Presentation on theme: "Workshop 3: La donna Moderatori: G. Ippolito, M. Moroni Discussant: R. Iardino Overview epidemiologica e clinica A. dArminio Monforte."— Presentation transcript:
Workshop 3: La donna Moderatori: G. Ippolito, M. Moroni Discussant: R. Iardino Overview epidemiologica e clinica A. dArminio Monforte
HIV e donne Overview epidemiologica e clinica Antonella dArminio Monforte Clinica di Malattie Infettive e Tropicali Dipartimento di Medicina, Chirurgia e Odontoiatria Università di Milano
Outline Epidemiological data on HIV in women in Europe Women vulnerabibility to HIV Women sexuality Disease progression in women Response to antiretrovirals Women and HIV clinical trials Long term safety and tolerability in women
Prevalence of HIV patients who are women Percentage of adults (15+) living with HIV who are women 1990–2007* UNAIDS. Report on the Global AIDS Epidemic. 2008
Percent of young people living with HIV who are female UNAIDS/UNICEF, 2001 UNAIDS 2007 Report on the Global AIDS Epidemic
HIV in women in Europe The proportion of HIV-infected patients who are women is highest in the UK and France 1,2 Women with HIV in Western Europe are a diverse population. 1,2 1.Synovate data – women in Europe 2010 review 2.Le VS et al. Lancet Infect Dis 2010; 10:682-7 EU5 FR GER IT SP UK
Ethnic origin of treated HIV patients in European countries Source: HIV Monitor Q1-10.
Women: Demographics in Europe Mode of transmissionWestCentralEast Injecting drug user Transfusion recipient Heterosexual contact Mother-to-child Nosocomial infection Other/undetermined Total %100 New HIV diagnoses in women by mode of transmission (%); by WHO European geographic area in 2006 HIV/AIDS Surveillance in Europe Women and HIV/AIDS: Confronting the crisis. 2004
Womens vulnerability to HIV Biological factors 1–3 –Greater surface area of tissues in female sexual organs, delicate tissues that can tear easily –Ejaculate in direct contact with vaginal and cervical mucosal tissue –Ejaculate released in larger quantities with higher viral load than female secretions Psychological factors 2,4 –Gender norms and inequalities (control over avoiding risk behaviour, frequency and nature of sexual interactions) Violence 4 –Forced sex may cause damage –May prevent women from safe-sex negotiations, being tested, disclosing HIV status, receiving treatment European Study Group on Heterosexual Transmission of HIV. Comparison of female to male and male to female transmission of HIV in 563 stable couples. BMJ 1992; 304(6830): Pan American Health Organization. Gender and HIV. Accessed November Larkin J et al. HIV in women: recognizing the signs. Medscape General Medicine 1999: 1(1). WHO. Gender inequalities and HIV. Accessed November
HIV transmission risk Type of exposure (From a source known as HIV positive) Risk of HIV transmission per exposure Accidental needle stick0.2%-0.4% Mucosal membrane exposure0.1% Receptive Oral SexVaried from 0 to 6.6% Insertive vaginal sex 0.1% Insertive anal sex 0.1% Receptive vaginal sex0.01%-0.15 % Receptive anal sex 3% Sharing IDUs needle0.7% Transfusion90-100% Higher viral load and STIs increase transmission risk
There are currently no women-specific means to prevent transmission of HIV Male circumcision (MC) 1,2 –MC does not prevent HIV transmission to women Especially if male viral load >50,000 copies –Transmission highest if sexual intercourse resumed soon after circumcision –MC may alter mens risk behaviour –MC effective at reducing HIV transmission & STDs to men Microbicides 3,4 –Microbicides not currently a valid preventative option: Many clinical trials are not completed due to high incidence of pregnancy among the study cohorts Pregnant women having to withdraw due to unknown risks of the microbicide on the foetus Now switch from anti-microbial to anti-retroviral based compounds (HAART) –Concerns with resistance development –Not contraceptive Vaccines 4 –Vaccines are an important potential response to womens vulnerability to HIV infection 1.Wawer M et al. CROI 2008;Abstract #33LB 2.Quinn et al NEJM Courtney A. Schreiber. A little bit pregnant?... The significance of subclinical pregnancy in clinical trials. HPTN Annual Meeting, Washington, February Physician panel - personal communication
