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

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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 Dermatolgy,
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
Anuradha

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.


Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020

Important Notice

Reviews
Year : 2008 | Month : October | Volume : 2 | Issue : 5 | Page : 1119 - 1125

HIV Entry Inhibitors: Current Status

SAHA L

E.mail:lekhasaha@rediffmail.com

Correspondence Address :
E.mail:lekhasaha@rediffmail.com

Abstract

Current therapeutic intervention in HIV infection relies upon 20 different drugs. Despite the impressive efficacy shown by these drugs, we are confronted with an unexpected frequency of adverse effects such as mitochondrial toxicity, lipodystrophy and resistance, not only to individual drugs, but to entire drug classes. Thus, there is now a great need for new antiretroviral drugs with reduced toxicity, increased activity against drug-resistant viruses and a greater capacity to reach tissue sanctuaries of the virus. Two different HIV molecules have been selected as targets of drug inhibition so far: reverse transcriptase and protease. Drugs that target the interactions between the HIV envelope and the cellular receptor complex are a `new entry’ into the scenario of HIV therapy, and have recently raised great interest because of their activity against multi-drug resistant viruses.
There are several compounds that are at different developmental stages in the pipeline to counter HIV entry(Table/Fig 2), some of which include:
i) the attachment inhibitor dextrin – 2 – sulfate;
ii) the inhibitors of the glycoprotein (gp) 120/CD4 interaction PRO 542, TNX 355 and BMS 488043;
iii) the co-receptor inhibitors subdivided in those targeting CCR5 and those targeting CXCR4 and
iv) fusion inhibitors enfuvirtide (T-20) and tifuvirtide (T-1249).

Keywords

: HIV entry inhibitors, Mechanism of entry, Current status, Future

Mechanism of Entry
HIV surface proteins bind to CD4 (a member of the immunoglobulin super family), thereby anchoring the virus to the surface of the host cell and enabling additional interactions with a co-receptor protein (usually a member of the chemokines receptor family) (1). The main co-receptors used by HIV-1 are chemokine receptors CCR5 and CXCR4. The viral surface protein gp120 has a high degree of genetic variability in HIV-1 isolates. Assessment of the amino acid sequence of different HIV-1 strains led to the identification of five variable (V1-V5) and four constant (C1-C4) regions in gp120 (2). The expression of CCR5 or CXCR4 on different CD4 + target cells, defines their susceptibility to infection by the corresponding CCR5 (R5) or CXCR4 (X4) HIV-1 strain. Thus, the use of a specific co-receptor determines virus cell tropism. Moreover, some HIV-1 strains can use both CCR5 and CXCR4, and they are referred to as dual tropic (D) R5X4 strains. Some patients have mixtures (M) of R5 and X4 HIV-1 isolates.

After CD4-virus binding and co-receptor engagement, conformational changes in gp120 enables gp41 to reorient parallel to viral and cellular membranes and promote the events leading to fusion between the two membranes. Thereafter, the present model to explain membrane fusion, assumes a transient intermediate state in which gp41 spans both viral and cellular membranes (3). A six-helix bundle, the gp41 structure is believed to form before fusion and serve to bring the membranes into close apposition, enabling fusion-pore formation and virus internalization. The most promising HIV entry inhibitors being developed are those targeting HIV co-receptors. (Table/Fig 1)

Attachment Inhibitors
Dextrin – 2 – Sulfate (4)
Sulfated polysaccharides or polyanions such as dextran sulfate and heparin have been shown to inhibit binding of V3 loop antibodies to HIV-1 gp120 in-vitro. Dextrin-2-sulfate (D2S) is a synthetic derivative of dextrin which exhibits the most favorable combination of high anti-HIV-1 activity and low anticoagulant activity, when compared to other structural analogues of sulfated polysaccharides(4)An intravaginal gel formation of D2S (0.125%) is currently being developed by ML Laboratories, and is under evaluation as a topical microbicide. There was no evidence of systemic toxicity or genital epithelial disruption, attributable to the D2S gel. Clinical trials of the D2S gel have been approved by the UK Medicines Control Agency, and the US FDA has approved trials of D2S in the UK, US and South Africa.

Inhibitors Of Gp 120 / CD4 Interaction(5)
The inhibitors of Gp 120/ CD4 interaction are PRO 542, TNX 355 and BMS 488043. PRO 542 (CD4 – IgG2) is a tetravalent recombinant antibody. PRO 542 is currently being developed by Progenics pharmaceuticals, and has been tested in two phase I / II clinical trials. TNX 355 is a humanized monoclonal antibody directed against the extracellular domain 2 of human CD4. It prevents post-viral binding conformational changes required for successful entry of HIV into the cell. TNX 355 is being developed by Tanox, and currently under clinical development.
BMS 488043 is a small molecule which blocks viral entry by preventing the binding of gp120 to cellular CD4 receptors. This compound was discovered by Bristol-Myers-Squibb, and is currently in phase II / III development with the company.

