1 7 th CROI, San Francisco, 2010 . Hotel AC, Barcelona – February 26 th 2010
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Transcript of 1 7 th CROI, San Francisco, 2010 . Hotel AC, Barcelona – February 26 th 2010
17th CROI, San Francisco, 2010.Hotel AC, Barcelona – February 26th 2010
17th CROI, San Francisco, 2010.Hotel AC, Barcelona – February 26th 2010
Dr. José M. MiróInfectious Diseases Service - ICMiD
Hospital Clinic - IDIBAPS University of Barcelona
Barcelona (Spain)
Dr. José M. MiróInfectious Diseases Service - ICMiD
Hospital Clinic - IDIBAPS University of Barcelona
Barcelona (Spain)
Summary: Opportunistic Infections HCV/HBV Co-Infections & Tumors
Summary: Opportunistic Infections HCV/HBV Co-Infections & Tumors
E-mail address: [email protected] address: [email protected]
When to start cART Tuberculosis 2009 Influenza A(H1N1) Other opportunistic infections & IRIS HCV & HBV co-infections Tumors
When to start cART Tuberculosis 2009 Influenza A(H1N1) Other opportunistic infections & IRIS HCV & HBV co-infections Tumors
OIs, Hepatitis Coinfections & Tumors
OIs, Hepatitis Coinfections & Tumors
Immediate vs. Deferred cART in the Setting of Acute AIDS-Related OIs (ACTG A5164)
Zolopa AR, et al. PLoS ONE. 2009;4(5):e5575.
Immediate vs. Deferred cART in the Setting of Acute AIDS-Related OIs (ACTG A5164)
Zolopa AR, et al. PLoS ONE. 2009;4(5):e5575.
Study day Study day
EnrollmentEnrollment
Opportunistic infections* Treatment
Starts
Opportunistic infections* Treatment
Starts
Immediate Arm
Start ART
Immediate Arm
Start ART
Deferred ArmStart ART
Deferred ArmStart ART
RecommendedStart window
RecommendedStart window
48wks48
wks
48wks48
wks
-14-14 00 22 2828 4242 8484 224224
Study schemaStudy schema
12 days vs. 45 days
*TB excluded !!!*TB excluded !!!
Results Through 48 WeeksResults Through 48 Weeks
• No difference in primary endpoint of virologic suppression• No difference in IRIS (10 immediate, 13 deferred) or need for ART changes
Prob
abili
ty o
f sur
vivi
ng
with
out
deat
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IDS
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Prob
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out
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h/ne
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IDS
defin
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Immediate ARTDeferred ARTImmediate ARTDeferred ART
000.00.0
0.20.2
1.001.00
44 88 1212 1616 2020 2424 2828 3232 3636 4040 4444 4848
0.10.1
0.90.9
0.80.8
0.70.7
0.60.6
0.50.5
0.40.4
0.30.3
116116
9494
HR=0.5399%CI (0.25,1.09)P=0.023
HR=0.5399%CI (0.25,1.09)P=0.023
Early cART less new AIDS events or death
MonthsMonths
Immediate vs. Deferred cART in the Setting of Acute AIDS-Related OIs (ACTG A5164)
Zolopa AR, et al. PLoS ONE. 2009;4(5):e5575.
Immediate vs. Deferred cART in the Setting of Acute AIDS-Related OIs (ACTG A5164)
Zolopa AR, et al. PLoS ONE. 2009;4(5):e5575.
Characteristics Total Immediate DeferredCD4 (cells/mm3) Median (IQR) 29 (10-55) 31 (12-54) 28 (10-56)
HIV RNA (log10) Median (IQR)
5.07(4.71-5.63)
5.07 (4.74-5.59)
5.08(4.64-5.64)
No Prior ART N (%) 259 (92) 131 (93) 128 (91)
PCP N (%) 177 (63) 88 (62) 89 (63)
BI N (%) 34 (12) 17 (12) 17 (12)
Other OI N (%) 71 (25) 36 (26) 35 (25)
Crypto / Histo N (%) 45 (16) 20 (14) 25 (18)
Toxoplasmosis N (%) 13 (5) 9 (6) 4 (3)
CMV N (%) 6 (2) 4 (3) 2 (1)
MAC N (%) 6 (2) 3 (2) 3 (2)
Multiple OI/BI w/in 30 days 33% 32% 33%*TB excluded !!!*TB excluded !!!
Immediate vs. Deferred cART in the Setting of Acute AIDS-Related OIs (ACTG A5164)
Zolopa AR, et al. PLoS ONE. 2009;4(5):e5575.
Immediate vs. Deferred cART in the Setting of Acute AIDS-Related OIs (ACTG A5164)
Zolopa AR, et al. PLoS ONE. 2009;4(5):e5575.
• Retrospective multicohort studyRetrospective multicohort study
• Hospital cohorts: Italy (6), Spain (1), UK (1) and Canada (1).
• Study population: Study population: All patients with an AIDS diagnosis between 30 days before and 14 days after HIV diagnosis, recruited between 1997 and 2004.
• Patients included in the study: 760
• Retrospective multicohort studyRetrospective multicohort study
• Hospital cohorts: Italy (6), Spain (1), UK (1) and Canada (1).
• Study population: Study population: All patients with an AIDS diagnosis between 30 days before and 14 days after HIV diagnosis, recruited between 1997 and 2004.
