MID 41. Antiretroviral Therapy. The Life Cycle of HIV-1. Nucleoside Analog RT Inhibitors. Antiretroviral Agents

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1 Antiretroviral Agents Antiretroviral Therapy Scott. Hammer,.D. Every step in viral life cycle is a potential antiviral target Currently there are 7 classes of FDA approved agents - Nucleoside analog reverse transcriptase inhibitors (NsTs) - Nucleotide analog reverse transcriptase inhibitor (NtT) - Non-nucleoside reverse transcriptase inhibitors (NNTs) - Protease inhibitors (Ps) - Fusion inhibitor (enfuvirtide)» Entry inhibitor which targets the virus - CC5 antagonist inhibitors (maraviroc)» Entry inhibitor which targets the host - ntegrase inhibitors (raltegravir) Drugs must be used in combination to be effective - This has led to dramatic reductions in morbidity and mortality where AT has been introduced effectively Current therapies are imperfect - Toxicities - Drug resistance ZD monox Alternative NT monox Combination NT x ntroduction of NNT s Antiretroviral resistance Pathogenetic concepts Evolution of Antiretroviral Therapy End of ZD monox era Benefit of combination x proven ntroduction of protease inhibitors e-emergence of NNT s ntroduction of viral load monitoring Elucidation of viral dynamics nowledge of viral reservoirs Capacity for immune restoration mportance of chemokine receptors eductions in morbidity & mortality ntroduction of resistance testing etabolic complications of therapy eality of new classes of agents Swings in approach to x A rollout in developing countries Nucleoside (ns) and Nucleotide (nt) Analog T nhibitors Zidovudine (ZD, AZT) Didanosine (dd) Zalcitabine (ddc) Stavudine (d4t) nst s amivudine (3TC) Abacavir (ABC) Emtricitabine (FTC) Tenofovir disoproxil fumarate (TDF) ntt N.B.: Four fixed dose combinations are approved: ZD + 3TC (Combivir ); ZD + 3TC + ABC (Trizivir ); 3TC + ABC (Epzicom ); FTC + TDF (Truvada ) The ife Cycle of H-1 Structural Protein and Enzyme Precursors Nucleoside Analog T nhibitors iral NA iral DNA iral NA 1. Binding and infection 2. everse transcription and integration of viral DNA 3. Transcription and translation 4. odification and assembly 5. Budding and final assembly Zidovudine Didanosine

2 Nucleoside Analog T nhibitors Non-Nucleoside T nhibitors First class of anti-h agents developed Active vs. H-1 and H-2 Need to undergo intracellular anabolic phosphorylation to triphosphate form of the drug or metabolic intermediate to be active vs. H echanism - NT-TP s inhibit the H T by competing with normal nucleoside triphosphates for incorporation into growing proviral DNA chain - iral DNA chain elongation terminated» Absence of 3 -OH group on sugar moiety prevents addition of another nucleotide - iral replication ceases Nevirapine Efavirenz Nucleotide Analog T nhibitors Tenofovir disoproxil fumarate (TDF) - A prodrug - Contains a phosphate group so only needs to be diphosphorylated intracellularly to be active» Tenofovir-diphosphate is the active moiety - Competiive inhibitor of H T Non-Nucleoside T nhibitors Second class of anti-h agents developed Potent but subject to rapid emergence of resistance Active vs. H-1 (except Group O) nactive vs. H-2 Parent molecules are the active moieties echanism - NNT s inhibit the H-1 T by binding to hydrophobic pocket on the enzyme close to the active site» ay lock active site in an inactive conformation Non-Nucleoside T nhibitors H T: Structure Nevirapine (NP) Delavirdine (D) Efavirenz (EFZ) Etravirine (ET) Huang H, Chopra, erdine G & Harrison SC: Science 1998;282:

