An Update On HIV An Update On HIV Pharmacotherapy Pharmacotherapy Gonzalo M.L. Bearman MD,MPH Gonzalo M.L. Bearman MD,MPH Assistant Professor of Medicine Assistant Professor of Medicine Associate Hospital Epidemiologist Associate Hospital Epidemiologist
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An Update On HIV An Update On HIV PharmacotherapyPharmacotherapy
Gonzalo M.L. Bearman MD,MPHGonzalo M.L. Bearman MD,MPHAssistant Professor of MedicineAssistant Professor of Medicine
–– HIV epidemiologyHIV epidemiology–– HIV natural historyHIV natural history–– Viral Dynamic and three compartment model of HIV infectionViral Dynamic and three compartment model of HIV infection
•• Current Current AntiretroviralsAntiretrovirals–– Nucleoside/Nucleotide AnalogsNucleoside/Nucleotide Analogs–– NNRTINNRTI–– PIPI–– Fusion InhibitorsFusion Inhibitors–– Once daily dosingOnce daily dosing
•• Highlight important toxicities and drug interactionsHighlight important toxicities and drug interactions•• DHHS guidelines for the use of DHHS guidelines for the use of antiretroviralsantiretrovirals•• Treatment failureTreatment failure
–– Compliance and barriers to adherenceCompliance and barriers to adherence
Natural History of HIV Infection INatural History of HIV Infection I
•• 10 billion new 10 billion new virionsvirions created and created and cleared dailycleared daily
•• 200 million CD4 cells destroyed daily 200 million CD4 cells destroyed daily (twice the rate of replacement by the (twice the rate of replacement by the hematopoietichematopoietic system)system)
Ho et al, Nature 1995;373:123Ho et al, Nature 1995;373:123
MACS cohort, MACS cohort, MellorsMellors,et al. Ann Intern Med 1997;126:946,et al. Ann Intern Med 1997;126:946
with with hepatomegaly hepatomegaly and and steatosis steatosis is rareis rare•• 1.3 cases/1,000 person years of NRTI exposure1.3 cases/1,000 person years of NRTI exposure
–– Must correlate blood lactate level with clinical presentationMust correlate blood lactate level with clinical presentation
•• Treatment Treatment –– Cessation of HAARTCessation of HAART–– Supportive managementSupportive management
Newer formulations and once daily Newer formulations and once daily dosing.dosing.•• Didanosine Didanosine ECEC-- once daily dosingonce daily dosing•• Stavudine Stavudine XRXR--once daily dosingonce daily dosing•• LamivudineLamivudine--300 mg 300 mg po qdpo qd•• NevirapineNevirapine--400 mg 400 mg po qdpo qd•• AtazanavirAtazanavir--400mg 400mg po qdpo qd•• TenofovirTenofovir--300 mg 300 mg po qdpo qd•• EmtricitabineEmtricitabine-- 200mg 200mg po qdpo qd
New nucleoside RTINew nucleoside RTI
•• EmtricitabineEmtricitabine ((EmtrivaEmtriva))–– One Capsule, Once daily One Capsule, Once daily
•• 200mg 200mg po qdpo qd–– Chemically structure similar to Chemically structure similar to Epivir Epivir (3TC)(3TC)
•• Clinical trials suggest that efficacy is similar to Clinical trials suggest that efficacy is similar to Epivir Epivir in in treatment naive patientstreatment naive patients
–– Likely not effective on Likely not effective on lamivudine lamivudine resistant virusresistant virus
•• Clinical activity against hepatitis B virus.Clinical activity against hepatitis B virus.–– Common side effects include headache, diarrhea, Common side effects include headache, diarrhea,
nausea and rashnausea and rash