Co-Receptor Antagonists (6)
A number of `first generation’ molecules have been halted in their clinical development against HIV-infection. These include the CXCR4 antagonist AMD100, which is not being further developed because of cardiac abnormalities (7). In an analogous manner, ancriviroc (SHC-C, SCH 351125), a CCR5 antagonist, has been discontinued because of heart conduction abnormalities (prolonged QT intervals) at the highest doses (6). ALX 404C, initially developed as a Tat antagonist, but shown to be also more effective as a CXCR4 antagonist, is no longer under consideration for development, because oral formulations are unlikely to be produced, while TAK 779, a CCR5 antagonist, has been discontinued because of local toxicity around subcutaneous injection sites(6). Nevertheless, many new compounds which are now in development hold promise for the near future.

CCR5 Antagonists
It is not surprising to enlist many candidate drugs targeting CCR5, since CCR5 is the co-receptor mainly used for HIV transmission. Furthermore, R5 viruses remain present in approximately 50-60% of individuals who progress to AIDS, whereas a switch to X4 viruses occurs in the remaining 40-50% of individuals with disease progression, and is associated with a rapid decline of CD4 + T cells.

1. Maraviroc (UK427857) (8)
Maraviroc has been approved by US FDA in October 2007. Maraviroc inhibits the binding of chemokines (ccmolif) ligand 3 (CCL3, also known as MIP-1α), and CCL5 (RANTES) (natural ligands of CCR5) to cell-membrane preparations of CCR5-expressing cells, and block CCR5 – signaling events after binding of chemokines (9). Pharmacokinetic data suggest that drug absorption is rapid, with maximum concentrations achieved 1-4 hrs after dosing (9). Maraviroc has biphasic elimination, with a measured terminal half life of 9-14 hrs, following single doses. Maraviroc is a CYP 3A4 substrate; thus concentrations are increased by potent CYP 3A4 inhibitors (such as Ketoconazole, saquinavir and ritonavir) and decreased by CYP 3A4 inducers (such as rifampicin and efavirenz)(9).

Studies have demonstrated the efficacy of short-term (10 days) Maraviroc monotherapy at a dose of 100 mg twice a day (8), and have also assessed the efficacy and safety of maraviroc in patients who received 150 or 300 mg once a day, or twice a day. Adverse events (e.g. diarrhoea, nausea, headache and fatigue) were recorded in about 90% of patients, but the rate was not different from that in the placebo plus optimized background regimen group (9). One of the major concerns with the use of CCR5 inhibitors, is the potential switch from R5 (CCR5 – using) to X4 (CXCR4 – using) viruses.

2. Vicriviroc (SCH 41760, SCH-D) (10)
Vicriviroc specifically binds to CCR5, and blocks cell migration that depends on CCL3, CCL4 and CCL5, and CCR5-dependent intracellular signaling at nanomolar concentrations. The plasma half-life of Vicriviroc is around 3-4 hrs. This drug does not substantially inhibit CYP450 enzymes, but it is a substrate for CYP3A4. Protease inhibitors such as ritonavir might enhance the plasma concentration of maraviroc and vicriviroc(10).

Vicriviroc shows broad antiviral activity against genotypic ally diverse R5-tropic HIV-I isolates in the nanomolar range. In studies, vicriviroc given as monotherapy in HIV-infected treatment-naïve patients for 14 days lowered the HIV RNA content by up to 1.6 log10. The doses which used in these studies are 25, 50 or 75 mg, once a day for 2 weeks. However, during follow-up, upto 57% (those at the lowest dose of 25 mg) of patients who were given vicriviroc showed a rebound in viral load to more than 50 copies per ml, compared with only 4% of patients in the efavirenz group (11).

Resistance to CCR5 drugs can also appear in the absence of a co-receptor switch. HIV-I might become resistant to vicriviroc or maraviroc by using CCR5, to which the inhibitor remains bound. Studies have shown that the virus might revert to R5 after discontinuation of CCR5 treatment (12),(13). Mutations conferring resistance to CCR5 inhibitors, in the absence of a co-receptor switch, are often present in the V3 region of gp120: in cell culture experiments and in vivo (12).

3. Aplaviroc (GSK873140) (14)
Aplaviroc is a novel spirodiketopiperazine (SDP) based CCR5 antagonist,,but because of potential toxic effects on the liver, later clinical trials of Aplaviroc were stopped(14).