Influence of gender on ARV penetration Penetration of ARVs into the male and female genital tracts is sex specific 1 –Drugs that achieve high concentrations in genital secretions may be candidate drugs for pre- or post-sexual exposure prophylaxis –Data on drug penetration into the female genital tract have lagged behind studies in men by many years –Recent data shows that, of all the ARVs, N(t)RTIs reach concentrations in cervicovaginal fluid (CVF) that exceed corresponding blood plasma (BP) levels 2 1. Taylor et al. CurrOpinHIVAIDS 2010;5: Kwara et al. CID 2008;46:
Women, HIV and sexuality Presence of a stable relationship HIV status of the partner Disclosure of HIV positive status
Usual known HIV pos partner n=515 Usual HIV unknown partner n=556 Occasional known HIV pos partner n=63 Occasional HIV unknown partner n=739 Non available information n=63 Partner characteristics in heterosexually-infected men and women- the Icona cohort Total (n=1936) IC O N Italian Cohort Naive Antiretroviral A Male Female %
Impact of HIV on psychosexual wellbeing Safer sexRelationships Interest in sex Sexual enjoyment Changing sexual behaviour Safer sex practice Commitment to safer sex and condom use Control Disclosure, rejection and acceptance Concordance Relationship strategies HIV Sex
Factors contributing to sexual dysfunction in HIV-infected women Neurological impairments Endocrine problems Cardiovascular disease Treatment related Infective causes Other issues e.g. surgery, radiotherapy Psychogenic factorsOrganic factors AnxietyEconomicSocio-cultural Grief reactions Drug abuse Depression Loss of partner Lipodystrophy/ Body image Fertility issues Relationship issues Sexual/ physical abuse Fear of infecting others Lack of sexual desire Guilt/shamePregnancy
Progression of HIV diseases according to sex Is there any differences of disease progression in females? Is there a biological plausability for such differences?
Lower Viral Load in women CD4 count StudyN Moore (VI)*1173 Sterling (1999)71 Evans42 Sterling (2001)202 Moore (V)* Farzadegan527 Anastos (IV)*2859 Rezza415 Lyles149 Moroni2011 Anastos (III)* Moore (IV)* Katenstein391 Junghans (H)*1337 Junghans (IDU)* Anastos (II)* Moore (III)* Bush40 Anastos (I)* Moore (II)* Moore (I)* Kalish494 Viral load lower in women Viral load higher in women Gandhi M, et al. CID 2002 Women have lower numbers of circulating HIV-RNA copies than men, particularly at higher CD4 cell count
Prins M, AIDS 1999 Women seroconverted for HIV, developed AIDS and died from AIDS at higher CD4 cell counts than men, although differences were only statistically significant at AIDS onset. Higher CD4+ T-cell counts in women during early infection
CASCADE Collaboration, JAIDS 2003 The rate of CD4 cell count decline did not differ significantly by sex
No differences in clinical progression among women & men Prins M, AIDS 2005
Why might there be gender differences in response to antiretrovirals? Potential for differences in drug absorption, metabolism, excretion –Body size –Body fat content –Concentration of enzymes responsible for drug metabolism –Hormonal effects Gonadotrophins and circulating steroids Hormone replacement therapy Pregnancy Oral contraceptives (drug interactions) Adherence Delays in initiation Patterson K et al. HIV Med. 2007;8:
Association between female gender and decreased likelihood of HAART use Nicastri E, JAC 2006 Lack of insurance, lower socioeconomic status, alcoholism, psichiatric co-morbility? Less ARV prescription by physicians? Lower retention in care? Risk of not receiving HAART
International guidelines and women Current guidelines for the treatment of HIV in adults include little or no guidance on the treatment of women 1-4 … except in the setting of pregnancy 1. DHHS 2009 guidelines 2. EACS version 5.2 guidelines 3. BHIVA : Gazzard et al. HIVMed 2008;9: IAS- USA recommendations: Thompson et al. JAMA 2010;304: www.aidsinfo.nih.govicalsociety.org. 3. BHIVA IAS- USA rec Specific guidelines for women are currently in development: Treating Women with HIV in the UK 2010, J Anderson & MA Johnson /PregnancyPub.pdf es/PerinatalGL.pdf
Limitations with women data from clinical trials Women are under-represented Studies are under-powered for gender comparison Pregnancy is either an exclusion or reason for withdrawal StudynProportion of women 2NN121637% GS % Abbott M % ACTG % ACTG % GS % DMP % Abbott M0-730 Derived from a slide of John Bartlett, CROI 2006
Women are under-represented in ARV-naive comparison trials Trial designProportion female (%) Citation KLEAN 1 LPV/r bid vs FPV/r bid22Eron et al. Lancet 2006;368:476 GEMINI 2 LPV/r bid vs SQV/r bid20Walmsley et al. EACS Spain, 2007, abstract PS1/4 ACTG A LPV/r bid self- administered (SA) vs LPV/r qd SA vs LPV/r qd 22Mildvan et al. CROI, USA, 2007, abstract 138. ARTEMIS 4 LPV/r bid or qd vs DRV/r qd 30De Jesus et al. ICAAC, USA, 2007, abstract LBA H-718b M LPV/r bid vs LPV/r qd22Gathe et al. CROI, USA, 4–6 Feb 2008, Abstract 775 CASTLE 6 LPV/r bid vs ATV/r qd31Molina et al. Lancet 2008;372:646.
Clinical trial data in women: ACTG 5142 and ARTEMIS ACTG 5142 compared EFV and LPVr given with two NRTIs versus an NRTI-sparing regimen in ART-naive patients 1 –20% of the patients in this trial were female –A greater risk of virologic failure was associated with female sex (HR 1.38, 95% CI 1.01–1.89) 1. Riddler et al. N Engl J Med 2008;358: Fourie et al. IAS 2009, poster CDB072. ARTEMIS, a randomised, controlled, trial comparing DRV/r with LPV/r in treatment-naive patients examined 96-week efficacy and safety according to gender, age and race 2 The efficacy of DRV/r and LPV/r at 96 weeks was not different between men and women Adverse events were also similar by gender
Clinical trial data in women: CASTLE CASTLE demonstrated similar efficacy of ATV/r and LPV/r based ART, and analysed 96- week efficacy and safety by gender –The CASTLE study population included 31% women –Confirmed virologic responses at 96 weeks were slightly lower in women (ITT analysis) –Change in CD4 count from baseline was similar between the sexes –Discontinuation rates were higher in women (21% ATV/r; 29% LPV/r) than in men (14% ATV/r; 18% LPV/r) Johnson et al. EACS 2009 VR-OC (on treatment)CVR NC=F (ITT)
Clinical trial data in women: GRACE ITT-TLOVR-non-VF censored ITT-TLOVR GRACE was designed to evaluate sex-based differences in outcomes for patients receiving DRV/r- based therapy; it recruited 287 women and 142 men Confirmed virologic response rates at 96 weeks were slightly lower for women than men (ITT TLOVR) discontinued treatment (32.8 vs 23.2; p = 0.042) Adverse events were similar between the sexes; the most common grade 2 to 4 AEs considered at least possibly treatment related in women and men were nausea (5.2% and 2.8%, respectively, diarrhoea (4.5% and 4.9%) and rash (2.1% and 2.8%) A higher proportion of women than men Currier et al. Ann Intern Med. 2010;153:349–57.