• Patients included in the study: 760
Patients Presenting With AIDS in the HAART Era: A Collaborative Cohort AnalysisMussini C et al. AIDS 2008, 22:2461–2469
Patients Presenting With AIDS in the HAART Era: A Collaborative Cohort AnalysisMussini C et al. AIDS 2008, 22:2461–2469
• P. jiroveciiP. jirovecii pneumonia (PCP) pneumonia (PCP)• TuberculosisTuberculosis• Esophageal candidiasisEsophageal candidiasis• CNS toxoplasmosisCNS toxoplasmosis• CMV diseaseCMV disease• Kaposi’s sarcomaKaposi’s sarcoma• NHLNHL• Other Opportunistic InfectionsOther Opportunistic Infections
• P. jiroveciiP. jirovecii pneumonia (PCP) pneumonia (PCP)• TuberculosisTuberculosis• Esophageal candidiasisEsophageal candidiasis• CNS toxoplasmosisCNS toxoplasmosis• CMV diseaseCMV disease• Kaposi’s sarcomaKaposi’s sarcoma• NHLNHL• Other Opportunistic InfectionsOther Opportunistic Infections
268 (35%)268 (35%)168 (22%)168 (22%)94 (12%)94 (12%)65 (9%)65 (9%)51 (7%)51 (7%)65 (9%)65 (9%)28 (4%)28 (4%)
115 (15%)115 (15%)
268 (35%)268 (35%)168 (22%)168 (22%)94 (12%)94 (12%)65 (9%)65 (9%)51 (7%)51 (7%)65 (9%)65 (9%)28 (4%)28 (4%)
115 (15%)115 (15%)
Patients Presenting With AIDS in the HAART Era: A Collaborative Cohort AnalysisMussini C et al. AIDS 2008, 22:2461–2469
Patients Presenting With AIDS in the HAART Era: A Collaborative Cohort AnalysisMussini C et al. AIDS 2008, 22:2461–2469
Survival outcomes and effect of early vs. deferred cART among HIV-1-infected patients diagnosed at the time of
an AIDS-defining event in Europe and Canada: a collaborative cohort analysis (1997-2004)
Survival outcomes and effect of early vs. deferred cART among HIV-1-infected patients diagnosed at the time of
an AIDS-defining event in Europe and Canada: a collaborative cohort analysis (1997-2004)
The objectives os this study were: 1) to analyze the clinical progression (new AIDS event or death)
among persons diagnosed with HIV at the time of an AIDS-defining event (TB, PCP, other OI, KS or lymphoma); and,
2) to assess the impact on outcome of timing of cART initiation in these individuals.
The objectives os this study were: 1) to analyze the clinical progression (new AIDS event or death)
among persons diagnosed with HIV at the time of an AIDS-defining event (TB, PCP, other OI, KS or lymphoma); and,
2) to assess the impact on outcome of timing of cART initiation in these individuals.
Miro JM, 529Miro JM, 529
Characteristics of patients in study, overall and stratified by immediate/deferred treatment
• Overall, the characteristics of patients receiving immediate and deferred treatment were broadly similar with the exception of some differences by country and age. Those treated immediately were slightly older.
• cART regimens were similar in both groups.
• Patients with KS were more likely to be treated immediately (P= 0.02).
• Overall, the characteristics of patients receiving immediate and deferred treatment were broadly similar with the exception of some differences by country and age. Those treated immediately were slightly older.
• cART regimens were similar in both groups.
• Patients with KS were more likely to be treated immediately (P= 0.02).
All patients Immediate Deferred p-value
N (% of total) 429 (100.0) 202 (47.1) 227 (52.9)
Male sex 333 (77.8) 154 (76.6) 179 (78.9) 0.66
Risk group IDU 43 (10.0) 18 (8.9) 25 (11.0) Homosexual 102 (23.8) 49 (24.3) 53 (23.4) Heterosexual 147 (34.3) 71 (35.2) 76 (33.5) Other 137 (31.9) 64 (31.7) 73 (32.2) 0.90
Age (years) Median (IQR) 39 (33, 47) 40 (33, 49) 39 (33, 47) 0.20
CD4 count (cells/mm3) Median (IQR) 36 (13, 104) 36 (12, 112) 34 (14, 98) 0.67
HIV RNA (log10 copies/ml)
Median (IQR) 5.3 (4.6, 5.7) 5.2 (4.3, 5.7) 5.4 (4.8, 5.8) 0.04
Country Italy 175 (40.8) 92 (45.5) 83 (36.6) Spain 92 (21.5) 42 (20.8) 50 (22.0) UK 114 (26.6) 55 (27.2) 59 (26.0) Canada 48 (11.2) 13 (6.4) 35 (15.4) 0.02
Type of AIDS event TB 93 (21.7) 39 (19.3) 54 (23.8) 0.31
PCP 178 (41.5) 82 (40.6) 96 (42.3) 0.80 KS 43 (10.0) 28 (13.9) 15 (6.6) 0.02 Lymphoma 10 (2.3) 3 (1.5) 7 (3.1) 0.35 Other 160 (37.3) 78 (38.6) 82 (36.1) 0.67
Type of ART NNRTI-based 117 (28.2) 50 (24.8) 67 (31.5) PI-based 261 (62.9) 136 (67.3) 125 (58.7) Other 37 (8.9) 16 (7.9) 21 (9.9) 0.19
Total follow-up (years) Median (IQR) 2.1 (0.8, 4.0) 2.4 (0.9, 4.0) 2.0 (0.7, 4.1) 0.07
Miro JM, 529Miro JM, 529
Kaplan Meier plot showing the cumulative proportion of patients with clinical progression (new AIDS event or death), according to the type of AIDS-defining diagnosis disease.
