A cylindrically symmetric "micro-Mott" electron polarimeter.

A small, novel, cylindrically symmetric Mott electron polarimeter is described. The effective Sherman function, Seff, or analyzing power, for 20 kV Au target bias with a 1.3 keV energy loss window is 0.16 ± 0.01, where uncertainty in the measurement is due primarily to uncertainty in the incident electron polarization. For an energy loss window of 0.5 keV, Seff reaches its maximum value of 0.24 ± 0.02. The device's maximum efficiency, I/Io, defined as the detected count rate divided by the incident particle rate, is 3.7 ± 0.2 × 10(-4) at 20 keV. The figure-of-merit of the device, η, is defined as Seff (2)IIo and equals 9.0 ± 1.6 × 10(-6). Potential sources of false asymmetries due to detector electronic asymmetry and beam misalignment have been investigated. The new polarimeter's performance is compared to published results for similar compact retarding-field Mott polarimeters, and it is concluded that this device has a relatively large Seff and low efficiency. SIMION(®) electron trajectory simulations and Sherman function calculations are presented to explain the differences in performance between this device and previous designs. This design has an Seff that is insensitive to spatial beam fluctuations and, for an energy loss window >0.5 keV, negligible background due to spurious ion and X-ray production at the target.

Cefazolin versus Nafcillin for Methicillin-Sensitive Staphylococcus aureus Bloodstream Infection in a California Tertiary Medical Center.

Recent observational studies have suggested possible reductions in mortality in patients receiving cefazolin versus antistaphylococcal penicillins. We examined 90-day mortality in patients receiving cefazolin compared to nafcillin for methicillin-susceptible Staphylococcus aureus (MSSA) bloodstream infection (BSI). We identified persons with MSSA BSI admitted to San Francisco General Hospital from January 2008 to July 2013 through a hospital-wide infection surveillance system and confirmed 90-day mortality using U.S. national vital registries. We included persons receiving cefazolin or nafcillin as the predominant intravenous antimicrobial agent; all participants received inpatient Infectious Diseases service consultation. We estimated the association between receipt of cefazolin and 90-day risk of death by multivariate logistic regression, including a propensity score for receiving cefazolin as the second predictor. Of 230 MSSA BSI cases, 30 received nafcillin and 70 received cefazolin as the predominant antimicrobial; 10 died within 90 days, 5 from each group. Unadjusted analysis showed substantial but not statistically significant reduced odds of death in those receiving cefazolin (odds ratio, 0.38; 95% confidence interval [CI], 0.10 to 1.44). Multivariate analysis with propensity scores found a similar adjusted odds ratio (0.40; 95% CI, 0.09 to 1.74; P = 0.22). We found a large reduction in 90-day mortality in those receiving cefazolin compared to nafcillin for MSSA BSI, but this finding was not statistically significant. The magnitude of effect seen in this and other studies justifies further study.

Feasibility and effectiveness of a brief, intensive phylogenetics workshop in a middle-income country.

There is an increasing role for bioinformatic and phylogenetic analysis in tropical medicine research. However, scientists working in low- and middle-income regions may lack access to training opportunities in these methods. To help address this gap, a 5-day intensive bioinformatics workshop was offered in Lima, Peru. The syllabus is presented here for others who want to develop similar programs. To assess knowledge gained, a 20-point knowledge questionnaire was administered to participants (21 participants) before and after the workshop, covering topics on sequence quality control, alignment/formatting, database retrieval, models of evolution, sequence statistics, tree building, and results interpretation. Evolution/tree-building methods represented the lowest scoring domain at baseline and after the workshop. There was a considerable median gain in total knowledge scores (increase of 30%, p<0.001) with gains as high as 55%. A 5-day workshop model was effective in improving the pathogen-applied bioinformatics knowledge of scientists working in a middle-income country setting.

Transmission of GB virus type C via transfusion in a cohort of HIV-infected patients.

