Morbidity During the 5 Years Following Initiation of Protease Inhibitor Therapy in HIV-infected Patients.

Vincent Le Moing1, Geneviève Chêne2, Lise Cuzin3, Catherine Barennes2, Séverine Ansart4, Firas Al Kaïed5, Charlotte Lewden2, Pierre de Truchis6, Michel Dupon7, François Raffi8 and the APROCO/COPILOTE study group.

1Montpellier University Hospital, 2INSERM U 593, Bordeaux, 3Toulouse University Hospital, 4Brest University Hospital,

5Bichat-Claude Bernard, Paris, 6Raymond Poincaré Hospital, Garches, 7Bordeaux University Hospital, 8Nantes University Hospital, France

Contact information:Dr Vincent Le MoingMaladies Infectieuses et TropicalesHôpital Gui de ChauliacF 34295 Montpellier Cedexv-le_moing@chu-montpellier.fr

H-516

Abstract

Background: Prospective cohort studies with long-term follow-up are well adapted to detect emerging morbidity.Methods: APROCO/COPILOTE cohort study enrolled 1281 HIV-infected pts at the time of initiation of protease inhibitor therapy in 1997-99. Investigators have to declare deaths, HIV related events and other events defined as severe: biological grade 3 or 4, life-threatening or leading to hospitalisation. Clinical experts assess whether events are related to AIDS (ADE), to antiretroviral drugs (severe adverse events (SAE)), or neither to AIDS nor to antiretrovirals (other severe events (OSE)). Cumulative probability of events at 5 years were estimated by the Kaplan-Meier method.Results: At 5 yrs, cumulative probability of death was 10%, it was 16% for ADE or death, 30% for SAE and 35% for OSE. Cumulative probability of the most frequent SAE or OSE were: bacterial infections 11%, liver diseases 11%, cardio-vascular diseases 6%, cancers 3% (including Hodgkin disease 1%), depression/suicide 3%. Progression to ADE or death was less frequent than SAE and OSE during whole follow-up and in every category of pts except those who initiated PI therapy with CD4 < 50/mm3 (ADE or death: 38%, SAE: 35%, OSE: 33%). SAE and OSE were more frequent in pts co-infected with hepatitis viruses (ADE or death: 18%, SAE: 43%, OSE: 42%) and in pts who contracted HIV infection through iv drug use (ADE or death: 14%, SAE: 39%, OSE: 39%). Conclusion: Severe events neither related to AIDS nor to antiretroviral therapy have became the most frequent morbid events in HIV-infected pts treated with HAART. This finding points out the need to develop research tools to better analyse the

epidemiology of this emerging morbidity in patients on prolonged HAART.

Background

Effectiveness of Highly active antiretroviral therapy (HAART) in preventing AIDS-defining events (ADE) and death due to HIV has been clearly demonstrated.

Diseases unrelated to HIV may however emerge during this lifelong therapy and counterbalance, at least in part, this protective effect, whatever this emerging morbidity is related to antiretroviral drugs or not.

Prospective cohort studies with long-term follow-up and particular attention given to clinical events are well adapted to detect such an emerging morbidity.

The APROCO-COPILOTE cohort study (ANRS CO 8) has been specifically designed in 1997 to reach this goal.

We describe the morbidity observed in the APROCO-COPILOTE cohort study during the 5 first years of HAART.

Patients and methodsThe APROCO-COPILOTE cohort study enrolled 1281 HIV-infected patients at the initiation of a protease inhibitor (PI)-containing regimen during two periods in 1997-1999.

Patients are followed every 4 months. Investigators have to declare deaths, HIV related events according to the CDC 1993 classification and other events defined as severe, i.e. biological grade 3 or 4, life-threatening or leading to hospitalisation or prolongation of hospitalisation.

The Events Validation Committee of 8 clinician experts assess collegially whether each event is defining AIDS (ADE), is possibly attributable to antiretroviral drugs (severe adverse events according to EMEA guidelines (SAE)), or neither related to AIDS nor to antiretroviral drugs (other severe events (OSE)).

Cumulative probability of severe events at 5 years were estimated by the Kaplan-Meier method.