Miro JM, 529Miro JM, 529
Factors associated with clinical progression (new AIDS event or death)
Model 1: No adjustment Model 2: Fully adjusted model Model 3: Parsimonious model
RH 95% CI p-value RH 95% CI p-value RH 95% CI p-value
Deferred vs. immediate treatment 2.00 (1.37, 2.92) 0.0003 1.89 (1.27, 2.82) 0.002 1.85 (1.25, 2.73) 0.002
AIDS-defining event TB - - - 1.01 (0.64, 1.59) 0.96 - - - PCP - - - 1.26 (0.75, 2.12) 0.38 - - - KS - - - 1.95 (1.07, 3.58) 0.03 - - - Lymphoma - - - 2.15 (0.75, 6.22) 0.16 2.51 (1.01, 6.21) 0.05
Female - - - 1.16 (0.72, 1.86) 0.55 - - -
Risk group Heterosexual - - - 1 - - - - - Homosexual - - - 0.69 (0.34, 1.40) 0.31 - - - IDU - - - 0.66 (0.38, 1.14) 0.14 - - - Other - - - 0.91 (0.56, 1.46) 0.68 - - -
Age (per 5 years older) - - - 1.09 (0.99, 1.19) 0.07 1.10 (1.01, 1.20) 0.02
CD4 count (per 50 cells/mm3 higher) - - - 0.95 (0.87, 1.04) 0.27 - - -
Viral load (per log10 higher) - - - 1.26 (1.04, 1.52) 0.02 1.30 (1.08, 1.56) 0.006
Miro JM, 529Miro JM, 529
ConclusionsConclusions
• Older patients and those with a higher VL (>100K) or lymphoma at HIV diagnosis had a worse outcome.
• Patients who “deferred” cART had almost twice the risk of clinical progression than those who initiated cART immediately
• Whilst the results of this study confirm the findings from ACTG 5164, the small number of patients with KS or lymphoma in our study, and the potential for confounding, means that it remains important to conduct RCTs to validate our findings.
• Older patients and those with a higher VL (>100K) or lymphoma at HIV diagnosis had a worse outcome.
• Patients who “deferred” cART had almost twice the risk of clinical progression than those who initiated cART immediately
• Whilst the results of this study confirm the findings from ACTG 5164, the small number of patients with KS or lymphoma in our study, and the potential for confounding, means that it remains important to conduct RCTs to validate our findings.
Miro JM, 529Miro JM, 529
A5221/STRIDE A5221/STRIDE CAMELIA CAMELIA SAPITSAPIT
ENDPTENDPT
SITESSITES
No No
ARMSARMS
800/800800/800
Africa, Asia, SA, NAAfrica, Asia, SA, NA
429/429429/429660/660660/660
CambodiaCambodia South AfricaSouth Africa
Imm vs. 8-24Imm vs. 8-24Imm vs. 8Imm vs. 8Imm vs. 8-12Imm vs. 8-12
Death, AIDSDeath, AIDS DeathDeath DeathDeath
When to Start cART during TB treatment When to Start cART during TB treatment
When to start cART Tuberculosis 2009 Influenza A(H1N1) Other opportunistic infections & IRIS HCV & HBV co-infections Tumors
When to start cART Tuberculosis 2009 Influenza A(H1N1) Other opportunistic infections & IRIS HCV & HBV co-infections Tumors
OIs, Hepatitis Coinfections & Tumors
OIs, Hepatitis Coinfections & Tumors
Paper # 102Effectiveness of Isoniazid Preventive Therapy in Reducing Mortality in Patients on ARTCraig Innes et al. South Africa.
Paper # 102Effectiveness of Isoniazid Preventive Therapy in Reducing Mortality in Patients on ARTCraig Innes et al. South Africa.
Paper # 103Efficacy of a 6-month vs a 36-month Regimen for Prevention of Tuberculosis in HIV-infected Persons in India: A Randomized Clinical TrialSoumya Swaminathan et al. India.
Paper # 103Efficacy of a 6-month vs a 36-month Regimen for Prevention of Tuberculosis in HIV-infected Persons in India: A Randomized Clinical TrialSoumya Swaminathan et al. India.
Paper # 104LBRandomized, Placebo-controlled Trial of 6 vs 36 Months Isoniazid TB Preventive Therapy for HIV-infected Adults in BotswanaTaraz Samandari et al. Botswana.
Paper # 104LBRandomized, Placebo-controlled Trial of 6 vs 36 Months Isoniazid TB Preventive Therapy for HIV-infected Adults in BotswanaTaraz Samandari et al. Botswana.
Isoniazid Preventive Therapy (IPT) in HIV-infected Patients
YES
Better 6 mo.
Better 36 mo.
Samandari T. 104LB. Samandari T. 104LB.
IPT in HIV-infected Patients in Botswana: 6 vs. 36 months
Samandari T. 104LB. Samandari T. 104LB.
IPT in HIV-infected Patients in Botswana: 6 vs. 36 months
Samandari T. 104LB. Samandari T. 104LB.
IPT in HIV-infected Patients in Botswana: 6 vs. 36 months
Samandari T. 104LB. Samandari T. 104LB.
IPT in HIV-infected Patients in Botswana: 6 vs. 36 months
Samandari T. 104LB. Samandari T. 104LB.
IPT in HIV-infected Patients in Botswana: 6 vs. 36 months
Samandari T. 104LB. Samandari T. 104LB.
