Comparative analyses of published cost effectiveness models highlight critical considerations which are useful to inform development of new models.

Background: Comparative analyses of published cost effectiveness models provide useful insights into critical issues to inform the development of new cost effectiveness models in the same disease area.Objective: The purpose of this study was to describe a comparative analysis of cost-effectiveness models and highlight the importance of such work in informing development of new models. This research uses genotypic antiretroviral resistance testing after first line treatment failure for Human Immunodeficiency Virus (HIV) as an example.Method: A literature search was performed, and published cost effectiveness models were selected according to predetermined eligibility criteria. A comprehensive comparative analysis was undertaken for all aspects of the models.Results: Five published models were compared, and several critical issues were identified for consideration when developing a new model. These include the comparator, time horizon and scope of the model. In addition, the composite effect of drug resistance prevalence, antiretroviral therapy efficacy, test performance and the proportion of patients switching to second-line ART potentially have a measurable effect on model results. When considering CD4 count and viral load, dichotomizing patients according to higher cost and lower quality of life (AIDS) versus lower cost and higher quality of life (non-AIDS) status will potentially capture differences between resistance testing and other strategies, which could be confirmed by cross-validation/convergent validation. A quality adjusted life year is an essential outcome which should be explicitly explored in probabilistic sensitivity analysis, where possible.Conclusions: Using an example of GART for HIV, this study demonstrates comparative analysis of previously published cost effectiveness models yields critical information which can be used to inform the structure and specifications of new models.

Targeting the third '90': introducing the viral load champion.

Objective: To move closer to achieving the third target of the UNAIDS 90-90-90 goals, we prospectively implemented a viral load (VL) champion (VLC) program aimed at enhancing VL monitoring and recognition of treatment failure. Design: Three clinics in eThekwini, Kwa-Zulu Natal (low-, medium- and high-volume, encompassing 9184 patients overall) were each assigned a VLC. We employed a descriptive analysis (chart audit) to compare the pre-intervention period to a 1-year post-intervention period. The number of patients with a VL test performed 6 and 12 months after the intervention was calculated as a proportion of VL tests due at those time points (VL completion rate). Results: The pre-implementation VL completion rate at the three sites was respectively 68% (140/205 patients), 54% (84/155 patients) and 64% (323/504 patients), and the 6-month post-implementation completion rate increased to 83% (995/1194 patients), 90% (793/878 patients) and 99% (3101/3124 patients) (P < 0.0001 for each site). VL completion rates remained significantly higher at 12 months post-implementation, with an average cumulative VL completion rate of >90% across all facilities. Conclusion: We demonstrate a successful, multifaceted, quality-improvement intervention centered on a clinic-level VLC which, taken to scale, has important implications for attaining the third UNAIDS 90-90-90 target.

Objectif : Dans le but de se rapprocher de l'atteinte de la troisième cible des objectifs 90-90-90 du Programme commun des Nations Unies sur le VIH/Sida (ONUSIDA), nous avons prospectivement mis en œuvre un programme « champion de la charge virale ¼ (VLC) visant à améliorer le suivi de la charge virale (VL) et la reconnaissance de l'échec du traitement.Schéma : Trois centres à eThekwini, Kwa-Zulu Natal (volume faible, moyen et élevé, soit 9184 patients au total), ont été chacun affectés au VLC. Nous employons une analyse descriptive (audit de dossiers) afin de comparer la période avant l'intervention à la période d'un an qui a suivi l'intervention. Le nombre de patients ayant eu un test VL 6 et 12 mois après l'intervention a été calculé comme une proportion de test VL exigibles à ces dates respectivement (taux d'achèvement du VL).Résultats : Le taux d'achèvement du VL avant la mise en route dans trois sites a été de 68% (140/205 patients), 54% (84/155 patients) et 64% (323/504 patients), respectivement, et le taux d'achèvement à 6 mois après la mise en œuvre a augmenté à 83% (995/1194 patients), 90% (793/878 patients) et 99% (3101/3124 patients), respectivement (P < 0,0001 pour chaque site). Les taux d'achèvement du VL sont restés significativement plus élevés à 12 mois après la mise en œuvre, avec un taux cumulé moyen du VL >90% dans toutes les structures.Conclusion : Nous avons montré la qualité d'une intervention d'amélioration réussie à multiples facettes, centrée sur le VLC au niveau des centres qui­à plus grande échelle­a des implications majeures pour l'atteinte de la troisième cible 90-90-90 de l'ONUSIDA.