3 NNT s: Drug nteractions etabolized by CYP3A4 isozyme of hepatic p450 system NP and EFZ are inducers of CYP3A4 D is an inhibitor of CYP3A4 Potential for major drug interactions with numerous H (esp. P s) and non-h agents Do not prescribe without first checking for potential drug interactions - ay be contraindications or need for dose adjustment(s) Protease nhibitors Third class of anti-h agents developed Potent - evolutionized therapy following introduction in 1996 Active vs. H-1 and H-2 echanism - P s inhibit the H protease by binding to active site and preventing the cleavage of gag and gag-pol precursor polyproteins - irions are produced but they are incomplete and noninfectious Protease nhibitors Protease Structure: utations Associated With educed in vitro Susceptibility to opinavir Saquinavir (SQ)* itonavir (T) ndinavir (D)* Nelfinavir (NF) Amprenavir (AP)* opinavir/ritonavir (P/r)* Atazanavir (AT)* Fosamprenavir (fos-ap)* Tipranavir (TP)* Darunavir (D)* *Typically prescribed with low-dose ritonavir for pharmacologic boosting. opinavir is coformulated with ritonavir. Protease nhibitors P s: Drug nteractions etabolized by CYP3A4 isozyme of hepatic p450 system nhibit CYP3A4 to varying degrees - itonavir is one of the most potent CYP3A4 inhibitors known» Basis for using low-dose T as pharmacoenhancer of other P s» One approved P, P, is coformulated with T Potential for major drug interactions with numerous H (esp. NNT s) and non-h agents Do not prescribe without first checking for potential drug interactions - ay be contraindications or need for dose adjustment(s) ndinavir itonavir

4 H Entry Target cell membrane ENF Enfuvirtide nhibition of H Fusion gp41 H1 X X H2 iral membrane eceptor Binding Fusion ntermediate X H2- Zipping X Six-Helix Bundle Formation ENF nhibition Enfuvirtide (Fusion nhibitor): echanism of Action CC5 Antagonist: araviroc odel for H-Cell Fusion Percentage of H Co-receptor Usage Target cell membrane gp41 H1 Study/Source Homer cohort 1 C & W cohort 2 Demarest 3 Population Naive Naive Naive N % 81% 88% X4 <1% <1% 0% 5/X4 18% 19% 12% H2 TOO 1/2 4 Experienced % 4% 34% iral membrane eceptor Binding Fusion ntermediate H2- Zipping Six-Helix Bundle Formation iroogic 5 ACTG Experienced Experienced > % 49% *This table may not include all available reported data. ajority of data are generated in the developed world (subtype B) 2% 4% 50% 47% 1 Brumme Z, et al. J nfect Dis. 2005;192: oyle GJ, et al. J nfect Dis. 2005;191: Demarest J, et al. CAAC Abstract H Whitcomb J, et al. CO Abstract Paxinos EE, et al. CAAC Abstract Wilkin T, et al. CO Abstract 655.

5 CC5 antagonist CC5 Antagonists Target H Binding and Fusion With CD4+ T Cells ntegrase nhibitor: altegravir CD4 CC5 T-cell surface Binding of CC5 Antagonist Causes a Conformational Change H ntegration CD4 CC5 CC5 antagonist T-cell surface H-1 gp41 gp120 altegravir: An H-1 ntegrase nhibitor N N O O H N O N N O - + H N O F CD4 CC5 CC5 antagonist T-cell surface echanism of action - nhibits DNA strand transfer from provirus into host cell genome a key step in viral integration process Potent in vitro activity» C 95 = 33 n ± 23 n in 50% human serum» Active against: - multi-drug resistant H-1 - CC5 and CXC4 H-1» H resistant to raltegravir remains sensitive to other ATs» Synergistic in vitro with all ATs tested