IPT in HIV-infected Patients in Botswana: 6 vs. 36 months
Samandari T. 104LB. Samandari T. 104LB.
IPT in HIV-infected Patients in Botswana: 6 vs. 36 months
Comparing a new IP-10 based test with the QuantiFERON In Tube test for diagnosing pulmonary
tuberculosis in an HIV-endemic population
Aabye MG, 770Aabye MG, 770IP-10 (monocyte derived chemokine) is induced upon Mtb. specific antigen stimulation of
whole blood with from patients with active TB infection but not from uninfected patients.IP-10 (monocyte derived chemokine) is induced upon Mtb. specific antigen stimulation of
whole blood with from patients with active TB infection but not from uninfected patients.
Effect of HIV Infection on 2-Month Treatment Outcome of Therapy for Pulmonary Tuberculosis
Disease in Two Clinical Trials
Bliven E, 782Bliven E, 782
Effect of HIV Infection on 2-Month Treatment Outcome of Therapy for Pulmonary Tuberculosis
Disease in Two Clinical Trials
Bliven E, 782Bliven E, 782
When to start cART Tuberculosis 2009 Influenza A(H1N1) Other opportunistic infections & IRIS HCV & HBV co-infections Tumors
When to start cART Tuberculosis 2009 Influenza A(H1N1) Other opportunistic infections & IRIS HCV & HBV co-infections Tumors
OIs, Hepatitis Coinfections & Tumors
OIs, Hepatitis Coinfections & Tumors
0
20
40
60
80
100
120
S1
8
S2
0
S2
2
S2
4
S2
6
S2
8
S3
0
S3
2
S3
4
S3
6
S3
8
S4
0
S4
2
S4
4
S4
6
S4
8
S5
0
HIV+ A(H1N1)+
NoHIV+ A(H1N1)+
Number of HIV- & HIV+ patients positive for influenza A (H1N1) per calendar week in Barcelona (Spain)
Number of HIV- & HIV+ patients positive for influenza A (H1N1) per calendar week in Barcelona (Spain)
Martinez E, 802LBMartinez E, 802LB
HIV+ (n=56) Characteristics• Route of transmission (n, %)
– MSM: 26 (46)– IDU: 18 (32)– Heterosexual: 12 (21)
• Years from HIV-1 diagnosis (median, IQR) 14 (5 – 19)• Nadir CD4 (absolute) (median, IQR) 222 (134 – 379)• Nadir CD4 (%) (median, IQR) 18 (14 – 22)• Log HIV-1 RNA zenit (median, IQR) 5.2 (4.7 – 5.5)• Prior/current C events (n, %) 16 (29)
• Hepatitis C (n, %) 21 (38)
At influenza A (H1N1) diagnosis:• CD4 (absolute) (median, IQR) 583 (370 - 715)• CD4 (%) (median, IQR) 26 (23 – 33)• CD4 (absolute) (median, IQR) 995 (828 – 1485)• CD4 (%) (median, IQR) 50 (41 – 60)• Log HIV-1 RNA (median, IQR) 1.7 (1.7 – 1.7)• Patients with log HIV-1 RNA >50 copies/mL (n, log HIV-1 RNA) 3 (2.7, 3.5, and 4.3)
Martinez E, 802LBMartinez E, 802LB
Absolute CD4 (cells/mm3) at influenza A (H1N1) diagnosis
0
5
10
15
20
25
30
Absolute CD4 at influenza A (H1N1) diagnosis
<50
50-100
101-150
151-200
201-500
501-1000
>1000
<200/mm3: 9%
Martinez E, 802LBMartinez E, 802LB
HIV+ (n=56) HIV- (n=168) P valueDemographics
Men (n, %) 44 (79) 74 (44) 0.0001 Age (years) (mean, SD) 44 ± 8 39 ± 15 0.0153 Active smoker (n, %) 30 (54) 21 (13) 0.0001 Travel / contacts (n, %) 4 (7%) 40 (24) 0.0066 Co-morbidities (n, %) 8 (14) 103 (61) 0.0001Specific co-morbidities
COPD /asthma (n, %) 3 (5) 44 (26)
Neoplasia (n, %) (solid/hemathologic)
2 (4) (0/2)
12 (7)(4/8)
Pregnancy (n, %) 0 (0) 18 (11)
Drug-induced immunesupression (n, %) 1 (2) 12 (7)
Diabetes mellitus (n, %) 1 (2) 7 (4)
Cirrhosis (n, %) 1 (2) 2 (1)
Toxic abuse (drugs / alcohol) (n, %) 0 (0) 2 (1)
Chronic kidney disease (n, %) 0 (0) 1 (1)
Obesity (BMI >30 kg/m2) (n, %) 0 (0) 3 (2)
Ischemic CV disease (n, %) 0 (0) 2 (1)
Demographic characteristics and comorbities Demographic characteristics and comorbities
Martinez E, 802LBMartinez E, 802LB
HIV+ (n=56) HIV- (n=168) P value
Dysthermia (n, %) 56 (100) 159 (95) 0.1691Cough (n, %) 48 (86) 145 (86) 0.9111Arthromyalgias (n, %) 44 (79) 128 (76) 0.7148Tiredness (n, %) 38 (68) 128 (76) 0.2176Headache (n, %) 22 (39) 78 (46) 0.3518Sore throat (n, %) 21 (38) 46 (27) 0.1521GI symptoms (n, %) 21 (38) 31 (19) 0.0035
