Charles I Okwundu

Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high risk individuals

BACKGROUNDnMore than 30 years into the global HIV/AIDS epidemic, infection rates remain alarmingly high, with over 2.7 million people becoming infected every year. There is a need for HIV prevention strategies that are more effective. Oral antiretroviral pre-exposure prophylaxis (PrEP) in high-risk individuals may be a reliable tool in preventing the transmission of HIV.nnnOBJECTIVESnTo evaluate the effects of oral antiretroviral chemoprophylaxis in preventing HIV infection in HIV-uninfected high-risk individuals.nnnSEARCH METHODSnWe revised the search strategy from the previous version of the review and conducted an updated search of MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE in April 2012. We also searched the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov for ongoing trials.nnnSELECTION CRITERIAnRandomised controlled trials that evaluated the effects of any antiretroviral agent or combination of antiretroviral agents in preventing HIV infection in high-risk individualsnnnDATA COLLECTION AND ANALYSISnData concerning outcomes, details of the interventions, and other study characteristics were extracted by two independent authors using a standardized data extraction form. Relative risk with a 95% confidence interval (CI) was used as the measure of effect.nnnMAIN RESULTSnWe identified 12 randomised controlled trials that meet the criteria for the review. Six were ongoing trials, four had been completed and two had been terminated early. Six studies with a total of 9849 participants provided data for this review. The trials evaluated the following: daily oral tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) versus placebo; TDF versus placebo and daily TDF-FTC versus intermittent TDF-FTC. One of the trials had three study arms: TDF, TDF-FTC and placebo arm. The studies were carried out amongst different risk groups, including HIV-uninfected men who have sex with men, serodiscordant couples and other high risk men and women.Overall results from the four trials that compared TDF-FTC versus placebo showed a reduction in the risk of acquiring HIV infection (RR 0.51; 95% CI 0.30 to 0.86; 8918 participants). Similarly, the overall results of the studies that compared TDF only versus placebo showed a significant reduction in the risk of acquiring HIV infection (RR 0.38; 95% CI 0.23 to 0.63, 4027 participants). There were no significant differences in the risk of adverse events across all the studies that reported on adverse events. Also, adherence and sexual behaviours were similar in both the intervention and control groups.nnnAUTHORS CONCLUSIONSnFinding from this review suggests that pre-exposure prophylaxis with TDF alone or TDF-FTC reduces the risk of acquiring HIV in high-risk individuals including people in serodiscordant relationships, men who have sex with men and other high risk men and women.

Optimal Timing of Antiretroviral Therapy Initiation for HIV-Infected Adults With Newly Diagnosed Pulmonary Tuberculosis: A Systematic Review and Meta-analysis

