Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Bhanu K Bhakhri

"The Journal of Clinical and Diagnostic Research (JCDR) has been in operation since almost a decade. It has contributed a huge number of peer reviewed articles, across a spectrum of medical disciplines, to the medical literature.
Its wide based indexing and open access publications attracts many authors as well as readers
For authors, the manuscripts can be uploaded online through an easily navigable portal, on other hand, reviewers appreciate the systematic handling of all manuscripts. The way JCDR has emerged as an effective medium for publishing wide array of observations in Indian context, I wish the editorial team success in their endeavour"



Dr Bhanu K Bhakhri
Faculty, Pediatric Medicine
Super Speciality Paediatric Hospital and Post Graduate Teaching Institute, Noida
On Sep 2018




Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
I wish all success to your journal and look forward to sending you any suitable similar article in future"



Dr Mohan Z Mani,
Professor & Head,
Department of Dematolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011

Important Notice

Reviews
Year : 2009 | Month : October | Volume : 3 | Issue : 5 | Page : 1805 - 1812

Recent Advances In Antiretroviral Therapy

KAMAT T S*,RATABOLI P V**, PHIRKE V R***, MANGRULE S A****

*2nd YearPost-graduateStudentin Pharmacology,***3rdyearPostgraduate student in Pharmacology,***M.D. pharmacology,asstprof,Krishna instituteofMedicalsciences,Karad.**M.D.pharmacology,asstprof,Goa Medical College, Goa.

Correspondence Address :
Dr Tejas Satchit Kamat,Dept of
Pharmacology,Krishna institute of
medical sciences,Malkapur-Karad,Satara-Maharashtra.Pin code: 415110. Mobile:09890307995.e.mail:drtejaskamat@gmail.com

Abstract

Despite significant progress in the study of human immunodeficiency virus (HIV) infection over the past few years, it still remains a leading cause of death throughout the world. The field of antiretrovirals is dramatically growing. 25 antiretroviral drugs have been approved by the US-FDA till date. The development of newer antiretrovirals has dramatically altered the progression of the disease and has improved the quality of life in many HIV-infected patients. Over the last two years, three novel antiretroviral drugs, maraviroc (CCR5 antagonist), raltegravir (integrase inhibitor) and etravirine (a second generation non nucleoside reverse transcriptase inhibitor) have been approved by the FDA and several others are in the pipeline. This review discusses the pharmacology of the three novel antiretroviral agents. Drugs which are currently in the pipeline and the latest HIV treatment guidelines have also been addressed.

Keywords

Newer antiretrovirals, maraviroc, raltegravir, etravirine, pipeline drugs

Introduction
The United States center for disease control and prevention (CDC) defines Acquired Immunodeficiency Syndrome (AIDS) as any HIV-infected individual with a CD4+ T cell count of <200 cells/mm3, regardless of the presense of symptoms or opportunistic infections. The history of AIDS dates back to 1981 when the first case was described in the United States. In 1983-84, French and American scientists confirmed the causative agent to be a retrovirus, the human immunodeficiency virus (HIV)(1). Today, 25 years after the isolation of HIV, more than 33 million individuals are infected and are living with HIV all over the world. In 2007 itself, 2.7 million individuals became newly infected and 2 million died of HIV globally (2).

Zidovudine, the first effective antiretroviral for the treatment of HIV infection, was approved in 1987, 3 years after HIV was isolated (3). The field of antiretrovirals is dramatically growing. Currently, 25 antiretrovirals belonging to 5 different classes have been approved by the FDA and are available for use in the US (Table/Fig 1).

