Tratamiento antirretroviral como prevención de la infección por VIH: una perspectiva clínica

Transcripción

1 Tratamiento antirretroviral como prevención de la infección por VIH: una perspectiva clínica Antonio Antela Hospital Clínico Universitario Santiago de Compostela III Encuentro VIH/SIDA. Madrid, 22.Octubre.2013

2 Esquema Qué es el TAR como prevención (TcP)? Por qué debemos implementar el TcP? Cuáles son las evidencias clínicas sobre el uso del TcP? Cuáles son las consecuencias del TcP? El TcP como una herramienta más en la prevención del VIH.

3 Qué es el TcP? La administración de TAR a una persona que vive con VIH, para reducir el riesgo de transmisión del VIH a través de las relaciones sexuales. El TAR se administra antes de que fuera indicado segun las recomendaciones oficiales de inicio de TAR.

4 Qué no es TcP? TcP no es Profilaxis pre-exposición (PreP). En la PreP se administra TAR a una persona que no está infectada por VIH, y que eventualmente tiene un comportamiento de riesgo para adquirir la infección por VIH. PreP intenta prevenir la transmisión del VIH a la persona que toma TAR, mientras que TcP intenta evitar la transmisión del VIH desde la persona que toma TAR.

5 Por qué debemos implementar el TcP? La epidemia de VIH está lejos de estar controlada. La infección por VIH no diagnosticada es muy prevalente e incrementa el riesgo de transmisión. La presentación tardía de la infección por VIH, como expresión de infección oculta, es aún muy frecuente. Existe cada vez más evidencia de las ventajas del tratamiento temprano del VIH.

6 Por qué debemos implementar el TcP? Evidencias del TcP como expansión del TARGA: Tratar a las personas VIH (+) antes parece reducir la carga vírica comunitaria y de esta forma reduce la transmisión del VIH en la comunidad. Tratar a las personas VIH (+) antes reduce la transmisión del VIH en algunos contextos. La transmisión en parejas serodiscordantes se reduce tratando antes al miembro VIH (+): HPTN 052.

7 La epidemia de VIH está lejos de estar controlada.

8 HIV infections diagnosed in 2011 New diagnoses per 100,000 population < 2 2 to < to < Missing or excluded data The rate of HIV diagnoses per 100,000 population increased by 16% between 2004 and 2011, from 6.6 (42,189 cases) to 7.6 in 2011 (53,974 cases)* * Among the 50 countries that have reported consistently European Centre for Disease Prevention and Control/WHO Regional Office for Europe. HIV/AIDS surveillance in Europe Stockholm: European Centre for Disease Prevention and Control; 2012.

9 Number of cases Trends of reported HIV diagnoses, by transmission mode and year of diagnosis, adjusted for reporting delay, EU/EAA, Year of diagnosis Heterosexual, excluding cases originating from sub-saharan Africa Heterosexual cases originating from sub-saharan Africa Men who have sex with men Injecting drug users Mother-to-child transmissions Other / undetermined Data not included from Estonia, Italy, Poland, Spain European Centre for Disease Prevention and Control/WHO Regional Office for Europe. HIV/AIDS surveillance in Europe Stockholm: European Centre for Disease Prevention and Control;

10 New HIV infections in London s MSM increased from 2011 to 2012: (definite): (provisional): 1720 (rise in 21%) (estimated): 1900 (rise in 33%) Possible relationship with high-risk drug practices. In the whole UK, new HIV diagnoses in MSM increased from 3010 (2011) to 3240 (2012), with a rise of 8%. Some of this rise could be attributed to an increase in HIV testing (17%). Concerns also with HCV new infections and reinfections.

11 La infección por VIH no diagnosticada es muy prevalente e incrementa el riesgo de transmisión.

12 Undiagnosed HIV infection in Europe It is reported that as many as one-third of those infected in the European Union countries are unaware of their HIV status [1] and in some eastern European countries up to 60% of persons living with HIV/AIDS are undiagnosed [2]. 1. European Centre for Disease Prevention and Control. HIV prevention in Europe: action, needs and challenges; 2 3 October 2006; Stockholm, Sweden. 2. Hamers FF, Phillips AN. Diagnosed and undiagnosed HIV-infected populations in Europe. HIV Med 2008; 9:6 12.