The epidemiology and natural history of tuberculosis (TB) has been altered by HIV infection in resource-limited settings (1). HIV is the most potent risk factor for reactivation of latent TB and progression to active TB after primary exposure or reinfection (2). Without antiretroviral therapy (ART), the risk for death during TB treatment in HIV-infected adults ranges from 16% to 37% among those with CD4+ T-cell counts greater than 0.350109 cells/L (1, 310). Initiation of ART concomitantly with anti-TB drugs during treatment of drug-susceptible pulmonary TB remains challenging for many reasons, including patients adherence to multiple antiretroviral and anti-TB drugs (11, 12), drugdrug interactions (for example, between rifampicin-based TB treatment and ART, including nevirapine or ritonavir-boosted protease inhibitors) (1315), overlapping adverse effects of TB drugs and ART (14), and frequency of the TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) (610). The optimal timing of ART initiation in HIV-infected persons with newly diagnosed TB who have begun TB treatment requires further definition. Current World Health Organization (WHO) guidelines recommend that TB treatment be started first and followed by ART as soon as possible within the first 8 weeks of starting TB treatment and within the first 2 weeks for patients with profound immunosuppression (CD4+ T-cell counts <0.050109 cells/L). These guidelines state that there is low-quality evidence for the optimal timing of ART initiation for HIV-infected patients with newly diagnosed TB who have CD4+ T-cell counts greater than 0.350109 cells/L. Since publication of the WHO guidelines and various expert reviews (16, 17), further data have emerged, including a large, randomized trial conducted under programmatic settings within health services in sub-Saharan Africa (18). To provide an up-to-date summary of reliable evidence that could be used to inform the updating of international guidelines, we conducted a systematic review of trials evaluating the effectiveness and safety of early versus delayed or deferred ART initiation in HIV-infected adults with newly diagnosed pulmonary TB and various degrees of immunosuppression. Methods The study background, rationale, and methods were specified in advance and documented in a study protocol registered in the PROSPERO database (CRD42012001884). Data Sources and Searches We searched the PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases from January 1980 to May 2015. We used keywords related to TB and HIV, and there were no language restrictions. Further, we searched abstracts from major HIV/AIDS or infectious diseases conferences (from 2008 onward), including the Conference on Retroviruses and Opportunistic Infections; the International AIDS Conference; the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; the International Conference on Antimicrobial Agents and Chemotherapy; and the Infectious Diseases Society of America Conference. In addition, we manually checked the reference lists of identified studies. Study Selection Three authors independently evaluated the eligibility of studies obtained from our literature search. Disagreements were resolved by discussion, and agreement was reached by consensus. We included only randomized, controlled trials that compared early initiation of ART (commenced 1 to 4 weeks after the start of TB treatment) with delayed initiation (commenced 8 to 12 weeks after the start of TB treatment) or deferred initiation (commenced at the end of 6 months of TB treatment) in HIV-infected adults with newly diagnosed pulmonary TB. The primary outcomes considered included all-cause mortality and TB-IRIS; secondary outcomes were HIV-1 RNA suppression rates (viral load <400 copies/mL), TB cure rates, grade 3 or 4 adverse events (excluding TB-IRIS events), and loss to follow-up. Data Extraction and Quality Assessment Three authors independently extracted and compared the data. For each included study, details on the design, population characteristics, intervention, and outcome measures were extracted and the risk of bias was evaluated. Discrepancies were resolved by reaching consensus through discussion. We used the Cochrane Collaborations tool (19) for assessing the risk of bias of the individual studies and evaluated 6 domains: sequence generation, allocation concealment, blinding of outcome assessors, incomplete outcome data (whether the investigators reported completeness of outcome data, including attrition and exclusions from the analysis, and whether missing data were imputed using appropriate methods), selective outcome reporting (assessed by checking the published protocols and contacting authors), and other sources of bias. Risks of bias due to blinding of outcome assessors and incomplete outcome data were assessed for each study but not for each outcome. We reported each domain as having a low, unclear, or high risk of bias. The main outcome measures were all-cause mortality and TB-IRIS. We contacted authors of included studies for additional unpublished data to use in our planned subgroup analysis and risk-of-bias assessment. Data Synthesis and Analysis We used a fixed-effect meta-analysis for combining data when it was reasonable to assume that studies were estimating the same underlying treatment effect. We assessed heterogeneity among trials by inspecting the forest plots, using the chi-square test for heterogeneity with a 10% level of statistical significance and the I 2 statistic to quantify the degree of heterogeneity (19, 20). When trials could not be combined for meta-analysis because of clinical heterogeneity (for example, a wide range of baseline CD4+ T-cell counts) or statistical heterogeneity (I 2> 50%; that is, >50% of the variation is due to heterogeneity rather than chance [21]), we used narrative syntheses. The results of individual trials were displayed graphically to provide a succinct summary of evidence. Subgroup analyses were prespecified to explore the effects in participants with different baseline CD4+ T-cell counts (<0.050109 cells/L vs. >0.050109 cells/L). We used Stata, version 13 (StataCorp), and Review Manager, version 5.2 (Nordic Cochrane Centre), for the meta-analysis. Role of the Funding Source This study received no funding. Results Study Characteristics Figure 1 shows the process of study identification and selection. The literature search yielded 346 citations. After review of the title and abstract, we selected 9 full-text articles for critical reading. One trial (22) that recruited patients with tuberculous meningitis did not meet the inclusion criteria and was excluded. A total of 8 trials (18, 2329), which included a total of 4568 participants with HIV and TB, met the inclusion criteria. The Appendix Table shows the characteristics of these trials. The trials were conducted in sub-Saharan Africa, Asia, and the United States between 2005 and 2013 and published between 2011 and 2015. The mean age of the participants ranged from 32 to 38 years, and the percentage of men ranged from 48% to 84%. Five trials compared early ART with delayed ART (2529). One trial compared early ART with deferred ART (18). Another trial, SAPiT (Starting ART at Three Points in TB) (23, 24), randomly assigned participants into 3 groups: early, delayed, or deferred ART initiation. Patients in all included trials were treated for TB with 6 months of standard short-course chemotherapy and 2 months of isoniazid, rifampicin, ethambutol, and pyrazinamide followed by 4 months of isoniazid and rifampicin. The ART regimens consisted of efavirenz with 2 nucleoside analogues. Figure 1. Summary of evidence search and selection. Appendix Table. Characteristics of Included Trials Risk of Bias of Included Trials The risk-of-bias assessments of the included trials are shown in Figure 2. Allocation sequence generation was adequate in all trials and allocation concealment was adequate in 6 trials and unclear in the remaining 2. All of the trials except for TB-HAART (An Evaluation of the Impact of Early Initiation of Highly Active Anti-Retroviral Therapy [HAART] on TB Treatment Outcomes for TB Patients Co-infected With HIV) (18) were open-label trials in which participants, investigators, and clinical staff were not blinded to treatment allocation. Three trials masked outcome assessors to treatment allocation, but the remaining trials did not state whether they did the same. In 1 trial (29), the rate of discontinuation was statistically significantly higher in the early ART initiation group than the delayed ART initiation group (12.5% vs. 1.6%; P= 0.007), which made the potential risk of bias from incomplete data high. No evidence of selective outcome reporting was detected. Although the studies seemed to be free of other sources of bias, 1 trial (29) had unequal recruitment to trial groups (88 vs. 62 participants), which raised questions about the fidelity of the randomization process. No evidence of baseline imbalance was, however, detected in this trial (29). Figure 2. Risk-of-bias assessment of included trials. CAMELIA = Cambodian Early Versus Late Introduction of Antiretrovirals; SAPiT = Starting ART at Three Points in TB; STRIDE = Immediate Versus Deferred Start of Anti-HIV Therapy in HIV-Infected Adults Being Treated for Tuberculosis; TB-HAART = An Evaluation of the Impact of Early Initiation of HAART on TB Treatment Outcomes for TB Patients Co-infected With HIV; TIME = Appropriate Timing of HAART in Co-infected HIV/TB Patients. Early Versus Delayed Initiation of ART All-Cause Mortality Overall, patients randomly assigned to early ART (11.2% [161 of 1441 patients]) had a lower all-cause mortality than those receiving delayed ART (13.8% [171 of 1239 patients]) at the end of follow-up (6 trials; relative risk [RR], 0.81 [95% CI, 0.66 to 0.99]; I 2= 0%) (Figure 3). In a prespecified subgroup analysis, early ART r

