Presentation on theme: "Overview epidemiologica e clinica A. d’Arminio Monforte"— Presentation transcript:
1 Overview epidemiologica e clinica A. d’Arminio Monforte Workshop 3: “La donna”Moderatori: G. Ippolito, M. MoroniDiscussant: R. IardinoOverview epidemiologica e clinicaA. d’Arminio Monforte
2 Overview epidemiologica e clinica HIV e donneOverview epidemiologica e clinicaAntonella d’Arminio MonforteClinica di Malattie Infettive e TropicaliDipartimento di Medicina, Chirurgia e OdontoiatriaUniversità di Milano
3 Outline Epidemiological data on HIV in women in Europe Women vulnerabibility to HIVWomen sexualityDisease progression in womenResponse to antiretroviralsWomen and HIV clinical trialsLong term safety and tolerability in women
4 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
5 Percent of young people living with HIV who are female Young people are severely affected by HIV, with close to 12 million young people aged were reported to be living with HIV/AIDS in 2001.Half of all new infections – over 7000 daily – are occurring among young people, and two-thirds of all new infections are among young women.No other region in the world as in Sub-Saharan Africa approaches these HIV prevalence rates or displays such a disproportionate impact on women and girls: 77% of all HIV-positive women live in sub-Saharan Africa.A 2007 WHO report has updated these data recently. However only trends (>25% decreases) were listed in a few African countries including Cote d’Ivoire, Kenya, Malawi & Zimbabwe.SourcesUNAIDS/UNICEF 2001; UNAIDS, 2007 AIDS Epidemic UpdateUNAIDS/UNICEF, 2001UNAIDS 2007 Report on the Global AIDS Epidemic
6 HIV in women in EuropeThe proportion of HIV-infected patients who are women is highest in the UK and France 1,2Women with HIV in Western Europe are a diverse population.1,2EU5 FR GER IT SP UKSynovate data – women in Europe 2010 reviewLe VS et al. Lancet Infect Dis 2010; 10:682-7
7 Ethnic origin of treated HIV patients in European countriesEU FR GER IT SP UKSource: HIV Monitor Q1-10.
8 Women: Demographics in Europe New HIV diagnoses in women by mode of transmission (%); by WHO European geographic area in 2006Mode of transmissionWestCentralEastInjecting drug user3.47.618.2Transfusion recipient0.61.50.03Heterosexual contact72.152.835.4Mother-to-child22.214.171.124Nosocomial infection0.060.05Other/undetermined22.534.646.1Total %100This table displays the number of new HIV diagnoses in women by mode of transmission route for Western, Central, and Eastern Europe in 2006.For all regions of Europe, the main route of transmission (that is known) of HIV is primarily heterosexual contact.However, in the East a large number of women acquired HIV through injecting drug use.Central Europe accounts for the least number of newly diagnosed cases of HIV in women (460).Eastern Europe had the highest total number of new cases of HIV diagnosed in women overall (24,637).Fortunately, the lowest numbers (for all regions) were due to nosocomial (or hospital acquired) mode of transmission.For Western European countries that reported HIV cases in 2006:The contribution of injecting drug use varied substantially between countries in the West.Heterosexual contact is the primary route of transmission of HIV in women in Europe.Injecting drug use is also a significant infection route in Eastern Europe. However caution must be paid to the large size of the ‘other/undetermined’ groups.References1.HIV/AIDS Surveillance in Europe. 2007; Available at:2. Women and HIV/AIDS: Confronting the crisis. 2004; UNAIDS/UNFPA/UNIFEM. Available at:3. Women and HIV/AIDS: Confronting the crisis, 2004.HIV/AIDS Surveillance in Europe. 2007Women and HIV/AIDS: Confronting the crisis. 2004
9 Women’s vulnerability to HIV Biological factors1–3Greater surface area of tissues in female sexual organs, delicate tissues that can tear easilyEjaculate in direct contact with vaginal and cervical mucosal tissueEjaculate released in larger quantities with higher viral load than female secretionsPsychological factors2,4Gender norms and inequalities (control over avoiding risk behaviour, frequency and nature of sexual interactions)Violence4Forced sex may cause damageMay prevent women from safe-sex negotiations, being tested, disclosing HIV status, receiving treatmentMale to female heterosexual HIV transmission is 1.9 times more likely than female to male1A number of biological factors contribute to the increased susceptibility of womenFor example, women have a larger area of mucosal tissue that can tear during sexual intercourse2Semen contains a higher titre of HIV compared with vaginal secretions and comes into direct contact with the mucosal membranes of the female3Gender inequalities and stigma may restrict the