Groupe d’Etude APROCO-COPILOTE

Conseil Scientifique :

Comité de Pilotage : Investigateurs principaux : C. Leport, F. Raffi,

Coordonnateurs méthodologistes : G. Chêne, R. Salamon,

Coordonnateurs Sciences sociales : J-P. Moatti, J. Pierret, B. Spire

Coordonnateurs virologues : F. Brun-Vézinet, H. Fleury, B. Masquelier,

Coordonnateurs pharmacologues : G. Peytavin, R. Garraffo

Coordonnateur clinicien : V. Le Moing

Autres membres : F. Ballereau, D. Costagliola, P. Dellamonica, C. Katlama, L. Meyer, M. Morin, D. Salmon, A. Sobel,

Comité de Validation des Evénements : L. Cuzin, M. Dupon, X. Duval, V. Le Moing, B. Marchou, T. May, P. Morlat, C. Rabaud, A. Waldner-Combernoux

Coordination de projet : F. Collin

Observateurs : JF. Delfraissy, J. Dormont, C. Grillot-Courvalin, M. Garré, Y. Souteyrand, JL. Vildé

Monitorage et analyse C Alfaro, F Alkaied, C Barennes, S Boucherit, AD Bouhnik, C Brunet-François, MP Carrieri, M Courcoul, JL Ecobichon, M François, V Journot, R Lassalle, JP Legrand, C Lewden, E Pereira, M Préau, C Roussillon, A Taieb, V Villes, H Zouari

Promoteur Agence Nationale de Recherches sur le Sida (ANRS, Action Coordonnée n°7).

Soutien : Collège des Universitaires de Maladies Infectieuses et Tropicales (CMIT ex APPIT), SidactionEnsemble contre le Sida, et laboratoires : Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Glaxo-SmithKline, Merck Sharp et Dohme, Roche.

Centres investigateurs :Amiens (Pr JL. Schmit), Angers (Dr JM. Chennebault), Belfort (Dr JP. Faller), Besançon (Pr JL. Dupond, Dr JM. Estavoyer,Pr R. Laurent), Bobigny (Pr A. Krivitzky), Bordeaux (Pr J. Beylot, Pr M. Dupon, Pr M.Longy-Boursier, Pr JM. Ragnaud), Bourg-en-Bresse (Dr P. Granier), Brest (Pr M. Garré), Caen (Pr R. Verdon), Compiègne (Dr P. Veyssier), Corbeil Essonnes (Dr A. Devidas), Créteil (Pr A. Sobel), Dijon (Pr H. Portier), Garches (Pr C. Perronne), Lagny (Dr P. Lagarde), Libourne (Dr J. Ceccaldi), Lyon (Pr D. Peyramond),

Meaux (Dr C. Allard), Montpellier (Pr J. Reynes), Nancy (Pr T. May), Nantes (Pr F. Raffi), Nice (Pr JP. Cassuto, Pr P. Dellamonica), Orléans (Dr P. Arsac), Paris (Pr Bricaire, Pr Cabane, Pr Caulin, DrCessot, Pr Girard, Pr Herson, Pr Molina, Pr G.Pialoux, Pr D. Salmon, Pr Vildé, Pr Yéni), Poitiers (Pr B. Becq-Giraudon), Reims (Pr G. Rémy), Rennes (Pr C. Michelet), Saint-Etienne (Pr F. Lucht), Saint-Mandé (Pr T. Debord), Strasbourg (Pr JM. Lang), Toulon (Dr JP. de Jaureguiberry), Toulouse (Pr B. Marchou), Tours (Pr P. Choutet).

ResultsBaseline characteristics of patients enrolled in APROCO/COPILOTE cohort study

• male 77%, median age 37 years

• Previously treated with antiretroviral drugss: 57%

• Median CD4+ cell count: 275/mm3, median plasma HIV RNA: 4.4 log10 copies/ml

•HCV Ab+: 25%, HBs Ag+: 5%.