Brief school-based interventions and behavioural outcomes for substance-using adolescents

BACKGROUNDnAdolescent substance use is a major problem in and of itself, and because it acts as a risk factor for other problem behaviours. As substance use during adolescence can lead to adverse and often long-term health and social consequences, it is important to intervene early in order to prevent progression to more severe problems. Brief interventions have been shown to reduce problematic substance use among adolescents and are especially useful for individuals who have moderately risky patterns of substance use. Such interventions can be conducted in school settings. This review set out to evaluate the effectiveness of brief school-based interventions for adolescent substance use.nnnOBJECTIVESnTo evaluate the effectiveness of brief school-based interventions in reducing substance use and other behavioural outcomes among adolescents compared to another intervention or assessment-only conditions.nnnSEARCH METHODSnWe conducted the original literature search in March 2013 and performed the search update to February 2015. For both review stages (original and update), we searched 10 electronic databases and six websites on evidence-based interventions, and the reference lists of included studies and reviews, from 1966 to February 2015. We also contacted authors and organisations to identify any additional studies.nnnSELECTION CRITERIAnWe included randomised controlled trials that evaluated the effects of brief school-based interventions for substance-using adolescents.The primary outcomes were reduction or cessation of substance use. The secondary outcomes were engagement in criminal activity and engagement in delinquent or problem behaviours related to substance use.nnnDATA COLLECTION AND ANALYSISnWe used the standard methodological procedures outlined by The Cochrane Collaboration, including the GRADE approach for evaluating the quality of evidence.nnnMAIN RESULTSnWe included six trials with 1176 adolescents that measured outcomes at different follow-up periods in this review. Three studies with 732 adolescents compared brief interventions (Bls) with information provision only, and three studies with 444 adolescents compared Bls with assessment only. Reasons for downgrading the quality of evidence included risk of bias of the included studies, imprecision, and inconsistency. For outcomes that concern substance abuse, the retrieved studies only assessed alcohol and cannabis. We generally found moderate-quality evidence that, compared to information provision only, BIs did not have a significant effect on any of the substance use outcomes at short-, medium-, or long-term follow-up. They also did not have a significant effect on delinquent-type behaviour outcomes among adolescents. When compared to assessment-only controls, we found low- or very low-quality evidence that BIs reduced cannabis frequency at short-term follow-up in one study (standardised mean difference (SMD) -0.83; 95% confidence interval (CI) -1.14 to -0.53, n = 269). BIs also significantly reduced frequency of alcohol use (SMD -0.91; 95% CI -1.21 to -0.61, n = 242), alcohol abuse (SMD -0.38; 95% CI -0.7 to -0.07, n = 190) and dependence (SMD -0.58; 95% CI -0.9 to -0.26, n = 190), and cannabis abuse (SMD -0.34; 95% CI -0.65 to -0.02, n = 190) at medium-term follow-up in one study. At long-term follow-up, BIs also reduced alcohol abuse (SMD -0.72; 95% CI -1.05 to -0.40, n = 181), cannabis frequency (SMD -0.56; 95% CI -0.75 to -0.36, n = 181), abuse (SMD -0.62; 95% CI -0.95 to -0.29, n = 181), and dependence (SMD -0.96; 95% CI -1.30 to -0.63, n = 181) in one study. However, the evidence from studies that compared brief interventions to assessment-only conditions was generally of low quality. Brief interventions also had mixed effects on adolescents delinquent or problem behaviours, although the effect at long-term follow-up on these outcomes in the assessment-only comparison was significant (SMD -0.78; 95% CI -1.11 to -0.45).nnnAUTHORS CONCLUSIONSnWe found low- or very low-quality evidence that brief school-based interventions may be more effective in reducing alcohol and cannabis use than the assessment-only condition and that these reductions were sustained at long-term follow-up. We found moderate-quality evidence that, when compared to information provision, brief interventions probably did not have a significant effect on substance use outcomes. It is premature to make definitive statements about the effectiveness of brief school-based interventions for reducing adolescent substance use. Further high-quality studies examining the relative effectiveness of BIs for substance use and other problem behaviours need to be conducted, particularly in low- and middle-income countries.

Optimal timing of antiretroviral therapy initiation for HIV-infected adults with newly diagnosed pulmonary tuberculosis

