir) with two to three NRTIs (clinician-selected, without resistance testing); or with raltegravir; or alone as protease inhibitor monotherapy (discontinued after week 96). We tested genotypic resistance on stored baseline samples in patients in the protease inhibitor and NRTI group and calculated the predicted activity of prescribed second-line NRTIs. We measured viral load in stored samples for all patients obtained every 12-16 weeks. This trial is registered with Controlled-Trials.com (number ISRCTN 37737787) and ClinicalTrials.gov (number NCT00988039). FINDINGS: Baseline genotypes were available in 391 (92%) of 426 patients in the protease inhibitor and NRTI group. 176 (89%) of 198 patients prescribed a protease inhibitor with no predicted-active NRTIs had viral suppression (viral load <400 copies per mL) at week 144, compared with 312 (81%) of 383 patients in the protease inhibitor and raltegravir group at week 144 (p=0·02) and 233 (61%) of 280 patients in the protease inhibitor monotherapy group at week 96 (p<0·0001). Compared with results with no active NRTIs, 95 (85%) of 112 patients with one predicted-active NRTI had viral suppression (p=0·3) and 20 (77%) of 26 patients with two or three active NRTIs had viral suppression (p=0·08). Over all follow-up, greater predicted NRTI activity was associated with worse viral load suppression (global p=0·0004). INTERPRETATION: Genotypic resistance testing might not accurately predict NRTI activity in protease inhibitor-based second-line ART. Our results do not support the introduction of routine resistance testing in ART programmes in low-income settings for the purpose of selecting second-line NRTIs. FUNDING: European and Developing Countries Clinical Trials Partnership, UK Medical Research Council, Institito de Salud Carlos III, Irish Aid, Swedish International Development Cooperation Agency, Instituto Superiore di Sanita, WHO, Merck.

Diagnosis of viral hepatitis.

PURPOSE OF REVIEW: Chronic 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 FINDINGS: Key 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. SUMMARY: Future 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.

HIV Drug Resistance Mutations in Non-B Subtypes After Prolonged Virological Failure on NNRTI-Based First-Line Regimens in Sub-Saharan Africa.

OBJECTIVE: To determine drug resistance mutation (DRM) patterns in a large cohort of patients failing nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy regimens in programs without routine viral load (VL) monitoring and to examine intersubtype differences in DRMs. DESIGN: Sequences from 787 adults/adolescents who failed an NNRTI-based first-line regimen in 13 clinics in Uganda, Kenya, Zimbabwe, and Malawi were analyzed. Multivariable logistic regression was used to determine the association between specific DRMs and Stanford intermediate-/high-level resistance and factors including REGA subtype, first-line antiretroviral therapy drugs, CD4, and VL at failure. RESULTS: The median first-line treatment duration was 4 years (interquartile range 30-43 months); 42% of participants had VL ≥100,000 copies/mL and 63% participants had CD4 <100 cells/mm. Viral subtype distribution was A1 (40%; Uganda and Kenya), C (31%; Zimbabwe and Malawi), and D (25%; Uganda and Kenya), and recombinant/unclassified (5%). In general, DRMs were more common in subtype-C than in subtype-A and/or subtype-D (nucleoside reverse transcriptase inhibitor mutations K65R and Q151M; NNRTI mutations E138A, V106M, Y181C, K101E, and H221Y). The presence of tenofovir resistance was similar between subtypes [P (adjusted) = 0.32], but resistance to zidovudine, abacavir, etravirine, or rilpivirine was more common in subtype-C than in subtype-D/subtype-A [P (adjusted) < 0.02]. CONCLUSIONS: Non-B subtypes differ in DRMs at first-line failure, which impacts on residual nucleoside reverse transcriptase inhibitor and NNRTI susceptibility. In particular, higher rates of etravirine and rilpivirine resistance in subtype-C may limit their potential utility in salvage regimens.

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

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.

Who to test and how to test for chronic hepatitis C infection - 2016 WHO testing guidance for low- and middle-income countries.

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.

