La terapia antiretrovirale nella donna e la nascita di un bambino non infetto

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1 La terapia antiretrovirale nella donna e la nascita di un bambino non infetto Andrea Antinori INMI Lazzaro Spallanzani IRCCS, Roma ART for HIV Prevention: The Hypothesis The quantity of HIV in plasma (and genital secretions) is the prime determinant of whether someone with HIV will transmit the virus to a sexual partner [1] Initiation of ART results in early and sustained reductions in plasma and genital HIV levels Led to the hypothesis that ART use would result in decreased infectiousness Transmission Rate per 100 Person-Yrs Quinn TC, et al. N Engl J Med. 2000;342: HIV-1 RNA (copies/ml) 1

2 402 mother infant pairs, the rate of transmission of HIV-1 was 7.6% (95% CI, 4.3 to 12.3 percent) with zidovudine treatment and 22.6% (95% CI, 17.0 to 29.0 percent) with placebo (P <0.001). Sperling RS, et al. N Engl J Med,

3 Prevalence of HIV infection, by population group in Italy Suligoi B, et al. Ann Ist Super Sanità, 46;1,2010 Percent of women receiving ARV medicines to prevent vertical transmission, by region, Source: 2016 Global AIDS Response Progress Reporting and UNAIDS 2016 estimates. 3

4 Trends of reported HIV diagnosis by transmission mode and year of diagnosis, adjusted for reporting delay (EU/EEA, ) Number of cases 10,000 8,000 6,000 4,000 2, Year of diagnosis Heterosexual, excluding cases originating from Sub-Saharan African countries Heterosexual cases originating from Sub-Saharan African countries MSM IDU Mother-to-child transmission Other/undetermined Despite multiple efforts to reduce new HIV infections, the number of new diagnoses remains stable In MSM subgroup, the number of HIV diagnosis increased by 11% from 2006 to 2012 IDU, injection drug users; MSM, men who have sex with men European Centre for Disease Prevention and Control/WHO Regional Office for Europe: HIV/AIDS surveillance in Europe 2012 MTCT rates in diagnosed women UK & Ireland MTCT rate 2,5% 2,0% 1,5% 1,0% 0,5% 2.1% 1.4% 1.1% 0.72% 0.60% MTCT rate % 3000 (data reported to 2500 end June 2016) % Live births 0,0% (incomplete) Year of birth ~12,500 singleton births; significant decline in MTCT over time (p<0.001) Graph derived from data in Townsend et al. Earlier initiation of ART and further decline in mother-to-child HIV transmission rates, AIDS 2014; 28:

5 New HIV infections among children (aged 0 14 years) with and without the provision of antiretroviral medicines to prevent mother-to-child transmission, global, Source: UNAIDS 2016 estimates. Antenatal HIV screening strategies EU/EEA, 2013 survey The most common strategy (15/24) of antenatal screening for HIV in EU/EEA countries is opt-out screening, where pregnant women are tested as part of routine antenatal care unless they explicitly decline. Opt-in screening is the chosen strategy in six countries, where pregnant women are offered testing and must provide explicit consent. The Czech Republic, Slovakia and Spain reported universal screening for HIV with systematic testing of all pregnant women. Romania and Slovenia reported that they operated targeted antenatal HIV screening among women who inject drugs. European Centre for Disease Prevention and Control. Antenatal screening for HIV, hepatitis B, syphilis and rubella susceptibility in the EU/EEA. Stockholm: ECDC;

6 Pregnant women living with HIV In 5,700 deliveries to diagnosed women in UK and Ireland NSHPC, HIV diagnosis known at conception, on ART 51% Undiagnosed at delivery HIV diagnosed via antenatal screening 21% HIV diagnosis known but untreated at conception 28% HIV antenatal screening uptake >97% since 2011 French et al, HIV Medicine 2016 Icona cohort: 158 of 2,862 women experienced 169 pregnancies (88 in naives and 81 in 70 ART-experienced women) VL was detectable in 35.6% of women at delivery This was less likely with increasing calendar periods (adjusted OR per 1-year longer: 0.8, 95% CI 0.7 to 0.9, P = 0.007) D Arminio Monforte A, et al. J Acquir Immune Defic Syndr,

7 MTCT: Impact of duration of treatment and baseline HIV viral load Sub-group analysis: women on cart with VL<1000 Townsend et al. AIDS,