The epidemiology and natural history of tuberculosis (TB) has been altered by HIV infection in resource-limited settings (1). HIV is the most potent risk factor for reactivation of latent TB and progression to active TB after primary exposure or reinfection (2). Without antiretroviral therapy (ART), the risk for death during TB treatment in HIV-infected adults ranges from 16% to 37% among those with CD4+ T-cell counts greater than 0.350109 cells/L (1, 310). Initiation of ART concomitantly with anti-TB drugs during treatment of drug-susceptible pulmonary TB remains challenging for many reasons, including patients adherence to multiple antiretroviral and anti-TB drugs (11, 12), drugdrug interactions (for example, between rifampicin-based TB treatment and ART, including nevirapine or ritonavir-boosted protease inhibitors) (1315), overlapping adverse effects of TB drugs and ART (14), and frequency of the TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) (610). The optimal timing of ART initiation in HIV-infected persons with newly diagnosed TB who have begun TB treatment requires further definition. Current World Health Organization (WHO) guidelines recommend that TB treatment be started first and followed by ART as soon as possible within the first 8 weeks of starting TB treatment and within the first 2 weeks for patients with profound immunosuppression (CD4+ T-cell counts <0.050109 cells/L). These guidelines state that there is low-quality evidence for the optimal timing of ART initiation for HIV-infected patients with newly diagnosed TB who have CD4+ T-cell counts greater than 0.350109 cells/L. Since publication of the WHO guidelines and various expert reviews (16, 17), further data have emerged, including a large, randomized trial conducted under programmatic settings within health services in sub-Saharan Africa (18). To provide an up-to-date summary of reliable evidence that could be used to inform the updating of international guidelines, we conducted a systematic review of trials evaluating the effectiveness and safety of early versus delayed or deferred ART initiation in HIV-infected adults with newly diagnosed pulmonary TB and various degrees of immunosuppression. Methods The study background, rationale, and methods were specified in advance and documented in a study protocol registered in the PROSPERO database (CRD42012001884). Data Sources and Searches We searched the PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases from January 1980 to May 2015. We used keywords related to TB and HIV, and there were no language restrictions. Further, we searched abstracts from major HIV/AIDS or infectious diseases conferences (from 2008 onward), including the Conference on Retroviruses and Opportunistic Infections; the International AIDS Conference; the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; the International Conference on Antimicrobial Agents and Chemotherapy; and the Infectious Diseases Society of America Conference. In addition, we manually checked the reference lists of identified studies. Study Selection Three authors independently evaluated the eligibility of studies obtained from our literature search. Disagreements were resolved by discussion, and agreement was reached by consensus. We included only randomized, controlled trials that compared early initiation of ART (commenced 1 to 4 weeks after the start of TB treatment) with delayed initiation (commenced 8 to 12 weeks after the start of TB treatment) or deferred initiation (commenced at the end of 6 months of TB treatment) in HIV-infected adults with newly diagnosed pulmonary TB. The primary outcomes considered included all-cause mortality and TB-IRIS; secondary outcomes were HIV-1 RNA suppression rates (viral load <400 copies/mL), TB cure rates, grade 3 or 4 adverse events (excluding TB-IRIS events), and loss to follow-up. Data Extraction and Quality Assessment Three authors independently extracted and compared the data. For each included study, details on the design, population characteristics, intervention, and outcome measures were extracted and the risk of bias was evaluated. Discrepancies were resolved by reaching consensus through discussion. We used the Cochrane Collaborations tool (19) for assessing the risk of bias of the individual studies and evaluated 6 domains: sequence generation, allocation concealment, blinding of outcome assessors, incomplete outcome data (whether the investigators reported completeness of outcome data, including attrition and exclusions from the analysis, and whether missing data were imputed using appropriate methods), selective outcome reporting (assessed by checking the published protocols and contacting authors), and other sources of bias. Risks of bias due to blinding of outcome assessors and incomplete outcome data were assessed for each study but not for each outcome. We reported each domain as having a low, unclear, or high risk of bias. The main outcome measures were all-cause mortality and TB-IRIS. We contacted authors of included studies for additional unpublished data to use in our planned subgroup analysis and risk-of-bias assessment. Data Synthesis and Analysis We used a fixed-effect meta-analysis for combining data when it was reasonable to assume that studies were estimating the same underlying treatment effect. We assessed heterogeneity among trials by inspecting the forest plots, using the chi-square test for heterogeneity with a 10% level of statistical significance and the I 2 statistic to quantify the degree of heterogeneity (19, 20). When trials could not be combined for meta-analysis because of clinical heterogeneity (for example, a wide range of baseline CD4+ T-cell counts) or statistical heterogeneity (I 2> 50%; that is, >50% of the variation is due to heterogeneity rather than chance [21]), we used narrative syntheses. The results of individual trials were displayed graphically to provide a succinct summary of evidence. Subgroup analyses were prespecified to explore the effects in participants with different baseline CD4+ T-cell counts (<0.050109 cells/L vs. >0.050109 cells/L). We used Stata, version 13 (StataCorp), and Review Manager, version 5.2 (Nordic Cochrane Centre), for the meta-analysis. Role of the Funding Source This study received no funding. Results Study Characteristics Figure 1 shows the process of study identification and selection. The literature search yielded 346 citations. After review of the title and abstract, we selected 9 full-text articles for critical reading. One trial (22) that recruited patients with tuberculous meningitis did not meet the inclusion criteria and was excluded. A total of 8 trials (18, 2329), which included a total of 4568 participants with HIV and TB, met the inclusion criteria. The Appendix Table shows the characteristics of these trials. The trials were conducted in sub-Saharan Africa, Asia, and the United States between 2005 and 2013 and published between 2011 and 2015. The mean age of the participants ranged from 32 to 38 years, and the percentage of men ranged from 48% to 84%. Five trials compared early ART with delayed ART (2529). One trial compared early ART with deferred ART (18). Another trial, SAPiT (Starting ART at Three Points in TB) (23, 24), randomly assigned participants into 3 groups: early, delayed, or deferred ART initiation. Patients in all included trials were treated for TB with 6 months of standard short-course chemotherapy and 2 months of isoniazid, rifampicin, ethambutol, and pyrazinamide followed by 4 months of isoniazid and rifampicin. The ART regimens consisted of efavirenz with 2 nucleoside analogues. Figure 1. Summary of evidence search and selection. Appendix Table. Characteristics of Included Trials Risk of Bias of Included Trials The risk-of-bias assessments of the included trials are shown in Figure 2. Allocation sequence generation was adequate in all trials and allocation concealment was adequate in 6 trials and unclear in the remaining 2. All of the trials except for TB-HAART (An Evaluation of the Impact of Early Initiation of Highly Active Anti-Retroviral Therapy [HAART] on TB Treatment Outcomes for TB Patients Co-infected With HIV) (18) were open-label trials in which participants, investigators, and clinical staff were not blinded to treatment allocation. Three trials masked outcome assessors to treatment allocation, but the remaining trials did not state whether they did the same. In 1 trial (29), the rate of discontinuation was statistically significantly higher in the early ART initiation group than the delayed ART initiation group (12.5% vs. 1.6%; P= 0.007), which made the potential risk of bias from incomplete data high. No evidence of selective outcome reporting was detected. Although the studies seemed to be free of other sources of bias, 1 trial (29) had unequal recruitment to trial groups (88 vs. 62 participants), which raised questions about the fidelity of the randomization process. No evidence of baseline imbalance was, however, detected in this trial (29). Figure 2. Risk-of-bias assessment of included trials. CAMELIA = Cambodian Early Versus Late Introduction of Antiretrovirals; SAPiT = Starting ART at Three Points in TB; STRIDE = Immediate Versus Deferred Start of Anti-HIV Therapy in HIV-Infected Adults Being Treated for Tuberculosis; TB-HAART = An Evaluation of the Impact of Early Initiation of HAART on TB Treatment Outcomes for TB Patients Co-infected With HIV; TIME = Appropriate Timing of HAART in Co-infected HIV/TB Patients. Early Versus Delayed Initiation of ART All-Cause Mortality Overall, patients randomly assigned to early ART (11.2% [161 of 1441 patients]) had a lower all-cause mortality than those receiving delayed ART (13.8% [171 of 1239 patients]) at the end of follow-up (6 trials; relative risk [RR], 0.81 [95% CI, 0.66 to 0.99]; I 2= 0%) (Figure 3). In a prespecified subgroup analysis, early ART r

