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Tolrance des antirtroviraux Gestion des effets secondaires Cours IMEA/Fournier 14 Novembre 2006 Dr R.Landman

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Grade 1 : effet secondaire mineur aucune mesure correctrice, ni hospitalisation. Grade 2 : effet secondaire modr Mesures correctrices, pas dhospitalisation, ni arrt du traitement. Grade 3 : effet secondaire svre Traitements en milieu hospitalier, arrt des molcules utilises ou leur changement. Gestion des effets secondaires des ARV (ACTG )

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Grade 4 : effet secondaire gravissime Engage le pronostic vital, traitements en soins intensifs, avec arrt ou changement des ARV Grade 5 : effet secondaire mortel Evnement responsable directement ou indirectement du dcs. Gestion des effets secondaires des ARV (ACTG ) suite

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Table 5 Common ARV toxicities Hematological toxicity Drug-induced bone-marrow suppression, most commonly seen with AZT (anaemia, neutropaenia) Mitochondrial dysfunction Primarily seen with the NRTI drugs, including lactic acidosis, hepatic toxicity, pancreatitis, peripheral neuropathy, lipoatrophy, fat accumulation, myopathy osteopaenia Renal toxicity Nephrolithiasis commonly seen with IDV. Renal tubular dysfunction associated with TDF. Other metabolic abnormalities More common with PIs. Include hyperlipidaemia, insulin resistance and diabetes Allergic reactions Skin rashes and hypersensitivity reactions, more common with the NNRTI drugs but also seen with certain NRTI drugs, such as ABC and some PIs

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Toxicits du traitement de premire ligne et recommandations pour les substitutions ARV drug Common associated toxicitySuggested substitute ABCHypersensitivity reactionAZT or TDF or d4T DDI AZTSevere anaemia or neutropaenia Severe gastrointestinalintolerance TDF or d4T or ABC, DDI Lactic acidosisTDF or ABC d4T Lactic acidosis Lipoatrophy/metabolic syndrome TDF or ABC Peripheral neuropathyAZT or TDF or ABC

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ARV drugCommon associated toxicitySuggested substitute TDFRenal toxicity (renal tubular dysfunction) AZT or ABC or d4T EFVPersistent and severe central nervous system toxicity NVP or TDF or ABC (or any PI) Potential teratogenicity (first trimester of pregnancy or women not using adequate contraception) NVP or ABC 5or any PI) NVPHepatitisEFV or TDF or ABC (or any PI) Hypersensitivity reactionTDF or ABC (or any PI) Severe or life-theatening rash (Stevens-Johnson syndrome) Toxicits du traitement de premire ligne etrecommandations pour les substitutions

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Effets secondaires prcoces

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Effets secondaires des INRT * Anmie, neutropnie, thrombopnie * Hpatite * myalgies, myopathie * Pancratite * Neuropathie * Raction cutane * Hyperuricmie * Nphropathie * Zidovudine (AZT) * Stavudine, didanosine, lamivudine * Zidovudine * Stavudine, didanosine, lamivudine * D4T, AZT, DDI,3TC * Abacavir * Didanosine * Tnofovir

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Cytopathies mitochondriales * Acidose lactique. * Aprs traitement des femmes enceintes, nombreux cas observs chez les enfants - Cytopathies mitonchondriales : 8 cas - Encphalopathies mortelles : 3 cas

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6-months and 12-months outcomes after HAART initiation in naive-patients who started HAART 6-months12-months Patients in cohort*, number4,042 1,969 Dead (%)10 %12 % Lost to follow-up (%)8 %11 % Tranfered out (%)1 %2 % Still in active follow-up (%)81 %74 % Gain in CD4, /mm 3 (median, IQR) +137 (+74 ; +215) +164 (+95; +248) Gain in BMI, Kg/m 2 (median, IQR) + 1.9 (+0.5; +3.6) + 2.1 (+0.7; +4.3) Gain in Hg, g/L (median, IQR) +16 (+5 ; +29) + 19 (+8; +30) Source: Aconda/ISPED/EGPAF August 2006 report * Patients who started HAART at least 6 and 12 months before the 31st of July 2006, respectively

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Drug discontinuation : second-line regimen, by first-line regimen Source: Aconda/ISPED/EGPAF August 2006 report First-line regimen AZT 3TC EFV d4T 3TC EFV d4T 3TC NVP Number of patients*156716093318 At least one drug discontinuation183 (12%)260 (16%)332 (10%) Second-line regimen AZT 3TC EFV-10%4% d4T 3TC EFV5%- d4T 3TC NVP4% - 2 NRTIs + 1 NNRTI, others3%2%1% Median time between HAART start and regimen modification (months) 3.89.72.2 * All patients who started the given first line regimen > 1 month before July 31st 2006