Objetivo: Con el propósito de avanzar hacia el cumplimiento del tercer elemento del objetivo «90-90-90¼ del Programa Conjunto de las Naciones Unidas sobre el VIH/SIDA (ONUSIDA), se introdujo un programa con un promotor del seguimiento de la viremia, encaminado a reforzar la vigilancia de la concentración vírica y el reconocimiento del fracaso terapéutico.Método: En cada uno de tres consultorios de eThekwini, en Kwa-Zulu Natal (con una carga asistencial baja, intermedia y alta, que cubrían un total de 9184 pacientes) se nombró un promotor del seguimiento de la viremia. Mediante un análisis descriptivo, se comparó el período preintervención con un período posintervención de un año. El número de pacientes en quienes se practicó la viremia a los 6 y 12 meses después de la intervención se calculó como la proporción de las viremias previstas en estos puntos temporales (tasa de compleción de la viremia).Resultados: La tasa de compleción de la viremia en los tres centros fue como sigue: 68% (140/205 pacientes), 54% (84/155 pacientes) y 64% (323/504 pacientes) y a los 6 meses posintervención, esta tasa aumentó respectivamente a 83% (995/1194 pacientes), 90% (793/878 pacientes) y 99% (3101/3124 pacientes) (P < 0,0001 para cada centro). Las tasas de compleción de la viremia permanecieron significativamente más altas a los 12 meses posintervención con una tasa acumulada superior al 90% en todos los establecimientos.Conclusión: Se puso en evidencia una intervención polifacética eficaz de mejoramiento de la calidad centrada en un promotor clínico del seguimiento de la viremia en cada consultorio, cuya aplicación en una escala más amplia, tendría importantes repercusiones en favor del cumplimiento del tercer elemento del objetivo «90-90-90¼ del ONUSIDA.

Double-dose lopinavir-ritonavir in combination with rifampicin-based anti-tuberculosis treatment in South Africa.

BACKGROUND: The optimal treatment for tuberculosis (TB) in human immunodeficiency virus (HIV) infected patients in resource-poor settings receiving lopinavir-ritonavir (LPV/r) based second-line antiretroviral therapy (ART) has yet to be determined. In South Africa, clinicians are advised to use 'double-dose' LPV/r dosed at 800 mg/200 mg twice daily during anti-tuberculosis treatment. METHODOLOGY AND PRINCIPLE FINDINGS: We conducted a retrospective study of HIV-infected patients who received ≥2 months of double-dose LPV/r-based ART during concomitant rifampicin-containing anti-tuberculosis treatment. We used standard definitions for TB and HIV outcomes; virological failure was defined as a viral load >1000 copies/ml. During co-administration, gastro-intestinal toxicity occurred in 9/25 (36%) patients, a symptomatic rise in aspartate aminotransferase or alanine aminotransferase of any grade was noted in 3 (12%), with two Grade 3 events, and 3 (12%) patients required treatment discontinuation. Outcomes were favourable, with 20/25 (80%) patients achieving TB treatment success and virological failure observed among 3 (12%) patients during co-administration. CONCLUSION: We found the use of double-dose LPV/r during simultaneous standard anti-tuberculosis treatment to be an effective and reasonably well tolerated interim strategy.

Safety of midazolam for sedation of HIV-positive patients undergoing colonoscopy.

OBJECTIVES: Because of concerns regarding interactions between midazolam and antiretroviral therapy (ART), alternative sedatives are sometimes used during procedural sedation. Our objective was to compare outcomes in patients on ART who received intravenous (iv) midazolam vs. iv diazepam, a second-line agent, during colonoscopy. METHODS: We conducted a retrospective analysis of adult HIV-positive patients who underwent colonoscopy over a 3.5-year period. Primary outcomes were sedation duration, nadir systolic blood pressure (SBP), nadir oxygen saturation, abnormal cardiac rhythm, and change in level of consciousness using a standardized scale. We calculated rates of adverse events according to benzodiazepine use and identified risk factors for complications using univariate and multivariate analyses. RESULTS: We identified 136 patients for this analysis: 70 received midazolam-based sedation and 66 received a diazepam-based regimen. There were no significant differences between the two groups with respect to sedation duration (mean 48.0 vs. 45.7 minutes for the midazolam and diazepam groups, respectively; P = 0.68), nadir SBP (mean 97.0 vs. 101.6 mmHg; P = 0.06), nadir oxygen saturation (mean 94.6 vs. 94.8%; P = 0.72) or rate of abnormal cardiac rhythm (11.4 vs. 19.7%; P = 0.18). More patients in the midazolam group experienced a depressed level of consciousness (91% vs. 74% in the diazepam group; P = 0.0075), but no patient required reversal of sedation or became unresponsive. CONCLUSIONS: We did not find evidence that patients who received midazolam for procedural sedation had clinical outcomes statistically different from those who received diazepam. These findings should be confirmed in prospective studies or in a randomized controlled trial.

Clinical predictors for the aetiology of peripheral lymphadenopathy in HIV-infected adults.