4. Other CCR5 Antagonists(15)
Other CCR5 antagonists under various stages of clinical development,are PRO-140 (Progenics pharmaceuticals), TAK 220 (Takeda Chemical Industries) and AMD 887 (AnorMED).

Because HIV entry inhibitors are gaining importance as therapeutic agents, both genotypic and phenotypic assays which are used to assess drug resistance need to be in place, in particular, determination of the virus co-receptor is needed before initiation of a drug regimen containing a CCR5 inhibitor (9).

Adverse Events with CCR5 Antagonists (10)
Several studies have drawn attention to the role of CCR5 in innate immunity against several pathogens, including Toxoplasma gondii, West Nile Virus, Pox virus, tuberculosis and others. Genetic, biological or chemical CCR5 knockout could be simultaneously protective against some pathogens (i.e. HIV) and harmful for other processes implicated in pathogen containment (9).
The issue of potential adverse events with CCR5 antagonists was raised, when, in patients who received vicriviroc, five developed malignant tumours (four lymphoma and one gastric adenocarcinoma), suggesting a possible unpredicted target-related adverse effect. However, experts who reviewed the case histories, stated that they did not establish with any certainty, whether vicriviroc has a role in cancer (10).

CXCR4 ANTAGONISTS
The CXCR4 antagonists under development are AMD 11070(Anor MED) and KRH 2731(Kureha Chemical Industry Co. Limited). AMD 11070 is a strong and selective CXCR4 antagonist. It was equally active against X4 NRTI, NNRTI and PI resistant viruses. It was additive or synergistic when combined with other entry inhibitors (Enfuvirtide, AMD 887), reverse transcriptase (zidovudine, tenofavir) or protease inhibitors. This compound is currently under clinical trials (16) (17).

KRH 2731 (KRH-2731-5Hcl) is a novel orally bioavailable CXCR4 antagonist. It inhibited HIV-1X4 and R5X4 replication in animal models. The compound is under development by Kureha Chemical Industry Co. Limited.

Fusion Inhibitors(18)
1. Enfuvirtide
The large body of literature on Enfuvirtide, witnessed the record of Enfuvirtide as the first drug of the class of entry inhibitors to be approved in March 2003 by the US FDA, and to be licensed for the treatment of HIV-1 infection in the US, Australia and Europe (19).

Mechanism of Action (18)
Enfuvirtide is a synthetic analogue of the heptad repeat region (HR) 2 domain in gp41. Until recently, it was thought that Enfuvirtide interacted with HR1 to block the formation of the 6-helix bundle. However, recent research suggests that Enfuvirtide may target multiple sites in gp41 and gp120, including the gp120 co receptor binding site.

Pharmacokinetic Properties
Being a peptide, oral administration of enfuvirtide is not feasible, and on the other hand, intravenous administration is impractical and certainly not compatible with out patient self-administration. Nevertheless, several phase II and III clinical trials have shown that subcutaneous injection of enfuvirtide is generally well tolerated, and steady state concentrations of enfuvirtide are sustained for 12 hours following subcutaneous administration. Enfuvirtide has an apparent mean half-life of 3.8 hours after a single 90 mg subcutaneous dose. Absorption of enfuvirtide following subcutaneous administration to abdomen, thigh and arm was comparable, allowing HIV-1 infected patients the freedom to choose and to rotate, if necessary, the site of enfuvirtide injection among three anatomical sites.

Enfuvirtide did not inhibit the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 in an open label, crossover trial in 12 HIV infected adults (20).

Potential Drug Interactions
Enfuvirtide does not significantly affect the activity of the CYP enzymes or N-acetyltransferase. The presence of enfuvirtide had no clinically important or significant effects on the metabolism of the probe drugs. Enfuvirtide pharmacokinetics were not influenced by pretreatment with rifampicin or co-administration of ritonavir or saquinavir(21).

Therapeutic Efficacy
In the US, it is indicated in patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy, and in the EU, patients must be intolerant to previous antiretroviral regimens or have experienced treatment failure with at least one agent from each of the PI, NRTI and NNRTI classes.
The recommended dosage in adults aged >16 years is 90 mg twice daily, and in children and adolescents aged 6-16 years, it is 2 mg/kg twice daily, upto a maximum dosage of 90 mg twice daily.

Subcutaneous enfuvirtide improved virological and immunological outcomes in treatment-experienced HIV-infected adults who received 90 mg twice daily, in combination with an optimized background antiretroviral regimen compared with those who received optimized background therapy alone in the TORO trials. In the TORO trials (TORO 1, n=491 and TORO 2, n=504) a greater virological response to enfuvirtide at week 48 was observed in patients with a baseline viral load <5 log 10 copies / ml, baseline CD4 + cell count > 100 cells / L and prior treatment with < 10 antiretrovirals or > 2 active antiretrovirals in the background regimen. The rate of adherence to enfuvirtide treatment was high in the TORO trials, and most patients reported self-injection of enfuvirtide as `very easy’ or `easy’ at weeks 8, 24 and 48(22),(23).