BACKGROUND: GB virus C (GBV-C) infection is transmitted by blood exposure and associated with lower human immunodeficiency virus (HIV) load and slower HIV disease progression. Few studies describe predictors of acute GBV-C infection following transfusion in HIV-infected patients. METHODS: We used a limited-access database from the National Heart Lung and Blood Institute's Viral Activation Transfusion Study, a randomized controlled trial of leukoreduced versus nonleukoreduced transfusions received by HIV-infected, transfusion-naive patients. Blood samples from 489 subjects were tested for GBV-C markers in pretransfusion and posttransfusion samples. We estimated the risk of acquiring GBV-C RNA and predictors of GBV-C acquisition, using pooled logistic regression. RESULTS: GBV-C RNA was detected ≤120 days following the first transfusion in 22 (7.5%) of 294 subjects who were GBV-C negative before transfusion. The risk of GBV-C RNA acquisition increased with each unit transfused (odds ratio, 1.09; 95% confidence interval, 1.06-1.11). Lower baseline HIV load and use of antiretroviral therapy were associated with subsequent GBV-C RNA acquisition, after control for units of blood transfused. Leukoreduced status of transfused units was not associated with GBV-C transmission. CONCLUSIONS: Blood transfusion is associated with a significant risk of GBV-C acquisition among HIV-infected patients. Transmission of GBV-C by blood transfusion was inversely related to HIV load.

Developing WHO guidelines with pragmatic, structured, evidence-based processes: A case study.

Many guidelines, including those produced by the World Health Organisation (WHO), have failed to adhere to rigorous methodological standards. Operational examples of guideline development processes may provide important lessons learned to improve the rigour and quality of future guidelines. To this end, this paper describes the process of developing WHO guidelines on prevention and care interventions for adults and adolescents living with HIV. Using a pragmatic, structured, evidence-based approach, we created an organising committee, identified topics, conducted systematic reviews, identified experts and distributed evidence summaries. Subsequently, 55 global HIV experts drafted and anonymously submitted guideline statements at the beginning of a conference. During the conference, participants voted on statements using scales evaluating appropriateness of the statements, strength of recommendation and level of evidence. After review of voting results, open discussion, re-voting and refinement of statements, a draft version of the guidelines was completed. A post-conference writing team refined the guidelines based on pre-determined guideline writing principles and incorporated external comments into a final document. Successes and challenges of the guideline development process were identified and are used to highlight current issues and debates in developing guidelines with a focus on implications for future guideline development at WHO.

Development of a low-cost system for measuring conditional time-averaged gradients of SO2 and NH3.

A conditional time-averaged gradient (COTAG) system has been developed to provide direct long-term (weekly to monthly) average flux gradient measurements for a range of trace gases, between land and atmosphere. Over daily periods, atmospheric conditions can range from high stability, where the vertical gradients of ambient concentration are enhanced due to very small diffusivity, to highly unstable conditions, in which concentration gradients are small due to the intense turbulent activity of the surface layer. The large vertical gradients generated by high stability would bias the estimate of the actual flux: to avoid this, the COTAG system samples conditionally, within a carefully refined range of stability. A comparison with a continuous flux gradient system suggested that the removal of stable conditions from the sampling period does not substantially modify the evaluation of the long-term fluxes.

A simple screening tool for active tuberculosis in HIV-infected adults receiving antiretroviral treatment in Uganda.

SETTING: Reliable clinical algorithms that screen for active tuberculosis (TB) in human immunodeficiency virus (HIV) infected people initiating or receiving antiretroviral treatment (ART) in sub-Saharan Africa could reduce the need for diagnostic procedures. METHODS: We estimated the utility of six TB-related signs and symptoms, alone or in combination, compared with the Uganda Ministry of Health diagnostic guidelines for participants with prevalent (baseline), early ART (< or = 3 months on ART) and incident TB (>3 months on ART). RESULTS: Of 1995 participants screened for ART eligibility, 71 (3.6%) had prevalent TB. The presence of any one of the following: cough > or = 3 weeks, fever > or = 4 weeks, lymphadenopathy or baseline body mass index < or = 18 kg/m(2) had a sensitivity of 99% (95%CI 96-100), a specificity of 66% (95%CI 64-68) and a negative predictive value (NPV) of 100% (95%CI 99-100) for predicting active TB. During ART follow-up, TB incidence was 2.4 (95%CI 1.6-3.4)/100 person-years. The presence of cough > or = 3 weeks or general weakness was 100% sensitive (95%CI 99-100), 66% specific (95%CI 59-74) and had an NPV of 100% (95%CI 99-100). CONCLUSION: Use of a simple TB screening algorithm can accurately identify, in a resource-poor African setting, HIV-infected individuals who require further procedures to diagnose active TB.

Nuclear medicine in the assessment of differentiated thyroid cancer.