8 MTCT rates in Europe Country MTCT rate Time period France 0.7% Italy 1.0% Denmark 0.5% Sweden 0.6% Spain 1.6% UK 0.57% UK 0.4% Ukraine 2.2% 2013 Russia 3.5% 2013 Mandelbrot et al 2015, von Linstow et al 2010, Naver et al 2006, Chiappini et al 2011, Prieto et al 2012, personal comm. Inga Latysheva, Townsend et al 2014, French et al 2016 European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord Migrant women were more likely to be diagnosed in late pregnancy Adjusted OR for HIV diagnosis at 20 gest. weeks in women with unknown HIV status at conception Ref. group: native women Adjusted for factors including parity, time period, age, cohort 33% diagnosed late in migrant women vs 24% in native women % with late HIV diagnosis declined significantly over study period Favarato G, et al. Eur J Public Health,

9 Linee-guida SIMIT 2016 Terapia antiretrovirale di combinazione (cart) L indicazione al trattamento delle donne in gravidanza non deve discostarsi da quella al di fuori della gravidanza [AIII]. Analogamente agli uomini, le donne HIV positive devono iniziare un regime di terapia ARV al riscontro della positività per HIV, indipendentemente da conta di cellule CD4 e carica virale [AI]. In caso di riscontro di HIV durante la gravidanza si deve accelerare il più possibile l inizio della terapia. Gli obiettivi del trattamento sono: Ottenere una soppressione virale stabile (HIV-RNA non rilevabile). Mantenere la carica virale non rilevabile nelle donne che si trovano già in questa condizione all inizio della gravidanza. Realizzare il più rapidamente possibile una soppressione virale dell HIV fino a livelli non rilevabili nelle donne che iniziano il trattamento in gravidanza. Ottenere HIV-RNA non rilevabile al 3 trimestre, e in particolare a settimane e al momento del parto [1-6, 10]. Il Test di resistenza è raccomandabile in tutte le donne non ancora in trattamento ed in quelle in trattamento con HIV-RNA rilevabile. Laddove i tempi siano limitati va avviata empiricamente la terapia. Il TDM non è raccomandato di routine. Solo in caso di tossicità grave si può prendere inconsiderazione la interruzione della cart. Gli schemi terapeutici consigliati si basano su studi clinici effettuati in gravidanza che ne hanno dimostrato l efficacia (anche a lungo termine), la tossicità accettabile e la facilità nell uso. Antenatal ART resulted in significantly lower rates of early HIV transmission than zidovudine alone Fowler MG, et al. N Engl J Med,

10 Antiretroviral medicine regimen used in preventing mother-to-child transmission, global, Source: 2016 Global AIDS Response Progress Reporting and UNAIDS 2016 estimates. 10

11 DHHS Recommendations: Initial ART in Pregnant Women Guideline Status Preferred NRTIs 3TC/ABC FTC/TDF 3TC + TDF PIs Alternative 3TC/ZDV Lopinavir/RTV* Integrase Inhibitors Atazanavir/RTV* Darunavir/RTV* Raltegravir* NNRTIs Efavirenz* Rilpivirine* Insufficient data to recommend FTC/TAF Fosamprenavir Dolutegravir EVG/COBI EVG/COBI *In addition to 2-NRTI backbone. Must be used twice daily in pregnancy. Only if pretreatment HIV-1 RNA 100,000 copies/ml and CD4+ cell count 200 cells/mm 3. If adherence concerns or potential for ART discontinuation postpartum, a PI is preferred over INSTI to reduce resistance risk. DHHS Perinatal Guidelines. October

12 Linee-guida SIMIT 2016 Gravidanza. Come iniziare (Considerazioni sulla scelta dei farmaci/farmaci consigliati). Raltegravir can be used in standard dosages in HIV-infected pregnant women Geometric mean (with upper 95% confidence interval) raltegravir concentration time profiles during the third trimester of pregnancy (open squares) and postpartum (filled circles). Blonk MI, et al. Clin Infect Dis,

13 PROMISE: Efficacy and Safety Between treatment arms, no significant difference in primary safety or efficacy endpoints; continuing ART associated with lower HIV event rate Outcome, n (Rate/100 PY) Continue ART (n = 827) Stop ART (n = 825) HR (95% CI) Primary efficacy composite endpoint events Currier J, et al. AIDS Abstract THAB0103LB. 4 (0.21) 6 (0.31) 0.68 ( )* AIDS-defining events 2 (0.10) 3 (0.15) 0.67 ( ) Serious non-aids event Death 2 (0.10) 4 (0.20) 0.52 ( ) Primary safety composite endpoint events 260 (18.4) 232 (15.4) -- Composite of HIV/AIDS-related or WHO stage 2/3 events 57 (3.09) 99 (5.49) 0.56 ( ) WHO stage 2/3 events 39 (2.02) 80 (4.36) 0.47 ( ) *P =.54. Time to first grade 3/4 sign or symptom or grade 2-4 chemistry or hematology result. P =.08. P < (23%) pts in Continue ART arm experienced virologic failure; in pts with virologic failure who had resistance testing, 52/155 (34%) had evidence of resistance 13

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