FDA meta-analysis: response to ART by gender 1. Struble et al CROI, abstract 987b. 2. Soon G, et al. 50 th ICAAC; Boston, MA; September 12–15, 2010; Abst. H Favors Female (n=3) *(HIV RNA <50 copies/mL 95% CI) Total -100% -50% 0% 50% 100% FDA review of registrational trials from 2000–2008 1,2 –22,411 HIV+ subjects in 43 RCTs for 16 ARVs; 20% women –No significant gender differences in treatment response at week 48, discontinuation for AEs, loss to follow-up, or death –Higher rate of discontinuation for virologic failure in males (8.15%) than females (4.25%) In conclusion, there were no statistically or clinically significant differences in outcomes by gender Favors Male (n=6) Gender response rate difference for each treatment arm
31 Importance of women in clinical trials 50% of the HIV population are women Understanding and addressing the barriers to inclusion Ensuring that women have equal access to successful treatment 50% of the HIV population are women Biological and hormonal gender differences Bodyweight and fat distribution differences and their effects on drug absorption, distribution, metabolism and excretion Drugs should be tested in populations that reflect the end-users (including age, sex, ethnicity) Strong scientific rationale Strong social rationale Women for Positive Action is supported by a grant from Abbott
Long-term safety and tolerability of antiretroviral treatment in women Ofotokun. Top HIV Infect 2005;13:79 Barber et al. HIVMed 2009;10Suppl2:PE10.4/1 Murri et al. JAIDS 2003;34:184. Lucas et al. Ann Intern Med 1999;131:81. Observational studies show that women experience greater toxic effects with all classes of antiretroviral drugs Howard et al. AIDS 2002;16:2175–82 Antiretroviral adherence among HIV-infected women is poor: ranged from 64% (month 1) to 45% (month 6) in a study of 161 women Among 2179 women (59.4% of the population) in the UK CHIC study, treatment discontinuation was higher than in men Women had a higher incidence of adverse reactions than men (p = 0.008) Tedaldi et al. JAIDS 2008;47:441 Floridia et al. Pharmacol Res 2008;58:173–82 Available evidence suggests greater exposure of antiretroviral drugs in women than in men Women were 1.4 times more likely than men (p = 0.05) to interrupt ART because of toxicity
Possible sex differences in PK parameters relevant to ARVs BioavailabilityDistributionMetabolismElimination Pharmacokinetics Women acid, slower gastric emptying time (OCPs, pregnancy) Diet differences No consistent differences in gut CYP or p-gp Women weight less More proportional fat Varying plasma volumes Less organ flow Estrogen has effects on plasma binding proteins In vitro: F>M trend Progesterone CYP2A4 activity Hepatic g-gp M>F Smaller organs HepC and liver status Administration of concomitant medications can affect each stage & vary by sex Gandhi. Annu Rev Pharm Tox 2004; 2.Mirfazaelian EJ. Clin Pharm 2002; 1.Kobold. Hepatol 2003;
Difference in ARV concentrations based on gender ARVGender NVP Female Vdss/F ; T 1/2 ; oral cl (4) EFV (1) SQVFemale AUC 56%; C max 26% (2,4) RTVFemale AUC 22% (13) NFV (3) APV (4) LPV (4, 6,) IDVFemale AUC 13% (4) TPVFemale AUC (7) DRVFemale AUC 16.8% (4,5) ATV (4) (1) Ribaudo H, et al. 11 th CROI, San Francisco 2004, #132 & Pfister M et al. AAC 2003; 47: (2) Fletcher CV JID 2004 ;189: (3) Jackson KA et al. AAC 2000;44: (4) Package insert; (5) Collier AC. 46 th ICAAC, 2006.# H-1396; (6) Umeh O,14 th CROI, Los Angeles 2006, #786; (7) Solas, 8 th PK Workshop, Budapest 2007, #42
Reasons for poor adherence in HIV-infected women Women are less likely to be on an ARV if there are difficulties in taking medication openly at home 1 Lipodystrophy and poor body image can have negative effects on adherence 2–4 Medication effects on the body and body image are commonly listed reasons for non-adherence among women with HIV 5 Depression tends to be more common in women and is also linked to poor adherence 6 1. Sayles et al. JWomensHealth 2006;15:173– Ammassari et al. JAIDS 2002;31Suppl3:S140–4. 3. Guaraldi et al. HIVClinTrials 2003;4:99– Huang et al. AIDSResTher 2006;3: Sansone et al. Gen Hosp Psychiatry 2004;26: 487– Turner et al. JGenInternMed 2003;18:248–57.