Despite modern multi-modality treatment, 10-30% of patients treated for differentiated thyroid cancer (DTC) ultimately develop local recurrence or metastatic disease. These malignancies are frequently slow-growing and secondary surgical resection is often undertaken along with radioactive iodine treatment. Correlation of radiological imaging with nuclear medicine studies is essential for individualized treatment planning, and to optimize this management. Radiologists should be familiar with the interpretation of various nuclear medicine studies used to image differentiated thyroid neoplasms.

Antiretroviral regimens for patients with HIV who fail first-line antiretroviral therapy.

BACKGROUND: Highly active antiretroviral therapy has reduced the morbidity and mortality of patients with HIV/AIDS. A common first-line ART regimen includes a non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTIs). If treatment failure occurs, a change to second-line therapy is necessary. OBJECTIVES: This meta-analysis aimed to assess the optimum antiretroviral regimen for patients with HIV who fail first-line therapy (ART-naive) with d4T+3TC+NVP; d4T+3TC+EFV; ZDV+3TC+NVP; and ZDV+3TC+EFV. SEARCH STRATEGY: Electronic databases and conference proceedings were searched with relevant search terms without limits to language. SELECTION CRITERIA: Randomised controlled trials of HIV-infected adult patients administered second-line ART after virologic failure of a first-line regimen were included. The primary outcome measure included the proportion of patients achieving undetectable plasma HIV RNA concentration (viral load). Secondary outcome measures included change in mean CD4 cell count, clinical resolution of symptoms, rate of adverse events, rate of change in therapy for failure, rate of change in therapy for toxicity, and mortality. DATA COLLECTION AND ANALYSIS: Two authors assessed each reference for inclusion and exclusion criteria established a priori. Data were abstracted independently using a standardised abstraction form. MAIN RESULTS: Twenty-one records were identified in total, 6 of which were duplicates. None of the records met inclusion criteria. AUTHORS' CONCLUSIONS: There is insufficient evidence to evaluate second-line therapies in patients with HIV who fail first-line treatment with d4T+3TC+NVP; d4T+3TC+EFV; ZDV+3TC+NVP; and ZDV+3TC+EFV. Current recommendations are based on available resources and results from individualised treatment decisions based on resistance testing and clinician choice.

Imaging in the investigation of paraneoplastic syndromes.

Paraneoplastic syndromes are a heterogeneous group of disease presentations caused by underlying tumours. As they are non-metastatic in nature an intensive diagnostic evaluation is warranted to identify potentially curable lesions. The selection of the appropriate method of imaging is important in these cases, especially when history and physical examination are unrevealing. In this review the important paraneoplastic syndromes and underlying malignancies are discussed along with relevant imaging strategies.

Impact of large-angle scattering on diffusively backscattered halos.

We discuss the impact of large-angle scattering events in highly forward-scattering media on the spatial distribution of the diffusively reflected light. We show that, even for highly forward-scattering media, the reflected light near the incident beam axis is strongly dependent on the small number of large-angle scattering events. Reliable modeling of near-axis reflection thus requires accurate knowledge of the scattering phase function's behavior at large angles.

Antiretroviral post-exposure prophylaxis (PEP) for occupational HIV exposure.