power women have over their own lives and relationshipsWomen may have more limited power and control within relationships over the frequency and nature of sex, including use of condoms2,4Physical, sexual or emotional violence brings an additional burden4. Violent sex can heighten the risk of transmission by causing tears and lacerationsFear of violence may also prevent women from negotiating sexual behaviour, disclosing their HIV status and/or accessing healthcareReferencesEuropean 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 NovemberLarkin J et al. HIV in women: recognizing the signs. Medscape General Medicine 1999: 1(1).WHO. Gender inequalities and HIV. Accessed NovemberEuropean 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 NovemberLarkin J et al. HIV in women: recognizing the signs. Medscape General Medicine 1999: 1(1).WHO. Gender inequalities and HIV. Accessed November
10 HIV transmission riskType of exposure(From a source known as HIV positive)Risk of HIV transmission per exposureAccidental needle stick0.2%-0.4%Mucosal membrane exposure0.1%Receptive Oral SexVaried from 0 to 6.6%Insertive vaginal sex≤ 0.1%Insertive anal sexReceptive vaginal sex0.01%-0.15 %Receptive anal sex≤ 3%Sharing IDUs needle0.7%Transfusion90-100%This slide shows a literature review of risk exposure assessment. The table gives the different risk of HIV transmission by non-occupational exposures.However these estimates of transmission are not absolute. Every risk exposure depends on the type of exposure, but also on co-factors such as:Infectivity of the source (high plasma viral load increases risk)Genital oral ulcers, STDs or bleeding increases the risk of a sexual exposureFor accidental needle stick exposure, fresh blood, a depth injury or iv injection increases the risk of HIV transmission.ReferenceManagement of non-occupational post exposure prophylaxis to HIV (NONOPEP): sexual, injecting drug user or other exposures. Guidelines. (EURO-NONOPEP).Higher viral load and STIs increase transmission risk
11 There are currently no women-specific means to prevent transmission of HIV Male circumcision (MC)1,2MC does not prevent HIV transmission to women Especially if male viral load >50,000 copiesTransmission highest if sexual intercourse resumed soon after ‘circumcision’MC may alter men’s risk behaviourMC effective at reducing HIV transmission & STDs to menMicrobicides3,4Microbicides not currently a valid preventative option:Many clinical trials are not completed due to high incidence of pregnancy among the study cohortsPregnant women having to withdraw due to unknown risks of the microbicide on the foetusNow switch from anti-microbial to anti-retroviral based compounds (HAART)Concerns with resistance developmentNot contraceptiveVaccines4Vaccines are an important potential response to women’s vulnerability to HIV infectionRecent evidence on preventative strategies, such as male circumcision, has shown that male circumcision is may be effective at reducing HIV transmission to women from men. There have been conflicting results from other studies.The protective effect of male circumcision seems to be lost if the male has a high viral load (>50,000 copies). The Board agreed that male circumcision may not directly confer benefits to women. The male’s viral load is not always constant, and circumcision may change a man’s risk behaviour as they may feel ‘protected’.Pregnancy related design issues with recent clinical trials:Terminate women from trial when they become pregnant?- Carragurad trialInterrupt product use of microbicide while women are pregnant and resume product use after completion of pregnancy? HPTN 035Allow pregnant women to use product while pregnant? NONEAll these issues IMPACT ON THE EFFECTIVENESS of product.Incidence pregnancy rates needs to be considered for sample size calculation in future trials- prior site preparedness studies provide value in accurately estimating pregnancy rates in targets populations . This has led to a switch from antimicrobial to antiretroviral-based preventative products, which are not contraceptive. Women would then have to use an additional form of contraception, which may be impractical due to cost reasons.Using antiretroviral compounds, such as HAART agents, in these products raises some concerns with regard to the possibility of resistance development.Vaccines will be an important preventative option for women, since they can be used with or without a partner’s cooperation. It is therefore imperative that in the clinical trial process, sufficient numbers of women participate in trials. The licensing issues along is an important dimension to consider: vaccines must be tested in the intended target populations for their use.Unfortunately, vaccine