HIV HIV Antiretroviral Antiretroviral

TreatmentTreatmentBy: Richard BrittBy: Richard Britt

Dr. BuynakDr. Buynak

Spring 2006Spring 2006

Human Human Immunodeficiency VirusImmunodeficiency Virus

HIV is a Retrovirus which means:HIV is a Retrovirus which means: It contains a single-stranded RNA genomeIt contains a single-stranded RNA genome The HIV will incorporate it’s own genome The HIV will incorporate it’s own genome

into it’s host cell and hijack the normal into it’s host cell and hijack the normal functions of the cell to replicate itselffunctions of the cell to replicate itself

This process will eventually lead to cell This process will eventually lead to cell destructiondestruction

The target for HIV is the CD-4+ The target for HIV is the CD-4+ Helper T-Cells, which are the Helper T-Cells, which are the backbone of the immune system.backbone of the immune system.

SymptomsSymptoms

The Majority of Symptoms of an HIV infection The Majority of Symptoms of an HIV infection do not show up until the disease has already do not show up until the disease has already begun to damage the immune systembegun to damage the immune system

The incubation time for an HIV infection can The incubation time for an HIV infection can be several weeks to several yearsbe several weeks to several years

General symptoms include:General symptoms include: Lack of energy, weight loss, frequent fevers and Lack of energy, weight loss, frequent fevers and

sweats, persistent or frequent yeast infections, sweats, persistent or frequent yeast infections, persistent skin rashes or flakey skin, short-term persistent skin rashes or flakey skin, short-term memory loss, and mouth, genital, or anal sores memory loss, and mouth, genital, or anal sores from Herpes infectionsfrom Herpes infections

Opportunistic InfectionsOpportunistic Infections

HIV infection is usually discovered HIV infection is usually discovered when a patient is diagnosed with an when a patient is diagnosed with an unusually severe or persistent infectionunusually severe or persistent infection

Opportunistic infections include:Opportunistic infections include: Bacterial, Fungal, Parasitic, and Viral Bacterial, Fungal, Parasitic, and Viral

InfectionsInfections These infections will be more severe These infections will be more severe

because the person’s immune system because the person’s immune system will be surpressed by the HIV disease.will be surpressed by the HIV disease.

HIV DetailsHIV Details

RNA Genome is 9 kilobases long and RNA Genome is 9 kilobases long and contains 9 genes that encode 15 different contains 9 genes that encode 15 different protiensprotiens

Fusion targets of the viral surface Fusion targets of the viral surface envelope glycoprotiens is the CD4+ envelope glycoprotiens is the CD4+ receptor and its co-receptor CCR5 on the receptor and its co-receptor CCR5 on the surface of the T-lymphocytesurface of the T-lymphocyte

Envelope contains the following viral Envelope contains the following viral enzymes:enzymes: Reverse Transcriptase, Integrase, RNAse-HReverse Transcriptase, Integrase, RNAse-H

Basic StepsBasic Steps HIV fuses with host cell and releases its HIV fuses with host cell and releases its

genome and enzymes into the cellgenome and enzymes into the cell RNA genome is transcribed by Reverse RNA genome is transcribed by Reverse

Transcriptase into a single stranded viral Transcriptase into a single stranded viral DNADNA

Reverse Transcriptase acts as DNA Reverse Transcriptase acts as DNA Polymerase and transcribes the single Polymerase and transcribes the single stranded DNA into a Double Stranded Viral stranded DNA into a Double Stranded Viral DNADNA

DNA is then transported into the cell nucleus DNA is then transported into the cell nucleus and is integrated into the host cell DNA by and is integrated into the host cell DNA by the viral enzyme integrase.the viral enzyme integrase.

HIV LifecycleHIV Lifecycle

More Basic StepsMore Basic Steps

Normal functions of the cell resume Normal functions of the cell resume except now instead of transcribing RNA except now instead of transcribing RNA for the regular proteins of the cell it is for the regular proteins of the cell it is transcribing viral mRNAtranscribing viral mRNA

Viral Proteins are produced in one large Viral Proteins are produced in one large multi-protein chain from the viral mRNAmulti-protein chain from the viral mRNA

Viral Components move toward the cell Viral Components move toward the cell membrane and bud off into new membrane and bud off into new immature virionsimmature virions

HIV LifecycleHIV Lifecycle

More Basic StepsMore Basic Steps

Viral enzyme protease cleaves itself Viral enzyme protease cleaves itself from the viral protein massfrom the viral protein mass

The Viral Protease then matures the The Viral Protease then matures the virion by cutting up the protein mass virion by cutting up the protein mass into the individual viral enzymesinto the individual viral enzymes

The virion is a mature and infectious The virion is a mature and infectious virusvirus

HIV LifecycleHIV Lifecycle

Mature HIV VirusMature HIV Virus

Life Cycle Animation

Nucleoside Reverse Nucleoside Reverse Transcriptase Inhibitors Transcriptase Inhibitors

(NRTIs)(NRTIs) Zidovudine first drug in Zidovudine first drug in

this class approved by the this class approved by the FDA on March 20, 1987FDA on March 20, 1987

This class of drugs works This class of drugs works by inhibiting the action of by inhibiting the action of the viral enzyme reverse the viral enzyme reverse transcriptase.transcriptase.