BACKGROUND: Populations such as healthcare workers (HCWs), injection drug users (IDUs), and people engaging in unprotected sex are all at risk of being infected with the human immunodeficiency virus (HIV). Animal models show that after initial exposure, HIV replicates within dendritic cells of the skin and mucosa before spreading through lymphatic vessels and developing into a systemic infection (CDC 2001). This delay in systemic spread leaves a "window of opportunity" for post-exposure prophylaxis (PEP) using antiretroviral drugs designed to block replication of HIV (CDC 2001). PEP aims to inhibit the replication of the initial inoculum of virus and thereby prevent establishment of chronic HIV infection. OBJECTIVES: To evaluate the effects of antiretroviral PEP post-occupational exposure to HIV. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, AIDSearch, and the Database of Abstracts of Reviews of Effectiveness were searched from 1985 to January 2005 to identify controlled trials. There were no language restrictions. Because no controlled clinical trials were retrieved, the search was repeated on 31 May 2005 in MEDLINE, AIDSearch and EMBASE using a search strategy to identify analytic observational studies. Handsearches of the reference lists of all pertinent reviews and studies found were also undertaken. Experts in the field of HIV prevention were contacted. SELECTION CRITERIA: Types of studies: All controlled trials (including randomized clinical trials and controlled clinical trials). If no controlled trials were found, analytic studies (e.g. cohort and case-control studies) were considered. Descriptive studies (i.e. studies with no comparison groups) were excluded. Types of participants included:HCWs exposed to any known or potentially HIV contaminated product;anyone exposed to a needlestick contaminated by known or potentially HIV-infected blood or other bodily fluid in an occupational setting; andanyone exposed through the mucous membranes to an HIV-infected or potentially infected substance in occupational setting.Excluded: Sex workers (PEP post-sexual exposure is addressed in another Cochrane review (Martín 2005)). Types of interventions: Any intervention that administered single or combinations of antiretrovirals as PEP to people exposed to HIV through percutaneous injuries and/or occupational mucous membrane exposures when the HIV status of the source patient was positive or unknown. Studies comparing two types of PEP regimens were considered, as were studies comparing PEP with no intervention. Types of outcome measures:Incidence of HIV infection in those given PEP versus those given placebo or a different PEP regimen; Adherence to PEP; Complications of PEPTypes of outcome measures: Incidence of HIV infection in those given PEP versus those given placebo or a different PEP regimen; Adherence to PEP; Complications of PEP DATA COLLECTION AND ANALYSIS: Data concerning outcomes, details of the interventions, and other study characteristics were extracted by two independent authors (TY and JA) using a standardized data extraction form (Table 04). A third author (GK) resolved disagreements. The following information was gathered from each included study: location of study, date, publication status, demographics (e.g. age, gender, occupation, risk behavior, etc.) of participants/exposure modality, form of PEP used, duration of use, and outcomes. Odds ratios with a 95% confidence interval (CI) were used as the measure of effect. A meta-analysis was performed for adverse events where two-drug regimens were compared with three-drug regimens. Due to overlap between Puro 2000 and Puro 2005, the former was not included in the combined analysis. MAIN RESULTS: Effect of PEP on HIV seroconversionNo randomized controlled trials were identified. Only one case-control study was included. HIV transmission was significantly associated with deep injury (OR 15, 95% CI 6.0 to 41), visible blood on the device (OR 6.2, 95% CI 2.2 to 21), procedures involving a needle placed in the source patient's blood vessel (OR 4.3, 95% CI 1.7 to 12), and terminal illness in the source patient (OR 5.6, 95% CI 2.0 to 16). After controlling for these risk factors, no differences were detected in the rates at which cases and controls were offered post-exposure prophylaxis with zidovudine. However, cases had significantly lower odds of having taken zidovudine after exposure compared to controls (OR 0.19, 95%CI 0.06 to 0.52). No studies were found that evaluated the effect of two or more antiretroviral drugs for occupational PEP. Adherence to and complications with PEPEight reports from observational comparative studies confirmed findings that adverse events were higher with a three-drug regimen, especially one containing indinavir. However, discontinuation rates were not significantly different. AUTHORS' CONCLUSIONS: The use of occupational PEP is based on limited direct evidence of effect. However, it is highly unlikely that a definitive placebo-controlled trial will ever be conducted, and, therefore, on the basis of results from a single case-control study, a four-week regimen of PEP should be initiated as soon as possible after exposure, depending on the risk of seroconversion. There is no direct evidence to support the use of multi-drug antiretroviral regimens following occupational exposure to HIV. However, due to the success of combination therapies in treating HIV-infected individuals, a combination of antiretroviral drugs should be used for PEP. Healthcare workers should be counseled about expected adverse events and the strategies for managing these. They should also be advised that PEP is not 100% effective in preventing HIV seroconversion. A randomized controlled clinical trial is neither ethical nor practical. Due to the low risk of HIV seroconversion, a very large sample size would be required to have enough power to show an effect. More rigorous evaluation of adverse events, especially in the developing world, are required. Seeing that current practice is partly based on results from individual primary animal studies, we recommend a formal systematic review of all relevant animal studies.

Stavudine, lamivudine and nevirapine combination therapy for treatment of HIV infection and AIDS in adults.