Treatment of severe or progressive Kaposi's sarcoma in HIV‐infected adults

BACKGROUNDnKaposis sarcoma remains the most common cancer in Sub-Saharan Africa and the second most common cancer in HIV-infected patients worldwide. Since the introduction of highly active antiretroviral therapy (HAART), there has been a decline in its incidence.However, Kaposis sarcoma continues to be diagnosed in HIV-infected patients.nnnOBJECTIVESnTo assess the added advantage of chemotherapy plus HAART compared to HAART alone; and the advantages of different chemotherapy regimens in HAART and HAART naive HIV infected adults with severe or progressive Kaposis sarcoma.nnnSEARCH METHODSnWe searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and , GATEWAY, the WHO Clinical Trials Registry Platform and the US National Institutes of Healths ClinicalTrials.gov for ongoing trials and the Aegis archive of HIV/AIDS for conference abstracts. An updated search was conducted in July 2014.nnnSELECTION CRITERIAnRandomised trials and observational studies evaluating the effects of any chemotherapeutic regimen in combination with HAART compared to HAART alone, chemotherapy versus HAART, and comparisons between different chemotherapy regimens.nnnDATA COLLECTION AND ANALYSISnTwo review authors assessed the studies independently and extracted outcome data.We used the risk ratio (RR) with a 95% confidence interval (CI) as the measure of effect.We did not conduct meta-analysis as none of the included trials assessed identical chemotherapy regimens.nnnMAIN RESULTSnWe included six randomised trials and three observational studies involving 792 HIV-infected adults with severe Kaposis sarcoma.Seven studies included patients with a mix of mild to moderate (T0) and severe (T1) Kaposis sarcoma. However, this review was restricted to the subset of participants with severe Kaposis sarcoma disease.Studies comparing HAART plus chemotherapy to HAART alone showed the following: one trial comparing HAART plus doxorubicin,bleomycin and vincristine (ABV) to HAART alone showed a significant reduction in disease progression in the HAART plus ABV group (RR 0.10; 95% CI 0.01 to 0.75, 100 participants); there was no statistically significant reduction in mortality and no difference in adverse events. A cohort study comparing liposomal anthracyclines plus HAART to HAART alone showed a non-statistically significant reduction in Kaposis sarcoma immune reconstitution inflammatory syndrome in patients that received HAART plus liposomal anthracyclines (RR 0.49; 95% CI 0.16 to 1.55, 129 participants).Studies comparing HAART plus chemotherapy to HAART plus a different chemotherapy regimen showed the following: one trial involving 49 participants and comparing paclitaxel versus pegylated liposomal doxorubicin in patients on HAART showed no difference in disease progression. Another trial involving 46 patients and comparing pegylated liposomal doxorubicin versus liposomal daunorubicin showed no participants with progressive Kaposis sarcoma disease in either group.Studies comparing different chemotherapy regimens in patients from the pre-HAART era showed the following: in the single RCT comparing liposomal daunorubicin to ABV, there was no significant difference with the use of liposomal daunorubicin compared to ABV in disease progression (RR 0.78; 95% CI 0.34 to 1.82, 227 participants) and overall response rate. Another trial involving 178 participants and comparing oral etoposide versus ABV demonstrated no difference in mortality in either group. A non-randomised trial comparing bleomycin alone to ABV demonstrated a higher median survival time in the ABV group; there was also a non-statistically significant reduction in adverse events and disease progression in the ABV group (RR 11; 95% CI 0.67 to 179.29, 24 participants).An additional non-randomised study showed a non-statistically significant overall mortality benefit from liposomal doxorubicin as compared to conservative management consisting of either bleomycin plus vinblastine, vincristine or single-agent antiretroviral therapy alone (RR 0.93; 95% CI 0.75 to 1.15, 29 participants). The overall quality of evidence can be described as moderate quality. The quality of evidence was downgraded due to the small size of many of the included studies and small number of events.nnnAUTHORS CONCLUSIONSnThe findings from this review suggest that HAART plus chemotherapy may be beneficial in reducing disease progression compared to HAART alone in patients with severe or progressive Kaposis sarcoma. For patients on HAART, when choosing from different chemotherapy regimens, there was no observed difference between liposomal doxorubicin, liposomal daunorubicin and paclitaxel.