Gender, depression and adherence to HAART HIV-infected women are known to be particularly vulnerable to experiencing depressive symptoms Depression and adherence investigated in a cohort of 1827 female and 3246 male drug users Women were less adherent than men - 18% vs. 25% respectively (p=0.001) Women had more depression diagnoses - 34% vs. 29% respectively (p=0.001) However, women responded better to psychiatric care combined with antidepressants - AOR 1.92 vs respectively 1. Turner BJ. J Gen Intern Med 2003;18:
Survival is lowest in poorly adherent patients with depressive symptoms Lima VD et al. AIDS 2007:21: Center for Epidemiologic Studies Depression Scale, CES-D
HIV and women Conclusions HIV infected women are not a special population, but half of HIV infected subjects throughout the world Women vulnerability relies on biological and psychological factors Women are under-represented in clinical trials and thus efficacy and toxicity of HIV drugs are not adequately tested in women before drugs registration ART metabolism is different according to sex Finally, psychological variables, as well as social ones, may account for effectivenes of ART according to gender
GRUPPO WFPA ITALIA Coordinatori Adriana AmmassariINMI L Spallanzani Roma Antonella dArminio Monforte Clinica Malattie Infettive H San Paolo Milano Membri Enza AnzaloneDivisione Malattie Infettive Osp. Civile UmbertoI Frosinone Teresa BiniClinica Malattie Infettive H San Paolo Milano Antonella CastagnaClinica Malattie Infettive HSR Milano Anna Maria CattelanDivisione Malattie Infettive H Rovigo Antonella Cingolani Clinica Malattie Infettive UCSC Roma Gabriella DEttorreClinica Malattie Infettive Policlinico Umberto I Roma Fiorella Di SoraDivisione Malattie Infettive AO S. Giovanni-Addolorata Roma Miriam GargiuloDivisione Malattie Infettive H Cotugno Napoli Cristina GervasoniClinica Malattie Infettive H L Sacco Milano Nicoletta LadisaClinica Malattie Infettive Università Bari Giuseppina LiuzziINMI L Spallanzani Roma Rita MurriClinica Malattie Infettive UCSC Roma Cristina MussiniClinica Malattie Infettive Università Modena Paola NastaClinica Malattie Infettive Università Brescia Tiziana QuirinoDivisione Malattie Infettive H Busto Arsizio (VA) Raffaella RossoClinica Malattie Infettive Università Genova Annalisa SaracenoClinica Malattie Infettive Università Foggia Maria Paola TrottaINMI L Spallanzani Roma Francesca VichiDivisione Malattie Infettive Firenze
Didi Study: Obiettivi Obiettivo primario è quello di indagare la dimensione della salute sessuale, riproduttiva e emozionale nella donna con infezione da HIV. Sarà inoltre oggetto dellindagine identificare le variabili demografiche, cliniche, psicologiche o terapeutiche associate sia a una migliore o peggiore qualità della vita sessuale sia al desiderio di maternità.
Disegno e popolazione dello studio indagine conoscitiva una tantum a carattere trasversale A tutte le pazienti di sesso femminile afferenti in maniera consecutiva alla visita presso i centri clinici sarà proposta la partecipazione allindagine. Si prevede di intervistare circa 500 donne HIV-positive Criteri di inclusione: infezione da HIV documentata età >18 anni assenza di analfabetismo comprensione della lingua italiana consenso informato scritto
Il questionario auto-compilato auto-compilazione del questionario da parte delle donne incluse nello studio. Il questionario è strutturato in 9 sezioni: la storia ginecologica e riproduttiva il partner la sessualità il desiderio di maternità lo stato di salute psico-fisica Il vissuto emozionale la aderenza alla terapia antiretrovirale la religiosità/spiritualità alcune informazioni comportamentali e sociali