development trials to date have been unsuccessful. Again, as very few women were involved in the vaccine trials the issue of low-level women participation in clinical studies needs to be addressed. It was felt that Pharma could play a role here.Recent trials in East Africa have had more success recruiting women – the target of 35% women in VRC trial was met in Kenya, but anecdotal reports indicate that it is challenging to recruit women. Staff had to spend considerable effort, time and resources to recruit women. One reason given for so few women participating in clinical studies is that often women are unable to make their own decisions as their partners prevented them from volunteering.It was generally agreed by the Board that it will be some time before new, effective preventative compounds were available.ReferencesWawer M et al. CROI 2008;Abstract #33LBQuinn et al NEJM 20003. Courtney A. Schreiber. A little bit pregnant?... The significance of subclinical pregnancy in clinical trials. HPTN Annual Meeting, Washington, February 20054. Physician panel - personal communicationWawer M et al. CROI 2008;Abstract #33LBQuinn et al NEJM 20003. Courtney A. Schreiber. A little bit pregnant?... The significance of subclinical pregnancy in clinical trials. HPTN Annual Meeting, Washington, February 20054. Physician panel - personal communication
12 Influence of gender on ARV penetration Penetration of ARVs into the male and female genital tracts is sex specific1Drugs that achieve high concentrations in genital secretions may be candidate drugs for pre- or post-sexual exposure prophylaxisData on drug penetration into the female genital tract have lagged behind studies in men by many yearsRecent data shows that, of all the ARVs, N(t)RTIs reach concentrations in cervicovaginal fluid (CVF) that exceed corresponding blood plasma (BP) levels21. Taylor et al. CurrOpinHIVAIDS 2010;5:2. Kwara et al. CID 2008;46:
13 Women , HIV and sexuality Presence of a stable relationshipHIV status of the partnerDisclosure of HIV positive status
14 Partner characteristics in heterosexually-infected men and women- the Icona cohort ItalianCohortNaiveAntiretroviralA%MaleFemaleTotal (n=1936)Usual known HIV pos partnern=515Usual HIV unknown partner n=556Occasionalknown HIV pos partnern=63OccasionalHIV unknown partnern=739Non available informationn=63
15 Impact of HIV on psychosexual wellbeing Safer sexRelationshipsDecreased sexual desire, poor sexual satisfaction and sexual inactivity are common among those infected with HIV. This occurs for a variety of reasons including anxiety about transmission, loss of freedom during sex, fears of emotional distress, and reduced feeling of sexual attractiveness.1 However, a desire to become pregnant may provide motivation for sex for some womenKeegan et al. conducted a cross-sectional qualitative study to investigate sexual behaviours and relationships in 21 HIV-positive women, aged 22–54 years2Women were recruited from HIV clinics and the study was conducted via a hospital questionnaire distributed on a weekly basisThe questionnaire addressed topics of particular interest about the issues and dilemmas that HIV-positive women face regarding sex and relationshipsIssues of sexual function and enjoyment of women with HIV could be grouped under three broad categories: sex, safer sex and relationships. A number of dominant themes were identified, including:Difficulties with sexual functioning (lowered libido and reduced intimacy)Safer sex (personal dislike of condoms, lack of control, lack of suitable alternatives and tension between the desire to adhere to safer sex practices and concerns about rejection by a potential partner)Barriers to forming new relationships (fears of HIV disclosure and fears of infecting partners)Coping strategies including relationship avoidance and having casual partners to avoid disclosureReferencesSiegel K et al. Diminished sexual activity, interest, and feelings of attractiveness among HIV-infected women in two eras of the AIDS epidemic. Arch Sex Behav 2006; 35(4):Keegan A et al. Sex and relationships for HIV-positive women since HAART: A qualitative study. AIDS Patient Care STDs 2005; 19:Interest in sexSexual enjoymentChanging sexual behaviourSafer sex practiceCommitment tosafer sex and condom useControlDisclosure,rejection andacceptanceConcordanceRelationship strategies
