Nandi Siegfried

Therapeutic drug monitoring of antiretrovirals for people with HIV

BACKGROUNDnDespite the efficacy of combination antiretroviral therapy (ART) and the improvement in prognosis of those living with HIV/AIDS, a large proportion of individuals on ART does not achieve or maintain adequate virological suppression. Several tools have been proposed to enhance ART outcomes, including therapeutic drug monitoring (TDM) of antiretrovirals (ARVs). The aim of ARV TDM is to identify elevated (potentially toxic) or low (potentially sub-therapeutic) ARV concentrations. ARV TDM may thus optimise efficacy and minimise toxicity of ART.nnnOBJECTIVESnTo evaluate whether ARV TDM reduces mortality and morbidity of adult patients on ART. The primary outcome measures that have been assessed include death (all cause); occurrence of HIV-related events (death or AIDS-defining illness) and the proportion of patients achieving and maintaining an undetectable viral load, as defined by the authors.nnnSEARCH STRATEGYnWe conducted a comprehensive search including both published and unpublished studies in all languages in MEDLINE, EMBASE and The Cochrane Library, between January 1980 and January 2008. Databases listing conference abstracts and reference lists of articles were searched. Additional data were sought from relevant authors; however, no additional data were provided.nnnSELECTION CRITERIAnOnly randomized controlled trials conducted subsequent to the introduction of combination ART were included in this systematic review. Participants could be on either a protease inhibitor (PI)-based regimen or non-nucleoside reverse transcriptase (NNRTI)-based regimen and be either ARV-naive or -experienced.nnnDATA COLLECTION AND ANALYSISnTwo reviewers independently assessed and extracted data for analysis. Meta-analysis was conducted where appropriate. Where study outcomes could not be combined, a narrative review was performed. Outcome measures for dichotomous data were reported as a relative risk with 95% confidence intervals. Stratified analyses were conducted by ARV regimen and treatment groups. Heterogeneity between studies was anticipated; therefore, random effects models were chosen to generate pooled effects. Differences in the findings were assessed by the chi square test for heterogeneity (p <0.1) that was quantified by the Higgins I(2) statistic.nnnMAIN RESULTSnIdentified were 1408 records, and eight trials with a total of 1181 participants were included in the review. Trials were conducted in higher income earning countries between 2002 and 2007. Sample sizes ranged between 40 and 230. The methodological quality of the studies was judged to be generally good, although allocation concealment was reported in only three of the eight studies. A meta-analysis including three studies did not show any significant effect on virological suppression below 500 HIV-RNA copies/mL at one year (RR 1.28; [0.86, 1.92] chi(2) = 11.55 (P = 0.003), I(2) = 83%). Two trials including participants predominantly treated with unboosted PI-based regimens reported a 49% increased likelihood of achieving a HIV-RNA viral load below 500 copies/mL at 52 weeks (RR 1.49 [1.20, 1.83] chi(2) = 0.69 (P = 0.4), I(2) = 0%). Safety outcomes were reported in four studies and were similar between TDM and standard of care. Uptake of expert advice based on TDM results was good in two trials (>70%), but low (<35%) in the remaining three studies that reported uptake of the recommendations.nnnAUTHORS CONCLUSIONSnOur review does not support routine use of ARV TDM in ARV-naive or -experienced patients on either boosted PI or NNRTI ART regimens. TDM in treatment-naive participants on a PI-based ART regimen, particularly if unboosted by ritonavir, may improve virological outcomes. Trials were underpowered with small sample sizes, short durations of follow-up and generally poor uptake of TDM recommendations. As these trials were conducted in higher income earning countries, results may not be generalisable to resource-limited countries where the burden of HIV is heaviest.

Clinical practice guidelines within the Southern African Development Community: a descriptive study of the quality of guideline development and concordance with best evidence for five priority diseases.

BackgroundReducing the burden of disease relies on availability of evidence-based clinical practice guidelines (CPGs). There is limited data on availability, quality and content of guidelines within the Southern African Development Community (SADC). This evaluation aims to address this gap in knowledge and provide recommendations for regional guideline development.MethodsWe prioritised five diseases: HIV in adults, malaria in children and adults, pre-eclampsia, diarrhoea in children and hypertension in primary care. A comprehensive electronic search to locate guidelines was conducted between June and October 2010 and augmented with email contact with SADC Ministries of Health. Independent reviewers used the AGREE II tool to score six quality domains reporting the guideline development process. Alignment of the evidence-base of the guidelines was evaluated by comparing their content with key recommendations from accepted reference guidelines, identified with a content expert, and percentage scores were calculated.FindingsWe identified 30 guidelines from 13 countries, publication dates ranging from 2003-2010. Overall the scope and purpose and clarity and presentation domains of the AGREE II instrument scored highest, median 58%(range 19-92) and 83%(range 17-100) respectively. Stakeholder involvement followed with median 39%(range 6-75). Applicability, rigour of development and editorial independence scored poorly, all below 25%. Alignment with evidence was variable across member states, the lowest scores occurring in older guidelines or where the guideline being evaluated was part of broader primary healthcare CPG rather than a disease-specific guideline.ConclusionThis review identified quality gaps and variable alignment with best evidence in available guidelines within SADC for five priority diseases. Future guideline development processes within SADC should better adhere to global reporting norms requiring broader consultation of stakeholders and transparency of process. A regional guideline support committee could harness local capacity to support context appropriate guideline development.

Global health trials methodological research agenda: results from a priority setting exercise.

BackgroundMethodological research into the design, conduct, analysis and reporting of trials is essential to optimise the process. UK specialists in the field have established a set of top priorities in aid of this research. These priorities, however, may not be reflected in the needs of similar research in low- to middle-income countries (LMICs) with different healthcare provision, resources and research infrastructure. The aim of the study was to identify the top priorities for methodological research in LMICs to inform further research and ultimately to improve clinical trials in these regions.MethodsAn online, two-round survey was conducted from December 2016 to April 2017 amongst researchers and methodologists working on trials in LMICs. The first round required participants to suggest between three and six topics which they felt were priorities for trial methodological research in LMICs. The second round invited participants to grade the importance of a compulsory list of topics suggested by four or more individuals, and an optional list of the remaining topics.FindingsRounds 1 and 2 were completed by 412 and 314 participants, respectively. A wide spread of years of experience, discipline, current country of residence, origin of trials training and area of involvement in trials was reported. The topics deemed most important for methodological research were: choosing appropriate outcomes to measure and training of research staff.ConclusionBy presenting these top priorities we have the foundations of a global health trials methodological research agenda which we hope will foster future research in specific areas in order to increase and improve trials in LMICs.

Priority areas for cannabis and cannabinoid product research in South Africa

No abstract available.