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 testing (NAT). Testing for hepatitis C virus core antigen (HCVcAg) is a potential alternative to NAT. PURPOSE: To evaluate the accuracy of diagnosis of active HCV infection among adults and children for 5 HCVcAg tests compared with NAT. DATA SOURCES: EMBASE, PubMed, Web of Science, Scopus, and Cochrane Database of Systematic Reviews from 1990 through 31 March 2016. STUDY SELECTION: Case-control, cross-sectional, cohort, or randomized trials that compared any of 5 HCVcAg tests with an NAT reference standard. DATA EXTRACTION: 2 independent reviewers extracted data and assessed quality using an adapted QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) tool. DATA SYNTHESIS: 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. LIMITATIONS: 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. CONCLUSION: 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. PRIMARY FUNDING SOURCE: National Institutes of Health.

CD41 T cell recovery during suppression of HIV replication: an international comparison of the immunological efficacy of antiretroviral therapy in North America, Asia and Africa.

BACKGROUND: Even among HIV-infected patients who fully suppress plasma HIV RNA replication on antiretroviral therapy, genetic (e.g. CCL3L1 copy number), viral (e.g. tropism) and environmental (e.g. chronic exposure to microbial antigens) factors influence CD4 recovery. These factors differ markedly around the world and therefore the expected CD4 recovery during HIV RNA suppression may differ globally. METHODS: We evaluated HIV-infected adults from North America, West Africa, East Africa, Southern Africa and Asia starting non-nucleoside reverse transcriptase inhibitorbased regimens containing efavirenz or nevirapine, who achieved at least one HIV RNA level <500/ml in the first year of therapy and observed CD4 changes during HIV RNA suppression. We used a piecewise linear regression to estimate the influence of region of residence on CD4 recovery, adjusting for socio-demographic and clinical characteristics. We observed 28 217 patients from 105 cohorts over 37 825 person-years. RESULTS: After adjustment, patients from East Africa showed diminished CD4 recovery as compared with other regions. Three years after antiretroviral therapy initiation, the mean CD4 count for a prototypical patient with a pre-therapy CD4 count of 150/ml was 529/ml [95% confidence interval (CI): 517­541] in North America, 494/ml (95% CI: 429­559) in West Africa, 515/ml (95% CI: 508­522) in Southern Africa, 503/ml (95% CI: 478­528) in Asia and 437/ml (95% CI: 425­449) in East Africa. CONCLUSIONS: CD4 recovery during HIV RNA suppression is diminished in East Africa as compared with other regions of the world, and observed differences are large enough to potentially influence clinical outcomes. Epidemiological analyses on a global scale can identify macroscopic effects unobservable at the clinical, national or individual regional level.

Health benefits, costs, and cost-effectiveness of earlier eligibility for adult antiretroviral therapy and expanded treatment coverage: a combined analysis of 12 mathematical models.

BACKGROUND: New WHO guidelines recommend initiation of antiretroviral therapy for HIV-positive adults with CD4 counts of 500 cells per µL or less, a higher threshold than was previously recommended. Country decision makers have to decide whether to further expand eligibility for antiretroviral therapy accordingly. We aimed to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy and expanded treatment coverage. METHODS: We used several independent mathematical models in four settings-South Africa (generalised epidemic, moderate antiretroviral therapy coverage), Zambia (generalised epidemic, high antiretroviral therapy coverage), India (concentrated epidemic, moderate antiretroviral therapy coverage), and Vietnam (concentrated epidemic, low antiretroviral therapy coverage)-to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy under scenarios of existing and expanded treatment coverage, with results projected over 20 years. Analyses assessed the extension of eligibility to include individuals with CD4 counts of 500 cells per µL or less, or all HIV-positive adults, compared with the previous (2010) recommendation of initiation with CD4 counts of 350 cells per µL or less. We assessed costs from a health-system perspective, and calculated the incremental cost (in US$) per disability-adjusted life-year (DALY) averted to compare competing strategies. Strategies were regarded very cost effective if the cost per DALY averted was less than the country's 2012 per-head gross domestic product (GDP; South Africa: $8040; Zambia: $1425; India: $1489; Vietnam: $1407) and cost effective if the cost per DALY averted was less than three times the per-head GDP. FINDINGS: In South Africa, the cost per DALY averted of extending eligibility for antiretroviral therapy to adult patients with CD4 counts of 500 cells per µL or less ranged from $237 to $1691 per DALY averted compared with 2010 guidelines. In Zambia, expansion of eligibility to adults with a CD4 count threshold of 500 cells per µL ranged from improving health outcomes while reducing costs (ie, dominating the previous guidelines) to $749 per DALY averted. In both countries results were similar for expansion of eligibility to all HIV-positive adults, and when substantially expanded treatment coverage was assumed. Expansion of treatment coverage in the general population was also cost effective. In India, the cost for extending eligibility to all HIV-positive adults ranged from $131 to $241 per DALY averted, and in Vietnam extending eligibility to patients with CD4 counts of 500 cells per µL or less cost $290 per DALY averted. In concentrated epidemics, expanded access for key populations was also cost effective. INTERPRETATION: Our estimates suggest that earlier eligibility for antiretroviral therapy is very cost effective in low-income and middle-income settings, although these estimates should be revisited when more data become available. Scaling up antiretroviral therapy through earlier eligibility and expanded coverage should be considered alongside other high-priority health interventions competing for health budgets. FUNDING: Bill & Melinda Gates Foundation, WHO.