Nucleoside/tide Analogs: Nucleoside/tide Analogs: Selected Drug InteractionsSelected Drug Interactions•• ZDV and ZDV and ganciclovirganciclovir: : leukopenialeukopenia•• ZDV and ZDV and ribavirinribavirin: antagonism : antagonism in vitroin vitro•• ZDV and d4T: antagonism, decreased CDZDV and d4T: antagonism, decreased CD44
•• ddIddI, , ddCddC, d4T: PN, d4T: PN--causing agentscausing agents•• ddIddI and other and other pancreatitispancreatitis--causing agentscausing agents•• ddIddI and d4T: methadone decreases levelsand d4T: methadone decreases levels•• ddIddI and and tenofovirtenofovir: increased : increased ddIddI levelslevels•• tenofovirtenofovir and and atazanaviratazanavir: decreased : decreased atazanaviratazanavir levels levels
must ‘boost’ 300mg ofmust ‘boost’ 300mg of atazanaviratazanavir with 100mg of with 100mg of ritonavirritonavir
Structures of NNRTI Structures of NNRTI -- NVP, DLV, EFVNVP, DLV, EFV
efavirenz (EFV)nevirapine (NVP)
delavirdine (DLV)
NNRTI: ToxicityNNRTI: Toxicity•• RashRash
–– Majority are mild to moderate in severity, Majority are mild to moderate in severity, occuring occuring within within the first several weeks of therapythe first several weeks of therapy
–– Most are confined to Most are confined to cutaneous cutaneous reactions onlyreactions only-- do not do not involve mucous membranes.involve mucous membranes.
HIV Protease Inhibitors (2)HIV Protease Inhibitors (2)
amprenavir (APV) lopinavir (LPV)
atazanavir (ATV)
PI: ToxicityPI: Toxicity
•• SQV: GISQV: GI•• RTV: GI, RTV: GI, circumoralcircumoral paresthesiasparesthesias•• IDV: IDV: nephrolithiasisnephrolithiasis, incr. indirect , incr. indirect bilirubinbilirubin•• NFV: diarrheaNFV: diarrhea•• APV: GI, rashAPV: GI, rash•• LPV: GI, diarrheaLPV: GI, diarrhea•• ATV: increased indirect ATV: increased indirect bilirubinbilirubin•• PIs as a class: increased hepatic PIs as a class: increased hepatic transaminasestransaminases, ,
hyperglycemia, hyperglycemia, lipodystrophylipodystrophy and and lipidemialipidemia, , increased bleeding in hemophiliacsincreased bleeding in hemophiliacs
New PI formulation: New PI formulation: fosamprenavirfosamprenavir
•• LexivaLexiva: : fosamprenavirfosamprenavir–– ‘‘prodrug’ prodrug’ of of ageneraseagenerase ((amprenaviramprenavir))–– Likely will not be effective in patients who are Likely will not be effective in patients who are
resistant to resistant to ageneraseagenerase–– For PI experienced patientFor PI experienced patient
•• 700 mg 700 mg fosamprenavirfosamprenavir and 100mg and 100mg ritonavirritonavir bidbid–– Advantage over Advantage over amprenaviramprenavir
•• Easier dosingEasier dosing•• Decreased incidence of nausea, diarrhea, abdominal Decreased incidence of nausea, diarrhea, abdominal
pain and pain and rashrash
New PI: New PI: AtazanavirAtazanavir•• Indicated both for PI naïve and PI experienced Indicated both for PI naïve and PI experienced
patientspatients•• Once daily dosing; preferably taken with food to Once daily dosing; preferably taken with food to
–– PI naive: 400mg PI naive: 400mg po qdpo qd–– PI experienced:300mg PI experienced:300mg atazanaviratazanavir/100mg /100mg norvirnorvir–– Boosted 300mg Boosted 300mg atazanaviratazanavir/100mg /100mg norvir norvir when when
administered with either administered with either efavirenzefavirenz or or tenofovirtenofovir•• Side effectsSide effects
–– Increased indirect Increased indirect bilirubinbilirubin–– May not increase triglycerides and LDL as do other May not increase triglycerides and LDL as do other
protease inhibitorsprotease inhibitors•• Impact on Impact on lipodystrophy lipodystrophy and CAD not well known yetand CAD not well known yet