This is accomplished by This is accomplished by taking the place of a DNA taking the place of a DNA peptide and prematurely peptide and prematurely terminating the terminating the transcription processtranscription process

NRTIs are phosphorylated NRTIs are phosphorylated three times after they three times after they enter the cell to become enter the cell to become successful inhibitorssuccessful inhibitors Zidovudine

(AZT or azidothymidine)

Nucleotide Reverse Nucleotide Reverse Transcriptase Inhibitors Transcriptase Inhibitors

(NtRTIs)(NtRTIs) In the same class In the same class

of drugs as NRTIs of drugs as NRTIs however these are however these are not required to be not required to be phosphorylated phosphorylated after they enter after they enter the cell.the cell.

Same mechanism Same mechanism of action as NTRIsof action as NTRIsLife Cycle Animation

Tenofovir Disproxil Fumarate (Viread®)

Non-Nucleoside Reverse Non-Nucleoside Reverse Transcriptase Inhibitors Transcriptase Inhibitors

(NNRTIs)(NNRTIs) Also act as inhibitors of Also act as inhibitors of

the viral enzyme reverse the viral enzyme reverse transcriptase however transcriptase however mechanism of action is mechanism of action is differentdifferent

This class of drugs This class of drugs works by non-works by non-competitive inhibitioncompetitive inhibition

The drug binds to the The drug binds to the viral enzyme at a place viral enzyme at a place other than the active other than the active site and changes the site and changes the conformation of the conformation of the active site decreasing active site decreasing the enzyme’s affinity for the enzyme’s affinity for nucleoside binding.nucleoside binding.

Nevirapine (Viramune®)

Life Cycle Animation

Protease InhibitorsProtease Inhibitors These work by These work by

competitive inhibition of competitive inhibition of the viral enzyme the viral enzyme protease protease

These drugs irreversibly These drugs irreversibly bind to the active site of bind to the active site of protease preventing it protease preventing it from completing the from completing the maturation of the virionmaturation of the virion

Protease inhibitors Protease inhibitors prevent immature prevent immature virions from becoming virions from becoming mature, infectious mature, infectious VirusesViruses

Sequinavir (Invirase®)

Low Bioavailability

Ritonvir (Norvir®)

More successful because it inhibits Cytochrome P450 3A4 which breaks down Protease Inhibitors

Life Cycle Animation

Mature HIV VirusMature HIV Virus

Life Cycle Animation

Fusion InhibitorsFusion Inhibitors Newest Class of DrugsNewest Class of Drugs This drug binds to the This drug binds to the

glycoprotein gp41 in the glycoprotein gp41 in the viral envelope inhibiting viral envelope inhibiting its fusion with the CD4+ its fusion with the CD4+ receptor on the host cell receptor on the host cell and thus preventing the and thus preventing the cell’s infection.cell’s infection.

Usually used as a last Usually used as a last line option for most line option for most patient because it is only patient because it is only available as an injection available as an injection and its high costand its high cost More than $25000 per More than $25000 per

yearyear

Enfuvirtide (Fuzeon®)

Life Cycle Animation

Fusion Inhibitors vs. Other Fusion Inhibitors vs. Other Classes of DrugsClasses of Drugs

History of Drug History of Drug DevelopmentDevelopment

1985 – research on anti-viral medication begins1985 – research on anti-viral medication begins 1987 – First drug Zidovudine produced1987 – First drug Zidovudine produced

First NRTIFirst NRTI Early life extending properties except only temporarily Early life extending properties except only temporarily

worked as patients became immuneworked as patients became immune Mid-1990s – Protease Inhibitors and NNRTIs Mid-1990s – Protease Inhibitors and NNRTIs

DevelopedDeveloped 1995 – first protease inhibitor Sequinavir approved by the 1995 – first protease inhibitor Sequinavir approved by the

FDAFDA Low Bioavailability led to the development of a second Low Bioavailability led to the development of a second

protease inhibitor Ritonvirprotease inhibitor Ritonvir 1996 first NNRTI, Nevirapine approved by FDA1996 first NNRTI, Nevirapine approved by FDA

March 2003 – First Fusion Inhibitor Enfuvirtide March 2003 – First Fusion Inhibitor Enfuvirtide approve by FDAapprove by FDA