16 Factors contributing to sexual dysfunction in HIV-infected women Psychogenic factorsOrganic factorsAnxietyFertility issuesRelationship issuesTreatment relatedEconomicCardiovascular diseaseLoss of partnerLipodystrophy/Body imageDepressionDrug abuseNeurological impairmentsGuilt/shameGrief reactionsSexual dysfunction in HIV-infected women can be due to a number of factorsPsychogenic factors:Anxiety and depressionGuilt or shameDrug abuseGrief reactionsSocio-cultural and economic problemsSexual and physical abuseRelationship issues and stigma related to fear of infecting othersSexual issuesFertility issuesBody imagePregnancy-related concernsLipodystrophy (change in body shape)Organic factors:Neurological e.g. cortical, spinal, autonomic and sensory nerve relatedEndocrine problems e.g. oestrogen, testosterone, thyroid relatedCardiovascular disease e.g. atherosclerosis, hypertension, dyslipidaemiaTreatment related e.g. HAART, antidepressants, other medicationsInfective causes e.g. advanced HIV disease, genital herpes, candidiasisReferenceBell C et al. HIV-associated female sexual dysfunction–clinical experience and literature review. Int J STD AIDS 2006; 17:Endocrine problemsPregnancyFear of infecting othersSocio-culturalSexual/ physical abuseOther issues e.g. surgery, radiotherapyInfective causesLack of sexual desire
17 Progression of HIV diseases according to sex Is there any differences of disease progression in females?Is there a biological plausability for such differences?
18 Lower Viral Load in women Viral load lower in womenViral load higher in womenStudy NMoore (VI)* 1173Sterling (1999) 71Evans 42Sterling (2001) 202Moore (V)*Farzadegan 527Anastos (IV)* 2859Rezza 415Lyles 149Moroni 2011Anastos (III)*Moore (IV)*Katenstein 391Junghans (H)* 1337Junghans (IDU)*Anastos (II)*Moore (III)*Bush 40Anastos (I)*Moore (II)*Moore (I)*Kalish 49475067560052545037530022515075Women have lower numbers of circulating HIV-RNA copies than men, particularly at higher CD4 cell countCD4 countThis slide shows the results from a meta-analysis of cross-sectional and longitudinal studies of gender effects on viral load.These data show that HIV-infected women consistently have a 2-6-fold lower viral load than men:This remains true even after adjusting for age, race, mode of virus transmission, and ART usePossible biological explanations are:variations in VL over menstrual cycleoestrogen-mediated down-regulation of TNF-αdose-dependent inhibition of CCR5 expression in activated CD4s by progesteroneThese finding are significant as viral loads are frequently used to guide initiation and modification of ART.Several European board members also commented that they often saw a wider diversity of virus including other HIV strains, non-B subtypes, particularly in female migrant patients from Africa. This presented additional monitoring and treatment challenges as those patients infected with HIV-2 could not receive nNRTI-based ART, and PI options were limited to 3 or 4 options.Reference:Ghandi M et al. Clin Infect Dis : & Danel C et al. Abstract 776-WGandhi M, et al. CID 2002
19 Higher CD4+ T-cell counts in women during early infection 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.Figure shows the CD4 cell marker paths by gender obtained from fitting the basic mixed models including gender. Back transforming the predicted square root counts, the CD4 cell count at seroconversion was estimated to be 815 x 106 cells/l for women and 727 x 106 cells/l for men (P = 0.121). Both the decline up to(26 x 106 cells/l per month) and following 7 months from seroconversion (5 x 106 cells/l per month) did not significantly differ by gender (P = and 0.992, respectively). Restricting the analysis to those with a HIV-seroconversion interval of less than 2 years and recruited before or maximally 1 year after seroconversion did not alter these estimates appreciably. The CD4 cell count at onset of AIDS was estimated to be 146 x 106 cells/l for women and49 x 106 cells/l for men (P = 0.004). The monthly decline was approximately 6 x 106 cells/l up to 18 months before AIDS and was not significantly affectedby gender (P = 0.920). However, 18 months prior AIDS, the moment when the decline slightly accelerated, the slope became steeper for men (10 x 106 cells/lper month) than for women (7 x 106 cells/l per month) (P = 0.021). The CD4 count at death from AIDS was 44 x 106 cells/l for women and 22 x 106 cells/lfor men (P = 0.347). The decline prior to death was 5–8 x 106 cells/l per month. The gender effect on this decline was not significant (P = 0.956), although thecurves tended to converge slightly close to deathWomen 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.Prins M, AIDS 1999
20 The rate of CD4 cell count decline did not differ significantly by sexTabella: Estimated CD4 cell count at Sieroconversion differed significantly by sex,Figura: The rate of CD4 cell count decline did not differ significantly by sex; thus, on the square root scale, the difference between men and women observed at SC was stable throughout the HIV-1 incubation period (P = 0.235)CASCADE Collaboration, JAIDS 2003