HIV treatment options:
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) (3),(4)

These drugs require intracellular phosphorylation by host cell kinase enzymes to active triphosphate form, which then competitively inhibits the reverse transcriptase enzyme, thereby inhibiting the conversion of viral RNA to proviral DNA (reverse transcription). They are also incorporated in the growing viral DNA by reverse transcriptase and terminate chain elongation as they lack the 3-OH group. Toxicity is mainly due to the partial inhibition of human DNA polymerase (which is a mitochondrial enzyme) and includes anaemia, granulocytopaenia, myopathy, peripheral neuropathy, and pancreatitis. Lactic acidosis, hepatomegaly and hepatic steatosis ,which is a rare but potentially fatal complication associated with most NRTIs. They generally do not have clinically significant drug interactions as they are neither substrates for, nor induce/inhibit hepatic CYP450 enzymes.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (3),(4)

NNRTIs are non-competitive inhibitors that directly bind to the HIV-1 reverse transcriptase and induce a conformational change, resulting in the inactivation of the enzyme. Unlike NRTIs, they do not require intracellular phosphorylation for their action. They induce enzymes as well as are substrates for hepatic CYP450 enzymes. Pharmacokinetic drug interactions are thus an important consideration with the use of NNRTIs.

Rashes occur frequently with all NNRTIs, but are usually mild and self limiting. Rare cases of Stevens-Johnson syndrome have been reported.

Protease Inhibitors (Pis) (3),(4)

Protease inhibitors competitively inhibit the action of the protease enzyme and interferes with its cleaving function, resulting in the production of immature, non-infectious virus particles, thus preventing further rounds of infection. The most common side effects associated with their use are GI intolerance: nausea, vomiting and diarrhoea. Headache, dizziness, limb and facial tingling, numbness and rashes also occur. Lipodystrophy or a syndrome of the redistribution of body fat that includes abdominal obesity, buffalo hump and wasting of limbs and face has been observed. Raised triglycerides and cholesterol, insulin resistance and worsening of DM can occur. All PIs are substrates for CYP3A4 and different PIs either inhibit or induce specific CYP isoenzymes to a different extent. Drug interactions with them are common and are often unpredictable.

Fusion Inhibitor: Enfuvirtide (3),(4)
It is an HIV-derived synthetic peptide that binds to the HIV-1 envelope and prevents the fusion of viral and cellular membranes, thereby blocking the entry of the virus into the cell. Local injection site reactions like pain, erythema and induration at the site of infection are most prominent adverse effects. Some patients develop nodules and cysts, while 4-5% patients discontinue therapy due to adverse effects. It is available only for parenteral use.

Recent Advances
Two new classes of drugs, the CCR5 antagonist and the integrase inhibitor and a next generation NNRTI, have been recently approved by the FDA. The drugs in these classes are maraviroc, raltegravir and etravirine. These newer drugs are valuable options for use in patients with resistant strains of HIV.

Maraviroc
Maraviroc, the first agent in a novel class of antiretrovirals known as entry inhibitors, was granted accelerated approval by the FDA on August 6, 2007. It is approved for use in combination with other antiretroviral agents for the treatment of CCR5-tropic HIV-1 (R5 virus), in the treatment of experienced adults with the evidence of viral replication or against HIV-1 strains which are resistant to multiple antiretrovirals (5). The CCR5 tropism test should be carried out prior to starting maraviroc therapy.

Mechanism Of Action
Entry of HIV-1 into the host cell is an essential step in the life cycle of HIV. This process requires the attachment of the virus to both, the CD4 receptor and a chemokine receptor which serves as a co-receptor. HIV utilizes two different chemokine receptors for entry, the CCR5 and the CXCR4 receptors. While the CCR5-tropic variant of the virus is common in earlier HIV infections, viruses which are adapted to use the CXCR4 receptor gradually become dominant as the HIV infection progresses. Maraviroc prevents HIV infection of the host cells by selectively binding to and blocking the chemokine receptor CCR5 (5),(6). As such, CXCR4-tropic and dual-tropic HIV-1 entry is not inhibited by maraviroc.

Clinical Trials
In two phase III clinical studies which enrolled triple-class, treatment-experienced patients who experienced failure on their current antiretroviral regimens with detectable viraemia with only CCR5-tropic (R5) viral strains, Maraviroc, as compared with placebo, resulted in a significantly greater suppression of HIV-1 and greater increases in CD4 cell counts at 48 weeks when added to optimized background therapy (7).The efficacy of maraviroc in the treatment of naive patients and against CXCR4-tropic or mixed/dual-tropic viruses has not been established (5).

