Spatially targeted screening to reduce tuberculosis transmission in high-incidence settings.

As the leading infectious cause of death worldwide and the primary proximal cause of death in individuals living with HIV, tuberculosis remains a global concern. Existing tuberculosis control strategies that rely on passive case-finding appear insufficient to achieve targets for reductions in tuberculosis incidence and mortality. Active case-finding strategies aim to detect infectious individuals earlier in their infectious period to reduce onward transmission and improve treatment outcomes. Empirical studies of active case-finding have produced mixed results and determining how to direct active screening to those most at risk remains a topic of intense research. Our systematic review of literature evaluating the effects of geographically targeted tuberculosis screening interventions found three studies in low tuberculosis incidence settings, but none conducted in high tuberculosis incidence countries. We discuss open questions related to the use of spatially targeted approaches for active screening in countries where tuberculosis incidence is highest.

Improving TB case notification in northern Uganda: evidence of a quality improvement-guided active case finding intervention.

BACKGROUND: Strategies to identify and treat undiagnosed prevalent cases that have not sought diagnostic services on their own, are necessary to treat TB in patients earlier and interrupt transmission. Late presentation for medical services of symptomatic patients require special efforts to detect early and notify TB in high risk populations. An intervention that combined quality improvement with facility-led active case finding (QI-ACF) was implemented in 10 districts of Northern Uganda with the highest TB burden to improve case notification among populations at highest risk of TB. METHODS: Using QI-ACF intervention approach in 48 facilities, we; 1) targeted key vulnerable populations, 2) engaged district and facility teams in TB systems strengthening, 3) conducted systematic screening and diagnosis in vulnerable groups (people living with HIV, fishing communities, and prisoners), and 4) trained health workers on national x-ray diagnosis guidelines for smear-negative patients. Facility-led QI-ACF meant that health care providers identified the target population, mobilized and massively screened suspects, and addressed gaps in documentation. Chest X-ray diagnosis was promoted for smear-negative TB among those suspects whose sputum examination was negative. The effect of the intervention on case notification was then assessed separately over the post intervention period. RESULTS: Over all TB case notification in the intervention districts increased from 171 to 223 per 100,000 population between the baseline months of October-December 2016 and end line month of April-June 2017. TB patient contacts had the majority of TB positive cases identified during active case finding (40, 6.1%). Fishing communities had the highest TB positivity rate at 6.8%. Prisoners accounted for the lowest number of TB positive cases at 34 (2.3%). CONCLUSION: Targeting should be applied at all levels of TB intervention to improve yield: targeting districts and facilities with the lowest rates of case notification and targeting index patient contacts, HIV clients, and fishing communities. Screening tools are useful to guide health workers to identify presumptive cases. Efforts to improve availability of x-ray for TB diagnosis contributed to almost half of the new cases identified. Having all HIV patients who were eligible for viral load provide sputum for TB screening proved easy to implement.

Estimating the burden of invasive and serious fungal disease in the United Kingdom.

BACKGROUND: The burden of fungal disease in the UK is unknown. Only limited data are systematically collected. We have estimated the annual burden of invasive and serious fungal disease. METHODS: We used several estimation approaches. We searched and assessed published estimates of incidence, prevalence or burden of specific conditions in various high risk groups. Studies with adequate internal and external validity allowed extrapolation to estimate current UK burden. For conditions without adequate published estimates, we sought expert advice. RESULTS: The UK population in 2011 was 63,182,000 with 18% aged under 15 and 16% over 65. The following annual burden estimates were calculated: invasive candidiasis 5142; Candida peritonitis complicating chronic ambulatory peritoneal dialysis 88; Pneumocystis pneumonia 207-587 cases, invasive aspergillosis (IA), excluding critical care patients 2901-2912, and IA in critical care patients 387-1345 patients, <100 cryptococcal meningitis cases. We estimated 178,000 (50,000-250,000) allergic bronchopulmonary aspergillosis cases in people with asthma, and 873 adults and 278 children with cystic fibrosis. Chronic pulmonary aspergillosis is estimated to affect 3600 patients, based on burden estimates post tuberculosis and in sarcoidosis. CONCLUSIONS: Uncertainty is intrinsic to most burden estimates due to diagnostic limitations, lack of national surveillance systems, few published studies and methodological limitations. The largest uncertainty surrounds IA in critical care patients. Further research is needed to produce a more robust estimate of total burden.