21 No differences in clinical progression among women & men Prins M , AIDS 2005
22 Why might there be gender differences in response to antiretrovirals? Potential for differences in drug absorption, metabolism, excretionBody sizeBody fat contentConcentration of enzymes responsible for drug metabolismHormonal effectsGonadotrophins and circulating steroidsHormone replacement therapyPregnancyOral contraceptives (drug interactions)AdherenceDelays in initiationThis slide lists the reasons why women may respond differently to ART than men. Longer-term clinical studies evaluating the response to initial HAART regimen based on sex and age is required. Especially with the more efficacious and simplified ART regimens and the associated decrease in mortality.As previously stated, women especially when not pregnant often delay initiating treatment due to a multitude of social and economic reasons. In addition, there can be attitudinal differences as more women can be clinically depressed than men, and it is known that depression plays an important role in overall adherence to HAART therapy and viral load.In addition, delegates at the Advisory Board observed that the timing of diagnosis differs for women patients, they generally fall into 2 categories:(i) diagnosed while pregnant, or(ii) diagnosed as late presenters as an older comorbid women usually seeking treatment for an opportunistic infection.ReferencePatterson K, Napravnik S, Eron J, Keruly J, Moore R. Effects of Age and Sex on Immunological and Virological Responses to Initial HAART. HIV Med ; 8:Patterson K et al. HIV Med. 2007;8:
23 Association between female gender and decreased likelihood of HAART use Risk of not receiving HAARTLack of insurance, lower socioeconomic status, alcoholism, psichiatric co-morbility?Less ARV prescription by physicians?Lower retention in care?Nicastri E, JAC 2006
24 International guidelines and women Current guidelines for the treatment of HIV in adults include little or no guidance on the treatment of women1-4… except in the setting of pregnancySpecific guidelines for women are currently in development: Treating Women with HIV in the UK 2010, J Anderson & MA Johnson1. 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:
25 Limitations with women data from clinical trials Women are under-representedStudies are under-powered for gender comparisonPregnancy is either an exclusion or reason for withdrawalStudynProportion of women2NN121637%GS-90360226%Abbott M98-86365320%ACTG5095114719%ACTG38498018%GS-93450914%DMP-006450Abbott M0-730All the participants agreed that women are under-represented in clinical studies (usually around 20-35% of the total study population) for effective gender comparisons.Several suggestions were made to improve recruitment of women participants:Provide one form of barrier contraception FOC (protocol usually asks for 2)Consider the study duration, 96 weeks can too long particularly in women of child bearing ageGive guidance on drug:drug interaction regarding oral contraceptives, and if HAART is switched.Examples of challenges we heard anecdotally that we wanted to explore systematically through social research – e.g. exclusion criteria for pregnancy and lactation in face of pressures to bear children, concerns about requirement to use contraception , concerns about blood draw, particularly for women who already lose blood through menstruation, women’s roles as primary caretakers of the family [I can work on this]. We suspected that these issues were only the surface of gender-related challenges to recruitment and retention and ensuring a gender-sensitive trial environment. The impact of a range of known gender issues such as women’s relative lack of autonomy in decision-making or …. would need to be better understood.ReferenceDerived from a slide of John Bartlett, CROI 2006Physician panel – personal communicationDerived from a slide of John Bartlett, CROI 2006
26 Women are under-represented in ARV-naive comparison trials Trial designProportion female (%)CitationKLEAN1LPV/r bid vs FPV/r bid22Eron et al. Lancet 2006;368:476GEMINI2LPV/r bid vs SQV/r bid20Walmsley et al. EACS Spain, 2007, abstract PS1/4ACTG A50733LPV/r bid self-administered (SA) vs LPV/r qd SA vs LPV/r qdMildvan et al. CROI, USA, 2007, abstract 138.ARTEMIS4LPV/r bid or qd vs DRV/r qd30De Jesus et al. ICAAC, USA, 2007, abstract LBA H-718bMLPV/r bid vs LPV/r qdGathe et al. CROI, USA, 4–6 Feb 2008, Abstract 775CASTLE6LPV/r bid vs ATV/r qd31Molina et al. Lancet 2008;372:646.This slide shows several large clinical comparison trials of ARV regimens in treatment-naive patients. This includes CASTLE, which is a study comparing ATV and LPV and with a relatively large proportion of women.
