Toxicity of stavudine- and Toxicity of stavudine- and
nevirapine-containing nevirapine-containing
antiretroviral treatment regimens:antiretroviral treatment regimens:
incidence and risk factors after 3 years in a incidence and risk factors after 3 years in a
large cohort in Rwanda large cohort in Rwanda
Johan van Griensven
Background (1)Background (1)
90% of ART regimens in low-90% of ART regimens in low-income countries use fixed dose income countries use fixed dose combination of: combination of: Stavudine (d4T) Stavudine (d4T) Lamivudine (3TC)Lamivudine (3TC) Nevirapine (NVP)Nevirapine (NVP)
Background (2)Background (2)
Long-term toxicity well-described Long-term toxicity well-described in high-income countriesin high-income countries
Stavudine (d4T)Stavudine (d4T) Abandoned for reasons of toxicityAbandoned for reasons of toxicity First choice in low-income countriesFirst choice in low-income countries
Nevirapine (NVP)Nevirapine (NVP) significant morbidity/mortalitysignificant morbidity/mortality contra-indicated for higher CD4 counts contra-indicated for higher CD4 counts
(> 250)(> 250)
ObjectivesObjectives
Assess incidence, timing and risk Assess incidence, timing and risk factors of toxicity with D4T and factors of toxicity with D4T and NVP in RwandaNVP in Rwanda
Methods (1): SettingMethods (1): Setting ART program ART program
in 2 urban in 2 urban health health centers, Kigalicenters, Kigali
3,417 patients 3,417 patients started on started on ART by Dec 07ART by Dec 07
Open cohort: Open cohort: 90% in care 90% in care
by 2 years of by 2 years of ARTART
Diagnostic Diagnostic tools availabletools available
ARV KMK
ARV KNN
Methods (2)Methods (2)
Study populationStudy population N= 2,970N= 2,970 2,667 started stavudine-based regimen 2,667 started stavudine-based regimen
(90.6%)(90.6%) 2,694 started nevirapine-based regimen 2,694 started nevirapine-based regimen
(89.6%)(89.6%) Side-effects/toxicitySide-effects/toxicity
WHO definitions (grading)WHO definitions (grading) Symptomatic hyperlactatemia/lactic acidosisSymptomatic hyperlactatemia/lactic acidosis LipoatrophyLipoatrophy
Methods (3)Methods (3) Side-effects/toxicitySide-effects/toxicity
WHO definitions (grading)WHO definitions (grading) Symptomatic hyperlactatemia/lactic acidosisSymptomatic hyperlactatemia/lactic acidosis LipoatrophyLipoatrophy
Probabilities of ‘time to first severe Probabilities of ‘time to first severe toxicity’ requiring treatment change toxicity’ requiring treatment change (KM)(KM)
related to NVP and D4T related to NVP and D4T A risk factor analysisA risk factor analysis
multivariate Cox proportional hazards multivariate Cox proportional hazards modellingmodelling
WHO stageWHO stage stage I (6.5%)stage I (6.5%) stage II (28.4%)stage II (28.4%) stage III (56.6%)stage III (56.6%) stage IV (8.5%)stage IV (8.5%)
Baseline CD4 count: 162 cells/µLBaseline CD4 count: 162 cells/µL Median time on ART: 1.5 yearsMedian time on ART: 1.5 years
Results (1): baseline Results (1): baseline characteristicscharacteristics
Results (2): NVP toxicityResults (2): NVP toxicity
Severe toxicity (drug-substitution): Severe toxicity (drug-substitution): 6.4% (170)6.4% (170) Rash: 4.9% (130)Rash: 4.9% (130) Hepatitis: 1.5% (40) Hepatitis: 1.5% (40)
Early toxicityEarly toxicity Within first 6 months of treatment for 90 %Within first 6 months of treatment for 90 %
Not clearly different from what Not clearly different from what reported in high and low-income reported in high and low-income countriescountries