Citation classics in systematic reviews and meta-analyses : who wrote the top 100 most cited articles?

Background Systematic reviews of the literature occupy the highest position in currently proposed hierarchies of evidence. The aims of this study were to assess whether citation classics exist in published systematic review and meta-analysis (SRM), examine the characteristics of the most frequently cited SRM articles, and evaluate the contribution of different world regions. Methods The 100 most cited SRM were identified in October 2012 using the Science Citation Index database of the Institute for Scientific Information. Data were extracted by one author. Spearman’s correlation was used to assess the association between years since publication, numbers of authors, article length, journal impact factor, and average citations per year. Results Among the 100 citation classics, published between 1977 and 2008, the most cited article received 7308 citations and the least-cited 675 citations. The average citations per year ranged from 27.8 to 401.6. First authors from the USA produced the highest number of citation classics (n=46), followed by the UK (n=28) and Canada (n=15). The 100 articles were published in 42 journals led by the Journal of the American Medical Association (n=18), followed by the British Medical Journal (n=14) and The Lancet (n=13). There was a statistically significant positive correlation between number of authors (Spearman’s rho=0.320, p=0.001), journal impact factor (rho=0.240, p=0.016) and average citations per year. There was a statistically significant negative correlation between average citations per year and year since publication (rho = -0.636, p=0.0001). The most cited papers identified seminal contributions and originators of landmark methodological aspects of SRM and reflect major advances in the management of and predisposing factors for chronic diseases. Conclusions Since the late 1970s, the USA, UK, and Canada have taken leadership in the production of citation classic papers. No first author from low or middle-income countries (LMIC) led one of the most cited 100 SRM.

Home‐ or community‐based programmes for treating malaria

BACKGROUNDnMalaria is an important cause of morbidity and mortality, in particular among children and pregnant women in sub-Saharan Africa. Prompt access to diagnosis and treatment with effective antimalarial drugs is a central component of the World Health Organizations (WHO) strategy for malaria control. Home- or community-based programmes for managing malaria are one strategy that has been proposed to overcome the geographical barrier to malaria treatment.xa0nnnOBJECTIVESnTo evaluate home- and community-based management strategies for treating malaria.nnnSEARCH METHODSnWe searched the Cochrane Central Register of Controlled Trials published in The Cochrane Library; MEDLINE; EMBASE; Science Citation Index; PsycINFO/LIT; CINAHL; WHO clinical trial registry platform; and the metaRegister of Controlled Trials up to September 2012.nnnSELECTION CRITERIAnRandomized controlled trials (RCTs) and non-RCTs that evaluated the effects of a home- or community-based programme for treating malaria in a malaria endemic setting.nnnDATA COLLECTION AND ANALYSISnTwo authors independently screened and selected studies, extracted data, and assessed the risk of bias. Where possible the effects of interventions are compared using risk ratios (RR), and presented with 95% confidence intervals (CI). The quality of the evidence was assessed using the GRADE approach.nnnMAIN RESULTSnWe identified 10 trials that met the inclusion criteria. The interventions involved brief training of basic-level health workers or mothers, and most provided the antimalarial for free or at a highly subsidized cost. In eight of the studies, fevers were treated presumptively without parasitological confirmation with microscopy or a rapid diagnostic test (RDT). Two studies trained community health workers to use RDTs as a component of community management of fever.Home- or community-based strategies probably increase the number of people with fever who receive an appropriate antimalarial within 24 hours (RR 2.27, 95% CI 1.79 to 2.88 in one trial; RR 9.79, 95% CI 6.87 to 13.95 in a second trial; 3099 participants, moderate quality evidence). They may also reduce all-cause mortality, but to date this has only been demonstrated in rural Ethiopia (RR 0.58, 95% CI 0.44 to 0.77, one trial, 13,677 participants, moderate quality evidence).Hospital admissions in children were reported in one small trial from urban Uganda, with no effect detected (437 participants, very low quality evidence). No studies reported on severe malaria. For parasitaemia prevalence, the study from urban Uganda demonstrated a reduction in community parasite prevalence (RR 0.22, 95% CI 0.08 to 0.64, 365 participants), but a second study in rural Burkina Faso did not (1006 participants). Home- or community-based programmes may have little or no effect on the prevalence of anaemia (three trials, 3612 participants, low quality evidence). None of the included studies reported on adverse effects of using home- or community-based programmes for treating malaria.In two studies which trained community health workers to only prescribe antimalarials after a positive RDT, prescriptions of antimalarials were reduced compared to the control group where community health workers used clinical diagnosis (RR 0.39, 95% CI 0.18 to 0.84, two trials, 5944 participants, moderate quality evidence). In these two studies, mortality and hospitalizations remained very low in both groups despite the lower use of antimalarials (two trials, 5977 participants, low quality evidence).nnnAUTHORS CONCLUSIONSnHome- or community-based interventions which provide antimalarial drugs free of charge probably improve prompt access to antimalarials, and there is moderate quality evidence from rural Ethiopia that they may impact on childhood mortality when implemented in appropriate settings.Programmes which treat all fevers presumptively with antimalarials lead to overuse antimalarials, and potentially undertreat other causes of fever such as pneumonia. Incorporating RDT diagnosis into home- or community-based programmes for malaria may help to reduce this overuse of antimalarials, and has been shown to be safe under trial conditions.