Rinorrhea (n, %) 18 (32) 57 (34) 0.8063Expectoration (n, %) 23 (41) 57 (34) 0.3330Dyspnea (n, %) 10 (18) 36 (21) 0.5667
Clinical symptomsClinical symptoms
Martinez E, 802LBMartinez E, 802LB
Influenza A (H1N1) at presentationInfluenza A (H1N1) at presentation
HIV+ (n=56) HIV- (n=168) P value
Days from onset (mean, SD) 2.8 ± 1.6 3.2 ± 2.0 0.1359
Axillar temperature (ºC) (mean, SD) 37.9 ± 0.9 37.7 ± 1.0 0.1685
Delayed influenza A (H1N1) diagnosis (n, %) 4 (7) 21 (13) 0.2702
Pneumonia (n, %) 5 (9) 42 (25) 0.0105
Respiratory failure (n, %) 5 (9) 36 (219 0.0362
Martinez E, 802LBMartinez E, 802LB
Concommitant bacteria detected
HIV+ (n=56) HIV- (n=168) P
value
• Concommitant bacteria * (n, %) 4 (7) 13 (8) 0.8842
– S. pneumoniae 3 9
– S. aureus 0 4
– Capnocytophaga spp 1 0
* Detected from blood cultures and/or urine antigens and/or valid respiratory samples
Martinez E, 802LBMartinez E, 802LB
Prognosis
HIV+ (n=56) HIV- (n=168) P Value
Days at hospital (mean, SD) 1.1 ± 2.3 2.0 ± 3.4 0.0812
>1 day at hospital (n, %) 15 (27) 70 (42) <0.05
Complications after admission (n, %) 7 (13) 18 (11) 0.7132
Anti-influenza therapy (oseltamivir) (n, %)
53 (95) 119 (71) 0.0003
Antibiotic therapy (n, %) 29 (52) 82 (49) 0.6997
Clinical recovery <1 week (n, %) 43 (77) 94 (56) 0.0056
Evolution to death (n, %) 0 (0) 3 (2) 0.7372
Martinez E, 802LBMartinez E, 802LB
CD4 and CD8 changes from influenza A (H1N1) diagnosis until 4-6 weeks later
Influenza A (H1N1) diagnosis
(n=56)
4-6 weeks post-diagnosis
(n=51)
Change
CD4 cells (mm3) Median (IQR)
583(370 – 715)
466(275 – 702)
-15(-44, 39)
CD4 cells (%) Median (IQR)
26.3(22.7 – 33.4)
26.5(21.5 – 33.2)
-0.4(-0.8, 2.3)
CD8 cells (mm3) Median (IQR)
995(828 – 1485)
917(631 – 1250)
-14(-122, 77)
CD8 cells (%) Median (IQR)
49.7(40.6 – 59.59
48.5(42.8 – 56.5)
0.7(-2.8, 1.5)
Log HIV-1 RNA (copies/mL) Median (IQR)
1.7(1.7 – 1.7)
1.7(1.7 – 1.7)
0(0, 0)
Martinez E, 802LBMartinez E, 802LB
Conclusions
• HIV infection did not make 2009 influenza A
(H1N1) more severe.
• 2009 Influenza A (H1N1) did not have a major
impact on HIV infection control.
Martinez E, 802LBMartinez E, 802LB
METHODSOngoing randomized (1:1) patient-blinded trial, HIV-1-infected adult patients,
- either receiving HAART (HIV viral load <50 copies/mL )- or not receiving HAART (without indication for treatment)
Group A: AS03A-adjuvanted H1N1v vaccine 3.75µg HA n=154Group B: Non-adjuvanted H1N1v vaccine 15µg HA n=152
Randomization
D42 D182 D364D0 D21Follow-upSamples
D91
Vaccination (IM)
Immunogenicity of one dose of influenza A H1N1v 2009 vaccine formulated with and without AS03A-adjuvant in HIV+ adults
Preliminary Report of the ANRS 151 Randomized HIFLUVAC TrialOdile LAUNAY et al, ANRS, Paris, France
Stratification according to HAART vs no HAART at baseline
STUDY POPULATION: 306 patients : 237 on HAART, 69 untreated
Median age : 47 years (IQR, 40-54); 19% were female; Median CD4: 536 cells/μL (IQR, 413–715) ; 556 (treated patients), 517 (untreated)
STUDY POPULATION: 306 patients : 237 on HAART, 69 untreated
Median age : 47 years (IQR, 40-54); 19% were female; Median CD4: 536 cells/μL (IQR, 413–715) ; 556 (treated patients), 517 (untreated) Launay O, 804LBLaunay O, 804LB
Pre and post-vaccination seroprotection rates and GMTs
Seroprotection rate % (95% CI)
AS03A-adjuvanted H1N1v vaccine 3.75 µg HA (Group A)
Non-adjuvanted H1N1v vaccine15 μg HA (Group B)
B w/o HAART
n=33
A HAARTn=115
A w/o HAART
n=35
B HAARTn=115
010203040506070
8090
100
0
50
100
150
200
250
300
A Totaln=150
B Totaln=148
D0 D21 D0 D21 D0 D21 D0 D21 D0 D21 D0 D21
GM
T (95% C
I)
Regulatoryrequirements
CONCLUSIONA single dose of H1N1v vaccine was well tolerated and induces high immune response in this population.Higher immunogenicity (seroprotection rate and GMT) was obtained with the AS03A-adjuvanted H1N1v vaccine.