BACKGROUND: A favourable regimen for people infected with HIV/AIDS is one that provides optimal efficacy, durability of antiretroviral activity, tolerability, and has low adverse effects and drug-drug interactions. The combination of the non-nucleoside reverse transcriptase inhibitor nevirapine (NVP), and two nucleoside reverse transcriptase inhibitors, stavudine (d4T) and lamivudine (3TC), is widely used as first-line therapy, especially in low-resource countries. Analysis of the efficacy, durability and tolerability of the regimen is thus important to clinicians, consumers and policy-makers living in both rich and poor countries. OBJECTIVES: To examine the efficacy of the stavudine, lamivudine and nevirapine regimen for the treatment of HIV infection and AIDS in adults. SEARCH STRATEGY: We used the comprehensive search strategy developed specifically by the Cochrane HIV/AIDS Review Group to identify HIV/AIDS randomised controlled trials, and searched the following electronic databases: MEDLINE (searched July 2004); Embase (searched October 2004); and CENTRAL (July 2004). This search was supplemented with a search of AIDSearch (April 2005) to identify relevant conference abstracts, as well as searching reference lists of all eligible articles. The search was not limited by language or publication status. SELECTION CRITERIA: Randomised controlled trials of the stavudine, lamivudine and nevirapine regimen, compared with any other regimens for treating HIV/AIDS, in antiretroviral treatment-naive or antiretroviral treatment-experienced adults. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the methodological quality of the trials and extracted data. MAIN RESULTS: Our search resulted in 1,148 records, of which two studies described trials that met our inclusion criteria. One trial was a small single-centre Australian trial of 70 antiretroviral-naive participants, while the other trial was a large, multicentre trial, conducted in 14 countries, of 1,216 antiretroviral-naive participants. In both trials over 60% of participants were male. As the therapeutic combinations compared in both trials were not identical, it was not possible to conduct a meta-analysis to increase the power of the results. The main findings, therefore, are from the much larger trial, which was of a high quality. This trial found that there was no statistically significant difference in the efficacy (measured by treatment failure) between nevirapine and efavirenz (EFZ), when used in combination with 3TC and d4T (RR = 1.16; 95%CI: 0.95, 1.41). There was no statistically significant difference between once daily or twice-daily dosing of NVP, when used in combination with 3TC and d4T (RR = 1.00; 95%CI: 0.83; 1.21). It also showed that, compared with NVP plus EFZ, 3TC and d4T, a once-daily dosing of NVP, in combination with 3TC and d4T, performs better in averting treatment failure (RR = 0.82; 95%CI: 0.67, 1.00) than does twice-daily dosing of NVP with 3TC and d4T (RR = 0.82; 95%CI: 0.69; 0.97). Frequency of toxicity was higher in participants receiving NVP, compared with EFZ. AUTHORS' CONCLUSIONS: The combination of nevirapine, 3TC and d4T is as efficacious as a combination of efavirenz, 3TC and d4T. Once-daily NVP with twice-daily 3TC and d4T is as efficacious as twice-daily NVP, 3TC and d4T. However, toxicity may be increased in the once-daily NVP regime. Additional trials of sufficient duration are required to provide better evidence for the use of this combination as a first line therapy. Ideally, trials should use standardised assessment measures especially with respect to measuring viral load, so that results can be compared and combined in meta-analyses.

A meta-analysis of the effect of high weight on asthma.

BACKGROUND: Prevalence rates for both overweight and asthma have been increasing among children in developed countries over the past two decades. Some recent studies have postulated a causal relation between these but have lacked power to form a definitive conclusion. AIM: To estimate the effect of high body weight in childhood on the future risk of asthma. METHODS: Medline search (1966 to October 2004), supplemented by manual search of reference lists and grey literature. Cohort studies that examined high body weight at birth or during childhood and future outcome of asthma were included. Data from each study were extracted on exposure status, clinical outcome, and study characteristics. RESULTS: A total of 402 studies were initially identified, of which 12 met the inclusion criteria. The combined results from four studies that examined the effect of high body weight during middle childhood on the outcome of subsequent asthma showed a 50% increase in relative risk (RR 1.5, 95% CI 1.2 to 1.8). The combined results from nine studies that examined the effect of high birth weight on subsequent asthma had a pooled RR of 1.2 (95% CI 1.1 to 1.3). There was consistency among the results in sensitivity analyses examining studies containing only estimates of odds ratios, studies containing only the outcome of physician diagnosis of asthma, and studies including all definitions of high body weight. CONCLUSIONS: Children with high body weight, either at birth or later in childhood, are at increased risk for future asthma. Potential biological mechanisms include diet, gastro-oesophageal reflux, mechanical effects of obesity, atopy, and hormonal influences. Further research might elucidate the causal pathway, which could improve our understanding of the pathophysiology of asthma and perhaps lead to knowledge of potential preventive interventions.

Antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV.