6 Nucleoside T s Zidovudine (ZD) Didanosine (dd) Zalcitabine (ddc) Stavudine (d4t) amivudine (3TC) Abacavir (ABC) Emtricitabine (FTC) Nucleotide T Tenofovir DF (TDF) Antiretroviral Agents Approved in the U.S. Non-Nucleoside T s Nevirapine (NP) Delavirdine (D) Efavirenz (EFZ) Etravirine (ET) ntegrase nhibitor altegravir (A) N.B.: Six fixed-dose combinations are approved: ZD + 3TC (Combivir ); ZD + 3TC + ABC (Trizivir ); ABC + 3TC (Epzicom ); FTC + TDF (Truvada ); P + T (aletra ); TDF + FTC + EF (Atripla ) Protease nhibitors Saquinavir (SQ) itonavir (T) ndinavir (D) Nelfinavir (NF) Amprenavir (AP) opinavir/r (P/r) Atazanavir (AT) Fosamprenavir (Fos-AP) Tipranavir (TP) Darunavir (D) Fusion nhibitor Enfuvirtide (T-20) CC5 Antagonist araviroc (C) ationale for nitiation of Therapy Before CD4 Cell Counts Fall to 350/μ - Uncontrolled H replication and resultant immune activation associated with non-ads illnesses» Cardiovascular» Hepatic» enal» alignancies - Patients with CD4 counts >350/μ and H-1 NA levels >400 copies/m have greater morbidity and mortality than those with viral suppression» Definition of H-related disease progression should be revisited - Potential for decreased horizontal H-1 transmission Non-ADS Conditions Since 2006, a number of non-ads conditions have been described to be associated with uncontrolled H-1 viremia, even in persons with relatively well preserved CD4 cell counts (e.g., >350/mm 3 ) - Cardiovascular events - Hepatic disease - enal disease - alignancies Direct effect of H-1 on organ systems, associated immune activation and/or other mechanisms may be involved Active area of investigation edefining H-related disease progression and influencing decision of when to start AT When to Start Therapy: Balance Tipping in Favor of Earlier nitiation Drug toxicity Preservation of limited x options ater Potency, durability, simplicity and safety of current regimens mproved formulations and P Enhanced adherence Diminished emergence of resistance ore treatment options ecognition of deleterious effect of uncontrolled viremia at all CD4 levels Earlier nitiation of Therapy in Established H nfection: Considerations Patient s disease stage - Symptomatic status - CD4 cell count - Plasma H-1 NA level - Presence of, or risk factors for, non-ads conditions» Cardiovascular, hepatic and renal disease Patient s commitment to therapy Philosophy of treatment - Pros and cons of early intervention When to Start Antiretroviral Therapy easure ecommendation Comments Symptomatic H disease Therapy recommended Asymptomatic H disease CD4 <350/µl Therapy recommended ecommendation strengthened since 2006 CD4 >350 Therapy should be considered and decision individualized Examples Correlates of faster H disease progression: High viral load (>100,000 NA copies/ml) apidly declining CD4 (>100/µl per year) Coexistent conditions influenced by uncontrolled viremia: Presence of, or high risk for, cardiovascular disease Active HB or HC coinfection H-associated nephropathy

7 Choice of nitial egimen At baseline: Evaluate for hepatitis B or C coinfection, diabetes mellitus, hyperlipidemia, coronary artery disease, renal disease, other comorbid conditions and medications Perform resistance testing Assess for pregnancy or risk thereof egimen: Nonnucleoside reverse transcriptase inhibitor (NNT)-based or itonavir (r)-boosted protease inhibitor (P)-based Either (NNT or P/r) combined with a dual nucleoside/nucleotide reverse transcriptase inhibitor (nt) component Antiretroviral Therapy Failure Clinical - Disease progression» Needs to be distinguished from immune reconstitution syndrome mmunologic - CD4 cell count decline irologic - Plasma H-1 NA rise Choice of nitial egimen (cont d) Component Drugs Comments NNT component efavirenz EF: teratogenic in 1 st trimester NP (alternative): increased risk of hepatotoxicity in women with CD4 >250/µl and men with CD4 >400/µl P/r component Dual nt component lopinavir/r, atazanavir/r, fosamprenavir/r, darunavir/r or saquinavir/r tenofovir/emtricitabin e or abacavir/lamivudine AT/r: diminished hyperlipidemic potential; care with antacids D/r: important role in treatment-experienced patients ZD/3TC: alternative ABC: Screen for HA-B*5701 to decrease risk of HS;?increased risk of cardiovascular disease ABC/3TC:?efficacy when viral load >100,000 c/ml easons for Drug Failure esistance Adherence Pharmacologic factors nsufficiently potent regimens Sanctuaries Cellular mechanisms of resistance Host immune status Simplification of Therapy D ZD 3TC EF/TDF/FTC imitations of Currently Available Agents Some regimens remain complex - Particularly for treatment experienced patients or those who may have primarily acquired drug resistant virus» Approximately 10% of new infections are with drug resistant virus in the U.S. and Europe Negative effects on quality of life Toxicities, particularly metabolic - Hyperlipidemia, fat redistribution, insulin resistance, decreased bone density, mitochondrial dysfunction Drug class cross resistance Drug interactions (esp. for NNTs and Ps) Submaximal potency Cost