Oral human papillomavirus infection and head and neck cancers in HIV-infected individuals.

PURPOSE OF REVIEW: HIV-infected individuals are living longer due to effective antiretroviral therapy and may therefore have a greater opportunity to develop human papillomavirus (HPV)-associated malignancies. This review describes the risk factors and burden of oral HPV infection and HPV-associated head and neck cancer (HNC) among HIV-infected individuals. RECENT FINDINGS: Oral HPV infection is commonly detected in HIV-infected individuals and is elevated among those with a higher number of lifetime oral sexual partners, current tobacco use and immunosuppression. There are limited data on the natural history of oral HPV, but initial studies suggest that the majority of infections clear within 2 years. Although HIV-infected individuals are at a much higher risk of most HPV-associated cancers than the general population, studies suggest HIV-infected individuals have a more modest 1.5-4-fold greater risk for HPV-associated HNC. SUMMARY: HIV-infected individuals are living longer, have a high prevalence of oral HPV infection and have many of the currently determined risk factors for HPV-associated HNC.

Assessment of antigenemia assay for the diagnosis of cytomegalovirus gastrointestinal diseases in HIV-infected patients.

We conducted a single-center prospective study to evaluate the utility of cytomegalovirus (CMV) antigenemia assay for the diagnosis of CMV-gastrointestinal disease (GID). The study subjects were HIV-infected patients with CD4 count ≤200 µL/cells who had undergone endoscopy. A definite diagnosis of CMV-GID was made by histological examination of endoscopic biopsied specimen. CMV antigenemia assay (C10/C11 monoclonal antibodies), CD4 count, HIV viral load, history of HAART, and gastrointestinal symptoms as measured by 7-point Likert scale, were assessed on the same day of endoscopy. One hundred cases were selected for analysis, which were derived from 110 cases assessed as at high-risk for CMV-GID after endoscopy screening of 423 patients. Twelve patients were diagnosed with CMV-GID. Among the gastrointestinal symptoms, mean bloody stool score was significantly higher in patients with CMV-GID than in those without (2.5 vs. 1.7, p=0.02). The area under the receiver-operating characteristic curve of antigenemia was 0.80 (95%CI 0.64-0.96). The sensitivity, specificity, positive likelihood ratio (LR), and negative LR of antigenemia were 75.0%, 79.5%, 3.7, and 0.31, respectively, when the cutoff value for antigenemia was ≥1 positive cell per 300,000 granulocytes, and 50%, 92.0%, 5.5, and 0.55, respectively, for ≥5 positive cells per 300,000 granulocytes. In conclusion, CMV antigenemia seems a useful diagnostic test for CMV-GID in patients with HIV infection. The use of ≥5 positive cells per 300,000 granulocytes as a cutoff value was associated with high specificity and high positive LR. Thus, a positive antigenemia assay with positive endoscopic findings should allow the diagnosis of CMV-GID without biopsy.

Oral conditions and their social impact among HIV dental patients, 18 years on.

BACKGROUND: A study undertaken in 1992-1993 identified that HIV-infected dental patients were substantially disadvantaged with regard to the social impact of their oral disease. The oral pain experienced by HIV-positive patients prior to the introduction of combination antiretroviral therapy (cART) was attributable to specific features of HIV-related periodontal disease and other oral manifestations of HIV such as candida infections and xerostomia. A repeat of this study in 2009-2010 provided additional information in the post-cART era. METHODS: Data were collected from three sources: the 2009-2010 HIV-positive sample, the National Survey of Adult Oral Health (NSAOH) and the original 1992-1993 study. Collation of data was by clinical and radiographic oral examination. Information about the social impact of oral conditions was obtained from the Oral Health Impact Profile. RESULTS: The caries experience of the 2009-2010 HIV-positive sample was improved with statistical significance for both mean DMFT and mean DT, while the presence of HIV-related periodontal disease still occurs. Statistically significant improvements were achieved for prevalence and severity of oral health related quality of life. CONCLUSIONS: The need for timely access to oral health care with a focus on prevention is essential for HIV-positive individuals whose health is impacted by chronic disease, smoking and salivary hypofunction.