During the 5 first years of follow-up (5316 patients-years):• 101 patients died; incidence: 1.9/100 pts-years (95% CI: 1.6-2.3)

• 120 pts had 179 ADE (15 non Hodgkin lymphoma); incidence: 3.4/100 pts-years (95% CI: 2.9-3.9)

• 431 SAE were observed; incidence: 8.3/100 pts-years (95% CI: 7.5-9.0)

• 676 OSE were observed; incidence: 13.0/100 pts-years (95% CI: 12.0-14.0)

Causes of death:

• AIDS n = 35 (35%)

• Non AIDS-defining cancer not related to HBV or HCV n = 13 (13%)

• HBV or HCV n = 8 (8%)

• Non AIDS-defining infection n = 7 (7%)

• Accident n = 7 (7%)

• Cardio-vascular disease n = 5 (5%)

• Intoxication or overdose n = 5 (5%)

• Pancreatitis n = 4 (4%)

• Suicide n = 4 (4%)

• Sudden unexplained death n = 3 (3%)

• Metabolic disease n = 2 (2%)

• Iatrogenic n = 2 (2%)

• Unknown n = 6 (6%)

Cumulative probability at 5 years of the most frequent non AIDS-defining events (SAE and OSE)

•bacterial infections: 11%; n = 168; incidence: 3.2/100 pts-years

• all considered as OSE, among them 50% were respiratory infections

• liver diseases 11%; n = 140; incidence: 2.7/100 pts-years

• ALT levels > 5 ULN: 9.5%; 57% were observed in pts co-infected with HCV or HBV; 78% were classified as SAE

• other livers diseases: 1.5%; 57% were observed in pts co-infected with HCV or HBV; 78% were classified as SAE

• cardio-vascular diseases 6%; n = 76; incidence = 1.5/100 pts-years

•50% of them were classified as SAE

• 37% were coronarian heart disease

•33% were venous thrombo-embolic events

• depression or suicide: 3%; n = 50; incidence = 1.0/100 pts-years

• 29% were classified as SAE

• cancer: 3%; n = 36; incidence = 0.7/100 pts-years

• Hodgkin disease: 1%

Cumulative probability of severe events at 5 years. Severe events = grade 3 or 4, life-threatening, requiring hopsitalisation or prolongation of hospitalisation

APROCO-COPILOTE cohort study 1997-2004

Deaths

Severe Adverse Events

AIDS-Defining Events

Other Severe Events

Cumulative probability (%) of severe events

according to some characteristics At 1 year At 3 yrs At 5 yrs ADE or

death SAE OSE ADE or

death SAE OSE ADE or

death SAE OSE

Baseline CD4+ cell count (/mm3)

<50 24 20 16 33 28 26 38 35 33 50-100 12 13 9 17 30 19 21 32 25 100-200 6 15 11 11 23 21 17 33 28 200-350 4 12 6 6 22 16 11 26 24 >= 350 2 10 8 5 21 20 11 29 29 IV drug use as risk factor for HIV infection

Yes 5 22 20 10 36 33 14 39 39 No 6 12 9 10 22 19 15 29 27 CDC stage C Oui 21 15 17 28 25 31 34 32 39 Non 3 12 8 6 23 20 11 29 29 Co-infection with HCV or HBV

Yes 4 25 14 12 35 32 18 43 42 No 7 12 9 10 19 18 15 25 25

Discussion / Conclusion

Summary of results

In the HAART era, severe events apparently unrelated to HIV have became the most frequent morbid events in HIV-infected patients.

This higher frequency of non HIV-related severe events was observed in every category of patients except those who already had AIDS at baseline or had a baseline a CD4+ cell count < 50/mm3.

Non-HIV related severe morbidity was predominant even during the very first months of HAART

This emerging morbidity was more frequent in patients who presumably acquired HIV infection through iv drug use and in patients co-infected with hepatitis B or C virus.

Limits of our study

Attribution of non HIV-related events to antiretroviral drugs is very difficult, notably in case of events in which a causal relationship with therapy is suspected but has not been firmly established, like cardiovascular events or liver diseases. The classification of events as severe adverse events or other severe events may thus have been somewhat biased.

Even if all events are qualified as severe according to validated scores, they may not have the same consequences on suvival and quality of life. For example, it may not be totally valid to compare HIV-related and non HIV-related morbidity.

Perspectives

Taking care of HIV-infected patients will need more and more a multidisciplinary approach.

It is highly desirable to develop specific research tools to better anlyse this emerging morbidity.

Due to the high heterogeneity of events and to the relatively low frequency of each particular event, collaboration between cohorts is necessary to study the determinants of apparently emerging diseases, like it has been done for metabolic and cardiovascular events (D.A.D collaboration).