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Dr, what Dr, what ’ ’ s wrong with my s wrong with my VL and CD4 ????. They VL and CD4 ????. They are now not improving are now not improving !!!! !!!!
Dr, whatDr, what’’s wrong with my s wrong with my VL and CD4 ????. They VL and CD4 ????. They are now not improving are now not improving !!!!!!!!
ARV Treatment FailureARV Treatment Failure
Dr. Ernesto Hernandez PerezDr. Ernesto Hernandez PerezCDC GreyCDC Grey’’s Hospitals Hospital
CASE PRESENTATIONCASE PRESENTATION
26 Year old female tested HIV positive in 2002 26 Year old female tested HIV positive in 2002 at Tb clinic, Hx. of STD, oral thrush and PTB on at Tb clinic, Hx. of STD, oral thrush and PTB on 2002, completed 6 months treatment.2002, completed 6 months treatment.Started at CDC GreyStarted at CDC Grey’’s 23/07/2002 s 23/07/2002 CD4CD4 20 20 , , started HAART Regimen 1a modified privately started HAART Regimen 1a modified privately (DDL,3TC, EFV)(DDL,3TC, EFV)Developed Molluscum Contagiosum on face and Developed Molluscum Contagiosum on face and diarrhoea 2 hrs after tablets.diarrhoea 2 hrs after tablets.
CASE PRESENTATIONCASE PRESENTATIONAbscess Right nipple.Abscess Right nipple.14/01/2003 come for review blood results, 14/01/2003 come for review blood results, satisfactory, satisfactory, CD4 117 CD4 117 ..C/o epigastric pain radiating round to the C/o epigastric pain radiating round to the back left side, no other GIT symptoms.back left side, no other GIT symptoms.Good appetite gained Good appetite gained 21 kgs21 kgs in 6 months.in 6 months.Plan Dx: Amylase and lactate, review in a Plan Dx: Amylase and lactate, review in a week.week.
CASE PRESENTATIONCASE PRESENTATION21/01/2003 back for results, lactate 21/01/2003 back for results, lactate 5.18 5.18 Amylase Amylase 177177 , LFT normal, clinically stable but , LFT normal, clinically stable but tired, abdomen negative.tired, abdomen negative.Problem: Problem: Hyperlactatemia ,Pancreatitis?.Hyperlactatemia ,Pancreatitis?.Plan Dx: Review in a week time.Plan Dx: Review in a week time.Plan Rx: substitute drugs started Kaletra, 4 Plan Rx: substitute drugs started Kaletra, 4 caps bid (for D4T and 3TC) and EFV 600 mgs caps bid (for D4T and 3TC) and EFV 600 mgs nocte. nocte. 28/01/2003 better, Amylase 91 normal lactate 28/01/2003 better, Amylase 91 normal lactate normal.normal.
CASE PRESENTATIONCASE PRESENTATION
24/06/2003 doing very well gained 6 Kgs 24/06/2003 doing very well gained 6 Kgs more CD4 more CD4 293!!,293!!, Chol Chol 6,56,5 TG 1,3 TG 1,3 normal.normal.Plan repeat Lipids in 3/12.Plan repeat Lipids in 3/12.23/09/2003 Asymptomatic, Chol 6,29, TG 23/09/2003 Asymptomatic, Chol 6,29, TG 1,25 normal.1,25 normal.Plan continue same treatment, repeat Plan continue same treatment, repeat blood in 3/12.blood in 3/12.
