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

Optimization of diarylazines as anti-HIV agents with dramatically

Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants.Fil: Bollini, Mariela. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cisneros, José A.. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados Unido

Drug-Drug Interactions Among Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) Medications

One-fourth of individuals diagnosed with the human immunodeficiency virus concomitantly have the hepatitis C virus infection. Since the discovery of highly active antiretroviral therapy, liver complications have become the leading cause of morbidity and mortality in HIV-HCV coinfected individuals. Optimal treatment in this patient population is critical, as coinfection has been linked to deterioration of both disease states. The objective of this review article is to highlight the current literature on drug-drug interactions between HIV and HCV treatments. The management of the treatment of coinfection patients has been covered extensively in numerous other publications

Preferred antiretroviral drugs for the next decade of scale up

Global commitments aim to provide antiretroviral therapy (ART) to 15 million people living with HIV by 2015, and recent studies have demonstrated the potential for widespread ART to prevent HIV transmission. Increasingly, countries are adapting their national guidelines to start ART earlier, for both clinical and preventive benefits. To maximize the benefits of ART in resource-limited settings, six key principles need to guide ART choice: simplicity, tolerability and safety, durability, universal applicability, affordability and heat stability. Currently available drugs, combined with those in late-stage clinical development, hold great promise to simplify treatment in the short term. Over the longer-term, newer technologies, such as long-acting formulations and nanotechnology, could radically alter the treatment paradigm. This commentary reviews recommendations made in an expert consultation on treatment scale up in resource-limited settings

Predicted residual activity of rilpivirine in HIV-1 infected patients failing therapy including NNRTIs efavirenz or nevirapine

This is an open access article under the CC BY-NC-ND license - http://creativecommons.org/licenses/by-nc-nd/4.0/"Rilpivirine is a second-generation nonnucleoside reverse-transcriptase inhibitor (NNRTI) currently indicated for first-line therapy, but its clinical benefit for HIV-1 infected patients failing first-generation NNRTIs is largely undefined. This study quantified the extent of genotypic rilpivirine resistance in viral isolates from 1212 patients upon failure of efavirenz- or nevirapine-containing antiretroviral treatment, of whom more than respectively 80% and 90% showed high-level genotypic resistance to the failing NNRTI. Of all study patients, 47% showed a rilpivirine resistance-associated mutation (RPV-RAM), whereas preserved residual rilpivirine activity was predicted in half of the patients by three genotypic drug resistance interpretation algorithms. An NNRTI-dependent impact on rilpivirine resistance was detected. Compared with the use of nevirapine, the use of efavirenz was associated with a 32% lower risk of having a RPV-RAM and a 50% lower risk of predicted reduced rilpivirine susceptibility. Most prevalent RPV-RAMs after nevirapine experience were Y181C and H221Y, whereas L100I+K103N, Y188L and K101E occurred most in efavirenz-experienced patients. Predicted rilpivirine activity was not affected by HIV-1 subtype, although frequency of individual mutations differed across subtypes. In conclusion, this genotypic resistance analysis strongly suggests that the latest NNRTI, rilpivirine, may retain activity in a large proportion of HIV-1 patients in whom resistance failed while they were on an efavirenz- or nevirapine-containing regimen, and may present an attractive option for second-line treatment given its good safety profile and dosing convenience. However, prospective clinical studies assessing the effectiveness of rilpivirine for NNRTI-experienced patients are warranted to validate knowledge derived from genotypic and phenotypic drug resistance studies.

New option for management of HIV-1 infection in treatment-naive patients: once-daily, fixed-dose combination of rilpivirine-emtricitabine-tenofovir

Fixed-dose combination tablets have become an important therapy option for patients infected with the human immunodeficiency virus. Fixed-dose combination rilpivirine-tenofovir-emtricitabine is a recently approved therapy option that has been extensively studied within the treatment-naïve population. When compared with efavirenz-based therapy, improved tolerability with rilpivirine-based therapy was balanced by higher rates of virologic failure to provide similar overall efficacy rates within the intention-to-treat analysis. As a result, providers will need to balance the potential for improved tolerability with fixed-dose combination rilpivirine-tenofovir-emtricitabine against a higher potential for virologic failure, particularly among patients with baseline viral loads above 100,000 copies/mL. Current treatment guidelines have recommended that fixed-dose combination rilpivirine-tenofovir-emtricitabine be an alternative therapy option for treatment-naïve patients and advise caution in those patients with high viral loads at baseline. Similar to other non-nucleoside reverse transcriptase inhibitor-based regimens, there are a number of drug interaction concerns with fixed-dose combination rilpivirine-tenofovir-emtricitabine that will necessitate monitoring and, in some cases, appropriate management. Additionally, the emergence of drug resistance to fixed-dose combination rilpivirine-tenofovir-emtricitabine has been well documented in clinical studies and close attention will be necessary in order to protect current and future therapy options. Overall, fixed-dose combination rilpivirine-tenofovir-emtricitabine is poised to provide an important therapy option for patients when appropriately applied

Development and Validation of Stability Indicating RP-HPLC Method for Estimation of Rilpivirine Hydrochloride in Tablet Dosage Form

A simple, sensitive, rapid and reproducible HPLC Method was developed and validated for estimation of Rilpivirine in the presence of degradation products generated from forced decomposition studies. The analysis was carried out on Hypersil BDS C18, 250 X 4.6mm, 5? column using a mixture of ammonium acetate Buffer (pH to 6.0 0.05) and Acetonitrile in the proportion 55:45 respectively as a mobile phase at a flow rate of 1.2 mL/minute. The wavelength selected for the analysis was 300 nm. The peak for Rilpivirine HCl was observed at 10.33 minute. A linear response was observed in the range of 12.5 - 62.5 ?g/mL with a correlation coefficient of 0.999. The method was validated for specificity, linearity, precision, accuracy and robustness. The obtained results were indicating that the method is selective in analysis of Rilpivirine in the presence of degradation products formed under various stress conditions