How developing world concerns need to be part of drug development plans: A case study of four emerging antiretrovirals

Clinical trials are usually designed to meet registration requirements in developed countries, and do not always address key concerns for use in developing countries. Four late-stage investigational new drugs - rilpivirine, etravirine, raltegravir and maraviroc - show potential to improve antiretroviral therapy. However, a number of issues could limit their use in developing countries, including dose selection, treatment strategy, combination with other drugs, use in specific populations and reliance on expensive tests. Key research questions relevant for developing countries need to be answered early in the drug development process to ensure maximum benefit for the majority

Safety and Efficacy of a Dapivirine Vaginal Ring for HIV Prevention in Women.

BACKGROUND: The incidence of human immunodeficiency virus (HIV) infection remains high among women in sub-Saharan Africa. We evaluated the safety and efficacy of extended use of a vaginal ring containing dapivirine for the prevention of HIV infection in 1959 healthy, sexually active women, 18 to 45 years of age, from seven communities in South Africa and Uganda. METHODS: In this randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned participants in a 2:1 ratio to receive vaginal rings containing either 25 mg of dapivirine or placebo. Participants inserted the rings themselves every 4 weeks for up to 24 months. The primary efficacy end point was the rate of HIV type 1 (HIV-1) seroconversion. RESULTS: A total of 77 participants in the dapivirine group underwent HIV-1 seroconversion during 1888 person-years of follow-up (4.1 seroconversions per 100 person-years), as compared with 56 in the placebo group who underwent HIV-1 seroconversion during 917 person-years of follow-up (6.1 seroconversions per 100 person-years). The incidence of HIV-1 infection was 31% lower in the dapivirine group than in the placebo group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.99; P=0.04). There was no significant difference in efficacy of the dapivirine ring among women older than 21 years of age (hazard ratio for infection, 0.63; 95% CI, 0.41 to 0.97) and those 21 years of age or younger (hazard ratio, 0.85; 95% CI, 0.45 to 1.60; P=0.43 for treatment-by-age interaction). Among participants with HIV-1 infection, nonnucleoside reverse-transcriptase inhibitor resistance mutations were detected in 14 of 77 participants in the dapivirine group (18.2%) and in 9 of 56 (16.1%) in the placebo group. Serious adverse events occurred more often in the dapivirine group (in 38 participants [2.9%]) than in the placebo group (in 6 [0.9%]). However, no clear pattern was identified. CONCLUSIONS: Among women in sub-Saharan Africa, the dapivirine ring was not associated with any safety concerns and was associated with a rate of acquisition of HIV-1 infection that was lower than the rate with placebo. (Funded by the International Partnership for Microbicides; ClinicalTrials.gov number, NCT01539226 .)

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Sustained release of the candidate antiretroviral peptides T-1249 and JNJ54310516-AFP from a rod insert vaginal ring

Administration of biomacromolecular drugs in effective quantities from conventional vaginal rings is hampered by poor drug permeability in the polymers from which rings are commonly constructed. Here, we report the formulation development and testing of rod insert rings for sustained release of the candidate antiretroviral peptides T-1249 and JNJ54310516-AFP (JNJ peptide), both of which have potential as HIV microbicides. Rod inserts were prepared comprising antiviral peptides T-1249 or JNJ peptide in combination with a hydrophilic excipient (sodium chloride, sodium glutamate, lactose or zinc acetate) dispersed at different loadings within a medical grade silicone elastomer. The inserts were tested for weight change and swelling when immersed in simulated vaginal fluid (SVF). Dye migration into the inserts was also assessed visually over 28 days. In vitro release of T-1249 and JNJ peptide from rings containing various insert types was tested. Weight change and degree of swelling of rods immersed in SVF was dependent on the type and concentration of excipient present. The rods displayed the following rank order in terms of weight change: sodium glutamate > zinc acetate ≈ sodium chloride > lactose. The weight change and degree of swelling of the inserts did not correlate with the level of dye uptake observed. In vitro release of T-1249 was improved through addition of lactose, sodium chloride and sodium glutamate, while release of JNJ peptide was improved through addition of sodium chloride or sodium glutamate. Sustained release of hydrophobic peptides can be achieved using a rod insert ring design formulated to include a hydrophilic excipient. Release rates were dependent upon the type of excipient used. The degree of release improvement with different inserts partially reflects their ability to imbibe surrounding fluid and swell in aqueous environments

In Vitro Evaluation of Nonnucleoside Reverse Transcriptase Inhibitors UC-781 and TMC120-R147681 as Human Immunodeficiency Virus Microbicides

The nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 (Dapivirine) effectively prevented human immunodeficiency virus (HIV) infection in cocultures of monocyte-derived dendritic cells and T cells, representing primary targets in sexual transmission. Both drugs had a favorable therapeutic index. A 24-h treatment with 1,000 nM UC-781 or 100 nM TMC120-R147681 prevented cell-free HIV infection, whereas 10-fold-higher concentrations blocked cell-associated HIV

Inhibition of vaginal transmission of HIV-1 in hu-SCID mice by the non-nucleoside reverse transcriptase inhibitor TMC120 in a gel formulation

OBJECTIVE: The development of drugs that can be used as topical microbicides is currently recognized as a priority area of research. DESIGN: A preclinical evaluation of the potential effectiveness of TMC120, a non-nucleoside reverse transcriptase inhibitor (NNRTI), as a topical microbicide to prevent vaginal HIV-1 transmission in a humanized severe combined immunodeficient (hu-SCID) mouse model. METHODS: Reconstituted mice received an intravaginal application of a TMC120-containing gel 20 min prior to a non-invasive vaginal challenge with cell-associated HIV. The possible cytotoxic effect of TMC120-containing-gel on lymphocytes was assessed and their in vivo migration was followed using fluorescently labelled human lymphocytes. Systemic infection was monitored by p24 antigen detection in culture supernatant from cocultured intraperitoneal cells using antigen capture enzyme-linked immunosorbent assay test and by the presence of integrated proviral HIV-1 DNA in DNA extracted from spleen cells. In vivo migration of labelled lymphocytes was examined by analysis of cells isolated from regional lymph nodes. RESULTS: In this model, systemic infection was successfully inhibited by the presence of TMC120-containing gel at vaginal level. The in vivo migration of human lymphocytes from the vagina to regional lymph nodes, following the deposition of TMC120-containing gel, excluded the possibility that inhibition of systemic infection was a result of NNRTI toxicity. CONCLUSIONS: Vaginal transmission of HIV was successfully prevented by the application of a gel formulation containing TMC120. This is the first evidence of the in vivo effectiveness of a microbicide preparation containing an NNRTI against cell-associated HIV.status: publishe