Prophylactic phototherapy for preventing jaundice in preterm or low birth weight infants

BACKGROUNDnLow birth weight and premature infants are at major risk for exaggerated hyperbilirubinaemia and jaundice that can lead to bilirubin encephalopathy. Phototherapy is the most common treatment for neonatal hyperbilirubinaemia and could be most effective in preventing the sequelae of hyperbilirubinaemia if initiated prophylactically.nnnOBJECTIVESnTo evaluate the efficacy and safety of prophylactic phototherapy for preterm (< 37 weeks gestational age) or low birth weight infants (birth weight < 2500 g).nnnSEARCH METHODSnWe searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3) on 31 March 2011,xa0MEDLINE (1950 to 31 March 2011), EMBASE (1980 to 31 March 2011) and CINAHL (1982 to 31 March 2011).nnnSELECTION CRITERIAnRandomised controlled trials or quasi-randomised controlled studiesxa0evaluating the effects of prophylactic phototherapy for preterm or low birth weight infants.nnnDATA COLLECTION AND ANALYSISnTwo authors independently obtained data from published articles. We performed fixed-effect meta-analysis for the outcomes: rate of exchange transfusion, cerebral palsy or other neurodevelopmental impairment, peak serum bilirubin level and all-cause mortality.nnnMAIN RESULTSnNine studies of 3449 participants were included. The rate of exchange transfusion was reduced in one study with liberal transfusion criteria (risk ratio (RR) 0.20; 95% confidence interval (CI) 0.13 to 0.31) but not in the other two more recent studies with stringent criteria (typical RR 0.66; 95% CI 0.19 to 2.28). There was no statistically significant difference in the rate of cerebral palsy (typical RR 0.96; 95% CI 0.50 to 1.85; two studies, 756 participants). However, one large study that reported on neurodevelopmental impairment (a composite outcome including cerebral palsy) found a slightly lower rate of neurodevelopmental impairment with prophylactic phototherapy (RR 0.85; 95% CI 0.74 to 0.99; 1804 participants). The prophylactic phototherapy group had lower peak bilirubin levels (mean difference (MD) -2.73; 95% CI -2.89 to -2.57; six studies, 2319 participants) and had fewer neonates with peak unconjugated serum bilirubin levels > 10 mg/dl (typical RR 0.27; 95% CI 0.22 to 0.33; three studies, 1090 participants) or peak unconjugated serum bilirubin levels > 15 mg/dl (typical RR 0.13; 95% CI 0.07 to 0.23; four studies, 1116 participants). There was no statistically significant difference in the rate of all-cause mortality between the two groups (typical RR 1.08; 95% CI 0.93 to 1.26; four studies, 3044 participants).nnnAUTHORS CONCLUSIONSnProphylactic phototherapy helps to maintain a lower serum bilirubin concentration and may have an effect on the rate of exchange transfusion and the risk of neurodevelopmental impairment. However, further well-designed studies are needed to determine the efficacy and safety of prophylactic phototherapy on long-term outcomes including neurodevelopmental outcomes.

Governance arrangements for health systems in low‐income countries: an overview of systematic reviews