BACKGROUND: Cryptococcal disease is an opportunistic infection that causes significant morbidity and mortality in adults with HIV. Primary prophylaxis with antifungal interventions may decrease cryptococcal disease incidence and associated mortality. OBJECTIVES: To assess the efficacy of antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV. SEARCH STRATEGY: We searched the following databases: MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), ClinicalTrials.gov, Database of Abstracts of Reviews of Effectiveness (DARE), Latin American and Caribbean Literature on the Health Sciences (LILACS), and the Cochrane Controlled Trials Register (CCTR). We reviewed abstracts from the following relevant conferences: International AIDS Conference, International AIDS Society Conference on HIV Pathogenesis and Treatment, and Conference on Retroviruses and Opportunistic Infections. We searched reference lists for all primary and other pertinent articles identified. We attempted to contact experts in the field, particularly primary authors of included studies, to better ensure completeness of included studies. We also approached pharmaceutical companies for any available and relevant unpublished data. The time period searched was from 1980 to August 2004. We placed no language restrictions on the search. Key words used include: meningitis, cryptococcal, cryptococcus, cryptococcosis, acquired immunodeficiency syndrome, human immunodeficiency virus, prophylaxis, chemoprevention, antifungal agents, and the Cochrane screen for randomized controlled trials. SELECTION CRITERIA: Randomized controlled trials using antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV were selected. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial eligibility and quality. Trial authors, experts, and pharmaceutical companies were contacted for additional and/or missing information. Data were abstracted by two reviewers. Data were pooled, where appropriate, to yield summary estimates. MAIN RESULTS: Five studies (N=1316) were identified. All study patients had CD4 cell counts <300 cells/microl, and the majority of patients had CD4 cell counts <150 cells/microl. When all five studies are analyzed as a single group (N=1316), the incidence of cryptococcal disease was decreased in those taking primary prophylaxis (RR 0.21, 95% CI 0.09, 0.46) compared to those taking placebo. However, there was no significant difference in overall mortality observed (RR 1.01, 95% CI 0.71, 1.44). When the three studies using itraconazole as the intervention were analyzed together (N=798), the incidence of cryptococcal disease was decreased in those taking itraconazole for primary prophylaxis (RR 0.12, 95% CI 0.03, 0.51) compared to those taking placebo; however, there was no significant difference in overall mortality (RR 1.12, 95% CI 0.70, 1.80). When the two studies using fluconazole as the intervention were analyzed together (N=518), the incidence of cryptococcal disease was decreased in those taking fluconazole for primary prophylaxis (RR 0.25, 95% CI 0.07, 0.87) compared to those taking placebo; however, there was no significant difference in overall mortality (RR 0.59, 95% CI 0.14, 2.62). AUTHORS' CONCLUSIONS: Antifungal primary prophylaxis with either itraconazole or fluconazole is effective in reducing the incidence of cryptococcal disease in adults with advanced HIV disease. However, neither of these interventions has a clear effect on overall mortality. Further research is needed to better understand these interventions and the populations in which they may be most effective.

Population-based interventions for reducing sexually transmitted infections, including HIV infection.

