chemical pathology ii hiv aids
TRANSCRIPT
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MANAGEMENT OF HIVMANAGEMENT OF HIV
INFECTED PATIENTSINFECTED PATIENTS&&
METABOLICMETABOLIC
COMPLICATIONS OFCOMPLICATIONS OF
HAARTHAART
A SEMINAR PRESENTATION BYA SEMINAR PRESENTATION BY
GROUP 3GROUP 3
Coordinator - Dr. S.A Adebisi
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INTRODUCTIONINTRODUCTION
Human Immunodeficiency Virus (HIV)Human Immunodeficiency Virus (HIV)infection is a chronic non curable butinfection is a chronic non curable butcontrollable condition.controllable condition.
The clinical manifestation of HIV infectionThe clinical manifestation of HIV infectionis a syndrome called Acquired Immuneis a syndrome called Acquired Immune
Deficiency Syndrome (AIDS)Deficiency Syndrome (AIDS)
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Management of HIV infectionManagement of HIV infection
involves the following steps:involves the following steps: Proper History takingProper History taking
Past medical history eg history of bloodPast medical history eg history of bloodtransfusiontransfusion
Social history eg multiple sexual partnersSocial history eg multiple sexual partners Family historyFamily history
Proper physical examinationProper physical examination Appropriate investigation eg lentiviral screeningAppropriate investigation eg lentiviral screening
testtest Treatment using both pharmacologic and nonTreatment using both pharmacologic and non--
pharmacologic approachpharmacologic approach
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AIMS OF MANAGEMENTAIMS OF MANAGEMENT
To alleviate the symptoms of AIDS in order toTo alleviate the symptoms of AIDS in order tomaintain proper physical and mental healthmaintain proper physical and mental health
To avoid transmission of the virusTo avoid transmission of the virus To provide appropriate palliative support as neededTo provide appropriate palliative support as needed To provide psychological support for patients asTo provide psychological support for patients as
well as their family and friendswell as their family and friends To achieve all these aims, a multidisciplinary teamTo achieve all these aims, a multidisciplinary team
approach is needed and patient confidentiality mustapproach is needed and patient confidentiality must
be strictly observed.be strictly observed.
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CURRENT TREATMENTCURRENT TREATMENT
GUIDELINESGUIDELINES Non Pharmacologic approachNon Pharmacologic approach
-- Strict confidentialityStrict confidentiality
-- Psychological support for patient as well asPsychological support for patient as well asfamily members, friends and care giversfamily members, friends and care givers-- Dietary advice and assessmentDietary advice and assessment-- Clear advice on reducing the risk of HIVClear advice on reducing the risk of HIV
transmissiontransmission Pharmacologic approachPharmacologic approach
--Use of Antiretroviral drugsUse of Antiretroviral drugs
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CLASSIFICATION OFCLASSIFICATION OF
ANTIRETROVIRAL DRUGSANTIRETROVIRAL DRUGS Reverse transcriptase inhibitorsReverse transcriptase inhibitors
Nucleoside analogues (NRTIs) eg Zidovudine,Nucleoside analogues (NRTIs) eg Zidovudine,Didanosine, LamivudineDidanosine, Lamivudine
Nucleotide analogues (NtRTIs) eg TenofovirNucleotide analogues (NtRTIs) eg Tenofovir Non nucleoside drugs eg Nevirapine, EfavirenzNon nucleoside drugs eg Nevirapine, Efavirenz
Protease inhibitors eg Nelfinavir, Amprenavir,Protease inhibitors eg Nelfinavir, Amprenavir,IndinavirIndinavir
Fusion inhibitors eg EnfurvitideFusion inhibitors eg Enfurvitide Integrase inhibitorsIntegrase inhibitors Entry inhibitorsEntry inhibitors
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None of these drugsNone of these drugs isis used alone in theused alone in thechemotherapy of HIV because of the highchemotherapy of HIV because of the highrisk of development of resistance thus arisk of development of resistance thus acombination therapy is employed in thecombination therapy is employed in theform of HAART (Highly Activeform of HAART (Highly Active
Antiretroviral Therapy) whichAntiretroviral Therapy) which is theis thecurrent WHO approved drug combinationcurrent WHO approved drug combinationregimenregimen
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Starting TherapyStarting Therapy
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INDICATIONS FOR THERAPYINDICATIONS FOR THERAPY1. Clinically advanced HIV disease1. Clinically advanced HIV disease
yy WHO Stage I or II HIV Disease with CD 4 Cell count
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Adherence
Access to medication
Life situation
Disease stage
Challenges to Successful HIV TherapyChallenges to Successful HIV Therapyand Considerations When Initiating Therapyand Considerations When Initiating Therapy
Replication rate - Viral load
Mutation rate resistance
Latent reservoirs of HIV
Virus Drug
Patient
Clinician
PotencyPotency PharmacokineticsPharmacokinetics
(dosage schedule)(dosage schedule)
TolerabilityTolerability
ToxicityToxicity
ConvenienceConvenience
ResistanceResistance
Clinician experience
Communication skills
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CHOICE OF DRUGS AND DRUGCHOICE OF DRUGS AND DRUG
COMBINATIONSCOMBINATIONSThe drug regimen used for starting therapyThe drug regimen used for starting therapy
must be formulated to suit each patientsmust be formulated to suit each patients
needsneedsTreatment is initiated with three drugsTreatment is initiated with three drugs
Two NRTIs, which form the backbone ofTwo NRTIs, which form the backbone of
the regimenthe regimen A boosted protease inhibitor or anA boosted protease inhibitor or an
NNRTINNRTI
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Basis of drug selectionBasis of drug selection
1.1. EffectivenessEffectiveness
2.2. Adherence issues eg Efavirenz is suitable for once dailyAdherence issues eg Efavirenz is suitable for once dailydosingdosing
3.3. Side effect profile and potential drug reactionsSide effect profile and potential drug reactions
4.4. Drug interactions e.g. Zidovudine blocks intracellularDrug interactions e.g. Zidovudine blocks intracellularphosphorylation of Stavudinephosphorylation of Stavudine
5.5. Resistance and cross resistance pattern of drugsResistance and cross resistance pattern of drugs
6.6. Psychologic state of the patient eg Drug of choice forPsychologic state of the patient eg Drug of choice fornaive patients include Abacavir, Didanosine, Lamivudine,naive patients include Abacavir, Didanosine, Lamivudine,Tenofovir and Zidovudine. Stavudine is notTenofovir and Zidovudine. Stavudine is notrecommended for such patients.recommended for such patients.
