7 Dec 2011

HIV behavior: -- Tackling the deadly virus

Dec 05, 2011: Ever since the discovery of creature immunodeficiency virus (HIV) as the cause of acquired immune deficiency syndrome (AIDS) in the 1980s, not single has this unstable virus been causing a raging pandemic across the globe, it has furthermore evaded numerous techniques and pathways designed to tackle this wicked virus.

While scientists were unavailable engaging in committed investigate tiresome to build a miracle vaccine to fight this dreaded virus, it has either frankly or indirectly claimed the lives of near 30 million public, according to UNAIDS. Also, in this area 34 million are now living with HIV.

Although this growing phenomenon of AIDS/HIV paints a depressing and grim picture of the development of extra drugs and therapies, here is thumbs down denying with the intention of here has indeed been progress since the commencement of HIV vaccine investigate, which roughly ongoing all through the in the dead of night 1980s. Hence, this year’s theme pro World AIDS Day which is experimental on December 1, is universal access and creature civil rights. Access to shape services remains low and majority of the infected public are uninformed of their HIV status. Two-thirds of patients with well ahead HIV infection sort out not make behavior, and two made known of three HIV-infected pregnant women sort out not benefit from antiretroviral prophylaxis.

Current responses to the pandemic be inflicted with proved unequal to the challenge posed by HIV. For each person who begins antiretroviral behavior, two public be converted into newly infected by the virus. The HIV promote is probable to grow to $10.6 billion by 2015, driven in part by extra drugs from Merck, Pfizer and Tibotec, according to Datamonitor.
Although here is intense amount of investigate being conceded made known in the meadow of vaccines, here are furthermore clinical trials underway pro the discovery of efficient drugs to handle the condition of AIDS. According to the International AIDS Vaccine Initiative (IAVI), here are a whole of 185 period I clinical trials with 9,603 volunteers; 17 period I/II trials with 1,645 volunteers; 17 period II clinical trials with 10,947 volunteers and three period III clinical trials with 24,303 volunteers.

The sales of standard HIV drugs Celsentri, Isentress and Atripla are estimated to get to $350 million, $400 million and $1.7 billion, correspondingly, by 2015. It is furthermore estimated with the intention of TMC125 sales will secure $200 million by 2015 while TMC278 will exceed more than $500 million in sales. Asia’s HIV pandemic is currently entering a following growth period, which may possibly get behind HIV prevalence to almost 10 million by 2020 if prolonged prevention hard work are not introduced.

The elusive vaccine

About 7,000 public a time are infected with HIV. An AIDS vaccine with 50 percent efficacy agreed to 30 percent of the population would ward off 5.6 million extra infections in low-and-middle-income countries from 2015 to 2030. So how has the progress been so far?
During the ahead of schedule years of investigate, scientists by both broadcast and confidential sectors tried leveraging on the the tried and tested path of creating an imitation of a part of an HIV envelope protein by using it as an antigen in their vaccine candidate, combining this with an adjuvant and in suspense with the intention of this vaccine candidate would trigger the production of neutralizing antibodies hostile to HIV. Unfortunately, this method did not verify to be quite as thriving as in the justification of hepatitis or creature papillomavirus.
There are three major reasons why HIV has proved such a amazing foe to vaccine designers and immune systems alike. First, it is by far the generally variable virus with the intention of scientists be inflicted with always encountered.

A digit of uncommon subtypes of the virus, renowned as clades, circulate in uncommon regions of the planet. Within persons clades here is extensive changeability, and, further than with the intention of, the virus mutates furiously surrounded by the public it has infected. Second, since thumbs down lone is renowned to be inflicted with vacant an HIV infection, we sort out not know which elements of the immune response should be engaged to control the virus and hence are uncertain how to imitate such responses. Finally, the immune logic has a very narrow window of opportunity in which to neutralize HIV previous to the virus establishes a lifetime infection.

With a mission to tackle HIV, numerous organizations like Therapeutics Research, Education, and AIDS Training in Asia (TREAT Asia), IAVI, UNAIDS (the establishment United Nations curriculum on HIV/AIDS), law and Melinda Gates Foundation, Rockefeller Foundation, Ford Foundation and others be inflicted with extended collaborations with investigate organizations in an effort to collate methodical minds in the quest pro producing the much yearned vaccine pro HIV.