BACKGROUND: Sexually transmitted infections (STI) are common in developing countries. The World Health Organisation (WHO) estimates that in 1999, 340 million new cases of syphilis, gonorrhoea, chlamydial infection and trichomoniasis occurred. Human immunodeficiency virus (HIV) infection is also common in developing countries. UNAIDS estimates that over 95% of the 40 million people infected with HIV by December 1999 live in developing countries (UNAIDS 2003). The STI and HIV epidemics are interdependent. Similar behaviours, such as frequent unprotected intercourse with different partners, place people at high risk of both infections, and there is clear evidence that conventional STIs increase the likelihood of HIV transmission. Several studies have demonstrated a strong association between both ulcerative and non-ulcerative STIs and HIV infection (Cameron 1989, Laga 1993). There is biological evidence, too, that the presence of an STI increases shedding of HIV, and that STI treatment reduces HIV shedding (Cohen 1997, Robinson 1997). Therefore, STI control may have the potential to contribute substantially to HIV prevention. OBJECTIVES: To determine the impact of population-based STI interventions on the frequency of HIV infection, frequency of STIs and quality of STI management. SEARCH STRATEGY: The following electronic databases were searched for relevant randomised trials or reviews:1) MEDLINE for the years 1966 to 2003 using the search terms "sexually transmitted diseases" and "human immunodeficiency virus infection"2) The Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness and the Cochrane Clinical Trials Register, in the most recent issue of the Cochrane Library3) The specialist registry of trials maintained by the Cochrane Infectious Diseases Group.4) EMBASE The abstracts of relevant conferences were searched, and reference lists of all review articles and primary studies were scanned. Finally, authors of included trials and other experts in the field were contacted as appropriate. SELECTION CRITERIA: Randomised controlled trials in which the unit of randomisation is either a community or a treatment facility. Studies where individuals are randomised were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the inclusion criteria to potential studies, with any disagreements resolved by discussion. Trials were examined for completeness of reporting. The methodological quality of each trial was assessed by the same two reviewers, with details recorded of randomisation method, blinding, use of intention-to-treat analysis and the number of patients lost to follow-up, using standard guidelines of the Cochrane Infectious Diseases Group. MAIN RESULTS: Five trials were included. Frequency of HIV infection: In Rakai, after 3 rounds of treatment of all community members for STIs, the rate ratio of incident HIV infection was 0.97 (95%CI 0.81 to 1.16), indicating no effect of the intervention. In Mwanza, the incidence of HIV infection in the intervention groups (strengthened syndromic management of STIs in primary care clinics) was 1.2% compared with 1.9% in the control groups (OR=0.58, 95% CI 0.42-0.70), corresponding to a 38% reduction (95%CI 15% to 55%) in HIV incidence in the intervention group. In the newest trial by Kamali et al, the rate ratio of behavioral intervention & STI management compared to control on HIV incidence was 1.00 (0.63-1.58, p=.98). These are consistent with Rakai data showing no effect of intervention. Frequency of STIs: In both Mwanza and Rakai, there was no significant reduction in gonorrhoea, chlamydia, urethritis, or reported STI symptoms among intervention communities. The prevalence ratio of syphilis between intervention and control groups in Rakai was 0.8 (95%CI 0.71-0.89), of trichmoniasis was 0.59 (0.38-0.91), and of bacterial vaginosis was 0.87 (0.74-1.02). In Mwanza, the prevalence of serologically diagnosed syphilis in the intervention community was 5% compared with 7% in the control community at the end of the trial (adjusted re7% in the control community at the end of the trial (adjusted relative risk 0.71 (95%CI 0.54-0.93). In Kamali et al, there was a significant decrease in gonorrhoea and active syphilis cases. Rate ratio for gonorrhoea was 0.29(0.12-0.71, p=0.016), active syphilis was 0.53(0.33-0.84,p=0.016). There was a trend towards significance with intervention on the use of condoms with the last casual partner; the rate ratio was 1.27(1.02-1.56,p=0.036). Quality of treatment: In Lima, following training of pharmacy assistants in STI syndromic management, symptoms were recognised as being due to an STI in 65% of standardised simulated patients (SSPs) visiting intervention and 60% of SSPs visiting control pharmacies (p=0.35). Medication was offered without referral to a doctor in most cases (83% intervention and 78% control, p=0.61). Of those SSPs offered medication, only 1.4% that visited intervention pharmacies and only 0.7% of those that visited control pharmacies (p=0.57) were offered a recommended regimen. Similarly in only 15% and 16% of SSP visits respectively was any recommended drug offered. However, education and counseling were more likely to be given to SSPs visiting intervention pharmacies (40% vs 27%, p=0.01). No SSPs were given partner cards or condoms. In Hlabisa, following the intervention targeting primary care clinic nurses (strengthened STI syndromic management and provision of STI syndrome packets containing recommended drugs, condom, partner cards and patient information leaflets), SSPs were more likely to be given recommended drugs in intervention clinics (83% vs 12%, p<0.005) and more likely to be correctly case managed [given correct drugs, partner cards and condoms] (88% vs 50%, p<0.005). There were no significant differences in the proportions adequately counseled (68% vs 46%, p=0.06), experiencing good staff attitude (84% vs 58%, p=0.07), and being consulted in privacy (92% vs 86%, p=0.4). There was no strong evidence of any impact on treatment-seeking behaviour, utilisation of services, or sexual behaviour in any of the four trials. REVIEWERS' CONCLUSIONS: There is limited evidence from randomised controlled trials for STI control as an effective HIV prevention strategy. Improved STI treatment services have been shown to reduce HIV incidence in an environment characterised by an emerging HIV epidemic (low and slowly rising prevalence), where STI treatment services are poor and where STIs are highly prevalent. There is no evidence for substantial benefit from treatment of all community members. The addition of the Kamali trial to the existing evidence supports the data from the Rakai trial of no effect. There are, however, other compelling reasons why STI treatment services should be strengthened, and the available evidence suggests that when an intervention is accepted it can substantially improve quality of services provided. The Kamali trial shows an increase in the use of condoms, a marker for improved risk behaviors. Further community-based randomised controlled trials that test a range of alternative STI control strategies are needed in a variety of different settings. Such trials should aim to measure a range of factors that include health seeking behaviour and quality of treatment, as well as HIV, STI and other biological endpoints.