Assessment of second-line antiretroviral regimens for HIV therapy in Africa.

BACKGROUND: The efficacy and toxic effects of nucleoside reverse-transcriptase inhibitors (NRTIs) are uncertain when these agents are used with a protease inhibitor in second-line therapy for human immunodeficiency virus (HIV) infection in resource-limited settings. Removing the NRTIs or replacing them with raltegravir may provide a benefit. METHODS: In this open-label trial in sub-Saharan Africa, we randomly assigned 1277 adults and adolescents with HIV infection and first-line treatment failure to receive a ritonavir-boosted protease inhibitor (lopinavir-ritonavir) plus clinician-selected NRTIs (NRTI group, 426 patients), a protease inhibitor plus raltegravir in a superiority comparison (raltegravir group, 433 patients), or protease-inhibitor monotherapy after 12 weeks of induction therapy with raltegravir in a noninferiority comparison (monotherapy group, 418 patients). The primary composite end point, good HIV disease control, was defined as survival with no new World Health Organization stage 4 events, a CD4+ count of more than 250 cells per cubic millimeter, and a viral load of less than 10,000 copies per milliliter or 10,000 copies or more with no protease resistance mutations at week 96 and was analyzed with the use of imputation of data (≤4%). RESULTS: Good HIV disease control was achieved in 60% of the patients (mean, 255 patients) in the NRTI group, 64% of the patients (mean, 277) in the raltegravir group (P=0.21 for the comparison with the NRTI group; superiority of raltegravir not shown), and 55% of the patients (mean, 232) in the monotherapy group (noninferiority of monotherapy not shown, based on a 10-percentage-point margin). There was no significant difference in rates of grade 3 or 4 adverse events among the three groups (P=0.82). The viral load was less than 400 copies per milliliter in 86% of patients in the NRTI group, 86% in the raltegravir group (P=0.97), and 61% in the monotherapy group (P<0.001). CONCLUSIONS: When given with a protease inhibitor in second-line therapy, NRTIs retained substantial virologic activity without evidence of increased toxicity, and there was no advantage to replacing them with raltegravir. Virologic control was inferior with protease-inhibitor monotherapy. (Funded by European and Developing Countries Clinical Trials Partnership and others; EARNEST Current Controlled Trials number, ISRCTN37737787, and ClinicalTrials.gov number, NCT00988039.).

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

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 RCT: hazard ratio 0.77, 95% confidence interval (CI) 0.34-1.76; 13 cohorts: relative risk (RR) 0.66, 95% CI 0.55-0.79], progression to AIDS or death (2 RCTs: RR 0.48, 95% CI 0.26-0.91; 9 cohorts: RR 0.70, 95% CI 0.40-1.24) and diagnosis of a non-AIDS-defining illness (1 RCT: RR 0.14, 95% CI 0.03-0.64; 1 cohort: RR 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 RCT: RR 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.

Optimal strategies for monitoring response to antiretroviral therapy in HIV-infected adults, adolescents, children and pregnant women: a systematic review.