TREAT Asia is a arrangement of clinics, hospitals, and investigate institutions working with civil society to ensure the safe and effectual manner of speaking of HIV/AIDS treatments right through Asia comforting. Facilitated by The Foundation pro AIDS Research (amfAR), TREAT Asia seeks to strengthen HIV/AIDS trouble, behavior, and management skills amongst healthcare professionals through education and training programs urban by experts in the region. Since 1985, amfAR has invested near $325 million in its programs and has awarded grants to more than 2,000 investigate teams worldwide.
The IAVI’s mission is to ensure the development of safe, effectual, reachable and preventive HIV vaccines pro aid right through the planet. The IAVI has collaboration with a digit of institutions in sub-Saharan Africa, India, the United Kingdom, Europe and the United States. They are engaged in HIV-related investigate with the intention of is essential both pro laying the basis pro large-scale efficacy trials (or period III trials) and pro informing the design of AIDS vaccine candidates.

One Asian initiative with the intention of managed to grab the world’s attention was the RV-144 trial, which is the leading HIV trial conducted in Asia so far. The study, which began in 2003, was an international collaborative effort with the intention of involved more than 16,000 Thai volunteers and hundreds of scientists and clinicians from Thailand, Europe and the United States. The manufactured goods tested was ALVAC HIV, the prime vaccine, manufactured by Sanofi Pasteur and AIDSVAX B/E, the booster vaccine used in the trial, urban by VaxGen.

The trials showed with the intention of the combination of the higher than vaccines lowered the rate of HIV infection by 31.2 percent compared to excuse. That was the initially particular evidence, since the discovery of the virus in 1983, with the intention of a vaccine hostile to HIV was eventually feasible. Sanofi says with the intention of the Thai period III trial collaborators are already working with international methodical experts to expedite the design and implementation of appropriate prospect studies, so with the intention of the repayment of this investigate will be unfilled as quickly as doable.

"This is a modest but noteworthy advance in the development of a vaccine hostile to HIV. The study investigators and the volunteers should be congratulated pro their bring about. The study results be inflicted with publicized pro the initially calculate with the intention of safe vaccines pro humans hostile to HIV can be urban. Equally more analyses be converted into unfilled, this will help additional development of vaccines. Despite the advances, it remains real with the intention of a ‘ready to aid vaccine’ is years, if not decades, away. Meanwhile, focus should take up again on evidence-informed combination HIV prevention programs with the intention of are ashore in creature civil rights. When vaccines be converted into unfilled they should be made universally unfilled and reasonably priced,’’ says the UNAIDS regional support team pro Asia comforting.

GSK is a further company with the intention of has been working towards producing an HIV vaccine. Their study of HIV vaccine 732462 is designed to determine whether administration of the GSK Biologicals HIV vaccine 732462 can principal to a reduction in viral load, and impression on the way of creature HIV-1 infection. Inside HIV-1 infected personnel who be inflicted with not yet ongoing antiretroviral therapy (ART), such a vaccine would potentially principal to delay in the admittance of behavior. This study is now in period II.

Inside a further occasion, Chinese scientists by the China’s National Centre pro AIDS/STD control and Prevention be inflicted with claimed to be inflicted with successfully conceded made known the initially period of clinical trial of an HIV vaccine and are likely to start the following stage in a hardly any months. With companies and institutions working absorbedly to bring an aim to this plaguing virus, perhaps here is light by the aim of the tunnel pro HIV vaccine and its researchers.

Evolving behavior

When scientists realized with the intention of preventive measures to handle HIV by earnings of vaccines was a tough task, all thankfulness to HIV’s constantly mutating envelope, they twisted their attention towards behavior of HIV. Undoubtedly, the generally thriving treatments pro HIV/AIDS has been the aid of antiretroviral drugs with the intention of constitute five antiretroviral drug classes: Fusion/entry inhibitors, integrase inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors. Research is furthermore underway into a type of drug which may possibly form a the makings extra drug rank, the maturation inhibitor. According to clinicaltrials.Gov, here are now 762 studies in period III trials relating HIV.