Pharmacokinetics
Maraviroc is rapidly absorbed orally and the absolute bioavailability ranges from 23% at a 100 mg dose to 33% at a 300 mg dose. It is approximately 76% plasma protein bound. Maraviroc is metabolized primarily by CPY3A4 and is also a substrate for P-glycoprotein (Pgp). It does not significantly influence the activity of major drug metabolizing enzymes. Its elimination occurs both in faeces (76%) and urine (20%), with a terminal half-life of 14-18 hours (5),(8),(9),(10).

Adverse Effects
It is well tolerated at clinically relevant doses, with most adverse events being mild or moderate and includes cough, upper respiratory tract infection, fever, muscle and joint pain, sleep disturbances, abdominal pain and dizziness due to postural hypotension (dose limiting side effect). The serious adverse effects reported are myocardial ischaemia and hepatitis, with the elevation of liver enzymes (5),(11).

Drug Interactions
Maraviroc being a CYP3A4 as well as a p-glycoprotein (Pgp) substrate may require dosage adjustments when administered with CYP- or Pgp-modulators. CYP3A/Pgp inhibitors such as ketoconazole, lopinavir/ritonavir, ritonavir, saquinavir and atazanavir increase maraviroc concentrations: dose reduction upto 50% may be required. CYP3A/Pgp inducers such as carbamazepine, phenytoin, phenobarbital, rifampin and efavirenz decrease maraviroc plasma concentrations: doubling the dose appears to compensate for induction.5,10,12 Tipranavir/ritonavir, a CPY3A inhibitor but a Pgp inducer, does not affect maraviroc pharmacokinetics (5). Maraviroc has no clinically relevant interactions with the CYP3A4 substrate midazolam, the NRTIs zidovudine and lamivudine, or the oral contraceptive steroids (13).

Dosage
It is available as 150 and 300 mg film coated tablets. The recommended dose is 300 mg twice daily, but the required dose adjustment when used with CYP3A4/Pgp modulators (5).

Raltegravir
Raltegravir is the first in a novel class of antiretroviral drugs known as integrase inhibitors. It was approved by the FDA in October 2007 for use in combination with other antiretroviral agents to treat HIV-1 infection in treatment-experienced adult patients who had an evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral regimens [14,(15)

Mechanism Of Action
Integrase is an enzyme which is essential for HIV-1 replication. It catalyses the insertion of HIV-1 DNA into the DNA of the human genome, making it possible for the infected cell to make new copies of HIV. Raltegravir specifically inhibits the final step in integration, that is the strand transfer of viral DNA to the host cell DNA, thus blocking the ability of HIV to replicate (14),(15),(16),(17).

Clinical Trials
In Phase III clinical studies which enrolled triple-class, treatment-experienced patients who experienced failure on their current antiretroviral regimens with detectable viraemia, raltegravir plus OBT provided significantly better viral suppression than OBT alone for at last 48 weeks (18).

Pharmacokinetics
Raltegravir is rapidly absorbed orally. The absolute bioavailability of raltegravir is approximately 32%. Raltegravir is approximately 83% bound to human plasma protein. The apparent terminal half-life of raltegravir is approximately 9 hours. It is primarily metabolized via UGT1A1-mediated glucuronidation and excreted in both faeces (51%) and urine (32%). No dose adjustment is necessary in patients with mild to moderate hepatic or severe renal impairment (14),(17).

Adverse Effects
Data regarding the safety of raltegravir is primarily obtained from the phase 2 studies (study 004 and 005) and the phase 3 (BENCHMRK) studies. Raltegravir was generally safe and well tolerated and was found to have a safety profile similar to that of placebo at all doses studied. There were no dose related toxicities. The most common adverse effects reported so far include diarrhoea, nausea, headache, nasopharyngitis and insomnia. Laboratory abnormalities include mild elevations in serum AST/ALT and creatinine phosphokinase (CPK). However, these are usually transient and do not require drug withdrawal (14),(15),(19).

Drug Interactions
Raltegravir is neither a substrate for cytochromes p450 enzymes, nor does it inhibit or induce cytochrome P450 enzymes. As such, interactions with other antiretrovirals like PIs and NNRTIs which are metabolized by the CYP450 system, are unlikely (14).However, strong inducers/inhibitors of UGT1A1 may affect the plasma concentrations of raltegravir. Caution is advocated while using raltegravir with potent inducers of UGT1A1 like Rifampin or with inhibitors like atazanavir(17).