Current ResearchCurrent ResearchHIV VaccineHIV Vaccine

Two methods of vaccine research Two methods of vaccine research showing promiseshowing promise Recombinant Subunit VaccinesRecombinant Subunit Vaccines Live Recombinant VaccinesLive Recombinant Vaccines

DisadvantagesDisadvantages

Recombinant Subunit VaccineRecombinant Subunit Vaccine If the recombinant viral envelope proteins that If the recombinant viral envelope proteins that

are included in the vaccine aren’t close enough in are included in the vaccine aren’t close enough in structure and composition to the actual HIV structure and composition to the actual HIV envelope proteins the antigens that are produced envelope proteins the antigens that are produced will be ineffective in fighting an actual HIV will be ineffective in fighting an actual HIV infectioninfection

Live Recombinant VaccineLive Recombinant Vaccine Can actually cause disease when it is trying to Can actually cause disease when it is trying to

prevent itprevent it Usually occurs when the person is Usually occurs when the person is

immunocompromisedimmunocompromised

SourcesSources Cervia, Joseph S. and Miriam A. Smith. “Enfuvirtide (T-20): A Novel Human Immunodeficiency Virus Type 1 Fusion Cervia, Joseph S. and Miriam A. Smith. “Enfuvirtide (T-20): A Novel Human Immunodeficiency Virus Type 1 Fusion

Inhibitor.” Inhibitor.” Clinical Infectious DiseasesClinical Infectious Diseases 2003; 37:1102-1106. NATAP.ORG. 5 April 2005. 2003; 37:1102-1106. NATAP.ORG. 5 April 2005. <http://www.natap.org/2003/oct/100703_1.htm>.<http://www.natap.org/2003/oct/100703_1.htm>.

Greenberg, Michael L. and Nick Cammack. “Resistance to enfuvirtide, the first HIV fusion inhibitor.” Greenberg, Michael L. and Nick Cammack. “Resistance to enfuvirtide, the first HIV fusion inhibitor.” The Journal of The Journal of Antimicrobial ChemotherapyAntimicrobial Chemotherapy. 2004 54(2):333-340. Oxford Journals; British Society for Antimicrobial Chemotherapy: . 2004 54(2):333-340. Oxford Journals; British Society for Antimicrobial Chemotherapy: 2004. 5 April 2006. <http://jac.oxfordjournals.org/cgi/content/full/54/2/333>.2004. 5 April 2006. <http://jac.oxfordjournals.org/cgi/content/full/54/2/333>.

““HIV/AIDS.” HIV/AIDS.” eMedicine Consumer HealtheMedicine Consumer Health. WebMD: 2003-2006. 5 April 2006. . WebMD: 2003-2006. 5 April 2006. <http://www.emedicinehealth.com/hivaids/article_em.htm>.<http://www.emedicinehealth.com/hivaids/article_em.htm>.

““HIV Fusion Inhibitor.” HIV Fusion Inhibitor.” PanacosPanacos. Panacos Pharmaceuticals Inc.: 2006. 5 April 2006. . Panacos Pharmaceuticals Inc.: 2006. 5 April 2006. <http://www.panacos.com/product_3.htm>.<http://www.panacos.com/product_3.htm>.

“ “HIV Lifecycle” HIV Lifecycle” Roche-HIV.comRoche-HIV.com. F. Hoffmann-La Roche Ltd.: 2006. 5 April 2006. . F. Hoffmann-La Roche Ltd.: 2006. 5 April 2006. <http://www.roche-hiv.com/Newsandfeatures/animations/lifecycle/lifecycle_animation.cfm?link=HIVTreatment#><http://www.roche-hiv.com/Newsandfeatures/animations/lifecycle/lifecycle_animation.cfm?link=HIVTreatment#>

““Maenza, Janine, and Charles Flexner. "Combination antiretroviral therapy for HIV infection." Maenza, Janine, and Charles Flexner. "Combination antiretroviral therapy for HIV infection." American Family American Family PhysicianPhysician 57.n11 (June 1998): 2789(10).  57.n11 (June 1998): 2789(10). InfoTrac OneFileInfoTrac OneFile. Thomson Gale. Southern Methodist University. 5 April 2006 . Thomson Gale. Southern Methodist University. 5 April 2006 <http://find.galegroup.com/itx/infomark.do?&contentSet=IAC-<http://find.galegroup.com/itx/infomark.do?&contentSet=IAC-Documents&type=retrieve&tabID=T002&prodId=ITOF&docId=A20881343&source=gale&userGroupName=txshracd25Documents&type=retrieve&tabID=T002&prodId=ITOF&docId=A20881343&source=gale&userGroupName=txshracd2548&version=1.0>.48&version=1.0>.