PI: Selected Drug InteractionsPI: Selected Drug Interactions
•• RTV increases levels of other PIs (1.5RTV increases levels of other PIs (1.5--40X)40X)•• RTV, NFV, APV lower oral contraceptive levelsRTV, NFV, APV lower oral contraceptive levels•• APV lowers methadone levelsAPV lowers methadone levels
–– New CategoryNew Category•• Fusion Inhibitors/entry inhibitorsFusion Inhibitors/entry inhibitors
–– Fuzeon Fuzeon binds to gp41 protein thus preventing viral binding and binds to gp41 protein thus preventing viral binding and entry into Tentry into T--cellscells
–– IndicationIndication•• For HAART experienced patient with resistant virusFor HAART experienced patient with resistant virus•• InjectableInjectable formulation with bid dosingformulation with bid dosing
–– Side effects:Side effects:•• Skin irritation at injection site is most commonSkin irritation at injection site is most common•• Fatigue, insomnia and peripheral neuropathyFatigue, insomnia and peripheral neuropathy
Combination Therapy: 3 vs. 2Combination Therapy: 3 vs. 2
33--drugs: ~75% drugs: ~75% HIV RNA <400 cps/ml HIV RNA <400 cps/ml (compared to 37%)(compared to 37%)
ZDV/3TC vs. ZDV/3TC vs. ZDV/3TC/NFVZDV/3TC/NFV
AgouronAgouron 511511(N=297)(N=297)SaagSaag, AIDS 2001, AIDS 2001
33--drugs: ~80% drugs: ~80% HIV RNA <500 cps/ml HIV RNA <500 cps/ml (compared to 30(compared to 30--45%)45%)
ZDV/3TC vs. IDV vs. ZDV/3TC vs. IDV vs. ZDV/3TC/IDVZDV/3TC/IDV
EARLY RX:EARLY RX:•• HIV disease is progressiveHIV disease is progressive•• Rx decreases HIV RNA Rx decreases HIV RNA
(and resistance) and (and resistance) and increases CDincreases CD44(and immune function)(and immune function)
•• 6+ years of 6+ years of virologicvirologicsuppression demonstratedsuppression demonstrated
•• ? Decrease transmission
DELAYED RX:DELAYED RX:•• Risk of clinical progression Risk of clinical progression
low in early diseaselow in early disease•• Practical factors Practical factors
(adherence, toxicity, quality (adherence, toxicity, quality of life outweigh benefits in of life outweigh benefits in earlyearly--disease)disease)
•• Long term effects unknownLong term effects unknown•• Preserve rx options? Decrease transmission Preserve rx options
Based on Based on DHHS Guidelines 11/10/03 <www.DHHS Guidelines 11/10/03 <www.aidsinfoaidsinfo..nihnih..govgov>>
Goal of Antiretroviral TherapyGoal of Antiretroviral Therapy
•• To suppress HIV RNA (viral load level) To suppress HIV RNA (viral load level) as low as possible, for as long as possibleas low as possible, for as long as possible
•• To preserve or enhance immune functionTo preserve or enhance immune function
•• To delay clinical progression of HIV diseaseTo delay clinical progression of HIV disease
–– AbacavirAbacavir+ + ZidovudineZidovudine+ (or + (or StavudineStavudine) + ) + LamivudineLamivudine•• Should only be used when an NNRTIShould only be used when an NNRTI--based or PIbased or PI--based regimen based regimen
cannot or should not be used as initial Rxcannot or should not be used as initial Rx–– egeg..-- drugdrug--drug interactions; regimen complexitydrug interactions; regimen complexity
•• Randomized clinical trial comparing triple NRTI Randomized clinical trial comparing triple NRTI vs vs PIPI--based based regimens:regimens:
–– Substantially higher rate of early Substantially higher rate of early virologic virologic nonnon--response was seen in response was seen in the 3the 3--NRTI arm.NRTI arm.