Abstract Background One target of the Sustainable Development Goals is to achieve universal health coverage, including financial risk protection, access to quality essential health‐care services and access to safe, effective, quality and affordable essential medicines and vaccines for all. A fundamental concern of governments in striving for this goal is how to finance such a health system. This concern is very relevant for low‐income countries. Objectives To provide an overview of the evidence from up‐to‐date systematic reviews about the effects of financial arrangements for health systems in low‐income countries. Secondary objectives include identifying needs and priorities for future evaluations and systematic reviews on financial arrangements, and informing refinements in the framework for financial arrangements presented in the overview. Methods We searched Health Systems Evidence in November 2010 and PDQ‐Evidence up to 17 December 2016 for systematic reviews. We did not apply any date, language, or publication status limitations in the searches. We included well‐conducted systematic reviews of studies that assessed the effects of financial arrangements on patient outcomes (health and health behaviours), the quality or utilisation of healthcare services, resource use, healthcare provider outcomes (such as sick leave), or social outcomes (such as poverty, employment, or financial burden of patients, e.g. out‐of‐pocket payment, catastrophic disease expenditure) and that were published after April 2005. We excluded reviews with limitations important enough to compromise the reliability of the findings. Two overview authors independently screened reviews, extracted data, and assessed the certainty of evidence using GRADE. We prepared SUPPORT Summaries for eligible reviews, including key messages, Summary of findings tables (using GRADE to assess the certainty of the evidence), and assessments of the relevance of findings to low‐income countries. Main results We identified 7272 reviews and included 15 in this overview, on: collection of funds (2 reviews), insurance schemes (1 review), purchasing of services (1 review), recipient incentives (6 reviews), and provider incentives (5 reviews). The reviews were published between 2008 and 2015; focused on 13 subcategories; and reported results from 276 studies: 115 (42%) randomised trials, 11 (4%) non‐randomised trials, 23 (8%) controlled before‐after studies, 51 (19%) interrupted time series, 9 (3%) repeated measures, and 67 (24%) other non‐randomised studies. Forty‐three per cent (119/276) of the studies included in the reviews took place in low‐ and middle‐income countries. Collection of funds: the effects of changes in user fees on utilisation and equity are uncertain (very low‐certainty evidence). It is also uncertain whether aid delivered under the Paris Principles (ownership, alignment, harmonisation, managing for results, and mutual accountability) improves health outcomes compared to aid delivered without conforming to those principles (very low‐certainty evidence). Insurance schemes: community‐based health insurance may increase service utilisation (low‐certainty evidence), but the effects on health outcomes are uncertain (very low‐certainty evidence). It is uncertain whether social health insurance improves utilisation of health services or health outcomes (very low‐certainty evidence). Purchasing of services: it is uncertain whether increasing salaries of public sector healthcare workers improves the quantity or quality of their work (very low‐certainty evidence). Recipient incentives: recipient incentives may improve adherence to long‐term treatments (low‐certainty evidence), but it is uncertain whether they improve patient outcomes. One‐time recipient incentives probably improve patient return for start or continuation of treatment (moderate‐certainty evidence) and may improve return for tuberculosis test readings (low‐certainty evidence). However, incentives may not improve completion of tuberculosis prophylaxis, and it is uncertain whether they improve completion of treatment for active tuberculosis. Conditional cash transfer programmes probably lead to an increase in service utilisation (moderate‐certainty evidence), but their effects on health outcomes are uncertain. Vouchers may improve health service utilisation (low‐certainty evidence), but the effects on health outcomes are uncertain (very low‐certainty evidence). Introducing a restrictive cap may decrease use of medicines for symptomatic conditions and overall use of medicines, may decrease insurers expenditures on medicines (low‐certainty evidence), and has uncertain effects on emergency department use, hospitalisations, and use of outpatient care (very low‐certainty evidence). Reference pricing, maximum pricing, and index pricing for drugs have mixed effects on drug expenditures by patients and insurers as well as the use of brand and generic drugs. Provider incentives: the effects of provider incentives are uncertain (very low‐certainty evidence), including: the effects of provider incentives on the quality of care provided by primary care physicians or outpatient referrals from primary to secondary care, incentives for recruiting and retaining health professionals to serve in remote areas, and the effects of pay‐for‐performance on provider performance, the utilisation of services, patient outcomes, or resource use in low‐income countries. Authors conclusions Research based on sound systematic review methods has evaluated numerous financial arrangements relevant to low‐income countries, targeting different levels of the health systems and assessing diverse outcomes. However, included reviews rarely reported social outcomes, resource use, equity impacts, or undesirable effects. We also identified gaps in primary research because of uncertainty about applicability of the evidence to low‐income countries. Financial arrangements for which the effects are uncertain include external funding (aid), caps and co‐payments, pay‐for‐performance, and provider incentives. Further studies evaluating the effects of these arrangements are needed in low‐income countries. Systematic reviews should include all outcomes that are relevant to decision‐makers and to people affected by changes in financial arrangements.

Factors that affect the uptake of community-based health insurance in low-income and middle-income countries: a systematic protocol

Introduction Many people residing in low-income and middle-income countries (LMICs) are regularly exposed to catastrophic healthcare expenditure. It is therefore pertinent that LMICs should finance their health systems in ways that ensure that their citizens can use needed healthcare services and are protected from potential impoverishment arising from having to pay for services. Ways of financing health systems include government funding, health insurance schemes and out-of-pocket payment. A health insurance scheme refers to pooling of prepaid funds in a way that allows for risks to be shared. The health insurance scheme particularly suitable for the rural poor and the informal sector in LMICs is community-based health insurance (CBHI), that is, insurance schemes operated by organisations other than governments or private for-profit companies. We plan to search for and summarise currently available evidence on factors associated with the uptake of CBHI, as we are not aware of previous systematic reviews that have looked at this important topic. Methods This is a protocol for a systematic review of the literature. We will include both quantitative and qualitative studies in this review. Eligible quantitative studies include intervention and observational studies. Qualitative studies to be included are focus group discussions, direct observations, interviews, case studies and ethnography. We will search EMBASE, PubMed, Scopus, ERIC, PsycInfo, Africa-Wide Information, Academic Search Premier, Business Source Premier, WHOLIS, CINAHL and the Cochrane Library for eligible studies available by 31 October 2013, regardless of publication status or language of publication. We will also check reference lists of included studies and proceedings of relevant conferences and contact researchers for eligible studies. Two authors will independently screen the search output, select studies and extract data, resolving discrepancies by consensus and discussion. Qualitative data will be extracted using standardised data extraction tools adapted from the Critical Appraisal Skills Program (CASP) qualitative appraisal checklist and put together in a thematic analysis where applicable. We will statistically pool data from quantitative studies in a meta-analysis; but if included quantitative studies differ significantly in study settings, design and/or outcome measures, we will present the findings in a narrative synthesis. This protocol has been registered with PROSPERO (ID=CRD42013006364). Dissemination Recommendations will be made to health policy makers, managers and researchers in LMICs to help inform them on ways to strengthen and increase the uptake of CBHI.