Frontiers in Clinical Drug Research: HIV

Acquired immunodeficiency syndrome (AIDS) could happen over a period of twenty years, this was first definition of disease entity that increased to greatness pandemic. The natural history of human immunodeficiency virus (HIV) infection is variable; however, the most infected individuals remain free of symptoms for 6-10 years after initial infection and bring into relation epidemic of apprehension was drawing their group and health care necessity. What was mostly done for HIV-patients and their families at the same moment was to ensure your suitable to afford at the same time health care and governed by emotion supports, despite express recognition our acknowledge infection. Actually, more than 30 antiretroviral drugs (not all are licensed or available in every country) were confirmed by Food and Drug Administration (FDA) and some others are under development and clinical trials. Despite major scientific efforts to find new cures and vaccines for HIV, hundreds or thousands of HIV-patients continue to die on a yearly basis, from secondary fungal infection. We urgently need to better understand the underlying immune-pathogenesis of HIV to enable better diagnosis and management in at-risk populations. The purpose of this chapter is to investigate the connections between demographic, familiarity and attitudes factors with HIV/AIDS, and emphasize the therapy tendencies on appointed years of emerging strategies.

The use of microbicidal agents for the prevention of HIV-1 transmission and consequent infection is emerging as a promising strategy for controlling this global epidemic. Sexual HIV-1 transmission in resource-limited regions is driven by gender inequalities imposing a particular burden on women and girls. Topical microbicide administration directly to the vagina could play an important role in HIV-1 prevention efforts, as this female-controlled approach leads to high local levels of anti-HIV-1 compounds, while resulting in low systemic exposure. After twenty years of clinical investigation, however, this dosing route has had limited success. In this chapter, we thoroughly review the current state of vaginal microbicide research for HIV-1 prevention. The vaginal route of HIV-1 infection is discussed along with an overview of the classes of microbicides currently under investigation, including: broad-spectrum (i.e., non-specific), specific (e.g., antiretroviral drugs), and biological (peptides, proteins, and bacteria) agents. Dosage forms (tablets/suppositories, films, gels, and intravaginal rings) are discussed along with the merits and challenges associated with each modality. An anatomical, histological, and physiological description of the vaginal mucosa links the applied and fundamental sections of the chapter. An introduction to the interplay between hormone regulation and the vaginal mucosa is provided, accompanied by a discussion of potential biomarkers of inflammation that may be used to evaluate microbicide safety. Host expression of membrane transporters and metabolizing enzymes is reviewed in detail, as both can influence local drug distribution and, hence, pharmacodynamic outcomes in HIV-1 prevention. The vaginal microbiome, and its interactions with the host, are likely to play a pivotal role in topical HIV-1 prophylaxis is discussed. Finally, ex vivo and animal models for evaluating candidate product efficacy are critically reviewed and the current state of clinical vaginal product evaluation is discussed.

Many years in the fight against the HIV/AIDS epidemic have resulted in remarkable and transformative progress in HIV treatment and prevention. Since the advent of the first antiretroviral drug (ARV) over two decades ago, the field of HIV has witnessed a rapid development of new drugs as seen nowhere else in the field of medicine. ARV drugs have significantly improved in efficacy, tolerability, and simplicity, and expanded access to these life-saving drugs has resulted in a dramatic decrease in HIV/AIDS-related morbidity and mortality. The advent of ARV drugs has also greatly energized the field HIV prevention. Initial successful antiretroviral prophylaxis to prevent mother-to-child HIV transmission of HIV are now strengthened with new evidence such as that from the landmark HIV Prevention Trials Network (HPTN) 052 showing that early initiation of ARV in serodiscordant couples decreased transmission of HIV-1 from the infected to the uninfected partner by 96%. This latter development in ARV drug research has advanced the concept of “Treatment as Prevention”. Encouragingly, ARV drugs were successfully used as oral pre-exposure prophylaxis in a number of trials, and recent findings of CAPRISA 004 trial showing the efficacy of tenofovir based-gel have provided the first proof-of-concept that an ARV-based microbicide could prevent sexual transmission of HIV in women.