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Drug discontinuation: Reasons Source: Aconda/ISPED/EGPAF August 2006 report First line regimen AZT 3TC EFV d4T 3TC EFV d4T 3TC NVP Number of patients *156716093318 At least one drug discontinuation183260332 Reason for changing drug Drug intolerance49%59%64% Morbidity event **2%1%26% Pregnancy33%13%- Treatment failure1% 2% Out of stock13%24%8% Other2% - * All patients who started the first line regimen > 1 month before July 31st 2006 ** Mainly tuberculosis

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Symptomes dclars par les patients sous AZT- 3TC-EFV, par mois de traitement (essai Trivacan ANRS 1269, Abidjan) Source: Danel JAIDS 2006

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Tolrance des INN Efavirenz.* Eruption cutane * Trbles neuropsychiques - Sensation divresse - Sd dpressif * Hypertransaminasmie risk si co-infection VHB/VHC Nvirapine.* Eruption cutane+++ - Toxidermie - Syndrome de Stevens-Johnson, Lyell * Hypertransaminasmie risk si co-infection VHB/VHC

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Posologie et tolrance des IP Indinavir Crixivan* Cp200, 400mg Trbles digestifs scheresse cutane cristallisation urinaire bilirubine Nelfinavir Viracept* Cp 250mg Diarrhe Eruption cutane Saquinavir HGC Invirase* Cp 200 mg Trbles digestifs Intensit faible ou modre

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Posologie et tolrance des IP Ritonavir Norvir* Gl 100mg. Trbles digestifs+++ Paresthsies pribuccales Lopinavir +RTV Kaltra* LPV133/33mg. Trbles digestifs,dlrs abdominales. chol, triglyc

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Effets secondaires tardifs

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Lipodystrophie et troubles mtaboliques Lipodystrophie * Lipoatrophie perte graisse ss-cutane * Lipohypertrophie accumulation de graisses * Forme mixte Troubles mtaboliques * Hyperglycmie - glycmie jeun> * Hypercholestrolmie - chol total> - chol ldl > - chol hdl< * Hypertriglycridmie >

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HIV-Associated Lipodystrophy Syndrome Changes in Fat Distribution Subcutaneous fat wasting Fat accumulation Intra-abdominal fat Localized Breast enlargement Buffalo hump Lipomata Limited data regarding differences between PI regimens

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Retentissement osseux

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Hip TDM: bilateral avascular osteonecrosis of the femoral head stage II-III (FICAT)

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Principales caractristiques des inhibiteurs de fusion PrsentationPosologieEffets secondaires Enfuvirtide T20 Fuzon* 90mg/ml 90mgX2/Jour en sous cutan Papule rythmateuse au site dinjection dans 95%

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Effets secondaires chez les femmes enceintes

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Effets secondaires chez la mre des HAART avec des INN * Effets secondaires plus frquents chez la femme enceinte que chez la femme non enceinte * HAART avec NVP non recommande chez la mre avec des CD4>250 cells/mm3 : risque de toxicit hpatique (OR~=12) survient au cours des 18 premires semaines (plus souvent dans le 6 premires semaines)

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Toxicit hpatique symptomatique li la nvirapine durant les six premires semaines de traitement avec un rgime incluant la NVP Selon les CD4 linitiation du traitement et selon le sexe (Boehringer-Ingelheim) CD4 linitiation Frquence 5,8% 2,2%

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Effets secondaires lis la NVP et au NFV Timmermans S et al. AIDS 2005;19:795-9 NevirapineNelfinavir Non enceinte Enceinte Non- enceinte Enceinte Effets secondaires(N=95)(N=58)P(N=91)(N=128)P Intolerance glucose5%9%0.427%30%0.001 Rash11%9%0.701% 0.80 Hpatite4%19%0.0034% 0.86 Glucose1%9%0.022%16%0.001 Comparaison de la toxicit chez 186 femmes enceintes et 186 femmes non enceintes dans 15 centres de sant en Allemagne Effets secondaires plus frquents chez les femmes enceintes pour certains rgimes

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En Afrique : Peu de donnes disponibles Recommandation de mettre les femmes enceintes sous HAART en 2004 Cohorte MTCT-Plus Abidjan avec 104 sous HAART : (AZT+3TC+NVP)(Tonwe CROI 2005) : 7,8 % des femmes enceintes ont prsent des effets secondaires de grade 3 et 4 ayant ncessit un changement de traitement pendant la grossesse 51 jours en moyenne aprs le dbut du traitement 2 cas de toxicit hpatique de grade 4 1 cas danmie svre et 5 cas de toxicit cutane de grade 3 Cohorte DREAM (Palombi, CROI 2005) 6,3% de toxicit hpatique (n=606 femmes)

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En Afrique : Peu de donnes disponibles Malawi (Bramson B, Toronto 2005) Femmes ayant des CD4>200/mm3 39 femmes sous AZT+3TC+NVP Dure moyenne sous traitement de 2,6 mois 3 cas de toxicit hpatique svre incluant un Syndrome de Stevens-Johnson et 1 cas de toxicit hpatique avec des manifestations cliniques

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En rsum * Peu de donnes disponible chez la femme enceinte * Surveillance hpatique * Effets secondaires peuvent avoir des consquences nfastes sur lissue des grossesses (prmaturit et de petits poids).