Increasing burden of liver disease in patients with HIV infection.

Introduction of effective combined antiretroviral therapy has made HIV infection a chronic illness. Substantial reductions in the number of AIDS-related deaths have been accompanied by an increase in liver-related morbidity and mortality due to co-infection with chronic hepatitis B and C viruses. Increases in non-alcoholic fatty liver disease and drug-induced hepatotoxicity, together with development of hepatocellular carcinoma, also potentiate the burden of liver disease in individuals with HIV infection. We provide an overview of the key causes, disease mechanisms of pathogenesis, and recommendations for treatment options including the evolving role of liver transplantation.

A microsimulation of the cost-effectiveness of maraviroc for antiretroviral treatment-experienced HIV-infected individuals.

PURPOSE: Maraviroc (MVC) is the first approved CCR5 antagonist. The aim of this study was to explore the cost-effectiveness of MVC in treatment-experienced or treatment-resistant HIV-infected adults. METHODS: The validated HIV microsimulation model ARAMIS was used to predict clinical and economic outcomes of treating patients with optimized background therapy (OBT) alone, as compared to a strategy of testing for the patient's viral tropism and treating with OBT with or without (+/-) MVC in a cohort corresponding to the MOTIVATE screening cohort. RESULTS: Compared to treatment with OBT alone, a treatment strategy of OBT +/- MVC (twice daily) according to tropism test result was predicted to increase CD4+ cell count after 5 years (from mean 249 to 360 cells/microL), undiscounted life expectancy (7.6 to 8.9 years), and quality-adjusted life years (QALYs; from 4.99 to 5.71) for an additional $40,500, giving an incremental cost-effectiveness ratio of $56,400 per QALY gained. The result was relatively insensitive to alternative clinical and cost assumptions within reasonable ranges, but for individuals with HIV susceptible to only two or fewer components of OBT, the ICER decreased to $52,000 per QALY gained. CONCLUSION: MVC is cost-effective, especially among individuals with few remaining options for active antiretroviral therapy.

[Assessment of antiviral immunity in pregnant women with mixed infection (HIV + CMV), living in Surgut].

Concomitant cytomegalovirus infection (CMVI), a classical opportunistic infection, is an important problem among HIV-infection pregnant women. CMVI in pregnant women runs mainly in the latent form with reactivation under physiological immunosuppression. Therefore the evaluation of immunoresponsiveness in HIV-infected pregnant women with mixed (HIV + CMV) infection becomes to be of particular urgency. Sixty-five women who were registered in the antenatal clinic of Surgut and its anti-AIDS center in 2005-2007 were examined. The examinees' sera were tested for CMV antibody titers by heterogenous solid-phase enzyme immunoassay (EIA) to determine the moment of infection and differentiation of primary infection, reinfection, or infectious process reactivation. Assay of plasma CMV DNA was carried out by the polymerase chain reaction technique to evaluate the activity of CMVI. The high spread of serological CMVI markers in the pregnant women of the Middle Ob Region necessitates monitoring this group, by obligatorily determining IgM, IgG, and their avidity.

Cost-effectiveness of raltegravir in antiretroviral treatment-experienced HIV-1-infected patients in Switzerland.