Peiperl, Laurence, Susa Coffey, and Paul Volberding. “HIV InSite Knowledge Base.” Comprehensive on-line textbook of Peiperl, Laurence, Susa Coffey, and Paul Volberding. “HIV InSite Knowledge Base.” Comprehensive on-line textbook of HIV disease from the University of California San Francisco and San Francisco General Hospital. Regents of the HIV disease from the University of California San Francisco and San Francisco General Hospital. Regents of the University of California: 2006. 5 April 2006. <http://hivinsite.ucsf.edu/InSite.jsp?page=KB>.University of California: 2006. 5 April 2006. <http://hivinsite.ucsf.edu/InSite.jsp?page=KB>.

Phillips, Kenneth D. "Protease inhibitors: a new weapon and a new strategy against HIV." Phillips, Kenneth D. "Protease inhibitors: a new weapon and a new strategy against HIV."  Journal of the Association of Journal of the Association of Nurses in AIDS CareNurses in AIDS Care 7.n5 (Sept-Oct 1996): 57(15).  7.n5 (Sept-Oct 1996): 57(15). InfoTrac OneFileInfoTrac OneFile. Thomson Gale. Southern Methodist University. 5 . Thomson Gale. Southern Methodist University. 5 April 2006 April 2006 <http://find.galegroup.com/itx/infomark.do?&contentSet=IAC-<http://find.galegroup.com/itx/infomark.do?&contentSet=IAC-Documents&type=retrieve&tabID=T002&prodId=ITOF&docId=A18944501&source=gale&userGroupName=txshracd25Documents&type=retrieve&tabID=T002&prodId=ITOF&docId=A18944501&source=gale&userGroupName=txshracd2548&version=1.0>.48&version=1.0>.

““Primate Lentivirus Group: HIV-1, HIV-2.” Primate Lentivirus Group: HIV-1, HIV-2.” Daniele FocosiDaniele Focosi. 2001-2005. 5 April 2006. . 2001-2005. 5 April 2006. <http://focosi.altervista.org/pathoviruses_HIV.html><http://focosi.altervista.org/pathoviruses_HIV.html>

Reisberg, Paul. “HIV Part 1.” Wellesley Chemistry Department: March 8, 1999. 5 April 2006. Reisberg, Paul. “HIV Part 1.” Wellesley Chemistry Department: March 8, 1999. 5 April 2006. <http://www.wellesley.edu/Chemistry/Chem101/hiv/HIV-1.html><http://www.wellesley.edu/Chemistry/Chem101/hiv/HIV-1.html>

““Simple Facts Project.” Simple Facts Project.” AIDS Treatment Data NetworkAIDS Treatment Data Network. The Network: 2002. 5 April 2005. . The Network: 2002. 5 April 2005. <http://www.aegis.com/factshts/network/sf.html>.<http://www.aegis.com/factshts/network/sf.html>.

Stanic, Anela, and Tulip K. Schneider. "Overview of antiretroviral agents in 2005." Stanic, Anela, and Tulip K. Schneider. "Overview of antiretroviral agents in 2005."  Journal of Pharmacy Journal of Pharmacy PracticePractice 18.4 (August 2005): 228.  18.4 (August 2005): 228. InfoTrac OneFileInfoTrac OneFile. Thomson Gale. Southern Methodist University. 07 February 2006 . Thomson Gale. Southern Methodist University. 07 February 2006 <http://find.galegroup.com/itx/infomark.do?&contentSet=IAC-<http://find.galegroup.com/itx/infomark.do?&contentSet=IAC-Documents&type=retrieve&tabID=T002&prodId=ITOF&docId=A137362742&source=gale&srcprod=ITOF&userGroupNDocuments&type=retrieve&tabID=T002&prodId=ITOF&docId=A137362742&source=gale&srcprod=ITOF&userGroupName=txshracd2548&version=1.0>.ame=txshracd2548&version=1.0>.

Zapor, Michael J., Cozza, Kelly L., et al. “Antiretrovirals, Part II: Focus on Non-Protease Inhibitor Antiretrovirals (NRTIs, Zapor, Michael J., Cozza, Kelly L., et al. “Antiretrovirals, Part II: Focus on Non-Protease Inhibitor Antiretrovirals (NRTIs, NNRTIs, and Fusion Inhibitors).” NNRTIs, and Fusion Inhibitors).” PsychosomaticsPsychosomatics; 45:6 (Nov – Dec 2004): 524-535. 5. April 2006 ; 45:6 (Nov – Dec 2004): 524-535. 5. April 2006 <http://psy.psychiatryonline.org/cgi/reprint/45/6/524>.<http://psy.psychiatryonline.org/cgi/reprint/45/6/524>.