13 Hall HI, et al. AIDS 2012; 26(7): Awareness of Serostatus Among People with HIV and Estimates of Transmission (US) People Living with HIV/AIDS ~1.1 million ~20% Unaware of Infection Accounting for New Sexually Transmitted HIV Infections Each Year ~50,000 ~49% of New Infections % ~80% Aware of Infection ~51% of New Infections 0

14 Transmission rate per 100 Person-years Mayor incidencia de transmisión sexual con mayores cargas víricas Mean (+SE) rate of heterosexual transmission of HIV-1 among 415 couples, according to the sex and the serum HIV-1 RNA level of the HIV-positive partner All subjects Male-to-Female Transmission Female-to-Male Transmission Quinn TC et al. N Engl J Med 2000;342: HIV-1 RNA (copies/ml) 1 4

15 La presentación tardía de la infección por VIH es aún muy frecuente.

16 Late presentation in Spain ( )

17 A consensus definition of late presentation in Europe >350 CD4 cells/mm 3 <350 CD4 cells/mm 3 Late presentation: <350 CD4 cells/mm 3 or an AIDS event 1 Advanced HIV disease: A late presenter with <200 CD4 cells/mm 3 or an AIDS defining event 2 Recent data (up to 2011) in new diagnoses indicates that late presentation according to the new definition accounts for more than 50% of new diagnoses in Spain 1. Antinori A, et al. HIV Medicine 2010; Published online ahead of print. Abstract available at: 2. Johnson M et al., Antivir Ther 2010, 15(Suppl 1):3 8.

18 Evidencias de las ventajas del tratamiento temprano del VIH.

19 CASCADE Cohort Supporting Earlier ART Initiation CASCADE: timing of HAART initiation and clinical outcomes N=9,455 patients with over 52,000 patient-years follow-up 812 (8.6%) developed AIDS; 544 (5.8%) died Starting therapy at CD4 <500 cells/mm 3 vs. deferring therapy was associated with lower hazard of AIDS/death and all-cause mortality CD4 Count (cells/mm 3 ) Cumulative Risk, % Defer Initiate 3-Year Adjusted Risk Difference (Defer vs. Initiate Tx) Number Needed to Treat Jonsson-Funk M, et al. WAIDS 2010; Vienna. #THLBB201 19

20 Latest CD4 count (cells/mm 3 ) D:A:D Lower Rate of AIDS-Related Mortality with Higher CD4 Count AIDS-related mortality < Relative rate (95% CI) fold increased rate of AIDS-related deaths for patients with CD4 count compared to >500 D:A:D Study Group. Arch Intern Med 2006;166:

21 Effect of early vs deferred ART for HIV on survival Kitahata M.M., et al. N Engl J Med 2009;360: April,

22 Mean CD4 Cell Count (cells/mm 3 ) Likelihood of Achieving a Normal CD4 Cell Count Dependent on CD4 at Initiation of Therapy 1000 Johns Hopkins HIV Clinical Cohort 1000 ATHENA National Cohort > < > < Years on ART Weeks from Starting ART Magnitude of increase in CD4 cell count greatest if therapy started at low CD4 cell counts, but greater likelihood of CD4 cell count normalization with earlier therapy Moore R, et al. Clin Infect Dis 2007;44(3): Gras L, et al. J Acquir Immune Defic Syndr 2007;45(2):

23 Initiating HAART > 350 cells/µl or > 500 cells/µl may decrease non-aids defining complications Cardiovascular Disease HOPS Cohort FIRST SMART Trial Cancer French Hospital Database Chiao CNS (HAND) CHARTER Renal & Bone Dao Ganesan 23

24 Evidencias del TcP como expansión del TARGA Tratar a las personas VIH (+) antes parece reducir la carga vírica comunitaria y de esta forma reduce la transmisión del VIH en la comunidad. Tratar a las personas VIH (+) antes reduce la transmisión del VIH en algunos contextos. La transmisión en parejas serodiscordantes se reduce tratando antes al miembro VIH (+): HPTN 052.

25 TcP como expansión del TARGA Tratar a las personas VIH (+) antes parece reducir la carga vírica comunitaria y de esta forma reduce la transmisión del VIH en la comunidad.