OBJECTIVES: The aim of the study was to determine the aetiology and clinical predictors of peripheral lymphadenopathy in HIV-infected individuals during the antiretroviral (ARV) era in a nontuberculosis endemic setting. METHODS: A multicentred, retrospective cohort study of peripheral lymph node biopsies in HIV-positive adults was carried out. A total of 107 charts were identified and reviewed for clinical features, lymphadenopathy size, and ARV use and duration. Biopsy results were categorized, and multivariate logistic regression determined independent predictors of lymphadenopathy aetiology. RESULTS: Evaluation of 107 peripheral lymph node biopsies revealed that 42.9% of peripheral lymphadenopathy was attributable to malignancy, 49.5% to reactive changes, and 7.5% to infections, with only 2.8% of all cases secondary to tuberculosis. Fevers, weight loss, ARV use, and lower viral loads are significantly associated with nonreactive lymphadenopathy. CONCLUSIONS: Lymphadenopathy is likely to be reactive or malignant in nontuberculosis endemic regions. Readily available clinical features can aid clinicians in predicting the underlying aetiology, those at risk for malignancy, and who to biopsy.

Clinical outcome of long-term survivors of progressive multifocal leukoencephalopathy.

Progressive Multifocal Leukoencephalopathy (PML) is a demyelinating disease of the brain caused by the polyomavirus JC (JCV) in immunosuppressed people. There is no cure for PML but 1-year survival has increased from 10% to 50% in HIV-infected individuals treated with highly active antiretroviral therapy. We describe herein the clinical outcome of 24 PML patients whose survival exceeded 5 years, with a mean follow-up of 94.2 months (range, 60-188 months). Of all patients, only two were females including one who had non-Hodgkin's lymphoma and was HIV negative. All 23 HIV-positive patients received highly active antiretroviral therapy, and additional experimental therapies were not associated with a better clinical outcome. Marked neurological improvement occurred in 4/24 (17%) of patients, while 11/24 (46%) had partial improvement and 9/24 (37%) remained stable. By the end of the period of observation, 8/24 (33%) of patients had no significant disability despite persistent symptoms (modified Rankin disability scale (MRDS) =1), 6/24 (25%) had slight disability and were living independently (MRDS=2), 5/24 (21%) were moderately disabled, requiring some help during activities of daily living (MRDS=3) and 5/24 (21%) had moderately severe disability, requiring constant help or institutionalisation (MRDS=4). Patients with cerebellar lesions tended to have a worse clinical outcome. MRI showed leukomalacia with ventricular enlargement secondary to destruction of the white matter at the site of previous PML lesions, and focal areas of subcortical atrophy with preservation of the cortical ribbon. Of 20 patients tested, 19(95%) had detectable CD8+ cytotoxic T-lymphocytes against JCV in their blood. In absence of a specific treatment, immunotherapies aiming at boosting the cellular immune response against JCV may improve the prognosis of PML.

Determinants of survival in progressive multifocal leukoencephalopathy.

BACKGROUND: We sought to characterize the role of immunologic, virologic, and radiologic determinants of survival in patients with progressive multifocal leukoencephalopathy (PML). METHODS: We recorded the clinical outcome of 60 patients with PML (73% HIV+) who were prospectively evaluated between 2000 and 2007 for the presence of JC virus (JCV)-specific CD8+ cytotoxic T-lymphocytes (CTL) in blood. RESULTS: Estimated probability of survival at 1 year was 52% for HIV+/PML and 58% for HIV- patients with PML. Patients with PML with detectable CTL within 3 months of diagnosis had a 1-year estimated survival of 73% compared to 46% for those without CTL (hazard ratio [HR] for death = 0.47, 95% confidence interval [CI] 0.13-1.75, p = 0.26). Patients with CTL response had an increased likelihood of having contrast enhancement of PML lesions and immune reconstitution inflammatory syndrome (odds ratio 3.7 and 7.8). Estimated 1-year survival was 48% in HIV+ patients with PML with CD4 count <200/microL at PML diagnosis compared to 67% in those with CD4 >200/microL (HR for death 1.41, 95% CI 0.27-7.38, p = 0.68). JCV DNA was detected in the urine of 48% and in the blood of 56% of patients with PML, but viruria and viremia were not associated with survival. CONCLUSIONS: The presence of JC virus (JCV)-specific cytotoxic T-lymphocytes (CTL) was associated with a trend toward longer survival in patients with progressive multifocal leukoencephalopathy (PML), which was more pronounced than the impact of CD4 count in HIV+ patients with PML early after diagnosis. Despite the association of contrast enhancement and immune reconstitution inflammatory syndrome with JCV-specific CTL, these cannot be considered as surrogate markers for the prognostic value of the CTL. Strategies aiming at improving the cellular immune response may improve the course of PML.