OBJECTIVES: Raltegravir, a novel integrase inhibitor, has shown great efficacy in reducing HIV viral load among treatment-experienced patients. A cohort state-transition model was used to assess the long-term effect of raltegravir treatment on costs and quality-adjusted life expectancy from a Swiss perspective. METHODS: Patients were stratified into health states according to opportunistic infection status, HIV RNA level, and CD4 count, with each group assigned a treatment cost and utility (quality of life) score. Model inputs came from published studies, clinical trials, and database analyses. Results were used to calculate incremental cost-effectiveness ratio (ICER) of raltegravir use, expressed in Swiss francs (CHF) as incremental cost/quality-adjusted life-year (QALY) gained. Future costs and QALYs were discounted at 3% per year. RESULTS: Five years of raltegravir treatment increased discounted quality-adjusted life expectancy by 3.73 years over placebo, with additional discounted cost of CHF 170,347, resulting in an ICER of CHF 45,687/QALY. ICERs ranged from CHF 42,751 to 53,478/QALY for treatment duration of 3 and 10 years, respectively. Results were most sensitive to changes in raltegravir treatment duration, source of estimated quality of life weights, and raltegravir price. CONCLUSIONS: Adding raltegravir to optimized background therapy was a cost-effective strategy for treatment-experienced patients in Switzerland.

Treatment of cryptococcal meningitis in resource limited settings.

PURPOSE OF REVIEW: Cryptococcal meningitis most commonly occurs in advanced HIV. Although diminishing in the developed world with antiretroviral therapy (ART), it remains a major problem in resource-limited settings. ART rollout will improve long-term HIV survival if opportunistic infections are effectively treated. Considering cryptococcal meningitis in that context, this review addresses excess morbidity and mortality in developing countries, treatment in areas of limited drug availability and challenges posed by combined anticryptococcal and HIV therapy. RECENT FINDINGS: From Early Fungicidal Activity (EFA) studies, amphotericin B-flucytosine is best induction therapy but often unavailable; high dose amphotericin B monotherapy may be feasible in some settings. Where fluconazole is the only option, higher doses are more fungicidal. Serum cryptococcal antigen testing may identify patients at highest disease risk and primary prophylaxis is effective; the clinical role of such interventions needs to be established. Timing of ART introduction remains controversial; early initiation risks Immune Reconstitution Disease (IRD) delays may increase mortality. SUMMARY: Amphotericin B based treatment is appropriate where possible. More studies are needed to optimize fluconazole monotherapy doses. Other research priorities include management of raised intracranial pressure, appropriate ART initiation and IRD treatment. Studies should focus on developing countries where problems are greatest.

Does less frequent routine monitoring of patients on a stable, fully suppressed cART regimen lead to an increased risk of treatment failure?

OBJECTIVE: To investigate whether HIV-infected patients on a stable and fully suppressive combination antiretroviral therapy (cART) regimen could safely be monitored less often than the current recommendations of every 3 months. DESIGN: Two thousand two hundred and forty patients from the EuroSIDA study who maintained a stable and fully suppressed cART regimen for 1 year were included in the analysis. METHODS: Risk of treatment failure, defined by viral rebound, fall in CD4 cell count, development of new AIDS-defining illness, serious opportunistic infection or death, in the 12 months following a year of a stable and fully suppressed regimen was assessed. RESULTS: One hundred thirty-one (6%) patients experienced treatment failure in the 12 months following a year of stable therapy, viral rebound occurred in 99 (4.6%) patients. After 3, 6 and 12 months, patients had a 0.3% [95% confidence interval (CI) 0.1-0.5], 2.2% (95% CI 1.6-2.8) and 6.0% (95% CI 5.0-7.0) risk of treatment failure, respectively. Patients who spent more than 80% of their time on cART with fully suppressed viraemia prior to baseline had a 38% reduced risk of treatment failure, hazard ratio 0.62 (95% CI 0.42-0.90, P = 0.01). CONCLUSION: Patients who have responded well to cART and are on a well tolerated and durably fully suppressive cART regimen have a low chance of experiencing treatment failure in the next 3-6 months. Therefore, in this subgroup of otherwise healthy patients, it maybe reasonable to extend visit intervals to 6 months, with cost and time savings to both the treating clinics and the patients.