CASE PRESENTATIONCASE PRESENTATION
13/01/2004 very well, asymptomatic, 13/01/2004 very well, asymptomatic, gaining weight, gaining weight, CD4 457!!!.CD4 457!!!.Restarted to be menstruating after a Restarted to be menstruating after a year.year.Plan Rx: stop prophylaxis, continue same Plan Rx: stop prophylaxis, continue same Rx. (Kaletra + EFV)Rx. (Kaletra + EFV)
CASE PRESENTATIONCASE PRESENTATION
14/12/2004 CD4 14/12/2004 CD4 7777??, VL ??, VL 2600026000Problems: Problems: DEFAULTEDDEFAULTED TREATMENT TREATMENT FAILUREFAILUREPlan Dx: repeat CD4 and VL in 6/12 time, Plan Dx: repeat CD4 and VL in 6/12 time, continue the same treatment.continue the same treatment.30/06/2005 CD4 79, VL 30/06/2005 CD4 79, VL 143556143556Plan Rx: continue same treatment, step up Plan Rx: continue same treatment, step up adherence counselling and repeat CD4, VL in adherence counselling and repeat CD4, VL in 3/12 time.3/12 time.
CASE PRESENTATIONCASE PRESENTATION
16/08/2005 comes with severe bronchitis 16/08/2005 comes with severe bronchitis ““not respondingnot responding”” to treatment, also oral to treatment, also oral thrush.thrush.Plan Dx. Sputum AFB culture/sensitivityPlan Dx. Sputum AFB culture/sensitivity
CASE PRESENTATIONCASE PRESENTATION
27/10/2005 patient depressed, coughing, 27/10/2005 patient depressed, coughing, sputa negative, CXR no active signs of Tb.sputa negative, CXR no active signs of Tb.CD4 CD4 104!104!, VL , VL 290000 290000 back to baseline.back to baseline.Assessment: treatment failure, viral Assessment: treatment failure, viral resistance.resistance.Plan DX: Viral Resistance test. Plan DX: Viral Resistance test. Plan Rx: continue same treatment and rePlan Rx: continue same treatment and re--evaluate after results.evaluate after results.
CASE PRESENTATIONCASE PRESENTATION
22/11/2005 Patient for review, feeling better, 22/11/2005 Patient for review, feeling better, gaining weigh; Viral Resistance report gaining weigh; Viral Resistance report comes and shows multi drug resistance.comes and shows multi drug resistance.
CASE PRESENTATIONCASE PRESENTATION
CASE PRESENTATIONCASE PRESENTATION
Plan Rx: Regimen change according to Plan Rx: Regimen change according to results; chosen 2NRTIs plus PI boosted results; chosen 2NRTIs plus PI boosted with Ritonavir as per discussion with with Ritonavir as per discussion with expert.expert.Plan Dx: Repeat VL and Cd4 after 3/12, Plan Dx: Repeat VL and Cd4 after 3/12, monitor FBC and clinical findings monthly monitor FBC and clinical findings monthly for 3/12.for 3/12.
CASE PRESENTATIONCASE PRESENTATION
30/03/2006 Patient for review and results doing30/03/2006 Patient for review and results doingwell asymptomatic, gaining weight VL well asymptomatic, gaining weight VL 420 !!420 !!CD4 CD4 151 !!151 !!. . Plan Dx: repeat VL and CD4 after 3/12.Plan Dx: repeat VL and CD4 after 3/12.Plan Rx: continue same special regimen.Plan Rx: continue same special regimen.
DISCUSSIONDISCUSSION
The definition of treatment failure The definition of treatment failure depends on method of monitoring depends on method of monitoring the patient, generally is accepted as the patient, generally is accepted as persistence or increasing in viral load persistence or increasing in viral load and/or marked and sustained drop in and/or marked and sustained drop in CD4 count and/or development of CD4 count and/or development of new or recurrent clinical events or new or recurrent clinical events or infection that changes the WHO infection that changes the WHO staging of a patient already in ARVT.staging of a patient already in ARVT.
