Impact of HIV-1 viral subtype on disease progression and response to antiretroviral therapy

Background. Our intention was to compare the rate of immunological progression prior to antiretroviral therapy (ART) and the virological response to ART in patients infected with subtype B and four non-B HIV-1 subtypes (A, C, D and the circulating recombinant form, CRF02-AG) in an ethnically diverse population of HIV-1-infected patients in south London. Methods. A random sample of 861 HIV-1-infected patients attending HIV clinics at King's and St Thomas' hospitals' were subtyped using an in-house enzyme-linked immunoassay and env sequencing. Subtypes were compared on the rate of CD4 cell decline using a multi-level random effects model. Virological response to ART was compared using the time to virological suppression (< 400 copies/ml) and rate of virological rebound (> 400 copies/ml) following initial suppression. Results. Complete subtype and epidemiological data were available for 679 patients, of whom 357 (52.6%) were white and 230 (33.9%) were black African. Subtype B (n = 394) accounted for the majority of infections, followed by subtypes C (n = 125), A (n = 84), D (n = 51) and CRF02-AG (n = 25). There were no significant differences in rate of CD4 cell decline, initial response to highly active antiretroviral therapy and subsequent rate of virological rebound for subtypes B, A, C and CRF02-AG. However, a statistically significant four-fold faster rate of CD4 decline (after adjustment for gender, ethnicity and baseline CD4 count) was observed for subtype D. In addition, subtype D infections showed a higher rate of virological rebound at six months (70%) compared with subtypes B (45%, p = 0.02), A (35%, p = 0.004) and C (34%, p = 0.01). Conclusions. This is the first study from an industrialized country to show a faster CD4 cell decline and higher rate of subsequent virological failure with subtype D infection. Further studies are needed to identify the molecular mechanisms responsible for the greater virulence of subtype D. © 2010 Easterbrook et al; licensee BioMed Central Ltd

Evidence for onward transmission of HIV-1 non-B subtype strains in the United Kingdom

An increasing proportion of new HIV diagnoses in the United Kingdom and other European countries are attributable to non-B subtype infections, mainly among black Africans with infections heterosexually acquired in sub-Saharan Africa. We examined whether there was evidence for onward transmission of non-B subtypes within an ethnically diverse HIV-1-infected cohort in South London. Three hundred eighty-four HIV-1-infected patients attending Kings College Hospital were subtyped using an in-house enzyme-linked immunoassay and env sequencing. Epidemiologic data were obtained from medical chart review and the patients' physician and were used to establish the most likely source and country of infection. Overall, 344 patients (154 black African, 148 white UK-born, and 42 black Caribbean) had an identifiable subtype. The prevalence of non-B subtypes among the black African, white, and black Caribbean patients was 96.8%, 14.2%, and 31%, respectively. Most non-B subtype infections were identified in black Africans (149 of 183 cases) and were mainly acquired in sub-Saharan Africa, but 22.9% (42 of 183 cases) of all non-B infections were probably acquired in the United Kingdom. Among the 21 white UK-born patients infected with a non-B subtype, 15 probably acquired the infection in the United Kingdom and only 6 of these patients reported a source sexual partner from an HIV endemic area. All 13 black Caribbean patients with a non-B infection most likely acquired their infection in the United Kingdom, most of whom (8 of 13 patients) were probably infected by a partner from an HIV endemic area. Potential acquisition of HIV infection in the United Kingdom was lowest among black African patients with a non-B infection, and most of these infections were probably acquired from a partner originating from an HIV endemic area. This study provides the first evidence for onward transmission of non-B subtypes in the United Kingdom, particularly among the black Caribbean populatio

Development of an env gp41-Based Heteroduplex Mobility Assay for Rapid Human Immunodeficiency Virus Type 1 Subtyping

The gp120 region of the human immunodeficiency virus type 1 (HIV-1) envelope (env) gene exhibits a high level of genetic heterogeneity across the group M subtypes. The heteroduplex mobility assay (HMA) has successfully been used to assign subtype classifications, but C2V5 primers often fail to amplify African strains. We developed an env gp41-based HMA for which the target sequence is amplified with highly conserved gp41 primers, known to efficiently amplify nucleic acids from HIV-1 group M, N, and O viruses. By using gp41 from a new panel of reference strains, the subtype assignments made by our modified HMA were concordant with those obtained by sequencing and phylogenetic analysis of 34 field strains from 10 countries representing subtypes A to G. Testing of field strains from Nigeria further demonstrated the utility of this modified assay. Of 28 samples, all could be amplified with gp41 primers but only 17 (60.7%) could be amplified with the standard C2V5 primers. Therefore, gp41-based HMA can be a useful tool for the rapid monitoring of prevalent subtypes in countries with divergent strains of circulating HIV-1

The IMI PROTECT project : purpose, organizational structure, and procedures

The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) initiative was a collaborative European project that sought to address limitations of current methods in the field of pharmacoepidemiology and pharmacovigilance. Initiated in 2009 and ending in 2015, PROTECT was part of the Innovative Medicines Initiative, a joint undertaking by the European Union and pharmaceutical industry. Thirty-five partners including academics, regulators, small and medium enterprises, and European Federation of Pharmaceuticals Industries and Associations companies contributed to PROTECT. Two work packages within PROTECT implemented research examining the extent to which differences in the study design, methodology, and choice of data source can contribute to producing discrepant results from observational studies on drug safety. To evaluate the effect of these differences, the project applied different designs and analytic methodology for six drug-adverse event pairs across several electronic healthcare databases and registries. This papers introduces the organizational structure and procedures of PROTECT, including how drug-adverse event and data sources were selected, study design and analyses documents were developed, and results managed centrally. Copyright © 2016 John Wiley & Sons, Ltd

A compilation of research working groups on drug utilisation across Europe.

BACKGROUND: The assessment of the benefit-risk of medicines needs careful consideration concerning their patterns of utilization. Systems for the monitoring of medicines consumption have been established in many European countries, and several international groups have identified and described them. No other compilation of European working groups has been published. As part of the PROTECT project, as a first step in searching for European data sources on the consumption of five selected groups of medicines, we aimed to identify and describe the main characteristics of the existing collaborative European working groups. FINDINGS: Google and bibliographic searches (PubMed) of articles containing information on databases and other sources of drug consumption data were conducted. For each working group the main characteristics were recorded.Nineteen selected groups were identified, focusing on: a) general drug utilisation (DU) research (EuroDURG, CNC, ISPE'S SIG-DUR, EURO-MED-STAT, PIPERSKA Group, NorPEN, ENCePP, DURQUIM), b) specific DU research: b.1) antimicrobial drugs (ARPAC, ESAC, ARPEC, ESGAP, HAPPY AUDIT), b.2) cardiovascular disease (ARITMO, EUROASPIRE), b.3) paediatrics (TEDDY), and b.4) mental health/central nervous system effects (ESEMeD, DRUID, TUPP/EUPoMMe). Information on their aims, methods and activities is presented. CONCLUSIONS: We assembled and updated information on European working groups in DU research and in the utilisation of five selected groups of drugs for the PROTECT project. This information should be useful for academic researchers, regulatory and health authorities, and pharmaceutical companies conducting and interpreting post-authorisation and safety studies. European health authorities should encourage national research and collaborations in this important field for public health