CONCLUSIONA single dose of H1N1v vaccine was well tolerated and induces high immune response in this population.Higher immunogenicity (seroprotection rate and GMT) was obtained with the AS03A-adjuvanted H1N1v vaccine.
• No short-term impact of vaccination on CD4 count or HIV viral load• Multivariate analysis: HCV/HBV co-infection and non-adjuvanted vaccine were negatively associated to seroprotection • No short-term impact of vaccination on CD4 count or HIV viral load• Multivariate analysis: HCV/HBV co-infection and non-adjuvanted vaccine were negatively associated to seroprotection
Launay O, 804LBLaunay O, 804LB
When to start cART Tuberculosis 2009 Influenza A(H1N1) Other opportunistic infections & IRIS HCV & HBV co-infections Tumors
When to start cART Tuberculosis 2009 Influenza A(H1N1) Other opportunistic infections & IRIS HCV & HBV co-infections Tumors
OIs, Hepatitis Coinfections & Tumors
OIs, Hepatitis Coinfections & Tumors
May Pneumocystis Prophylaxis Be Safely Discontinued in Virologically Suppressed Patients
With CD4 Counts Below 200 cells/μL?
May Pneumocystis Prophylaxis Be Safely Discontinued in Virologically Suppressed Patients
With CD4 Counts Below 200 cells/μL?
Incid
en
ce p
rim
ary
PC
P
per
10
00 P
YF
U (
95
% C
I)
0.1
1
10
100
1000
Off On Off On Off On Off On Off On Off On Off On Off On* Off On
Events
Median CD4!
Median VL!
5
68
2.6
76
51
5.1
30
163
4.9
5
70
2.6
2
152
3.2
8
150
4.9
11
530
2.6
8
489
3.4
44
415
4.6
5
320
2.6
0*
300
3.2
101-200cells/µL > 200 cells/µL
Low Middle High
*No events; incidence and lower bound of 95% CI=0.0; !During follow-up in strata; VL in log10copies/ml
Current VL
<100cells/µL
Low Middle High Low Middle High
Current CD4
Current use of PcP prophylaxis
5
70
3.4
6
64
3.2
4
300
4.7
4
168
3.4
7
156
2.6
2
170
2.6
31
46
5.1
Furrer H, 789Furrer H, 789
Prophylaxis PYFU PcP events Incidence per
1000 PYFU (95% CI)
On 3355 7 2.1( 0.8–4.3)
Off 1613 2 1.2 (0.2–4.5)
<400 <400 <400
Study Population• HIV-infected adults previously vaccinated with PPV 3-8 years earlier were randomized 2:1 to be revaccinated with PCV (Prevnar) or PPV (Pneumovax). A group of HIV-uninfected subjects (n=25) with no prior history of pneumococcal vaccination received a single injection of PCV.
Study Population• HIV-infected adults previously vaccinated with PPV 3-8 years earlier were randomized 2:1 to be revaccinated with PCV (Prevnar) or PPV (Pneumovax). A group of HIV-uninfected subjects (n=25) with no prior history of pneumococcal vaccination received a single injection of PCV.
Endpoints• The primary study endpoint was defined a priori as the proportion of subjects in the HIV infected PCV and PPV arms with positive antibody response to at least two of the four serotypes at day 60.- A positive response was defined as a 2-fold or greater rise in IgG level with a post-vaccination level value >1000 ng/mL
Endpoints• The primary study endpoint was defined a priori as the proportion of subjects in the HIV infected PCV and PPV arms with positive antibody response to at least two of the four serotypes at day 60.- A positive response was defined as a 2-fold or greater rise in IgG level with a post-vaccination level value >1000 ng/mL
Objective We evaluated the immunogenicity of revaccination of PCV compared with PPV in a RCT among HIV-infected adults to guide recommendations on revaccination of HIV-infected adults previously vaccinated with PPV.
Objective We evaluated the immunogenicity of revaccination of PCV compared with PPV in a RCT among HIV-infected adults to guide recommendations on revaccination of HIV-infected adults previously vaccinated with PPV.
A Randomized Clinical Trial Comparing Revaccination with Pneumococcal Polysaccharide Vaccine (PPV) to Pneumococcal
Conjugate Vaccine (PCV) among HIV-Infected Adults
Crum-Cianflone N, 814Crum-Cianflone N, 814
A Randomized Clinical Trial Comparing Revaccination with Pneumococcal Polysaccharide Vaccine (PPV) to Pneumococcal
Conjugate Vaccine (PCV) among HIV-Infected Adults
Crum-Cianflone N, 814Crum-Cianflone N, 814
1) Although revaccination with PCV was initially more immunogenic than PPV among HIVinfected adults, all such differences waned by day 180. 2) HIV-infected adults, despite ↑ CD4 counts and use of cART, had significantly lower immune responses to vaccination than HIV-uninfected group.
1) Although revaccination with PCV was initially more immunogenic than PPV among HIVinfected adults, all such differences waned by day 180. 2) HIV-infected adults, despite ↑ CD4 counts and use of cART, had significantly lower immune responses to vaccination than HIV-uninfected group.