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Drug CombinationsDrug Combinations
The preferred initial regimens areThe preferred initial regimens are
1.1. Zidovudine + Lamivudine + EfavirenzZidovudine + Lamivudine + Efavirenz
2.2. Tenofovir + Emtricitabine + EfavirenzTenofovir + Emtricitabine + Efavirenz
3.3. Zidovudine + Lamivudine + LopinavirZidovudine + Lamivudine + Lopinavirboosted with Ritonavirboosted with Ritonavir
4.4. Tenofovir + Emtricitabine + LopinazirTenofovir + Emtricitabine + Lopinazirboosted with Ritonavirboosted with Ritonavir
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MONITORING THERAPYMONITORING THERAPY
After initiation of TherapyAfter initiation of Therapy-- Viral load measured 4Viral load measured 4--8 wks to assess efficacy8 wks to assess efficacy
. In nave patients viral load of < 50. In nave patients viral load of < 50 copies per mls shouldcopies per mls shouldbe achievedbe achieved within 3within 3--6 months of therapy6 months of therapy
. In heavily pre. In heavily pre--treated patients viral load of 1000 copies per mlstreated patients viral load of 1000 copies per mlsshould beshould be achieved within 3achieved within 3--6 months of therapy6 months of therapy
-- Regular clinical assessment should includeRegular clinical assessment should include-- clinical history and examinationclinical history and examination-- WeightWeight-- HIV Viral loadHIV Viral load-- CD 4 countCD 4 count-- FBCFBC
-- Liver and renal function tests.Liver and renal function tests.-- Fasting lipid profileFasting lipid profile-- Blood GlucoseBlood Glucose
Viral load and CD 4 count to be measured at 12 wks or 3 monthlyViral load and CD 4 count to be measured at 12 wks or 3 monthlyintervalsintervals
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Drug InteractionsDrug Interactions
Both protease inhibitors and NNRTIs areBoth protease inhibitors and NNRTIs aremetabolized through the cytochrome P450metabolized through the cytochrome P450
dependent pathway and some are able todependent pathway and some are able toinhibit and induce hepatic cytochromeinhibit and induce hepatic cytochrome
P450 enzyme system thus theyre capableP450 enzyme system thus theyre capable
of influencing both their own and otherof influencing both their own and otherdrug metabolic rates.drug metabolic rates.