Current advances in HIV treatment and prevention through research and development of new ARV drugs are results of many years of continued efforts which should be best capitalized by ensuring proper adherence to ARV drugs. Adherence is crucial for the success of ARV drugs in HIV prevention and treatment. Non-adherence to antiretroviral medication leads to treatment failure and emergence of resistant strains of HIV, and existing data indicate that where pre-exposure prophylaxis failed to demonstrate efficacy, poor adherence was most likely the cause. Advances in ARV drug research may influence adherence in multiple ways, and also the interplay of factors, challenges, and barriers of adherence to ARV drugs in HIV treatment and prevention differ in notable aspects. This chapter intends to highlight the central role of adherence in HIV prevention and treatment in light of the current advances in ARV drug research. To better address this objective, a synopsis of the recent advances in ARV drugs and of the role of ARV drugs in HIV treatment and prevention is provided in the first part of the chapter.

In the HIV life cycle, the HIV-1 integrase enzyme plays a vital role to insert the HIV-1 proviral DNA into the host chromosome. It is a rational target to design inhibitors for HIV treatment and prevention. This chapter focuses on three FDA approved HIV-1 integrase strand transfer inhibitors (INSTIs); raltegravir, elvitegravir and dolutegravir. Raltegravir is the first approved HIV-1 integrase inhibitor. It blocks HIV-1 replication by inhibiting the strand-transfer activities of integrase with a rapid absorption (Tmax ~ 4 h). With twice daily dosing, approximately 83% of raltegravir is bound to human plasma proteins and its terminal elimination half-life is approximately 9 hours. For raltegravir, no adjustment of dosing is necessary for food, gender, age, body mass index, or hepatic and renal function. It has significant anti-HIV potency in both antiretroviral treatment-naïve and treatment-experienced patients. As the second approved HIV-1 integrase inhibitor, elvitegravir is absorbed rapidly with the Tmax being 3-4 h. The absorption of elvitegravir increased up to three folds when it was administered with food. It was approved to be used once daily as part of a fixed-dose combination, known as stribild, which is a complete regimen for the treatment of adults with antiretroviral treatment-naïve HIV-1 infection. Dolutegravir is a second-generation integrase inhibitor that has more rapid and sustained virologic suppression than raltegravir and elvitegravir. It is time to the maximum plasma concentration (Tmax) is 1 h. The terminal elimination half-life of dolutegravir is 13 ~ 14 h. Clinically, dolutegravir is a commonly used antiretroviral regiment for both treatmentnaïve and treatment-experienced patients. In summary, HIV-1 integrase inhibitors are a novel class of antiretroviral drug, which provide a tremendous advancement in AIDS treatment options.

Despite multiple therapeutic options available to HIV patients that include several classes of antiretrovirals (ARVs) the HIV pandemic has reportedly affected more than 35 million patients in 2014. Optimizing treatment success requires new ARV molecules and an adherence to treatment above 95%. Long-acting ARV formulations that could be administered every 1-3 months offer a promising solution to these two priorities.

Long-acting ARVs are available as nanoformulations, achieve high intracellular concentrations and a good tissue distribution. Thus, long-acting ARVs could be used for both pre and post-exposure prophylaxis as well as for the treatment of the HIV infections. Moreover, long-acting ARV could significantly increase adherence to treatment while also displaying fewer adverse effects and offering an economic alternative in non-adherent HIV infected patients failing on other ARV therapies. Still, there is insufficient data on these formulations and further studies on HIV patients are needed to assess issues related to the pharmacokinetics, safety, tolerance, efficacy and potential combinations with other ARV drugs. The longacting ARV candidates in the latest stages of development are GSK744 -an Integrase Strand Transfer Inhibitor and TMC278 -a Non-nucleoside Reverse Transcriptase Inhibitor.

The current chapter reviews the results of various trials on GSK744 and TMC278 longacting ARV candidates, their advantages and disadvantages compared with the ARV drugs already in use as well as the possibility to comply with HAART principles thus becoming a reliable alternative to current ARV drugs.