[CMV DNA detection in plasma using real-time PCR based on the SYBR-Green I dye method]. / Detección de ADN de CMV en plasma mediante PCR en tiempo real utilizando SYBR-Green I como señal de amplificación.

OBJECTIVE: The aim of this study is to assess a real-time PCR technique on the LightCycler 2.0 with SYBR-Green I detection as compared to another real-time PCR method based on detection with FRET (fluorescence resonance energy transfer) probes for the quantification of CMV DNA. METHODS: The two real-time PCR methods were used to test plasma samples from immunocompromised patients with clinically suspected CMV disease, patients under follow-up without symptoms, and healthy adults. A standard curve for quantitative analysis by the SYBR-Green I method was performed with 10-fold diluted solutions of DNA from the CMV Towne strain (ATCC VR-977) cultured in MRC-5 monolayer. In addition, frozen samples from patients positive for CMV pp65 antigenemia were also analyzed and results compared using the two real time PCR methods. RESULTS: The real-time PCR technique using SYBR-Green I on the LightCycler 2.0 was a highly specific, fast, simple and reliable test to quantify CMV; moreover, it was cost-effective. CONCLUSION: Quantification of CMV DNA in plasma using this sensitive, fast, low-cost method was advantageous for the diagnosis and follow up of patients with opportunistic CMV infection, which are increasingly more frequent in our daily hospital clinical practice.

Assessment of automated DNA extraction coupled with real-time PCR for measuring Epstein-Barr virus load in whole blood, peripheral mononuclear cells and plasma.

BACKGROUND: Epstein-Barr virus (EBV) DNA load monitoring in blood has been shown to be essential for the diagnosis of EBV-associated diseases. However, the methods currently used to assess EBV DNA load are often time-consuming and require prior blood separation. OBJECTIVES: The aim of this study was to evaluate the relative diagnostic value of EBV DNA load monitoring in whole blood, peripheral blood mononuclear cells (PBMCs) and plasma after automated DNA extraction using the MagNA Pure extractor followed by LightCycler real-time quantitative PCR (LC-PCR). STUDY DESIGN: First, EBV DNA load was assessed retrospectively after automated or manual extraction on 104 PBMC specimens. Second, EBV DNA load was determined prospectively with the automated extraction procedure in the whole blood, PBMCs and plasma of 100 samples from patients with EBV-related diseases (group 1, n = 20), HIV-seropositive individuals (group 2, n = 66), and healthy EBV carriers (group 3, n = 14). RESULTS: A good correlation was observed between automated and manual extraction on 104 PBMC specimens (r = 0.956; P < 0.0001). In the prospective study, 67 samples were positive in both whole blood and PBMCs, with a good correlation between EBV DNA loads in whole blood and PBMCs (r = 0.936; P < 0.0001). Only 18/100 samples were positive in plasma. Higher viral loads were regularly observed in the three blood compartments from group 1 than from groups 2 and 3. CONCLUSION: This study demonstrated that an automated extraction of EBV DNA is easier to perform in whole blood or plasma than in PBMCs and facilitates the standardisation of EBV DNA measurement by real-time quantitative PCR. The quantitative detection of EBV DNA load in whole blood appeared more sensitive than in plasma for infectious mononucleosis in immunocompetent patients, probably because of a rapid loss of plasmatic EBV DNA. In transplant patients, EBV DNA load monitoring in whole blood and in plasma turned out to be equivalent in terms of feasibility and accuracy for the early diagnosis of post-transplant lymphoproliferative diseases (PTLDs).

Incidence and management of cataract after retinal detachment repair with silicone oil in immune compromised patients with cytomegalovirus retinitis.