CMV-specific T Cell Responses are Higher in HIV-infected Patients
Naeger et al, submitted
Decreasing Asymptomatic CMV Replication with Valganciclovir Decreases Immune Activationin HIV+ Patients with CD4<350 despite cART
Hunt et al, CROI, 2010, P#380
Valganciclovir Reduces CD8+ T Cell Activation among HIV-infected Patients with Suboptimal CD4+ T cell Recovery
During Antiretroviral Therapy
Hunt P, 380Hunt P, 380
When to start cART Tuberculosis 2009 Influenza A(H1N1) Other opportunistic infections & IRIS HCV & HBV co-infections Tumors
When to start cART Tuberculosis 2009 Influenza A(H1N1) Other opportunistic infections & IRIS HCV & HBV co-infections Tumors
OIs, Hepatitis Coinfections & Tumors
OIs, Hepatitis Coinfections & Tumors
September 2009
SNPs that are inherited together are compiled into "haplotypes"
Single nucleotide polymorphisms (SNPs) are identified in DNA from multiple individuals
"Tag" SNPs are identifiedand genotyped
Genome-wide association studies
www.hapmap.org
~500,000 “tag SNPs” characterise ~10,000,000 SNPs
>90% of common human genetic variants
Genetic variation in IL28B strongly predicts spontaneous HCV clearance and response to anti-HCV therapy with Peg-INF and RBV.
IL28B encodes interferon-, an antiviral cytokine
Interferon- is a promising anti-HCV drug
Genetic variation in IL28B strongly predicts spontaneous HCV clearance and response to anti-HCV therapy with Peg-INF and RBV.
IL28B encodes interferon-, an antiviral cytokine
Interferon- is a promising anti-HCV drug
The Interleukin 28B (IL28B) Gene and HCV Recovery
rs12979860 (SNP near IL28B) on chromosome 19 is strongly associated with SVR
Response to HCV therapy Natural HCV clearance
Correlation of genetic variation in IL28Bwith HCV recovery rates in diverse ethnicities
Thomas DL et al. Nature. 2009;461:798-801.Thomas DL et al. Nature. 2009;461:798-801.Ge D, et al. Nature 2009;461:399-401. Ge D, et al. Nature 2009;461:399-401.
rs12979860 C allele frequency(SNP near IL28B)
SVR
(%)
Different frequencies in IL28B variants explain ethnical differences in HCV recovery ratesDifferent frequencies in IL28B variants explain ethnical differences in HCV recovery rates
Consistent effect of genetic variation in IL28Bon spontaneous HCV clearance
Rauch A, et al. Gastroenterology 2010; Jan 7. Thomas et al. Nature. 2009;461:798-801. Rauch A, et al. Gastroenterology 2010; Jan 7. Thomas et al. Nature. 2009;461:798-801.
Carriage of IL28B risk alleles predicts chronic HCV infectionCarriage of IL28B risk alleles predicts chronic HCV infection
HCV monoinfection
HIV/HCV coinfection
Consistent effect of genetic variation in IL28B on response to anti-HCV therapy with Peg-INF & RBV
Ge D, et al. Nature 2009;461:399-401. Tanaka Y, et al. Nat Genet 2009;41:1105-9. Suppiah V, et al. Nat Genet 2009;41:1100-4. Rauch A, et al. Gastroenterology 2010; Jan 7. Ge D, et al. Nature 2009;461:399-401. Tanaka Y, et al. Nat Genet 2009;41:1105-9. Suppiah V, et al. Nat Genet 2009;41:1100-4. Rauch A, et al. Gastroenterology 2010; Jan 7.
Odds ratio of treatment failure by rs8099917 carriage
Carriage of the rs8099917 risk allele predicts treatment failureCarriage of the rs8099917 risk allele predicts treatment failure
HIV/HCV coinfection (CROI 2010) # 163 di Iulio et al # 164 Nattermann et al # 165 Rallon et al # 656 Pineda et al
OBJECTIVES
• To evaluate the role of the IL28B rs12979860 SNP in HIV/HCV co-infection
– Response to pegIFN alpha plus RBV (SVR)– Spontaneous HCV clearance
• To assess the role of the IL28B rs12979860 SNP in HCV genotypes other than HCV-1
• To evaluate the role of the IL28B rs12979860 SNP in HIV/HCV co-infection
– Response to pegIFN alpha plus RBV (SVR)– Spontaneous HCV clearance
• To assess the role of the IL28B rs12979860 SNP in HCV genotypes other than HCV-1
Rallón NI, 165LBRallón NI, 165LB
IL28B SNP is associated with spontaneous HCV clearance in HIV patients
rs12979860 & SVR
p<0.0001
p=0.001
p=0.684
p=0.08775%
38%
65%
30%
86%81%
67%
25%
SV
R
All HCV-1 HCV-3 HCV-4
CC
CT/TT
Rallón NI, 165LBRallón NI, 165LB
Predictors of SVR in HIV/HCV Co-infection
Rallón NI, 165LBRallón NI, 165LB
SVR rates according to the number of protective factors
• Low serum HCV-RNA• HCV genotype 3• Lack of advanced liver fibrosis (Metavir F0-F2)• rs12979860 CC genotype (IL28B)
Rallón NI, 165LBRallón NI, 165LB
CONCLUSIONS
• A SNP at the IL28B gene in HIV/HCV coinfected patients is associated with:
Spontaneous HCV clearance (GT1/GT4)
Sustained virological response (GT1/GT4)
• IL28B genotyping should be part of the treatment decision algorithm in this difficult-to-treat population
• A SNP at the IL28B gene in HIV/HCV coinfected patients is associated with:
Spontaneous HCV clearance (GT1/GT4)
Sustained virological response (GT1/GT4)
• IL28B genotyping should be part of the treatment decision algorithm in this difficult-to-treat population
Rallón NI, 165LBRallón NI, 165LB
Phase 1b trials:• Comparable efficacy to IFN-α• Synergistic effect with IFN-α• Less side effects
- Tissue specific receptor expression
Phase 1b trials:• Comparable efficacy to IFN-α• Synergistic effect with IFN-α• Less side effects
- Tissue specific receptor expression
Interferon-: A promising HCV drug
Marcello T, et al. Gastroenterology 2006;131:1887-1898. Dodds MG, et al. EASL 2009. Lawitz E, et al. AASLD 2009. Shiffman M, et al. EASL 2009. Sommereyns et al. PLoS Pathog. 2008 14;4:e1000017. Marcello T, et al. Gastroenterology 2006;131:1887-1898. Dodds MG, et al. EASL 2009. Lawitz E, et al. AASLD 2009. Shiffman M, et al. EASL 2009. Sommereyns et al. PLoS Pathog. 2008 14;4:e1000017.