Results (3): Risk factorsResults (3): Risk factors
Skin toxicity: non-significantSkin toxicity: non-significant HepatotoxicityHepatotoxicity
BMI ≤20 kg/mBMI ≤20 kg/m22
Abnormal baseline liver testsAbnormal baseline liver tests No association with baseline CD4 No association with baseline CD4
count and sexcount and sex
Results (4): Risk factors Results (4): Risk factors for severe toxicityfor severe toxicity
Similar findings from several other Similar findings from several other African studiesAfrican studies
Contrasts with findings from high Contrasts with findings from high income countriesincome countries Female sexFemale sex CD4 count > 250 cells/µLCD4 count > 250 cells/µL
Results (5): Stavudine Results (5): Stavudine toxicitytoxicity
Neuropathy: 7.6% (206)Neuropathy: 7.6% (206) Lactic acidosis (SH/LA): 3.2% (85)Lactic acidosis (SH/LA): 3.2% (85) Lipoatrophy (body fat changes): 6.7% (180)Lipoatrophy (body fat changes): 6.7% (180) Total: 16.6% (448)Total: 16.6% (448)
Similar findings from other African countriesSimilar findings from other African countries
Results (6): Stavudine Results (6): Stavudine toxicitytoxicity
Results (7): Stavudine Results (7): Stavudine toxicitytoxicity
Results (8): LipoatrophyResults (8): Lipoatrophy
Results (9): Risk factorsResults (9): Risk factors
NeuroNeuro
pathypathyLactic Lactic acidosacidos
isis
LipoLipo
atrophatrophyy
Higher age (>35 Higher age (>35 years)years)
++++
Advanced WHO Advanced WHO stagestage
++++
Female sexFemale sex ++++++ ++++++
Higher baseline Higher baseline BMIBMI
++++++ ++++++
Conclusion (1)Conclusion (1) Toxicity of NVP similar to high-Toxicity of NVP similar to high-
income countriesincome countries Different risk factors? Different risk factors?
Risk factors different ?Risk factors different ? Different from rich countriesDifferent from rich countries
Allergy vs toxicity ?Allergy vs toxicity ? Implications for ART initiation and PMTCT Implications for ART initiation and PMTCT
protocolsprotocols Safe to give NVP when high baseline CD4 Safe to give NVP when high baseline CD4
counts ?counts ?
Conclusion (2) Conclusion (2)
D4T has severe, long-term toxicityD4T has severe, long-term toxicity Main concern isMain concern is
lactic acidosis: mortalitylactic acidosis: mortality Lipoatrophhy: acceptance and adherence ?Lipoatrophhy: acceptance and adherence ?
Implications for MSF?Implications for MSF?
Risk factorsRisk factors could help identify could help identify patients at higher risk of drug toxicitypatients at higher risk of drug toxicity
Develop Develop diagnostic and treatment diagnostic and treatment pathspaths with few diagnostic tools to with few diagnostic tools to ensure pro-active managementensure pro-active management
ART programs need alternativesART programs need alternatives tenofovir (TDF) or abacavir (ABV)tenofovir (TDF) or abacavir (ABV) at present prohibitively expensiveat present prohibitively expensive
AcknowledgementsAcknowledgements
Health Centres Kinyinya and Health Centres Kinyinya and KimironkoKimironko
MSF team Rwanda (2002-2007)MSF team Rwanda (2002-2007) Ministry of Health RwandaMinistry of Health Rwanda
CAT SUSPICION ACIDOSE LACTIQUE SANS TEST LACTATE
Autres causes de PP ou douleur abdominal peuvent mimer ou co-exister avec A.L.; Autres causes pour PP:
IO (TB?)/Palu Diarrhée chronique Echec virologique Dépression Malignité Diabète Malnutrition