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Drug Interactions may result in theDrug Interactions may result in the
followingfollowing1.1. Sub therapeutic or toxic drug levelsSub therapeutic or toxic drug levels
2.2. Risk of treatment failuresRisk of treatment failures
3.3. Development of viral resistanceDevelopment of viral resistance
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Circumstances that warrantCircumstances that warrant
stoppage of antiretroviral therapystoppage of antiretroviral therapy Cumulative toxicityCumulative toxicity Potential drug interaction with modificationPotential drug interaction with modification
needed to deal with another pressing problem.needed to deal with another pressing problem.E.g. treatment of Tuberculosis with antimicrobialE.g. treatment of Tuberculosis with antimicrobialagentsagents
Patients poor adherence which increases the riskPatients poor adherence which increases the riskof viral resistanceof viral resistance
Virologically failing therapy and multidrugVirologically failing therapy and multidrugresistant viral strainsresistant viral strains
Poor quality of life of patient despite treatmentPoor quality of life of patient despite treatment
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Limitations to HAART TherapyLimitations to HAART Therapy
1.1.Inability of the current drugs to clear HIV fromInability of the current drugs to clear HIV fromcertain intracellular poolscertain intracellular pools
2.2.The occurrence of serious side effectsThe occurrence of serious side effects3.3.Failure of strict drug adherenceFailure of strict drug adherence4.4.Complex drug interactionsComplex drug interactions5.5.The on going emergence of multiThe on going emergence of multi--drug resistantdrug resistant
viral strainsviral strains In case of resistance to HAART,In case of resistance to HAART,
-- MegaMega--HAART or Salvage therapyHAART or Salvage therapy-- one or two ARV that induce HIV mutationsone or two ARV that induce HIV mutations
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Main Reasons for Discontinuation ofMain Reasons for Discontinuation of
HAARTHAART
Other
8%
Toxicity
58%
Virological
Failure
14%
Nonadherence
20%
d Arminio Monforte et al. AIDS 2000;14:499-507d Arminio Monforte et al. AIDS 2000;14:499-507
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METABOLICMETABOLIC
COMPLICATIONSCOMPLICATIONSOFOF
HAARTHAART(Highly Active Antiretroviral Therapy)(Highly Active Antiretroviral Therapy)
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METABOLIC COMPLICATIONSMETABOLIC COMPLICATIONS
LipodystrophyLipodystrophy
Insulin resistanceInsulin resistance
Frank DiabetesFrank DiabetesMellitusMellitus
DyslipidaemiaDyslipidaemia
HyperbilirubinaemiaHyperbilirubinaemia
Bone DisordersBone Disorders
Lactic acidaemia &Lactic acidaemia &
acidosisacidosis PancreatitisPancreatitis
JaundiceJaundice
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LIPODYSTROPHYLIPODYSTROPHY
LipoatrophyLipoatrophy-- Peripheral and subcutaneous fat lossPeripheral and subcutaneous fat loss
-- Pathogenesis not clearly understood but some factorsPathogenesis not clearly understood but some factorshave been implicatedhave been implicated
-- Management involves change of drug regimen amongManagement involves change of drug regimen amongother practicesother practices
LipohypertrophyLipohypertrophy-- Dorsocervical fat accumulation patients may present asDorsocervical fat accumulation patients may present ashaving cushignoid syndromehaving cushignoid syndrome
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LipoatrophyLipoatrophy
Facial lipoatrophy characterised bysunken cheeks and hollow temples due to
buccal and subcutaneous fat loss
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LipohypertrophyLipohypertrophy
Fat redistribution in an HIV infected patient
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Metabolic SyndromeMetabolic Syndrome
Insulin Resistance & Frank type IIInsulin Resistance & Frank type IIdiabetesdiabetes
HyperinsulinaemiaHyperinsulinaemia
Impaired glucose intoleranceImpaired glucose intolerance
HypertriglyceridaemiaHypertriglyceridaemia
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Other lipid abnormalities andOther lipid abnormalities and
dyslipidaemiadyslipidaemia Increased high density lipoprotein (HDL)Increased high density lipoprotein (HDL)
Increased total cholesterolIncreased total cholesterol
HypertriglyceridaemiaHypertriglyceridaemia
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Managing dyslipidaemia in HIV-infected patients
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Bone disordersBone disorders
OsteopeniaOsteopenia
OsteoporosisOsteoporosis
As a result of high bone turnover withAs a result of high bone turnover withincreased levels of bone formation andincreased levels of bone formation andresorptionresorption
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Lactic acidosis and acidaemiaLactic acidosis and acidaemia
Characterised byCharacterised by Asymptomatic elevation of blood lactate levelsAsymptomatic elevation of blood lactate levels Acidemia is characterised by lactate levels > 2.5 mmol/LAcidemia is characterised by lactate levels > 2.5 mmol/L
Acidosis is characterised by an increase in venous lactateAcidosis is characterised by an increase in venous lactateconc. > 2.0mmol/L and pH levels < 7.30.conc. > 2.0mmol/L and pH levels < 7.30.Clinical features include constitutional symptoms such asClinical features include constitutional symptoms such asfatigue, malaise and weight loss. Multiorgan failure suchfatigue, malaise and weight loss. Multiorgan failure such
as dysarrthmias, respiratory failure, coma and evenas dysarrthmias, respiratory failure, coma and evendeath could occur.death could occur.
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ConclusionConclusion
The treatment of HIV infection has been complicated byThe treatment of HIV infection has been complicated byshortshort--term toxicities and longterm toxicities and long--term complications. Theterm complications. Thelatter were initially referred to as the components of thelatter were initially referred to as the components of the
"lipodystrophy syndrome." These complications are more"lipodystrophy syndrome." These complications are moreaccurately referred to as the morphologic and metabolicaccurately referred to as the morphologic and metaboliccomplications of HIV disease and ART. Although thesecomplications of HIV disease and ART. Although thesecomplications have been well described andcomplications have been well described andcharacterized, the mechanisms underlying theircharacterized, the mechanisms underlying their
occurrence remain elusive.occurrence remain elusive.These metabolic complications are life threatening andThese metabolic complications are life threatening andshould be taking into consideration in HIVshould be taking into consideration in HIV--infectedinfectedpatients and those patients on the HAART therapy.patients and those patients on the HAART therapy.
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