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Passage de ZDV/3TC TDF/FTC COMET : Passage de ZDV/3TC TDF/FTC Principale raison du changement : simplification du schma (86%) Tous les patients VL < 400 Semaine 24 % VL < 50 : 59% 76% (P < 0,001) Amliorations significatives des lipides et des taux de Hb Ruane P, et al. EACS 2005. Extrait PE7.3/5. Variation par rapport linclusion ZDV/3TC TDF/FTCValeur P Hmoglobine, Semaine 48, g/dl 0,6 (0,1, 1,2)< 0,001 ANC, Semaine 48, cellules/mm 3 265 (-245, 1100)< 0,001 CT, Sem. 12, mg/dl-13 (-29, 1)< 0,001 LDL, Sem. 12, mg/dl-8 (-24, 8)0,01 HDL, Sem. 12, mg/dl-4 (-8, 2)< 0,001 TG, Sem. 12, mg/dl-12,5 (-60, 24)0,039

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Impact du passage de d4T sur les lipides et la masse graisseuse Phase dextension en ouvert de 96 semaines de ltude 903 Donnes issues dun sous-groupe de patients recevant d4T pendant 144 semaines qui sont passs des TDF en ouvert pendant 48 semaines Zhong L, et al. EACS 2005. Extrait PE9.3/5. Variation moyenne des lipides jeun en Semaine 48 (mg/dl) TGCTLDLHDL -80 -60 -40 -20 0 -72 -38 -16 Masse graisseuse totale moyenne (kg) 0 4,2 4,4 Sem. 96Sem. 144 Sem. 48 aprs changement P < 0,001 4,6 4,8 5,0 5,02 (n = 74) 4,60 (n = 74) d4TTDF

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RAVE : Passage dun analogue de la thymidine ABC ou TDF Patients dprims avec lipoatrophie auto-dcrite sous NRTI analogues de la thymidine 105 patients randomiss pour remplacer les TA par Tnofovir, ou Abacavir La masse graisseuse totale a augment de la mme faon dans les deux bras sur 48 semaines Moyle G, et al. CROI 2005. Extrait 44LB. Variation de la masse graisseuse par DEXA en Semaine 48 (g) 393 522 1061 316 791 1046 0 200 400 600 800 1000 1200 MembreTroncGraisse totale TDF ABC Variation intragroupe de la masse graisseuse par rapport aux conditions linclusion : TDF (P = 0,01), ABC (P = 0,001)

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P = 0,97 Variation moyenne de la masse graisseuse par DEXA en Semaine 48 (g) 393 66 529 316 210 357 0 100 200 300 400 500 600 Tous les sujets ZDV linclusion d4T linclusion TDFABC n = 494412163728 Moyle G, et al. EACS 2005. Extrait PE9.3/2. RAVE : Facteurs prdictifs d'une faible rponse dans lamlioration de la masse graisseuse Facteurs associs la variation absolue de la masse graisseuse (analyse multivarie) ge Par tranches de 5 ans supplmentaires : 103 g moins de rcupration de graisse en Semaine 48 (P = 0,07) Analogue de la thymidine linclusion ZDV linclusion : 419 g moins de rcupration de graisse en Semaine 48 (P = 0,02)

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Table 6 Guiding principles in the management of ARV drug toxicity 1.Determine the seriousness of the toxicity. 2.Evaluate concurrent medications and establish whether the toxicity is attributable to an ARV drug or drugs or to a non-ARV medication taken at the same time. 3.Consider other disease processes (e.g. viral hepatitis in an individual on ARV drugs who develops jaundice) because not all problems that arise during treatment are caused by ARV drugs. 4.Manage the adverse event according to severity. In general: Grade 4: Severe life-threatening reactions: Immediately discontinue all ARV drugs, manage the medical event (i.e. symptomatic and supportive therapy) and reintroduce ARV drugs using a modified regimen (i.e., with an ARV substitution for the offending drug) when the patient is stabilized. a Grade 3: Severe reactions: Substitute the offending drug without stopping ART. a Grade 2: Moderate reactions: Consider continuation of ART as long as feasible. If the patient does not improve on symptomatic therapy, consider single-drug substitutions. a Grade1: Mild reactions are bothersome but do not require changes in therapy. 5.Stress the maintenance of adherence despite toxicity for mild and moderate reactions. 6. If there is a need to discontinue ART because of life-threatening toxicity, all ARV drugs should be stopped until the patient is stabilized.