"A investigate released by the US National Institutes pro Health (NIH) in 2011 showed antiretroviral behavior to be 96 percent effectual in preventing HIV transmission surrounded by sero-discordant couples. The substance of scaling up access to behavior is apparent,’’ says the UNAIDS regional support team pro Asia comforting.

The companies with the intention of are generally actively engaged in the development of these drug types include Gilead, Shionogi (Japan), ViiV Healthcare (a comprehensive specialist HIV company established by GlaxoSmithKline and Pfizer), Taimed Biologics (Taiwan), Bristol Myers and Avexa (Australia) to first name a hardly any. Some of the drugs urban by these companies be inflicted with entered the penultimate period III stage of clinical trials.

Gilead, by bestow, has three candidates in period III and lone in period I stage of clinical trials; Taimed has lone in period IIb; Shionogi and ViiV Healthcare be inflicted with two candidates in period II and lone in period III stage, ViiV Healthcare has two candidates in period II and Bristol Myers has lone in period III; Apricitabine (ATC, AVX754) by Avexa of Australia has discussed results from period II/III with the FDA and is proceeding with its development.
Speaking in this area the clinical trial progress of Taimed’s HIV drugs Ibalizumab (TMB-355) and TMB-358, Mr Jack Chen, the fiscal controller of TaiMed Biologics says, "In 2011, the period IIb clinical trial pro the TMB-355 intravenous formulation was clogged. Data analysis of the period IIb study was furthermore finalized and reported to FDA by June 2011."

Inside addition, the TMB-355 subcutaneous formulation is urban as the following generation drug to back up the pipeline. The monkey creature develop pro the pharmacokinetics suggests with the intention of the subcutaneous formulation spectacle the long-lasting and long-acting pharmacokinetic font with comparison to the intravenous lone. The company diplomacy to launch the money-making manufactured goods by the aim of 2013.

Gilead Sciences too has a handful of candidates designed to fight and handle HIV/AIDS in various phases of clinical trials. "We take up again to dedicate our HIV investigate and development hard work to advancing single-tablet regimens with the intention of take up valuable uncomplaining needs," says Dr Norbert Bischofberger, executive sub- president, investigate and development and chief methodical detective, Gilead Sciences.

The company recently submitted a extra drug attention to the US FDA pro marketing praise of Quad, a complete single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate pro the behavior of HIV-1 infection in adults. If standard, Quad would be the single once-daily, single-tablet regimen containing an integrase inhibitor.
Speaking in this area Quad, Dr Bischofberger says, "Based on data from our central studies, we believe with the intention of Quad has the the makings to be an valuable extra behavior option pro public living with HIV, and we are satisfied to be inflicted with reached this noteworthy achievement a reduced amount of than six weeks with unblinding of the following central period III study. The NDA is supported by 48-week data from two central period III studies in which Quad met its primary objective of non-inferiority as compared to Atripla (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) (Studies 102) and to a regimen containing ritonavir-boosted atazanavir (Studies 103). Complete data from Quad central studies will be presented by a methodical talks in 2012."

He additional says, "Based on the availability of data from both central Studies 102 and 103, we are currently working towards filing pro the US regulatory praise of Quad by the aim of the time. Quad may possibly be a blockbuster drug pro Gilead as all of the components are owned by the company. This may possibly be a the makings accomplishment amongst HIV patients who be inflicted with to cope with a enormous amount of pills on a day after day basis. What is uncommon is with the intention of Quad would be the initially drug to incorporate an integrase inhibitor, lone with the intention of is designed to check the skill of HIV to imitate.

If standard, Quad would be the single once-daily, single-tablet regimen containing an integrase inhibitor, a rank of antiretroviral drug designed to check the proceedings of integrase, a viral enzyme with the intention of inserts the viral genome into the genetic material of the host cell.
Elaborating on the contemporary Bristol-Myers Squibb and Gilead Sciences licensing agreement pro development and commercialization of fixed-dose combination containing Bristol-Myers Squibb’s protease inhibitor Reyataz (atazanavir sulfate) and Gilead’s cobicistat, Dr Bischofberger says, "Cobicistat provides us with the the makings to co-formulate with a variety of commercially unfilled HIV medicines with the intention of require boosting pro optimal efficacy, such as the protease inhibitor atazanavir." Gilead’s cobicistat is a pharmacoenhancing or "boosting" agent with the intention of increases blood levels of particular HIV medicines to potentially allow pro lone pill once-daily dosing.