Autres causes for douleur abdominale: Ulcère gastrique Hépatite, pancréatite IO ou IRIS: TB abdom., amoebiase, verminose, palu Intolérance GI médicaments
Autres causes dyspnée /hyperventilation ± choc:
Sepsis, cardiovasculaire, déhydratation, palu sévère Asthme, Anémie sévère
Suspicion hyperlactataemia / acidose lactique:
Perte de poids inexpliquée récente (p.e. > 2kg en 3 mois)
Douleur abdominale Nausée et vomissement Dyspnée, tachypnée sans cause
respiratoire Tachycardie inexpliqué GPT élevé sans explication évidente Asthénie et faiblesse progressive (en général après amélioration sous ARV) (myalgie, paresthésie, œdème MI)
Facteur de risques: Traitement d4T plusieurs mois Femmes et/ou obèse )
Faire revision du dossier Faire examen clinique complet (tension art,
poumons, abdomen, T) Mesurer Fréquence respiratoire (FR) Examens complémentaires (GE, GPT, NFS
(glycémie))
Cas modéré: FR<20 + symptômes plus prononcés(vomissements, douleurs) ou évolution subaiguë - Appeler médecin - Si pas présent et pas d'autre cause trouvée:
ARRETER ARV Si sous NVP/EFV: - Arrêt en deux phases - Arrêt NVP/EFV - Donner AZT/3TC 5-7j RDV médecin urgent
Cas limité: Symptômes limités et/ou peu progressives - Chercher et traiter autre causes: ? Quinine ? Albendazole /Flagyl ? Oméprazole - RDV après une semaine :
si symptômes persistent: RDV médecin au cours de la semaine pour envisager de changer d4T pour AZT
Cas sévère: -> Dyspnée (de repos); Signe alarme: FR > 20; tachycardie/palpitations - > vomissements +++ - > douleur abdominale +++; - > faiblesse musculaire; œdèmes périphériques - > GPT>5x - Appeler médecin pour arrêter en deux phase
- ARRET ARV IMMEDIAT - Appeler médecin pour arrêter en deux phases (considérer TDF/3TC ou Kaletra 2 x 4 co /j 5-7 jours) - si GPT élevé (≥100): considérer arrêt médicaments hépatotoxiques (CTX, fluco,…) - si CD4 chutés (ou bas): refaire CD4 (et CV si disponible et pas faite récemment) - Vomissements sévères ou condition générale altéré: Hospitalisation et hydratation: (Préférence S-Physiologique)
QUAND RECOMMENCER LES ARV (APRES A.L.) ? GENERALITES - en général recommencer ARV MIMIMUM 4 SEMAINES après l'arrêt - plus sévère est le cas, plus lente est la récupération, le plus longtemps on
attendra avant de recommencer les ARV - en général les symptômes améliorent progressivement dans les 1-2
semaines après arrêt ARV o souvent l'asthénie/paresthésie persiste le plus longtemps o si aucune amélioration 1-2 semaine après arrêt ARV, chercher
autres causes EVALUATION - attendre que le patient est asymptomatique pendant une-deux semaines
(sauf quelques paresthésies qui ont amélioré mais persistent encore un peu) - en cas de GPT élevé, attendre normalisation - poids stabilisé ou récupéré - faire l'examen de l'abdomen: douleur épigastrique/hypochondre droit à la
palpitation est un argument pour attendre encore un peu avec les ARV et réévaluer après 2 semaines
TRAITEMENT - si CTX arrêté, recommencer CTX suivi par les ARV deux-quatre semaines
plus tard si CTX bien toléré - Le jour de recommencement des ARV: refaire CD4 de base - Décision de recommencer des ARV et choix du régime après consultation médecin. En général: changer d4T pour AZT (faire suivi hémoglobine!)
Si signes cliniques associés de lipoatrophie très prononcés: considérér ténofovir (abacavir)
Si acidose lactique à cause de AZT: changer pour ténofovir (abacavir)
Si cas sévère et/ou récupération lente: changer pour ténofovir (abacavir)
Cas pronostique vital en jeu : Kaletra + NNRTI (plus de INRT !)
! Kaletra 2 x 4 co (interaction NNRTI) !