26 Months CVL, c/ml San Francisco Department of Public Health Earlier HIV Diagnosis & Initiation of Therapy Associated with Lower Community Viral Load (CVL) and Reduced Transmission 40 Diagnosis to start of ART, months HIV diagnosis to suppression, months 45, Minimum CVL (p = 0.003) Most recent CVL (p < 0.001) Maximum CVL (p = 0.010) Newly diagnosed HIV cases (p < 0.001) Both p < , , Diagnosed HIV cases, N Year CD4 at Initiation: Time from ART initiation to virologic suppression decreased from a mean of 18.8 months in 2004 to a mean of 2.8 months in 2009 (p < 0.001) Das M, et al. CROI Boston. # Year Irrespective of CVL measure the number of diagnosed HIV cases decreased over time (p < 0.001) Das M, et al. PLoS One 2010;5(6):e

27 % of patients UK CHIC HIV RNA levels of patients on and not on ART CD4 <200 cells/mm 3 HIV RNA >500 copies/ml Year Year Not on treatment On treatment Over the evaluated decade CD4 counts and viral loads have increased and reduced, respectively, in association with prevalence on ART Personal Communication. C Sabin, UK CHIC. Dataset

28 Estimated prevalence, % 2010 San Francisco MSM Modeling HIV Prevalence and Percentage Reduction in New Infections by Specific Test & Treat Strategy Predicted HIV Prevalence by ART Strategy Percent Reduction in New HIV Infections Year Tx<500 Tx All Test & Tx All %* 59% 76% Tx CD4<350 Tx CD4<500 Tx All Test+Tx All Year % 61% 81% %* 55% 81% *Implementing the current DHHS Guidelines of treating patients with CD4 <500 is predicted to result in 1,554 fewer HIV infections in 5 years and 4,940 less over 20 years. Charlebois E, et al. Clin Infect Dis 2011;52:1046-9

29 TcP como expansión del TARGA Tratar a las personas VIH (+) antes reduce la transmisión del VIH en algunos contextos.

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32 Between 2006 and 2010, ART coverage among all HIV (+) MSM increased from 49 to 60%, and the proportion of infectious men fell from 47 to 35%. Extending ART to all HIV (+) MSM with CD4+ <500/µL would have reduced the rate of infectious men from 35 to 29%, and halving the proportion undiagnosed would further have reduced this to 21%.

33 TcP como expansión del TARGA - La transmisión en parejas serodiscordantes se reduce tratando antes al miembro VIH (+): HPTN 052.

34 HPTN 052 Prevention of HIV-1 Infection with Early Antiretroviral Therapy Multicenter, international, randomized, NIH-funded Phase III study HIV serodiscordant adult couples ART-naïve, HIV-infected partner CD4 between N=1,763 couples HIV infected partner: 50% male Early Arm (n=886) Start ART when CD4 between Delayed Arm (n=877) Start ART when CD4 250 or AIDS diagnosis Primary Clinical Endpoint (in HIV-positive partner) Clinical Event: Pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death Primary Prevention Endpoint (in HIV-negative partner) Linked HIV transmission to HIV-1 negative partners DSMB recommended study be stopped early on 28 th April 2011 Adapted from Cohen MS, et al. N Engl J Med 2011; Cohen M, et al. IAS 2011; Rome. Oral #MOSY Grinsztejn B, et al. IAS 2011; Rome. Oral #MOSY0305 HPTN Study 052 Fact Sheet. Available at: Accessed 04 August 2011

35 Cumulative Probability HPTN 052 Clinical Events Analysis Clinical events Delayed arm: n=65 Early arm: n= Years since randomization Delayed Number at Risk Early Delayed Early Multivariate Analysis HR 95% CI Early Therapy vs. Delayed Therapy Baseline CD4 count (per 100 CD4 increment) Male sex vs. female sex Baseline viral load (per unit log 10 increment) Early therapy was associated with a 41% relative risk reduction in clinical events compared to delayed therapy Adapted from Cohen MS, et al. N Engl J Med 2011; Grinsztejn B, et al. IAS 2011; Rome. Oral #MOSY0305

36 Cumulative Probability HPTN 052 Partner-Linked HIV-1 Transmissions Linked transmissions Delayed arm: n=27 Early arm: n= Years since randomization Delayed Number at Risk Early Delayed Early Multivariate Analysis HR 95% CI Early Therapy vs. Delayed Therapy Baseline condom use (100% vs. <100%) Male sex vs. female sex Baseline CD4 count (per 100 CD4 increment) Baseline viral load (per unit log 10 increment) Early therapy was associated with a 96% relative risk reduction in partner-linked HIV-1 transmissions compared to delayed therapy Adapted from Cohen MS, et al. N Engl J Med 2011; Cohen M, et al. IAS 2011; Rome. Oral #MOSY0302