•• TenofovirTenofovir//abacavirabacavir//lamivudine lamivudine or or tenofovirtenofovir//didanosinedidanosine//lamivudinelamivudineshould not be used as a sole antiretroviral agent for naïve or should not be used as a sole antiretroviral agent for naïve or treatment experienced patientstreatment experienced patients
DHHS Treatment Guidelines:DHHS Treatment Guidelines:Not RecommendedNot Recommended•• SingleSingle--drug therapy (drug therapy (monotherapymonotherapy): not potent, rapid resistance): not potent, rapid resistance•• TwoTwo--drug therapy: rapid development of resistancedrug therapy: rapid development of resistance•• Certain nucleoside pairs and antiretroviral components:Certain nucleoside pairs and antiretroviral components:
•• Protease inhibitorsProtease inhibitors–– AtazanavirAtazanavir++indinavirindinavir: potential additive: potential additive hyperbilirubinemiahyperbilirubinemia–– Saquinavir Saquinavir hard gel capsule; poor bioavailability (4%)hard gel capsule; poor bioavailability (4%)
•• 3 3 ––NRTI regimens containingNRTI regimens containing–– abacavirabacavir++tenofovirtenofovir++lamivudine lamivudine or or didanosinedidanosine++tenofovortenofovor++lamivudinelamivudine
•• HydroxyureaHydroxyurea: promotes toxicity of : promotes toxicity of didanosinedidanosine, increased peripheral neuropathy and , increased peripheral neuropathy and pancreatitispancreatitis
What about Once Daily Dosing?What about Once Daily Dosing?Nucleoside/Nucleotide Analogues Nonnucleoside Reverse Transcriptase Inhibitors Protease Inhibitors
M o s t o f th e s e m e d ic a t io n s h a v e b e e n s tu d ie d in c o m b in a t io n w ith tw ic e -d a i ly d ru g s , b u t h a v e n o t b e e n s tu d ie d a s c o m p o n e n ts o f a n e n t i r e ly o n c e -d a i ly r e g im e n .
O n e tr ip le n u c le o s id e re g im e n , a b a c a v ir + la m iv u d in e + te n o fo v ir h a s re c e n tly b e e n fo u n d to h a v e a h ig h ra te o f v iro lo g ic f a i lu re a n d s h o u ld b e a v o id e d .
What about Once Daily Dosing?What about Once Daily Dosing?•• few efficacy studies of oncefew efficacy studies of once--daily antiretroviral combinations daily antiretroviral combinations
have been conductedhave been conducted•• most are small and nonrandomized and must therefore be most are small and nonrandomized and must therefore be
interpreted with cautioninterpreted with caution•• regimens most thoroughly studied containregimens most thoroughly studied contain didanosinedidanosine,,
efavirenzefavirenz, and, and lamivudinelamivudine oror emtricitabineemtricitabinedidanosine + emtricitabine** + efavirenz
At 24 weeks, viral load <50 in 81%, compared to 70% in d4T arm. At 60 weeks, virologic failure in 7% versus 15% of d4T arm (by KM probability).
163 Better virologic and CD4 response and fewer adverse events in FTC-containing regimen
Largest RCT of a once-daily regimen
[12, 14]
Once Daily Dosing has not been extensively studied and these are not regimens of choice by DHHS guidelines.
Once Daily Dosing has not been extensively studied and these are not regimens of choice by DHHS guidelines.