"This agreement represents a shared stanchness linking Gilead and Bristol-Myers Squibb to develop multiple behavior options with the intention of can take up party uncomplaining needs," says Dr Bischofberger. Both Reyataz (atazanavir sulfate) and Cobicistat are now in period III studies.
Although producing a miracle in the form of a vaccine pro preventing HIV might still be years away, here is hope pro patients living with HIV as here is constant effort to yield drugs much more efficient and safer than before drugs.

Ongoing clinical trials of candidate AIDS vaccines with support of IAVI IAVI B001 - clinical trial of Ad35-GRIN/ENV (US): This period I trial, made in collaboration with the University of Rochester Medical Center, evaluates the safety and immunogenicity of an AIDS vaccine candidate built into a vector with the intention of is based on serotype 35 of the adenovirus (Ad35).

IAVI B002 - Prime-boost trial of adjuvanted GSK investigational AIDS vaccine with Ad35-GRIN (Kenya, Uganda, Zambia): This period I trial is the initially to evaluate the safety and immunogenicity of a candidate comprising two components, counting a protein-based vaccine element urban and manufactured by GSK and a viral vector vaccine element manufactured by Transgene. This element is made from a version of Adenovirus serotype 35 (Ad35) with the intention of has been stripped of its skill to imitate inside cells.

The trial is sponsored by IAVI and will be conducted in relationship with GSK; the Kenya AIDS Vaccine Initiative in Nairobi; the Uganda Virus Research Institute-IAVI in Entebbe, Uganda; the Medical Research Council-Uganda; Virus Research Institute in Masaka, Uganda; and the Zambia Emory HIV Research Project in Lusaka, Zambia. This study will evaluate whether these two components used in combiation will yield broader and stronger immune responses.

IAVI B003/IPCAVD-004 - Prime-boost trial of Ad26.ENVA.01 and Ad35.ENV (US, Kenya, Rwanda, South Africa): This period I trial will evaluate the safety and immunogenicity of two adenovirus vector-based vaccines. It is a establishment effort of the Beth Israel Deaconess Medical Center; the HIV Vaccine Trials Network; the National Institute of Allergy and Infectious Diseases’ Division of AIDS; the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, the biopharmaceutical company, Crucell, and a digit of clinical trial centers.

Six clinical investigate centers are participating in B003/IPCAVD-004. The trial is difficult whether delivering these vaccines in sequential prime-boost combination will induce uncommon types of immune responses or enhance persons responses. Specifically, the strategy might induce both antibody and T-cell responses, and hence obtain a response of greater magnitude, broader effectiveness and longer duration than would either vaccine candidate lonely.

Completed clinical trials of candidate AIDS vaccines with support of IAVI

Prime-boost trial of ADVAX and TBC-M4 (India): Inside collaboration with the Indian Council of Medical Research (ICMR), IAVI, supported a period I clinical trial to evaluate the safety and immunogenicity of a prime-boost regimen of two AIDS vaccine candidates, ADVAX and TBC-M4.
Prime-boost trial of ADVAX and TBC-M4 (UK): This period I trial, conducted in collaboration with the Imperial College London and the St. Stephen’s AIDS Trust by the Chelsea and Westminster Hospital is a further randomized, dual blind, placebo-controlled trial of ADVAX and TBC-M4.
Intermittent pre-exposure prophylaxis (PrEP) (Kenya, Uganda): These small period I/II studies were launched in October 2009 by the Kenya AIDS Vaccine Initiative, in Nairobi, the Center pro Geographic Medical Research - Coast, in Kilifi, Kenya, and the Medical Research Council Centre element in Entebbe, Uganda. The PrEP studies were designed to determine whether tenofovir plus emtricitabine tablet administered on an intermittent or day after day basis is safe and acceptable. The studies furthermore compare adherence and drug levels linking the intermittent and day after day regimens. The studies were too small to evaluate whether intermittent or day after day PrEP is effectual in preventing HIV transmission.
Source: IAVI

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