Launay O, 623Launay O, 623
RCT Comparing the Efficacy and Safety of Four Intramuscular Double Doses and Four Intradermal Low Doses with Three Intramuscular Standard Doses of Hepatitis B vaccine in HIV infected persons:
Results of the ANRS HB03 VIHVAC-B Trial.
Subjects with anti-HBs > 10 mIU/ml at weeks 28 were defined as responders (main endpoint).Subjects with anti-HBs > 100 mIU/ml at week 28 were defined as high responders.
At weeks 0, 4 and 24 At weeks 0, 4, 8 and 24 At weeks 0, 4, 8 and 24
Launay O, 623Launay O, 623
RCT Comparing the Efficacy and Safety of Four Intramuscular Double Doses and Four Intradermal Low Doses with Three Intramuscular Standard Doses of Hepatitis B vaccine in HIV infected persons:
Results of the ANRS HB03 VIHVAC-B Trial.
Rodriguez C, 170LBRodriguez C, 170LB
Ultra-deep Sequencing Analysis Demonstrates Pre-existence of HBV Resistance Substitutions at Baseline in Patients Who Subsequently Develop Clinical Resistance
Conclusions: Ultra-deep sequencing is a new powerful tool to study HBV resistance to NUC. This technique allowed us to demonstrate that resistant HBV variants pre-exist to treatment administration and are selected in the presence of the NUC according to complex viral population dynamics.
Conclusions: Ultra-deep sequencing is a new powerful tool to study HBV resistance to NUC. This technique allowed us to demonstrate that resistant HBV variants pre-exist to treatment administration and are selected in the presence of the NUC according to complex viral population dynamics.
HBV variants isolated from 119 serial serum samples taken over 25 to 56 months from 7 patients who developed adefovir resistance on monotherapy were ultra-deep sequenced (Titanium kit on a 454 Genome Sequencer FLX; Roche Diagnostics Corporation). Analysis was carried out using ActivePerl 5.10.0.
When to start cART Tuberculosis 2009 Influenza A(H1N1) Other opportunistic infections & IRIS HCV & HBV co-infections Tumors
When to start cART Tuberculosis 2009 Influenza A(H1N1) Other opportunistic infections & IRIS HCV & HBV co-infections Tumors
OIs, Hepatitis Coinfections & Tumors
OIs, Hepatitis Coinfections & Tumors
Trends in Cumulative Incidence of Cancer among HIV-infected Patients in North America
Trends in Cumulative Incidence of Cancer among HIV-infected Patients in North America
Silverberg MJ, 758Silverberg MJ, 758
Ortiz M, 1019Ortiz M, 1019
High-Risk HPV (HR-HPV) prevalence by HIV-1 Status in Spanish Men Who Have Sex with Men (MSM) in an Out
Patient STD Clinic in Madrid (Spain)
*p<0.05*p<0.05
Ortiz M, 1019Ortiz M, 1019
High-Risk HPV (HR-HPV) prevalence by HIV-1 Status in Spanish Men Who Have Sex with Men (MSM) in a
prospective cohort of HIV-positive MSM belonging to CoRIS
Prevalence of HR-HPV infection is higher in anus than in cervix in women.A high prevalence of anal intraepithelial lesions is observed in HIV positive men.
Prevalence of HR-HPV infection is higher in anus than in cervix in women.A high prevalence of anal intraepithelial lesions is observed in HIV positive men.
Wilkin T, 1015Wilkin T, 1015
Safety and Immunogenicity of the Quadrivalent HPV Vaccine (qHPV) in HIV-Infected Men: Primary Results of AIDS
Malignancy Consortium Trial 052
Conclusions: The qHPV vaccine is generally safe, well tolerated, and highly immunogenic in HIV-infected men. Conclusions: The qHPV vaccine is generally safe, well tolerated, and highly immunogenic in HIV-infected men.
Background: HIV-infected men are at an increased risk of anal cancer. Human papillomavirus (HPV) vaccination may prevent anal cancer caused by vaccine types. However, the safety and immunogenicity of the quadrivalent vaccine in HIV-infected men are unknown.
Methods: Single-arm, open label study of the qHPV (types 6, 11, 16, 18) recombinant vaccine in HIV-infected adult men.
J. Del AmoP. Domingo
D.B. GoldsteinP. HuntD. Havlir
O. Launay
J. Del AmoP. Domingo
D.B. GoldsteinP. HuntD. Havlir
O. Launay
AcknowledgementsAcknowledgements
http://www.retroconference.org/2010http://www.retroconference.org/2010
C. ManzardoE. MartínezA. RauchI. Sereti
A. TelentiV.Soriano
C. ManzardoE. MartínezA. RauchI. Sereti
A. TelentiV.Soriano