Health Related QOL improved significantly in enfuvirtide plus optimized background therapy recipients as compared to those receiving optimized background therapy only (24).

Tolerability
According to a pooled analysis of 48 weeks TORO trial data, local injection-site reactions (pain / discomfort [96%], erythema [91%], induration [90%] and nodules or cysts [80%]) occurred in 98% of enfuvirtide recipients, on at least one occasion. Excluding injection site reactions, enfuvirtide was generally well tolerated. Pneumonia and lymphadenopathy occurred significantly more often with enfuvirtide plus optimized background therapy, than in optimized background therapy only. The incidence of systemic hypersensitivity reactions related to enfuvirtide was <1%. Tolerability data for enfuvirtide in children and adolescents are derived from clinical trials. Tolerability of the drug in this population is essentially similar to that observed in adults, with injection-site reactions as the most frequently reported adverse effect (22),(23).

Viral Resistance (25)
HIV resistance to enfuvirtide is primarily associated with mutations in the gene encoding for gp41. Resistance mutations were mapped to the usually highly conserved glycine-isoleucine-valine (GIV) sequence of the HR1 domain of gp41, following in-vitro pass aging of HIV in the presence of increasing concentrations of enfuvirtide. Development of the resistant phenotype is thought to require mutations in two of the three amino acid residues in the GIV sequence.

Resistance to other antiretroviral agents does not confer cross-resistance to enfuvirtide (25). Genotypic enfuvirtide resistance was rare in enfuvirtide naïve patients. The primary determinants of secondary resistance to enfuvirtide in isolates, recovered from patients who received enfuvirtide as monotherapy or in combination with other antiretrovirals, were mutations at gp41 amino acids 36-45(26).Resistant mutations often disappeared on discontinuation of enfuvirtide(27).

Pharmacoeconomic Considerations
The cost effectiveness of enfuvirtide has been analysed using decision-analysis models. In most analyses, the incremental cost-effectiveness ratios (ICERs) for enfuvirtide plus optimized background therapy, relative to optimized background therapy alone, were generally acceptable by current standards, remaining below the generally accepted thresholds of US$ 50,000 or 30,000 ₤ per life year, or quality-adjusted life-year (QALY) gained. The average cost of an enfuvirtide containing regimen is projected to range from US$ 1,617 to US$ 2,243 per 30 day supply. The 30 days cost for enfuvirtide alone is $ 1266(5).

Tifuvirtide (T-1249) (4)
Tifuvirtide is a second generation, once-daily HIV fusion inhibitor, also jointly developed by Trimeris and Roche. Similarly to enfuvirtide, tifuvirtide is administered subcutaneously, and blocks viral fusion by inhibiting the interaction of gp41 with the human cell. In case of enfuvirtide resistance, an alternative could be tifuvirtide. Inspite of promising results in phase I / II dose-escalation monotherapy studies, the announcement by Roche and Trimeris, that they have halted and put on indefinite hold further clinical development of tifuvirtide, was certainly a surprise. The decision was made not because of safety, efficacy and tolerability reasons, but because of challenges in achieving the technical profile required by the current investigational formulation of tifuvirtide. Despite halting clinical development of the drug, all participants now enrolled in clinical trial T-1249-105 will continue to receive free supplies of tifuvirtide to the 96-week endpoint, according to Roche. If necessary, Roche will amend the protocol to extend treatment with tifuvirtide beyond 96-weeks for patients who are still receiving a benefit.

The Future of HIV Entry Inhibitors
The recent addition of entry inhibitors to the therapeutic armamentarium against HIV-1 offers new hope for HIV infected individuals, ranging from the treatment naïve to heavily treatment-experienced individuals. Enfuvirtide, an approved HIV fusion inhibitor, has a pivotal role in optimizing response in treatment-experienced patients receiving new drug combination. Maraviroc, a CCR5 antagonist, has been approved by US FDA (October, 2007), and is at present, an expanded access programme for drug-experienced patients. Other entry inhibitors are in different stages of preclinical and clinical development. With more entry inhibitors completing the complex path towards a clear clinical benefit, the number of combinations with each other, and with the other existing drugs targeting different steps of the viral life-cycle, will grow exponentially. The expectation is that the final outcome may result in extra years of life gained for individuals engaged in the battle against the HIV disease. The very rapid process of development that led to the discovery of enfuvirtide, starting from the basic investigations on viral entry, will remain in biomedical records as a successful example of ‘bench to bedside’ research.

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