- SI NVP ARRETE >14 J: RECOMMENCER AVEC 200 MG/ J ET AUGMENTER APRES 14 J; SINON RECOMMENCER AVEC 200MG 2x/J
SUIVI
Visite chaque 2-4 semaines (selon sévérité de AL) pendant 2-3 mois
Assurer que le patient revient directement si les symptômes reviennent
Diagnostic tool: Diagnostic tool: AccutrendAccutrend
226 $/machine226 $/machine 2.3 $/test2.3 $/test Interfering factors:Interfering factors:
ExerciseExercise HydratationHydratation Nutrition ?Nutrition ? InfectionsInfections
malaria, TB ?malaria, TB ? Asymptomatic Asymptomatic
hyperlactatemiahyperlactatemia Action threshold ?Action threshold ? Clinical evaluationClinical evaluation
Drug related toxicity Events
(%)
Rate
/1000 py
Patients with toxicity-related drug
substitution (%) b
Nevirapine (n=2667) 6 m 12 m 24 m 36 m
Toxicity all 170 (6.4) 39 6.0 6.4 6.9 7.2
Skin toxicity 131 (4.9) 30 4.9 5.1 5.3 5.4
Liver toxicity 40 (1.5) 9 1.1 1.3 1.6 1.8
NVP-related toxicityNVP-related toxicity
D4T-related toxicityD4T-related toxicity
Drug related toxicity Events
(%)
Rate
/1000 py
Patients with toxicity-related drug
substitution (%) b
Stavudine (n=2694)
Toxicity all 448 (16.6) 107 2.6 8.6 22.5 35.4
Neuropathy 206 (7.6) 49 2.3 6.0 9.8 12.1
SH/LA a 85 (3.2) 20 0.2 2.0 4.5 6.0
Lipoatrophy (La) 180 (6.7) 43 0.0 1.0 9.2 19.8
SH/LA and/or La 248 (9.2) 59 0.3 2.6 12.9 24.2
Incidence of neuropathyIncidence of neuropathy
Severe neuropathy Severe neuropathy TotalTotal
RwandaRwanda 7.6 % 7.6 % --
SA SA (Durban)(Durban)
6.9 %6.9 %
SA (CapeT)SA (CapeT) 5.9 %5.9 % --
Kenya Kenya (slum)(slum)
3 %3 % 23 %23 %
UgandaUganda 9.3 % (subst 17 %)9.3 % (subst 17 %) 36 %36 %
Hyperlactatemia/lactic Hyperlactatemia/lactic acidosisacidosis
RwandaRwanda Substitution for 3.2 % of patients on d4TSubstitution for 3.2 % of patients on d4T IR 20/1000 patient yearsIR 20/1000 patient years 6 % by 3 years on ARV6 % by 3 years on ARV
South-AfricaSouth-Africa Soweto: 30/1000 patient years (CID, 2007) Soweto: 30/1000 patient years (CID, 2007) Durban: 30/1000 patient yearsDurban: 30/1000 patient years Cape Town: 19/1000 patient yearsCape Town: 19/1000 patient years
Botswana (CID, 2007), Uganda (JAIDS Botswana (CID, 2007), Uganda (JAIDS 2007)2007)
Acidose Acidose lactique/hyperlactatemielactique/hyperlactatemie
South-Africa (Clin Infect Dis, 2007) – South-Africa (Clin Infect Dis, 2007) – SowetoSoweto Symptomatic hyperlactatemia:Symptomatic hyperlactatemia:
20/1000 py20/1000 py Mortality 0 %Mortality 0 %
Lactic acidosis:Lactic acidosis: 10/1000 py10/1000 py Mortality 30 %Mortality 30 %
South-Africa – DurbanSouth-Africa – Durban 37/1000 py37/1000 py
DefinitionDefinition
Technical investigations: Technical investigations: CT/DEXA/MRI (Golden Standard)CT/DEXA/MRI (Golden Standard)
ClinicalClinical ““Lipodystrophy Case Definition Study” Lipodystrophy Case Definition Study”
QuestionnaireQuestionnaire Validated vs “golden standard”Validated vs “golden standard”
AnthropometricsAnthropometrics Rwanda: screening for long-term side-Rwanda: screening for long-term side-
effects integrated in routine careeffects integrated in routine care
1. Evaluation par le patient
Au visage 0 - + un peu □ moyen □ beaucoup □
Au cou 0 - + un peu □ moyen □ beaucoup □ Au seins 0 - + un peu □ moyen □ beaucoup □Au ventre 0 - + un peu □ moyen □ beaucoup □
Aux fesses 0 - + un peu □ moyen □ beaucoup □Aux bras 0 - + un peu □ moyen □ beaucoup □Au jambes 0 - + un peu □ moyen □ beaucoup □ 2. Evaluation par l’infirmière
Au visage 0 - + un peu □ moyen □ beaucoup □
Au cou 0 - + un peu □ moyen □ beaucoup □Au seins 0 - + un peu □ moyen □ beaucoup □Au ventre 0 - + un peu □ moyen □ beaucoup □
Aux fesses 0 - + un peu □ moyen □ beaucoup □Aux bras 0 - + un peu □ moyen □ beaucoup □Au jambes 0 - + un peu □ moyen □ beaucoup □ Depuis quand ces changements ont-ils commencé ? .….jours/semaine(s)/mois/année(s)
Symptômes associés (arguments pour acidose lactique) ? Depuis quand ?