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Table 7 Toxicities of first-line ARV and recommended drug substitutions First-line ARV drugMost frequent significant toxicity for the ARV drug Suggested first-line ARV drug substitution ABCHypersensitivity reactionAZT or TDF or d4T AZT Severe anaemia a or neutropaenia b Severe gastrointestinal intolerance c TDF or d4T or ABC Lactic acidosisTDF or ABC d d4T Lactic acidosis Lipoatrophy / metabolic syndrome e TDF or ABC d Peripheral neuropathyAZT or TDF or ABC TDFRenal toxicity (renal tubular dysfunction)AZT or ABC or d4T EFV Persistent and severe central nervous system toxicity f NVP or TDF or ABC Potential teratogenicity (first trimester of pregnancy or women not using adequate contraception) NVP or ABC NVP HepatitisEFV or TDF or ABC Hypersensitivity reactionTDF or ABC or any PI h Severe or life-threatening rash (Stevens-Johnson syndrome) g TDF or ABC

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AdverseEffect Major ARVs Recommendations Acute pancreatitisd4T and ddIDiscontinue ART. Give supportive treatment and laboratory monitoring. Resume ART with an NRTI with low pancreatic toxicity risk. AZT, ABC, TDF and 3TC are less likely to cause this type of toxicity. DiarrheaddI (buffered formulation), NVF, LPV/r and SQV/r Usually self-limited, without need to discontinue ART. Symptomatic treatment should be offered. Drug eruptions (mild to severe, including Stevens-Johnson syndrome or toxic epidermal necrolysis) NVP, EFV (rarely)In very mild cases, antihistamines and strict observation; there may be regression without need to change ART. If mild/moderate rash, non- progressing and without mucosal involvement or systemic signs, consider a single NNRTI substitution (i.e., from NVP to EFV). In moderate and severe cases, discontinue ART and give supportive treatment. After resolution, resume ART with 3 NRTI or 2 NRTI + PI regimens. Dyslipidemia, insulin resistance and hyperglycemia PIsConsider replacing the suspected PI by drugs with less risk of metabolic toxicity (e.g., NFV). Adequate diet, physical exercise and antilipemic drugs should be considered. GI intolerance, with taste changes, nausea, vomiting, abdominal pain and diarrhea. All ARVs (less frequent with d4T, 3TC, FTC and ABC) Usually self-limited, without need to discontinue ART. Symptomatic treatment should be offered. Hematological toxicities (particularly anemia and leucopenia) AZTIf severe (Hg5-fold the basal level, discontinue ART and monitor. After resolution, replace the drug most likely associated. Hyperbiliruubinemia (indirect)ATVGenerally asymptomatic, but can cause scleral icterus (without ALT elevations). Replace ATV for other PI. Hypersensitivity reaction with systemic respiratory,fever and without mucosal involvement. ABCDiscontinue ABC and do not restart. Symptomatic treatment. Reexposure may lead to a severe and potentially life-threatening reaction. Lactic acidosisAll NRTIs (particularly d4T and ddI) Discontinue ART and give supportive treatment. After clinical resolution, resume ART, replacing the offending ITRN. ABC, TDF and 3TC are less likely to cause this type of toxicity. Lipoatrophy and lipodystrophyAll NRTIs (particularly d4T) Early replacement of the suspected ARV drug (e.g., d4T for TDF or ABC). Consider esthetic treatment and physical exercises. Neuropsychiatric changes (sleep disturbances, depression, behavioral, concentration and personality changes) EFVUsually self-limited, without need to discontinue ART. Symptomatic treatment, if required. If previous psychiatric disturbance, there is a higher risk of more severe reaction. Effects may be enhanced by alcohol and other psychoactive drugs. Renal Toxicity (nephrolitiasis)IDVIf using IDV, interrupt IDV and offer hydration, laboratory monitoring and symptomatic treatment (50% recurrence rate). Consider replacing IDV for another PI. Renal Toxicity ( renal tubular dysfunction)TDFDiscontinue TDF and give supportive treatment. After clinical resolution, resume ART, replacing the offending drug. Peripheral neuropathyd4T and ddIConsider replacement by an NRTI with minimal or no neurotoxicity (AZT, TDF or ABC). Symptomatic treatment should be considered.

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Difficults de gestion * Non disponibilit * Limites du diagnostic biologique * Renforcement des capacits