Dosage
It is recommended in a dose of 400 mg orally, twice daily. No dose adjustment of raltegravir is required when it is co -administered with other antiretrovirals (14).

Etravirine
NNRTIs are potent inhibitors of HIV-1. However, the currently available agents which have been associated with the rapid development of resistance and cross-resistance within the class is extensive. Etravirine is a next generation NNRTI which has been approved by the US-FDA in January 2009 for use in combination with other antiretrovirals, for treatment-experienced adults with HIV strains which are resistant to existing NNRTIs (20),(21),(22).

Clinical Trials
Etravirine has demonstrated significant activity against the wild-type strains of HIV-1, as well as strains which are resistant to currently available NNRTIs. Further, the potential of HIV-1 developing resistance to etravirine appears to be lower than for first generation NNRTIs (23).In phase III trials (DUET I and II) in treatment experienced adult patients infected with HIV-1 resistant to NNRTI, patients receiving etravirine plus background therapy achieved a significantly greater reduction in viral load and a greater mean increase in CD4+ cell counts at 24 weeks than in patients receiving placebo plus BT (21),(23),(24),(25).


Adverse Effects
Etravirine is generally well tolerated and the adverse effects are mostly of mild to moderate severity, with a similar incidence to that of a placebo (except rash). The most frequently reported adverse effects were nausea and rash (21),(22),(24),(25). Other less common adverse events of etravirine include abdominal pain, fatigue, peripheral neuropathy, headache and hypertension. Rare cases of Stevens-Johnson syndrome have been reported with etravirine.

Drug Interactions
The dose adjustment of etravirine and/or other drugs is necessary while co-administration with drugs that are extensively metabolized by or those which induce/inhibit CYP3A, CYP2C9 and CYP2C19. Etravirine may inhibit the metabolism of certain anticoagulants (warfarin); antifungals (fluconazole); and benzodiazepines (diazepam), resulting in a clinically significant rise in plasma concentrations and toxicity (21).Etravirine is an inducer of CYP3A4 and hence, may result in altered plasma concentrations of CYP3A4 substrates if co-administered. It interacts differently with different PIs resulting in increased concentrations of some (amprenavir and nelfinavir), while decreasing the concentrations of others (atazanavir and indinavir). Etravirine concentrations may also be altered by different PIs. Etravirine should therefore not be administered with any unboosted PI or with boosted tipranavir, fosamprenavir, or atazanavir. It may be administered at normal doses with boosted darunavir and saquinavir and with caution with lopinavir/ritonavir.

Dosage
It is available as tablets containing Etravirine 100 mg. The recommended dose is 200 mg twice daily after meals.

Pipeline Drugs
NRTI: Apricitabine (ACT) (26).
ACT is currently under phase III clinical trials and has shown some activity against HIV strains which are resistant to other NRTIs. Resistance to apricitabine develops slowly as compared to other NRTIs such as lamivudine. In a phase IIb trial in drug-resistant HIV patients, ACT showed a greater reduction in the HIV viral load than any other NRTI in development. It is being studied as a first choice, second regimen drug for the treatment of HIV infection in patients who have failed the treatment with lamivudine. It has been well tolerated in phase II trials, the most adverse effects being mild and which includes headache, nasal congestion and myalgia. Apricitabine does not induce or inhibit any of the major CYP450 isoenzymes and hence, does not appear to have significant interactions with drugs which are metabolized by the hepatic CYP pathway.

NNRTIs: Rilpivirine (27)
Rilpivirine is being studied in Phase IIb trials for the treatment of HIV infection in treatment-naive patients as well as treatment-experienced patients with drug-resistant HIV. It is a well known high genetic barrier against the development of resistance. In phase IIa and ongoing phase IIb studies, it has been found to be as effective as efavirenz. It may offer the advantages of once daily dosing in treatment naĂŻve patients as well as that of having fewer side effects. Unlike efavirenz, it does not appear to cause central nervous system effects such as anxiety, sleep disturbance and depression. In trials conducted so far, it has not displayed any teratogenicity unlike other NNRTIs that are contraindicated in pregnancy.