PURPOSE: To determine the incidence of and risk factors for cataract and to describe the visual outcomes of cataract surgery in eyes with cytomegalovirus-related retinal detachments repaired with silicone oil. STUDY DESIGN: Retrospective cohort study. METHODS: A prospectively generated database of all patients with cytomegalovirus retinitis examined at a single tertiary care institution was used to identify all cases of retinal detachment between October 1983 and August 1997. Data on retinal detachment repair, development of cataract, and outcomes of cataract surgery were obtained retrospectively. RESULTS: Among 904 eyes of 587 immune-compromised patients diagnosed with cytomegalovirus retinitis, 198 eyes of 155 patients developed retinal detachment. Among these, 106 eyes of 90 patients underwent retinal detachment repair with silicone oil. The Kaplan-Meier estimated median time to cataract was 1.8 months after surgery with silicone oil. The adjusted relative risk of cataract in eyes that underwent retinal detachment repair with silicone oil compared with eyes that did not was 6.74 (P <.0001). Eight of the eyes that developed cataract underwent uncomplicated cataract surgery by phacoemulsification and posterior chamber intraocular lens implantation. Among these, six eyes experienced >or=2 lines of improvement in visual acuity. All developed posterior capsule opacification a median of 7 days after cataract surgery. Four of five eyes that that underwent neodymium:yttrium-aluminum-garnet laser capsulotomy experienced >or=2 lines improvement in visual acuity. CONCLUSIONS: There is a high incidence of cataract after surgery with silicone oil tamponade for cytomegalovirus-related retinal detachment. Posterior capsule opacification occurs rapidly after cataract surgery in these patients.

Molecular analysis of cerebrospinal fluid in viral diseases of the central nervous system.

The use of nucleic acid (NA) amplification techniques has transformed the diagnosis of viral infections of the central nervous system (CNS). Because of their enhanced sensitivity, these methods enable detection of even low amounts of viral genomes in cerebrospinal fluid. Following more than 10 years of experience, the polymerase chain reaction or other NA-based amplification techniques are nowadays performed in most diagnostic laboratories and have become the test of choice for the diagnosis of several viral CNS infections, such as herpes encephalitis, enterovirus meningitis and other viral infections occurring in human immunodeficiency virus-infected persons. Furthermore, they have been useful to establish a viral etiology in neurological syndromes of dubious origin and to recognise unusual or poorly characterised CNS diseases. Quantitative methods have provided a valuable additional tool for clinical management of these diseases, whereas post-amplification techniques have enabled precise genome characterisation. Current efforts are aiming at further improvement of the diagnostic efficiency of molecular techniques, their speed and standardisation, and to reduce the costs. The most relevant NA amplification strategies and clinical applications of to date will be the object of this review.

Cost effectiveness of human papillomavirus testing to augment cervical cancer screening in women infected with the human immunodeficiency virus.

PURPOSE: To determine the cost effectiveness of incorporating molecular testing for high-risk types of human papillomavirus into a cervical cancer screening program for women infected with the human immunodeficiency virus (HIV). SUBJECTS AND METHODS: We developed a Markov model to simulate the natural history of cervical cancer precursor lesions in HIV-infected women. Probabilities of progression and regression of cervical lesions were conditional on transient or persistent infection with human papillomavirus, as well as stage of HIV and effectiveness of antiretroviral therapy. Incorporating data from prospective cohort studies, national databases, and published literature, the model was used to calculate quality-adjusted life expectancy, life expectancy, lifetime costs, and incremental cost-effectiveness ratios for two main strategies: targeted screening-human papillomavirus testing is added to the initial two cervical cytology smears obtained after an HIV diagnosis and subsequent screening intervals are modified based on the test results; and universal screening-no testing for human papillomavirus is performed, and a single cytology screening interval is applied to all women. RESULTS: In HIV-infected women on anti-retroviral therapy, a targeted screening strategy in which cervical cytology screening was conducted every 6 months for women with detected human papillomavirus DNA, and annually for all others, cost $10,000 to $14,000 per quality-adjusted life year gained compared with no screening. A universal screening strategy consisting of annual cervical cytology for all women was 15% less effective and had a less attractive cost-effectiveness ratio. Targeted screening remained economically attractive in multiple sensitivity analyses, although when the overall incidence of cervical cancer precursor lesions was lowered by 75%, the screening interval for women with detected human papillomavirus DNA could be widened to 1 year. CONCLUSIONS: Adding human papillomavirus testing to the two cervical cytology smears obtained in the year after an HIV diagnosis, and modifying subsequent cytology screening intervals based on the results, appears to be an effective and cost-effective modification to current recommendations for annual cytology screening in HIV-infected women.