27 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 patients120% of the patients in this trial were femaleA greater risk of virologic failure was associated with female sex (HR 1.38, 95% CI 1.01–1.89)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 race2The efficacy of DRV/r and LPV/r at 96 weekswas not different between men and womenAdverse events were also similar by gender1. Riddler et al. N Engl J Med 2008;358: Fourie et al. IAS 2009, poster CDB072.
28 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 genderThe CASTLE study population included 31% womenConfirmed virologic responses at 96 weeks were slightly lower in women (ITT analysis)Change in CD4 count from baseline was similar between the sexesDiscontinuation rates were higher in women (21% ATV/r; 29% LPV/r) than in men (14% ATV/r; 18% LPV/r)CVR NC=F (ITT)VR-OC (on treatment)Johnson et al. EACS 2009
29 Clinical trial data in women: GRACE GRACE was designed to evaluate sex-based differences in outcomes for patients receiving DRV/r- based therapy; it recruited 287 women and 142 menConfirmed 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 menITT-TLOVR-non-VF censoredITT-TLOVRCurrier et al. Ann Intern Med. 2010;153:349–57.
30 FDA meta-analysis: response to ART by gender Gender response rate difference for each treatment armFDA review of registrational trials from 2000–20081,222,411 HIV+ subjects in 43 RCTs for 16 ARVs; 20% womenNo significant gender differences in treatment response at week 48, discontinuation for AEs, loss to follow-up, or deathHigher 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 genderFavors Female(n=3)*(HIV RNA <50 copies/mL 95% CI)Favors Male(n=6)Because women have been relatively under-represented in HIV clinical trials, the gender-specific response to ART is unclear. Here in this large meta analysis, there was no important difference between sexes in treatment response. As shown in the figure, there was a wide heterogeneity in response between trials that remains unexplained.Total-100% -50% 0% % %1. Struble et al CROI, abstract 987b.2. Soon G, et al. 50th ICAAC; Boston, MA; September 12–15, 2010; Abst. H-1812.
31 Importance of women in clinical trials Strong scientific rationaleStrong social rationale50% of the HIV population are womenBiological and hormonal gender differencesBodyweight and fat distribution differences and their effects on drug absorption, distribution, metabolism and excretionDrugs should be tested in populations that reflect the end-users (including age, sex, ethnicity)50% of the HIV population are womenUnderstanding and addressing the barriers to inclusionEnsuring that women have equal access to successful treatment31Women for Positive Action is supported by a grant from Abbott
32 Long-term safety and tolerability of antiretroviral treatment in women Howard et al. AIDS 2002;16:2175–82Antiretroviral adherence among HIV-infected women is poor: ranged from 64% (month 1) to 45% (month 6) in a study of 161 womenObservational studies show that women experience greater toxic effects with all classes of antiretroviral drugsAmong 2179 women (59.4% of the population) in the UK CHIC study, treatment discontinuation was higher than in menBarber et al. HIVMed 2009;10Suppl2:PE10.4/1Ofotokun. Top HIV Infect 2005;13:79Tedaldi et al. JAIDS 2008;47:441 Floridia et al. Pharmacol Res 2008;58:173–82Available evidence suggests greater exposure of antiretroviral drugs in women than in menWith the ageing HIV population, patients are now faced with longer periods of ART treatment. Therefore, the long-term safety and tolerability of ART is an increasingly important consideration.Women were 1.4 times more likely than men (p = 0.05) to interrupt ART because of toxicityWomen had a higher incidence of adverse reactions than men (p = 0.008)Murri et al. JAIDS 2003;34:184.Lucas et al. Ann Intern Med 1999;131:81.