8 Antiretroviral Therapy elated ipodystrophy ipoatrophy ipoaccumulation H esistance: Underlying Concepts mplications - esistance mutations may exist before drug exposure and may emerge quickly after it is introduced - Drugs which develop high level resistance with a single mutation are at greatest risk» e.g., 3TC, FTC, NNT s (nevirapine, efavirenz) - esistance to agents which require multiple mutations will evolve more slowly - Partially suppressive regimens will inevitably lead to emergence of resistance - A high genetic barrier needs to be set to prevent resistance» Potent, combination regimens allon PWG, Cooper DA and Carr A: H edicine 2001;2: utations Selected by nts/ntts H esistance: Underlying Concepts Zidovudine E D D N 118 T W YF QE E D T Genetic variants are continuously produced as a result of high viral turnover and inherent error rate of T - utations at each codon site occur daily» Survival depends on replication competence and presence of drug or immune selective pressure - Double mutations in same genome also occur but 3 or more mutations in same genome is a rare event - Numerous natural polymorphisms exist Stavudine D Didanosine Zalcitabine Abacavir E amivudine 44 D Emtricitabine N T D Y 115 F W YF QE Tenofovir 65 Pre-existence of esistant utants The Two Principal echanisms of esistance of H to Nucleoside Analogues iral replication cycles: /day T error rate: /base/cycle H genome: 10 4 bp Every point mutation occurs times/day Clavel F et al: N Engl J ed 2004;350:

9 utations Selected by NNTs utations Selected by Ps (cont d) ulti-nnt esistance ulti-nnt esistance: Accumulation of utations N Y G A C SA Y 188 Nelfinavir D N A F N AFT DS T S Nevirapine Y Y G N A C CH A Saquinavir/ ritonavir G A G T S AF TS Delavirdine Y Y P N C Tipranavir /ritonavir E Q H T N F G T AE P T D Efavirenz Y Y G P N C SA H echanism of esistance of H to Nonnucleoside everse-transcriptase nhibitors H-1 Protease Dimer Binding with a Protease nhibitor (Panel A) and a Drug-Sensitive (Wild-Type) Protease Juxtaposed against a Drug-esistant Protease (Panel B) Clavel F et al: N Engl J ed 2004;350: Clavel F et al: N Engl J ed 2004;350: utations Selected by Ps utations in the gp41 Envelope Gene Associated With esistance to Enfuvirtide Atazanavir +/-ritonavir G FC E E G F D A G Q Y E CSTA T F TA T N ATF S Enfuvirtide G Fosamprenavir ritonavir F S AFT S Darunavir/ ritonavir G S F 89 G 36 D S A E Q 39 Q N N First heptad repeat (H1 egion) H T D ndinavir/ ritonavir A G T SA AFT opinavir/ ritonavir F A G F F A A P T S AFT S TS

10 araviroc esistance Csens virus Cres virus Adults and Children Estimated to be iving with H in 2007 Free receptor wt gp120 gp120 binding site on CC5 High affinity utated gp120 recognizes CC5 Cres gp120 differently High affinity C ( ) Bound to CC5 Binding site Disrupted by C ery low affinity Binding site NOT disrupted by C High affinity Adapted from osley et al. 13th CO 2006; abstract 598.