The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells.

To avoid detection by CTL, HIV encodes mechanisms for removal of class I MHC proteins from the surface of infected cells. However, class I downregulation potentially exposes the virus-infected cell to attack by NK cells. Human lymphoid cells are protected from NK cell cytotoxicity primarily by HLA-C and HLA-E. We present evidence that HIV-1 selectively downregulates HLA-A and HLA-B but does not significantly affect HLA-C or HLA-E. We then identify the residues in HLA-C and HLA-E that protect them from HIV down-regulation. This selective downregulation allows HIV-infected cells to avoid NK cell-mediated lysis and may represent for HIV a balance between escape from CTL and maintenance of protection from NK cells. These results suggest that subpopulations of CTL and NK cells may be uniquely suited for combating HIV.

HIV-1 directly kills CD4+ T cells by a Fas-independent mechanism.

The mechanism by which HIV-1 induces CD4(+) T cell death is not known. A fundamental issue is whether HIV-1 primarily induces direct killing of infected cells or indirectly causes death of uninfected bystander cells. This question was studied using a reporter virus system in which infected cells are marked with the cell surface protein placental alkaline phosphatase (PLAP). Infection by HIV-PLAP of peripheral blood mononuclear cells (PBMCs) and T cell lines leads to rapid depletion of CD4(+) T cells and induction of apoptosis. The great majority of HIV-induced T cell death in vitro involves direct loss of infected cells rather than indirect effects on uninfected bystander cells. Because of its proposed role in HIV-induced cell death, we also examined the Fas (CD95/Apo1) pathway in killing of T cells by HIV-1. Infected PBMCs or CEM cells display no increase in surface Fas relative to uninfected cells. In addition, HIV-1 kills CEM and Jurkat T cells in the presence of a caspase inhibitor that completely blocks Fas-mediated apoptosis. HIV-1 also depletes CD4+ T cells in PBMCs from patients who have a genetically defective Fas pathway. These results suggest that HIV-1 induces direct apoptosis of infected cells and kills T cells by a Fas-independent mechanism.

CD4 down-modulation during infection of human T cells with human immunodeficiency virus type 1 involves independent activities of vpu, env, and nef.

The human immunodeficiency virus type 1 (HIV-1) genes vpu, env, and nef have all been implicated in modulating the levels of cell surface CD4 on infected cells. To quantitatively assess the relative contribution of each gene product to the regulation of CD4 during HIV infection of Jurkat T cells and peripheral blood mononuclear cells, we have developed an infectious HIV reporter system which expresses different combinations of these genes. To distinguish infected cells in the early or late stages of infection from uninfected cells, these viruses were designed to express human placental alkaline phosphatase with the kinetics of either early or late viral genes. Flow cytometry to detect placental alkaline phosphatase and CD4 in infected cells showed that vpu, env, and nef are independently capable of down-modulation of CD4. As predicted by their respective expression patterns, nef down-modulated CD4 rapidly during the early phase of virus infection whereas vpu and env functioned late in the infection. In both Jurkat cells and peripheral blood mononuclear cells, a combination of the three genes was more efficient than any one or two genes, demonstrating that all three genes are required to achieve maximal CD4 down-modulation. In primary cells, down-modulation of CD4 was less efficient than in Jurkat cells and there was a stronger dependence on nef function for reducing cell surface CD4. HIV therefore has three genes that are able to independently down-modulate CD4; together, they can eliminate the bulk of cell surface CD4.

Diagnosis of Candida thyroiditis by fine needle aspiration.

Infective thyroiditis is an uncommon condition, and fungal infection of the thyroid gland is rare. We present a case of Candida thyroiditis in a patient with leukaemia and review the three previous reports of this entity in the world's literature. We conclude that Candida thyroiditis should be considered in immunosuppressed patients with known infection who develop fever and neck pain, that gallium scanning may help localise the infection to the thyroid gland; that fine needle aspiration is a useful diagnostic test, and that thyroid dysfunction is common with Candida thyroiditis.

Bacteriophage Mu: a transposing replicon.

Mu DNA replication has been carried out in vitro on cellophane discs in the presence of dBUTP. If the DNA is sheared to 80 kb pieces, the Mu replicas band anomalously in CsCl gradients between hybrid and light DNA density positions. The intermediate density DNA comprises semiconservatively replicated Mu sequences, flanked by unreplicated light DNA. This and previous data are consistent with replication occurring within Mu boundaries. Both the synthesis of Mu sequences and the intermediate density DNA are abolished by protein synthesis inhibition in vivo just prior to lysis on cellophane discs. These observations indicate that at least some steps in bona fide Mu transposition-replication are being observed in vitro.