IntegraseInhibitor:Elvitegravir(28)

It is being studied in Phase II trials for the treatment of HIV-1 infection in treatment - naive and treatment - experienced patients. It requires a small dose of the drug, ritonavir to boost its effectiveness. Such a combination of tablets may be suitable for once-daily dosing. It has been found to have a favourable safety profile, with the most common side effect in phase II studies being headache. No serious adverse events or discontinuations resulting from adverse events occurred in these studies. It displays additive to highly synergistic antiviral activity in vitro, with most of the NRTIs and PIs and does not appear to have any clinically significant drug interactions when used in combination with other antiretrovirals.

CCR5 Antagonist: Vicriviroc (29)
It is a novel, orally active entry and fusion inhibitor that holds promise for use in treatment experienced HIV patients infected with the CCR5 tropic virus which is resistant to enfuvirtide and other antiretrovirals. It has been well tolerated in phase II and ongoing phase III studies with most adverse effects being mild to moderate. The most common adverse events were nausea, headache, fatigue, pharyngitis and abdominal pain. It may be suitable for once daily dosing.

Maturation Inhibitor: Bevirimat (30)
This first-in-its-class maturation inhibitor is being evaluated as once-daily monotherapy for activity against HIV-1 in patients who are resistant to available treatments. Maturation is a late stage in viral reproduction, involving the processing of the Gag protein which is necessary for further infection of human cells. Bevirimat targets this late step in viral reproduction, resulting in the release of noninfectious viral particles and the termination of viral replication.

HIV Treatment Guidelines:(31),(32)
In 2008, the department of Health and Human Sciences (USA) published its latest recommendations for the treatment of HIV infection in adults:

Initiating Treatment: When To Start?

The eradication of HIV is still not being possible with the currently available antiretroviral regimens. The primary goal of antiretroviral therapy is to increase disease free survival by suppressing viral replication as much as possible and for as long as possible and the preservation of immunological functions.

The best time to initiate antiretroviral therapy still remains uncertain and debatable. Several authorities have framed and updated treatment guidelines from time to time. According to the current guidelines, treatment initiation is recommended in the following cases:

1. All cases of symptomatic HIV disease.
2. In asymptomatic cases, treatment has to be initiated before the CD4 cell count decreases to < 350 cells/mm3.
3. In symptomatic cases with a CD4 cell count of >350 cells/mm¬¬3, the treatment decision should be individualized. The patient’s readiness for initiation and adherence to therapy, individual risk of drug interactions, toxicity and the cost should be considered before starting treatment. The following are indications for initiating antiretroviral therapy irrespective of the CD4 cell count:
a. Rapid decline in the CD4 cell count (>100/μl per year).
b. Plasma HIV-1 RNA levels >100 000 copies/ml.
c. Risk factors for cardiovascular and other non-AIDS diseases and
d. Special cases such as pregnancy, HIV-associated nephropathy and co-infection with hepatitis B.

What To Start: Initial Treatment Options
Monotherapy, as was used initially for the treatment of HIV, is no longer recommended as it is associated with the rapid development of resistance. With newer insights into the pathogenesis of the HIV infection and the availability of several new and potent antiretrovirals belonging to different classes, a combination of at least 3 or more drugs known as highly active antiretroviral therapy (HAART) is now the preferred initial treatment. HAART has been found to be highly effective in suppressing HIV replication, reducing mortality and improving survival among HIV infected patients.

According to the current guidelines, patients who are naive to antiretroviral therapy should be started on the HAART regimen that contains either:
• 2 NRTIs + 1 NNRTI. Or
• 2 NRTIs + 1 PI (preferably with ritonavir boosting)

Conclusion

The development of newer antiretrovirals and advances in the management of HIV infection have dramatically altered the progression of the disease and improved the quality of life in many HIV infected individuals. However, despite the advances, HIV management still remains a difficult task because several problems like long term toxicities of antiretrovirals, drug interactions, development or resistance limit the effectiveness of HAART and pose major challenges in the management of HIV infection.

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