37 Summary of Treatment as Prevention Studies in Serodiscordant Couples Number of Couples Reduction in Transmission when HIV+ Partner on ART HPTN 052 1,2 (international) 1,763 96% Partners in Prevention Study 3 3,381 92% Uganda Study x more likely to transmit HIV with viral load >50,000 c/ml compared to <3,500 c/ml Rwanda and Zambia Study 5 2,993 79% Uganda Study No infections 1. Cohen MS, et al. N Engl J Med 2011; Cohen M, et al. IAS 2011; Rome. Oral #MOSY Donnell D, et al. Lancet 2010; Quinn T, et al. New Engl J Med 2000;342: Sullivan P, et al. CROI Montreal. Oral #52aLB. 6. Reynolds S, et al. AIDS 2011;25:4:

38 Cuáles son las consecuencias del TcP?

39 Mean Annual Total Costs Mean Annual Cost Per Patient US HIV Research Network (2006) Higher Cost of Medical Care for Late Presenters Data of 10,433 patients from 7 primary HIV care sites $ $ $ $ CD4 50 CD CD CD CD4 >500 $ $ $ $ CD4 50 CD CD CD CD4 >500 $ $ $ $5.000 $ $7.500 $5.000 $2.500 $0 $0 Total Costs Annual total cost of late care is ~2.5 times the cost of care for early therapy (CD4 > 500) Inpatient costs attributed the most to the total cost in late presenters *2006 US Dollars Adapted from Gebo KA, et al. AIDS 2010:24(17); ART Costs Inpatient Costs Outpatient Costs OI Px Costs

40 Average Cost per Patient per Year Economics of Initiation of ART Health Care Costs Following ART Initiation $ $ $ $1.938 $3.352 $ $ $ $ $ $ $1.206 $2.177 $ $971 $1.840 $ Other Medical Costs Non-HIV Pharmacy Costs HIV Pharmacy Costs Inpatient Costs Ambulatory Costs $ $5.000 Based on 2009 US dollars adjusted for Consumer Price Index Gallant JE, et al. IAS 2011; Rome. #MOPE204 $- $6.781 $5.499 $1.985 $3.748 $4.172 CD4 < 200 CD CD Total Cost $41,275 $28,391 $25,032 39% ($16,243) higher health care expenditure cost for late presenters (CD4 <200) compared to early presenters (CD )

41 Lifetime costs and quality-adjusted life years saved from HIV prevention Life years saved per infection averted: CD4+ count (cells/µl) Life years saved < > Treatment costs saved per infection averted: CD4+ count (cells/µl) Treatment costs saved < ,000 $ ,000 $ ,000 $ > ,000 $ Weighted average 330,000 $ Farnham PG, et al. J Acquir Immune Defic Syndr 2013; 64:

42 US$ (billions) Ahorro potencial de iniciar TAR en diferentes puntos temporales (RSA) 0 US$7.2 billion * US$17.3 billion * Treatment initiation CD4 <200 CD4 <350 CD4 <500 All CD US$28.7 billion * * Cumulative potential cost savings from Granich R et al. PLoS ONE 2012; 7:e

43 TcP en la pirámide de prevención del VIH Treatment as prevention Vaccine PrEP PMTCT STI treatment Male circumcision Microbicides Testing & counselling Education Drug & alcohol treatment Condoms Harm reduction Blood screening Fauci A. IAC Abstract MOPL

44 Percent(%) TcP sólo no es suficiente para impactar sobre la epidemia El diagnóstico temprano es clave Primary & undiagnosed HIV contributed to the majority of new diagnoses among MSM in the UK, Individuals with primary and undiagnosed HIV contributed to 82% of all new HIV diagnoses Primary infection Undiagnosed Diagnosed HIV+ ART naïve 7 HIV+ on ART Phillips AN et al. PLoS ONE 2013;8(2):e

45 La prevención del VIH recae en una serie de acciones que se encadenan y complementan Testing Counselling Test HIV-positive Adopt safer behaviours Linkage to care Enrol in care Retain in care Treat Maintain viral suppression Counselling / follow up Initiation of ART Adherence to ART Decrease in HIV transmission Wilson DP (2012) HIV Treatment as Prevention: Natural Experiments Highlight Limits of Antiretroviral Treatment as HIV Prevention. PLoS Med 9(7): e doi: /journal.pmed