DISCUSSIONDISCUSSION
So we can see:So we can see:A A -- Viral Viral ““failurefailure”” ( VL )( VL )B B -- Immunologic Immunologic ““failurefailure”” ( CD4 )( CD4 )C C -- Clinical Clinical ‘’‘’failurefailure’’’’ ( clinical events )( clinical events )
DISCUSSIONDISCUSSION
The main reason for failure is drug The main reason for failure is drug resistance which is a result of :resistance which is a result of :
a.a.-- Lower drug efficacyLower drug efficacyb.b.-- Sequencing strategy Sequencing strategy c.c.-- Virological failureVirological failured.d.-- Cross resistanceCross resistance
DISCUSSIONDISCUSSIONThere are many factors that influence There are many factors that influence resistance and should be cared when resistance and should be cared when treating patients:treating patients:a.a.-- Genetic barrierGenetic barrierb.b.-- Pharmacokinetic barrierPharmacokinetic barrierc.c.-- Prior ARVTPrior ARVTd.d.-- Viral replication rateViral replication ratee.e.-- Advanced disease stage Advanced disease stage f.f.-- NONNON--ADHERENCEADHERENCE
MECHANISM OF RESISTANCEMECHANISM OF RESISTANCE
HIGH REPLICATION
RATE
ERRORS IN RT
HIGH MUTATIONRATE
MUTANT VIRUSES
SURVIVAL OF THE FITTEST
RESISTANCE
QUASI-SPECIES/ VARIANTSMINORITY
SUB-POPULATION
SELECTIVE PRESSURE
DRUG EXPOSURE
MECHANISM OF RESISTANCEMECHANISM OF RESISTANCEMONOTHERAPYDUAL THERAPY
DRUG CONCENTRATION
GENOTYPIC RESISTANCE
FENOTYPIC RESISTANCE
SENSITIVITYRESISTANCE
VIRAL LOAD
DISCUSSIONDISCUSSIONBefore diagnose failureBefore diagnose failure
a. Exclude non adherence.a. Exclude non adherence.b. Both, viral load and CD4 should be b. Both, viral load and CD4 should be
taken in a taken in a ““clean environmentclean environment”” (no (no vaccines, viral infections, steroids, vaccines, viral infections, steroids, etc).etc).
c. History of treatment changes, non c. History of treatment changes, non suppressive therapy (mono, dual suppressive therapy (mono, dual therapy) or low drug concentration therapy) or low drug concentration (sub doses, mal absorption, etc.)(sub doses, mal absorption, etc.)
DISCUSSIONDISCUSSIONRESISTANCE TESTING LIMITATIONSRESISTANCE TESTING LIMITATIONS
Resistance testing most reliably identifies drugs Resistance testing most reliably identifies drugs that should be avoided but not that should be that should be avoided but not that should be active.active.Interpretation of results in patients who have Interpretation of results in patients who have received prior ARV agents is difficult because received prior ARV agents is difficult because resistance in minority species.resistance in minority species.A viral load of 500 to 1000 c/ml is required.A viral load of 500 to 1000 c/ml is required.Measure only dominant species at the time the Measure only dominant species at the time the test is performedtest is performed
DISCUSSIONDISCUSSIONRESISTANCE TESTING GUIDELINES (USA)RESISTANCE TESTING GUIDELINES (USA)
SEROCONVERSIONSEROCONVERSION
UNTREATED STABLISHED HIV INFECTIONUNTREATED STABLISHED HIV INFECTION
VIROLOGICAL FAILUREVIROLOGICAL FAILURE
MULTIPLE REGIMEN FAILUREMULTIPLE REGIMEN FAILURE
PREGNANCYPREGNANCY
What to do???What to do???
There are three treatment There are three treatment strategies proposed for drugstrategies proposed for drug--resistant HIVresistant HIV--1 infection.1 infection.
1.1.Use more and new drugs as Use more and new drugs as possible (Salvage therapy).possible (Salvage therapy).
2.2. Interruption of therapy.Interruption of therapy.3.3.Continuation of partially effective Continuation of partially effective
regimen.regimen.
Best approach for multi Best approach for multi failure patients still remains failure patients still remains unclear.unclear.