Once Daily Dosing Caveats:Once Daily Dosing Caveats:
•• Paucity of longPaucity of long--term clinical trials with term clinical trials with comparison to potent twice daily regimenscomparison to potent twice daily regimens
•• CaveatCaveat--consequences of a missed dose:consequences of a missed dose:–– May result in inadequate drug exposure over a May result in inadequate drug exposure over a
defined time perioddefined time period–– Consequent higher probability for development of Consequent higher probability for development of
Monitoring CDMonitoring CD44 cell countscell counts•• When to measureWhen to measure
–– baseline (at time of diagnosis, 2 specimens)baseline (at time of diagnosis, 2 specimens)–– ongoing evaluations every 3ongoing evaluations every 3--6 months6 months
•• Treatment decisionsTreatment decisions–– based on trend over time (at least 2 values)based on trend over time (at least 2 values)
•• Significant change is >30% of absolute CDSignificant change is >30% of absolute CD44value (or >3% of CDvalue (or >3% of CD44 percentage)percentage)
Monitoring viral loadMonitoring viral load•• When to measureWhen to measure
–– at baseline (2 specimens, 1at baseline (2 specimens, 1--2 weeks apart)2 weeks apart)–– prior to initiation of antiretroviral rxprior to initiation of antiretroviral rx–– 22--8 weeks after initiation of rx8 weeks after initiation of rx–– ongoing evaluations every 3ongoing evaluations every 3--4 months4 months
•• Do not measure within 2Do not measure within 2--4 weeks of acute 4 weeks of acute illness or immunizationillness or immunization
•• Minimum sign. change is 3Minimum sign. change is 3--fold or 0.5 logfold or 0.5 logDHHS Guidelines 11/10/03 <www.DHHS Guidelines 11/10/03 <www.aidsinfoaidsinfo..nihnih..govgov>>
13 HIV clinical cohort studies13 HIV clinical cohort studies10 Europe, 2 Canada, 1 US10 Europe, 2 Canada, 1 US12574 individuals starting 12574 individuals starting >>3 drug ART3 drug ART73% had HIV RNA <400 73% had HIV RNA <400 cpmcpm at 6 monthsat 6 months
Why Does Treatment Fail Patients?Why Does Treatment Fail Patients?
•• AdherenceAdherence–– Complicated regimens, heavy pill burden, toxicityComplicated regimens, heavy pill burden, toxicity
•• Baseline resistance or crossBaseline resistance or cross--resistanceresistance•• Use of less potent antiretroviral regimensUse of less potent antiretroviral regimens•• Sequential Sequential monotherapymonotherapy•• Drug levels and drug interactionsDrug levels and drug interactions•• Tissue reservoir penetrationTissue reservoir penetration•• Patient ‘not ready’ to take Patient ‘not ready’ to take antiretroviralsantiretrovirals
HIV Drug Resistance PreHIV Drug Resistance Pre--existsexists
•• HIV genome contains 10,000 nucleotidesHIV genome contains 10,000 nucleotides•• Mutation rate of HIV is ~3 X 10Mutation rate of HIV is ~3 X 10--55
•• 10 billion 10 billion virionsvirions produced dailyproduced daily•• Therefore all single (and many double) Therefore all single (and many double)
mutations are produced dailymutations are produced daily•• Leads to extensive viral diversityLeads to extensive viral diversity
HIV Drug ResistanceHIV Drug Resistance
•• Clinical resistanceClinical resistance–– Follow HIV RNA on antiretroviral therapyFollow HIV RNA on antiretroviral therapy
•• Genotypic resistanceGenotypic resistance–– Perform Perform in vitroin vitro assay to assess substitutions in assay to assess substitutions in
viral genetic sequence; correlate with drug viral genetic sequence; correlate with drug resistanceresistance
•• Phenotypic resistancePhenotypic resistance–– Perform Perform in vitroin vitro assay to assess growth of viral assay to assess growth of viral
strain in the presence of antiretroviral drugsstrain in the presence of antiretroviral drugs
Use of drug resistance assaysUse of drug resistance assays•• RecommendedRecommended
–– virologicvirologic failure on rxfailure on rx–– suboptimal HIV RNA suppression after starting rxsuboptimal HIV RNA suppression after starting rx–– acute HIV infectionacute HIV infection
•• ConsiderConsider–– chronic HIV infection prior to starting rxchronic HIV infection prior to starting rx
•• Not usually recommendedNot usually recommended–– after discontinuation of drugsafter discontinuation of drugs–– HIV RNA <1000 copies/mlHIV RNA <1000 copies/ml
Current Approach to Salvage RxCurrent Approach to Salvage Rx
•• Review antiretroviral history; assess adherence, Review antiretroviral history; assess adherence, tolerability, and PK issuestolerability, and PK issues
•• Distinguish first/second from multiple failuresDistinguish first/second from multiple failures•• Perform resistance testing while on drugsPerform resistance testing while on drugs•• Identify susceptible drugs/drug classesIdentify susceptible drugs/drug classes•• Consider novel strategies Consider novel strategies
(PK enhancement with RTV; (PK enhancement with RTV; multidrugmultidrug regimens)regimens)•• Consider newer agents through expanded access or Consider newer agents through expanded access or
clinical trialsclinical trials•• Design a regimen with Design a regimen with >>3 active drugs (if possible)3 active drugs (if possible)
Antiretroviral Rx: ConclusionsAntiretroviral Rx: Conclusions•• Antiretroviral rx suppresses HIV RNA, improves Antiretroviral rx suppresses HIV RNA, improves
immune immune fxfx, decreases disease progression and , decreases disease progression and prolongs survival.prolongs survival.