Paresthésie non □ un peu □ moyen □ beaucoup □ …..jours/sem/mois/années
Nausée non □ un peu □ moyen □ beaucoup □ …..jours/sem/mois/années
Vomissement non □ un peu □ moyen □ beaucoup □ …..jours/sem/mois/années
Diarrhée non □ un peu □ moyen □ beaucoup □ …..jours/sem/mois/années
Inappétence non □ un peu □ moyen □ beaucoup □ …..jours/sem/mois/années
Douleur non □ un peu □ moyen □ beaucoup □ …..jours/sem/mois/annéesabdominal
Gonflement non □ un peu □ moyen □ beaucoup □ …..jours/sem/mois/annéesabdominal
Dyspnée non □ un peu □ moyen □ beaucoup □ …..jours/sem/mois/années
repos □ effort □Fatigue non □ un peu □ moyen □ beaucoup □ …..jours/sem/mois/années Perte de poids …. kg en ….. jours/sem/mois Augmentation de poids …. kg en ….. jours/sem/mois Autres symptômes …………………………………………… Quand est-ce que ces symptôms ont-ils commencé ? …..jours/sem/mois/années
Frequency of Frequency of lipodystrophielipodystrophie
Cross-sectional evaluation (> 1 an sous Cross-sectional evaluation (> 1 an sous ARV, n=409)ARV, n=409) Lipodystrophy: 34 %Lipodystrophy: 34 %
Isolated lipoatrophy: 10 %Isolated lipoatrophy: 10 % Isolated lipohypertrophy: 5 %Isolated lipohypertrophy: 5 % Mixed presentation: 19 %Mixed presentation: 19 %
Moderate/severe > 60-70 %Moderate/severe > 60-70 % “ “Body changes disturbing” > 50 %Body changes disturbing” > 50 %
Cohort on d4T (severe lipoatrophy):Cohort on d4T (severe lipoatrophy): Substitution of lipoatrophie for 6.7 %Substitution of lipoatrophie for 6.7 % Incidence of 43/1000 pyIncidence of 43/1000 py 20 % by 3 years on ART20 % by 3 years on ART
Until recently rarely reportedUntil recently rarely reported First report coming from MSF Rwanda First report coming from MSF Rwanda
CROI, Feb 2006CROI, Feb 2006 South-AfricaSouth-Africa
Prospective cohort study (George)Prospective cohort study (George) 43 % lipodystrophy by 2 years onARV43 % lipodystrophy by 2 years onARV
Cape Town, 2007Cape Town, 2007 9 % substituted d4T for La by 3 ans of ARV9 % substituted d4T for La by 3 ans of ARV
Implementers meeting (2006), Durban:Implementers meeting (2006), Durban: Substitution for lipoatrophy: 73/1000 pySubstitution for lipoatrophy: 73/1000 py
Rwanda (KIST):Rwanda (KIST): Prevalence of 70 % by 3 years Prevalence of 70 % by 3 years
Incidence of La in Incidence of La in Africa ?Africa ?
Toxicity of ARVs (South-Toxicity of ARVs (South-Afr)Afr)
Toxicity of ARVs (South-Toxicity of ARVs (South-Afr)Afr)
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AZT
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