OBJECTIVE: The objective of this review was to examine different monitoring strategies (clinical, immunologic (CD4 T cell count measurement) and virologic (viral load measurement)) to inform revision of the 2013 WHO guidelines for antiretroviral therapy (ART) in low and middle-income countries. DESIGN: A systematic review. METHODS: We searched 10 databases, reference lists of included research studies and contacted experts in an attempt to identify all relevant studies regardless of language or publication status. We included both randomized controlled trials (RCTs) and observational studies. We selected studies that examined routine clinical monitoring (CM), immunologic monitoring (IM) or virologic monitoring (VM). CM involved clinical evaluation and basic laboratory blood testing without CD4 T cell count or viral load. Two authors independently assessed study eligibility, extracted data and graded methodological quality. RESULTS: A total of six studies were identified, including five RCTs and one observational study. Two RCTs among adults found an increased risk of AIDS-defining illness and mortality in CM compared to CM + IM. Two studies compared CM + IM to CM + IM + VM, with one finding a mortality advantage in the CM + IM + VM group. Duration of viremia and time to switching to a second-line regimen were longer in CM + IM compared to CM + IM + VM. Only one trial was conducted in children, and showed no difference in mortality comparing CM and CM+IM. No studies specifically studied pregnant women. CONCLUSION: CM + IM was shown to be beneficial in terms of a combined mortality and morbidity endpoint compared to CM alone. VM was associated with shorter duration of viremia and higher rates of switching, but an impact on mortality was not consistently shown. Pooled outcome estimates were possible with comparison of only CM to CM + IM. Further HIV research on different VL monitoring strategies is required. These data support the recommendation in the 2013 WHO ART guidelines for the use of VM to confirm and diagnose ART failure, and for the use of IM + CM when VM is not available.

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 than 1000 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.

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

OBJECTIVE: To determine the status of key national policies on the use of antiretroviral therapy (ART) at the time of the launch of the 2013 WHO consolidated guidelines as well as to track early progress towards adoption of these recommendations following dissemination. DESIGN: Descriptive analysis of global data on baseline ART policies as of June 2013 and early intentions to adopt the 2013 WHO for use of antiretroviral drugs guidelines as of November 2013. METHODS: Compilation of existing global reports on key HIV policies, review of national guidelines, data collection through annual drug procurement surveys and through guidelines dissemination meetings in each of the six WHO regions. RESULTS: Data were available from 124 low- and middle-income countries, including 97% of the 57 high-priority countries that have been identified by WHO and the Joint United Nations Program on HIV/AIDS (UNAIDS). At baseline, only one country reported recommending antiretroviral therapy (ART) at a CD4 T-cell count 250 cells/µl or less for adults and adolescents in 2013, whereas nine countries already recommended using CD4 T-cell count 500 cells/µl or less. Recommendations for ART initiation regardless of CD4 T-cell count for HIV-infected patients with tuberculosis (86%), hepatitis B (75%), all HIV-infected women who were pregnant or breastfeeding (option B+: 40%) or HIV-infected persons in a serodiscordant relationship (26%) had been nationally adopted as of June 2013. Eight of 67 countries (12%) already recommended treating all children less than 5 years of age. The triple antiretroviral combination of tenofovir + lamivudine (or emtricitabine) + efavirenz was recommended as the preferred first-line option for adults and adolescents more frequently (51%) than for pregnant women (38%), or for both adults/adolescents and pregnant women (28%; P < 0.05). Fewer than half (37%) of all countries reported recommending lopinavir/ritonavir for all HIV-infected children less than 3 years of age; 54% of countries reported recommending routine viral load monitoring, whereas only 41% recommended nurse-initiated ART. CONCLUSIONS: A number of key WHO policy recommendations on antiretroviral drug use were adopted rapidly by countries in advance of or shortly following the launch of the 2013 guidelines. Efforts are needed to support and track ongoing policy adoption and ensure that it is accompanied by the scale-up of evidence-based interventions.

Community and service provider views to inform the 2013 WHO consolidated antiretroviral guidelines: key findings and lessons learnt.