33 Possible sex differences in PK parameters relevant to ARVs PharmacokineticsBioavailabilityDistributionMetabolismEliminationWomen ↓ acid, slower gastric emptying time (OCPs, pregnancy)Diet differencesNo consistent differences in gut CYP or p-gpWomen weight lessMore proportional fatVarying plasma volumesLess organ flowEstrogen has effects on plasma binding proteinsIn vitro: F>M trendProgesterone ↑ CYP2A4 activityHepatic g-gp M>FSmaller organsHepC and liver statusThere is limited data on gender-based differences in ARV drug class exposure as a result of differences in body weight, absorption, intestinal and hepatic first-pass metabolism between the sexes.The extent of sex-based differences in pharmacological characteristics of ARV agents is not fully known, since these issues have received little rigorous study, and women are often under-represented in clinical trials.Similarly, it is not fully understood if levels of endogenous female hormones or other sex-linked biological factors, and other behavioural factors in the long term, may be an underlying cause of differences in clinical progression and response to treatment in HIV-infected men and women.ReferenceFletcher CV et al. JID 2004; 189:Patterson K et al. HIV Med. 2004; 8:Administration of concomitant medications can affect each stage & vary by sexGandhi. Annu Rev Pharm Tox 2004; 2.Mirfazaelian EJ. Clin Pharm 2002; 1.Kobold. Hepatol 2003;
34 Difference in ARV concentrations based on gender NVPFemale Vdss/F ↑; T1/2 ↓; ↔ oral cl (4)EFV↔ (1)SQVFemale AUC ↑ 56%; Cmax 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)ATVVdss/F = weight adjusted volume of distributionPer PI –increase volume minus decreased T1/2=no gender differReferences1. Ribaudo H, et al. 11th CROI, San Francisco 2004, #132 & Pfister M et al. AAC 2003; 47:130-72. Fletcher CV JID 2004 ;189:3. Jackson KA et al. AAC 2000;44:1832-74. Package insert5. Collier AC. 46th ICAAC, 2006.# H-13966. Umeh O,14th CROI, Los Angeles 2006, #7867. Solas, 8th PK Workshop, Budapest 2007, #42(1) Ribaudo H, et al. 11th 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. 46th ICAAC, 2006.# H-1396; (6) Umeh O,14th CROI, Los Angeles 2006, #786; (7) Solas, 8th PK Workshop, Budapest 2007, #42
35 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 home1Lipodystrophy and poor body image can have negative effects on adherence2–4Medication effects on the body and body image are commonly listed reasons for non-adherence among women with HIV5Depression tends to be more common in women and is also linked to poor adherence61. 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.
36 Gender, depression and adherence to HAART HIV-infected women are known to be particularly vulnerable to experiencing depressive symptomsDepression and adherence investigated in a cohort of female and 3246 male drug usersWomen 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 respectivelyHIV-infected women are known to be particularly vulnerable to experiencing depressive symptoms, and persistent depression has been associate with reduced adherence to HAART and significantly poorer survival. The relationship of gender, depression, medical care, and mental health care to adherence in 1,827 female and 3,246 male drug users on combination antiretroviral therapy was investigated.While women had lower adherence and an increased chance of being diagnosed with depression, there was a slightly stronger association between mental health care and adherence in women than in men. Women with a diagnosis of depression who received psychiatric care in combination with antidepressant therapy had nearly 2-fold greater adjusted odds of adherence than depressed women without either care.However, it was also thought that men were more likely to take advantage of mental health services available through drug-treatment programs than women do. This correlates to other evidence that indicates that women are less likely to receive care from an HIV specialty provider, or receive antiretroviral therapy.References:1. Turner BJ, Laine C, Cosler L et al. Relationship of gender, depression, and health care delivery with antiretroviral adherence in HIV –infected drug users. J Gen Intern Med 2003;18:2. Shapiro MF, Morton SC, McCaffey DF et al. Variations in the care of HIV infected adults in the United States: results from the HIV Cost and Services Utilisation Study. JAMA 1999;281:1. Turner BJ. J Gen Intern Med 2003;18:
37 Survival is lowest in poorly adherent patients with depressive symptoms These data are crude Kaplan-Meier survival probabilities for 563 patients with HIV, stratified by adherence and depressive symptoms levels. The results indicate that both depressive symptoms and adherence were associated with shorter survival among individuals with HIV accessing HAART. Given the high prevalence of depressive symptoms in HIV-positive patients and a strong association with adherence, improvement in the diagnosis and treatment of depression as well as adherence is required to maximize the effectiveness of HAART.However, some recent US data have also shown that good adherence, even in severely depressed patients, has a benefit in terms of overall survival.It is known that depression plays an important role in overall adherence to HAART and viral load. However it is difficult to tease out the interaction between depression, reporting of AEs, adherence and viral load in HIV+ patients. It is well known that depression has an impact on overall survival within the general population and not only in HIV+ sub population.ReferencesLima VD et al. The effect of adherence on the association between depressive symptoms and mortality among HIV-infected individuals first initiating HAART. AIDS 2007:21:Center for Epidemiologic Studies Depression Scale, CES-DLima VD et al. AIDS 2007:21:
38 HIV and women Conclusions HIV infected women are not a special population, but half of HIV infected subjects throughout the worldWomen vulnerability relies on biological and psychological factorsWomen are under-represented in clinical trials and thus efficacy and toxicity of HIV drugs are not adequately tested in women before drugs’ registrationART metabolism is different according to sexFinally, psychological variables, as well as social ones, may account for effectivenes of ART according to gender
39 GRUPPO WFPA ITALIA Coordinatori Adriana Ammassari INMI L Spallanzani RomaAntonella d’Arminio Monforte Clinica Malattie Infettive H San Paolo MilanoMembriEnza Anzalone Divisione Malattie Infettive Osp. Civile “UmbertoI” FrosinoneTeresa Bini Clinica Malattie Infettive H San Paolo MilanoAntonella Castagna Clinica Malattie Infettive HSR MilanoAnna Maria Cattelan Divisione Malattie Infettive H RovigoAntonella Cingolani Clinica Malattie Infettive UCSC RomaGabriella D’Ettorre Clinica Malattie Infettive Policlinico Umberto I RomaFiorella Di Sora Divisione Malattie Infettive AO “S. Giovanni-Addolorata” RomaMiriam Gargiulo Divisione Malattie Infettive H Cotugno NapoliCristina Gervasoni Clinica Malattie Infettive H L Sacco MilanoNicoletta Ladisa Clinica Malattie Infettive Università BariGiuseppina Liuzzi INMI L Spallanzani RomaRita Murri Clinica Malattie Infettive UCSC RomaCristina Mussini Clinica Malattie Infettive Università ModenaPaola Nasta Clinica Malattie Infettive Università BresciaTiziana Quirino Divisione Malattie Infettive H Busto Arsizio (VA)Raffaella Rosso Clinica Malattie Infettive Università GenovaAnnalisa Saraceno Clinica Malattie Infettive Università FoggiaMaria Paola Trotta INMI L Spallanzani RomaFrancesca Vichi Divisione Malattie Infettive Firenze
40 Didi Study: ObiettiviObiettivo primario è quello di indagare la dimensione della salute sessuale, riproduttiva e emozionale nella donna con infezione da HIV.Sarà inoltre oggetto dell’indagine identificare le variabili demografiche, cliniche, psicologiche o terapeutiche associate sia a una migliore o peggiore qualità della vita sessuale sia al desiderio di maternità.
41 Disegno e popolazione dello studio indagine conoscitiva una tantum a carattere trasversaleA tutte le pazienti di sesso femminile afferenti in maniera consecutiva alla visita presso i centri clinici sarà proposta la partecipazione all’indagine. Si prevede di intervistare circa 500 donne HIV-positiveCriteri di inclusione:infezione da HIV documentataetà >18 anniassenza di analfabetismocomprensione della lingua italianaconsenso informato scritto
42 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 riproduttivail partnerla sessualitàil desiderio di maternitàlo stato di salute psico-fisicaIl vissuto emozionalela aderenza alla terapia antiretroviralela religiosità/spiritualitàalcune informazioni comportamentali e sociali