•• The optimal time to begin therapy is not clear.The optimal time to begin therapy is not clear.•• The optimal initial rx is not clear, but there are The optimal initial rx is not clear, but there are
effective combination regimens available.effective combination regimens available.•• FirstFirst--line rx fails in 10line rx fails in 10--60% of patients.60% of patients.•• Resistance testing demonstrates benefits in selecting Resistance testing demonstrates benefits in selecting
antiretroviral therapy.antiretroviral therapy.•• There are a number of new drugs in development.There are a number of new drugs in development.•• Further research is needed.Further research is needed.
Question 1Question 1
•• EmtricitabineEmtricitabine (FTC) is similar in both structure (FTC) is similar in both structure and efficacy to which antiretroviral?and efficacy to which antiretroviral?–– A. A. StavudineStavudine–– B. B. NelfinavirNelfinavir–– C. C. TenofovorTenofovor–– D. D. LamivudineLamivudine
Question 2Question 2
•• Which would be a DEFINITE indication for Which would be a DEFINITE indication for initiating initiating antitretroviral antitretroviral therapy as per DHHS therapy as per DHHS guidelines?guidelines?–– A. Asymptomatic, CD4>250 but <350, VL > A. Asymptomatic, CD4>250 but <350, VL >
55,00055,000–– B. Asymptomatic, CD4<200, VL=30,000B. Asymptomatic, CD4<200, VL=30,000–– C. Asymptomatic, CD4>350, VL>55,000C. Asymptomatic, CD4>350, VL>55,000–– D. Asymptomatic, CD4>350, VL<55,000D. Asymptomatic, CD4>350, VL<55,000
Question 3Question 3
•• The most common side effect of the fusion The most common side effect of the fusion inhibitor Tinhibitor T--20 (20 (enfuvirtideenfuvirtide) is:) is:–– A. DiarrheaA. Diarrhea–– B. CNS side effectsB. CNS side effects-- vivid dreamsvivid dreams–– C. Skin irritation at injection site C. Skin irritation at injection site –– D. Hepatic D. Hepatic steatosis steatosis and lactic acidosisand lactic acidosis
Question 4Question 4
•• As per the DHHS guidelines, when is HIV As per the DHHS guidelines, when is HIV resistance testing not recommended?resistance testing not recommended?–– A. A. virologicvirologic failure while on treatmentfailure while on treatment–– B. suboptimal HIV RNA suppression after starting B. suboptimal HIV RNA suppression after starting
rxrx–– C. acute HIV infectionC. acute HIV infection–– D. HIV RNA <1000 copies/mlD. HIV RNA <1000 copies/ml
Question 5Question 5
•• Which most accurately describes the class Which most accurately describes the class level TOXICITY of protease inhibitors?level TOXICITY of protease inhibitors?–– A. Bone marrow suppression, anemiaA. Bone marrow suppression, anemia–– B. Increased hepaticB. Increased hepatic transaminasestransaminases, ,
hyperglycemia,hyperglycemia, lipodystrophylipodystrophy andand lipidemialipidemia, , increased bleeding in hemophiliacs.increased bleeding in hemophiliacs.
–– C. Lactic acidosis and hepatic C. Lactic acidosis and hepatic steatosissteatosis–– D. Rash and CNS side effects (vivid dreams)D. Rash and CNS side effects (vivid dreams)