Special histologic stains are rarely beneficial for the evaluation of HIV-related gastrointestinal infections.

During a 28-month period, endoscopic mucosal biopsy specimens from all HIV-infected patients were submitted for routine histologic evaluation. Immunoperoxidase staining for cytomegalovirus and herpesvirus antigens (esophagus), mycobacterial and fungal staining, and Gram staining of mucosal biopsy specimens were done. Special fungal and acid-fast stains were selectively performed in patients with absolute CD4 cell counts of less than 200 cells per microliter (200 x 10(6)/L) and/or with diarrhea and or wasting syndrome. Treatment was based on the endoscopic and histologic findings, and long-term follow-up was performed. The 121 symptomatic HIV-infected patients underwent 221 upper and/or lower endoscopies with 285 biopsy sites. The sensitivity and specificity of H&E staining for the diagnosis of gastrointestinal cytomegalovirus were 97% and 100%, respectively. The results of fungal and mycobacterial stains neither altered therapy nor identified previously undiagnosed infections in any patient. Long-term follow-up revealed no patient in whom an infection was missed on routine H&E, which affected outcome. Routine H&E staining is accurate for the diagnosis of gastrointestinal opportunistic infections in HIV-infected patients. Special histologic stains for fungal, mycobacterial, and viral infections did not increase the diagnostic yield or alter medical therapy but doubled the costs.

Monitoring cytomegalovirus retinitis prevalence in an HIV-seropositive cohort: the assessment of improvements observed following the introduction of highly active antiretroviral triple therapy.

This paper concerns the ophthalmic assessment of patients with acquired immunodeficiency syndrome (AIDS) for a number of eye conditions and in particular cytomegalovirus (CMV) retinitis. CMV has been the most common opportunistic infection associated with AIDS and the leading cause of blindness among AIDS patients. There have been early indications of a widespread fall in CMV prevalence internationally following the introduction of a new highly active antiretroviral triple (HAART) therapy. Our study sought to assess the position for Ireland. Our cohort was the entire population of stage IV AIDS patients attending the country's leading referral centre. The total number of patients examined was 167 and the period of examination was 1 May 1995 to 30 April 1997. HAART was introduced in March 1996, so the data permitted a 'before and after' comparison of various clinical findings. The incidence of new CMV cases was found to be 4 among the 102 patients examined in the first 12-month period and one among 107 patients examined in the second 12-month period. There were accompanying declines in HIV-related noninfectious retinal vasculopathy (HIVR), keratitis and other conditions. The findings are promising, but we argue that caution is needed in assessing long-term trends. In the paper we discuss a number of methodological issues in the collection and analysis of the clinical data and in the interpretation of results.

Applying the Cox proportional hazards model when the change time of a binary time-varying covariate is interval censored.

This paper develops methodology for estimation of the effect of a binary time-varying covariate on failure times when the change time of the covariate is interval censored. The motivating example is a study of cytomegalovirus (CMV) disease in patients with human immunodeficiency virus (HIV) disease. We are interested in determining whether CMV shedding predicts an increased hazard for developing active CMV disease. Since a clinical screening test is needed to detect CMV shedding, the time that shedding begins is only known to lie in an interval bounded by the patient's last negative and first positive tests. In a Cox proportional hazards model with a time-varying covariate for CMV shedding, the partial likelihood depends on the covariate status of every individual in the risk set at each failure time. Due to interval censoring, this is not always known. To solve this problem, we use a Monte Carlo EM algorithm with a Gibbs sampler embedded in the E-step. We generate multiple completed data sets by drawing imputed exact shedding times based on the joint likelihood of the shedding times and event times under the Cox model. The method is evaluated using a simulation study and is applied to the data set described above.