Three- or four- versus two-drug antiretroviral maintenance regimens for HIV infection.

BACKGROUND: Combination antiretroviral therapy administered to HIV-infected individuals has been shown to decrease viral replication, improve immunologic function and delay the progression of HIV infection. However, because patient adherence to complicated combination-therapy antiretroviral regimens is difficult and because of concerns regarding the cumulative toxicity of antiretroviral drugs, regimens that utilize fewer antiretroviral agents are desirable. OBJECTIVES: To compare the use three- or four- versus two-drug antiretroviral maintenance regimens following successful initial therapy for HIV infection. SEARCH STRATEGY: The following electronic databases were searched for relevant randomized trials or reviews: 1. MEDLINE for the years 1982-May 2003 using the search terms human immunodeficiency virus, antiretroviral therapy, maintenance therapy, zidovudine, lamivudine, indinavir, stavudine, saquinivir, nelfinavir, didanosine, zalcitabine, ritonovir, AIDS, anti-HIV agents, HIV infection and HIV seropositivity. 2. AIDSLINE for the years 1982- May 2003 using the search terms antiretroviral therapy, maintenance therapy, zidovudine, lamivudine, indinavir, stavudine, saquinivir, nelfinavir, didanosine, zalcitabine, ritonovir, anti-HIV agents. 3. The Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness and the Cochrane Clinical Trials Register in the Cochrane Library, through May 2003. 4. AIDSTRIALS, a specialist registry of current and completed trials maintained by the U.S. National Library of Medicine through May 2003. The abstracts of relevant conferences, including the International Conferences on AIDS, the Conference on Retroviruses and Opportunistic Infections, the Infectious Disease Society of America annual meeting and the Interscience Conference on Antimicrobial Agents and Chemotherapy, as indexed by AIDSLINE, were also reviewed. Reference lists of all review articles and primary articles identified were also searched. SELECTION CRITERIA: Randomized controlled trials in which HIV-infected adults who had successfully completed initial three- or four-drug antiretroviral therapy were randomized to maintenance therapy with three or four drugs or maintenance therapy with two drugs. Successful initial therapy was defined by a plasma viral load of less than 500 copies/ml. DATA COLLECTION AND ANALYSIS: Two reviewers assessed eligibility and trial quality. Attempts were made to contact the authors of the included abstract. Data on the number of patients experiencing loss of viral suppression were abstracted by two reviewers. The data were pooled, where appropriate, to yield odds ratios, using random effects models. MAIN RESULTS: Four trials were identified including three published studies and one abstract. Compared to three- or four-drug maintenance therapy, maintenance therapies including fewer drugs were associated with a higher risk of virologic failure (loss of HIV suppression to non-detectable levels). Combining the results of all four studies yielded an odds ratio of 5.55 (95% confidence interval, 3.14 - 9.80). Similar results were obtained when the one abstract was excluded (odds ratio, 5.48; 95% confidence interval, 2.82 - 10.65). Performing subgroup analyses of studies using similar induction and maintenance regimens gave similar results. Maintenance regimens of zidovudine and lamivudine compared to maintenance regimens with zidovudine, lamivudine and indinavir, were associated with significantly higher rates of virologic failure (odds ratio, 4.57; 95% confidence interval, 1.80 - 11.58). Similarly, maintenance regimens that discontinued one or more protease inhibitor after including them in induction therapy were also associated with a significantly higher risk of virologic failure (odds ratio, 6.15; 95% confidence interval, 3.40 -11.10). REVIEWER'S CONCLUSIONS: Although it is desirable to reduce the number of antiretroviral drugs given in combination therapy for reasons of compliance and toxicity, maintenance regimens with fewer drugs are associated with significantly increased resistance and risk of loss of viral suppression. Successful initial therapy, as evidenced by suppression of viral load, should not be modified in the maintenance phase unless clinically necessary.