OBJECTIVE: The objective was to evaluate community and healthcare worker (HCW) values and preferences on key topics to inform the development of the 2013 WHO consolidated guidelines for antiretroviral therapy in low and middle income countries. DESIGN: Cross-sectional e-survey and e-forum discussion; focus group discussions (FGDs) METHODS: : Data were collected on community perspectives regarding a range of potential clinical and operational recommendations in the 2013 guidelines between November 2012 and January 2013 through an e-survey (n = 1088) and e-forum (n = 955). Additional FGDs were held with people living with HIV (PLHIV) in Malawi and Uganda (n = 88) on antiretroviral therapy (ART) use among pregnant women. Two surveys were also undertaken on similar topics covered in the e-survey for health care workers caring for adults (n = 98) and children (n = 348). RESULTS: There were 1088 e-survey respondents from 117 countries: of whom 37.7% (298/791) were females, 49.9% (431/864) PLHIV, and 20.9% (174/831) from low-income countries. The proportion of e-survey respondents who supported raising the CD4 T-cell threshold for ART initiation in adults from 350 to 500 cells/µl was 51.0% (355/696), and regardless of CD4 T-cell count for all pregnant females 89.8% (607/676), HIV serodiscordant partners 71.9% (486/676), and all children on diagnosis of infection 47.4% (212/447). E-survey respondents strongly supported discontinuing use of stavudine (72.7%, 416/572), task-shifting/sharing from doctors to nurses (75.2%, 275/365) and from nurses to community health workers (71.1%, 261/367) as strategies to expand access to HIV testing, care, and treatment. Focus group discussion respondents identified service capacity, and social and legal concerns as key considerations influencing the decisions of women living with HIV to continue ART after the risk of vertical transmission has passed. Key lessons learnt in these consultations included the need for piloting and validation of questions; sufficient time to adequately disseminate the survey; and consideration of using FGDs and mobile phone technology to improve participation of people with limited internet access. CONCLUSION: Community participation in guideline development processes is important to ensure that their perspectives are considered in the resulting recommendations. Communities should be actively involved in the adaptation, implementation, and accountability processes related to the guidelines.

The impact and cost of the 2013 WHO recommendations on eligibility for antiretroviral therapy.

OBJECTIVES: The present study presents estimates of the number of people who would become newly eligible for antiretroviral therapy if all countries adopted the 2013 WHO treatment guidelines. It also shows the cost and impact that would result if coverage expanded to 80% of those eligible. METHODS: The AIDS Impact Model (AIM) and the Goals model within the Spectrum modelling system were used for these estimates. Projections of costs and AIDS deaths are based on estimates for 116 low-income and middle-income countries. Projections of impact on HIV incidence are based on simulation modelling for 24 high burden countries, with the results scaled up to represent all low-income and middle-income countries. RESULTS: If the 2013 guidelines were adopted universally, the number eligible for treatment would rise to 28.6 million in 2013. Achieving 80% coverage would mean 28 million on antiretroviral therapy by 2025, and would avert 2.9 million deaths and 3.9 million new infections from 2013 to 2025 compared with the 2010 guidelines. CONCLUSION: The 2013 guidelines significantly expand the number eligible for treatment. Reaching those newly eligible will require additional resources, but is likely to produce significant benefits.

Modeling the impact of early antiretroviral therapy for adults coinfected with HIV and hepatitis B or C in South Africa.

OBJECTIVE: There has been discussion about whether individuals coinfected with HIV and hepatitis C virus (HCV) or hepatitis B virus (HBV) (∼30% of all people living with HIV) should be prioritized for early HIV antiretroviral therapy (ART). We assess the relative benefits of providing ART at CD4 count below 500  cells/µl or immediate ART to HCV/HIV or HBV/HIV-coinfected adults compared with HIV-monoinfected adults. We evaluate individual outcomes (HIV/liver disease progression) and preventive benefits in a generalized HIV epidemic setting. METHODS: We modeled disease progression for HIV-monoinfected, HBV/HIV-coinfected, and HCV/HIV-coinfected adults for differing ART eligibility thresholds (CD4 <350  cells/µl, CD4 <500  cells/µl, immediate ART eligibility upon infection). We report disability-adjusted life-years averted per 100 person-years on ART (DALYaverted/100PYonART) as a measure of the health benefits generated from incremental changes in ART eligibility. Sensitivity analyses explored impact on sexual HIV and vertical HIV, HCV, and HBV transmission. RESULTS: For HBV/HIV-coinfected adults, a switch to ART initiation at CD4 count below 500  cells/µl from CD4 below 350  cells/µl generates 9% greater health benefits per year on ART (48 DALYaverted/100PYonART) than for HIV-monoinfected adults (44 DALYaverted/100PYonART). Additionally, ART at CD4 below 500  cells/µl could prevent 25% and 32% of vertical transmissions of HIV and HBV, respectively. For HCV/HIV-coinfected adults, ART at CD4 below 500  cells/µl generates 10% fewer health benefits (40 DALYaverted/100PYonART) than for HIV monoinfection, unless ART reduces progression to cirrhosis by more than 70% (33% in base-case). CONCLUSIONS: The additional therapeutic benefits of ART for HBV-related liver disease results in ART generating more health benefits among HBV/HIV-coinfected adults than HIV-monoinfected individuals, whereas less health benefits are generated amongst HCV/HIV coinfection in a generalized HIV epidemic setting.