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Overview epidemiologica e clinica A. d’Arminio Monforte

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1 Overview epidemiologica e clinica A. d’Arminio Monforte
Workshop 3: “La donna” Moderatori: G. Ippolito, M. Moroni Discussant: R. Iardino Overview epidemiologica e clinica A. d’Arminio Monforte

2 Overview epidemiologica e clinica
HIV e donne Overview epidemiologica e clinica Antonella d’Arminio Monforte Clinica di Malattie Infettive e Tropicali Dipartimento di Medicina, Chirurgia e Odontoiatria Università di Milano

3 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

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. Sources UNAIDS/UNICEF 2001; UNAIDS, 2007 AIDS Epidemic Update UNAIDS/UNICEF, 2001 UNAIDS 2007 Report on the Global AIDS Epidemic

6 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 EU5 FR GER IT SP UK Synovate data – women in Europe 2010 review Le VS et al. Lancet Infect Dis 2010; 10:682-7

7 Ethnic origin of treated HIV patients in
European countries EU FR GER IT SP UK Source: HIV Monitor Q1-10.

8 Women: Demographics in Europe
New HIV diagnoses in women by mode of transmission (%); by WHO European geographic area in 2006 Mode of transmission West Central East Injecting drug user 3.4 7.6 18.2 Transfusion recipient 0.6 1.5 0.03 Heterosexual contact 72.1 52.8 35.4 Mother-to-child 1.3 3.2 0.2 Nosocomial infection 0.06 0.05 Other/undetermined 22.5 34.6 46.1 Total % 100 This 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. References 1.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. 2007 Women and HIV/AIDS: Confronting the crisis. 2004

9 Women’s vulnerability to HIV
Biological factors1–3 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 factors2,4 Gender norms and inequalities (control over avoiding risk behaviour, frequency and nature of sexual interactions) Violence4 Forced sex may cause damage May prevent women from safe-sex negotiations, being tested, disclosing HIV status, receiving treatment Male to female heterosexual HIV transmission is 1.9 times more likely than female to male1 A number of biological factors contribute to the increased susceptibility of women For example, women have a larger area of mucosal tissue that can tear during sexual intercourse2 Semen contains a higher titre of HIV compared with vaginal secretions and comes into direct contact with the mucosal membranes of the female3 Gender inequalities and stigma may restrict the power women have over their own lives and relationships Women may have more limited power and control within relationships over the frequency and nature of sex, including use of condoms2,4 Physical, sexual or emotional violence brings an additional burden4. Violent sex can heighten the risk of transmission by causing tears and lacerations Fear of violence may also prevent women from negotiating sexual behaviour, disclosing their HIV status and/or accessing healthcare References 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 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

10 HIV transmission risk Type of exposure (From a source known as HIV positive) Risk of HIV transmission per exposure Accidental needle stick 0.2%-0.4% Mucosal membrane exposure 0.1% Receptive Oral Sex Varied from 0 to 6.6% Insertive vaginal sex ≤ 0.1% Insertive anal sex Receptive vaginal sex 0.01%-0.15 % Receptive anal sex ≤ 3% Sharing IDUs needle 0.7% Transfusion 90-100% 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 exposure For accidental needle stick exposure, fresh blood, a depth injury or iv injection increases the risk of HIV transmission. Reference Management 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)1,2 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 men’s risk behaviour MC effective at reducing HIV transmission & STDs to men Microbicides3,4 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 Vaccines4 Vaccines are an important potential response to women’s vulnerability to HIV infection Recent 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 trial Interrupt product use of microbicide while women are pregnant and resume product use after completion of pregnancy? HPTN 035 Allow pregnant women to use product while pregnant? NONE All 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. References Wawer M et al. CROI 2008;Abstract #33LB Quinn et al NEJM 2000 3. Courtney A. Schreiber. A little bit pregnant?... The significance of subclinical pregnancy in clinical trials. HPTN Annual Meeting, Washington, February 2005 4. Physician panel - personal communication Wawer M et al. CROI 2008;Abstract #33LB Quinn et al NEJM 2000 3. Courtney A. Schreiber. A little bit pregnant?... The significance of subclinical pregnancy in clinical trials. HPTN Annual Meeting, Washington, February 2005 4. Physician panel - personal communication

12 Influence of gender on ARV penetration
Penetration of ARVs into the male and female genital tracts is sex specific1 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) levels2 1. Taylor et al. CurrOpinHIVAIDS 2010;5: 2. Kwara et al. CID 2008;46:

13 Women , HIV and sexuality
Presence of a stable relationship HIV status of the partner Disclosure of HIV positive status

14 Partner characteristics in heterosexually-infected men and women- the Icona cohort
Italian Cohort Naive Antiretroviral A % Male Female Total (n=1936) 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

15 Impact of HIV on psychosexual wellbeing
Safer sex Relationships Decreased 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 women Keegan et al. conducted a cross-sectional qualitative study to investigate sexual behaviours and relationships in 21 HIV-positive women, aged 22–54 years2 Women were recruited from HIV clinics and the study was conducted via a hospital questionnaire distributed on a weekly basis The questionnaire addressed topics of particular interest about the issues and dilemmas that HIV-positive women face regarding sex and relationships Issues 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 disclosure References Siegel 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 sex Sexual enjoyment Changing sexual behaviour Safer sex practice Commitment to safer sex and condom use Control Disclosure, rejection and acceptance Concordance Relationship strategies

16 Factors contributing to sexual dysfunction in HIV-infected women
Psychogenic factors Organic factors Anxiety Fertility issues Relationship issues Treatment related Economic Cardiovascular disease Loss of partner Lipodystrophy/ Body image Depression Drug abuse Neurological impairments Guilt/shame Grief reactions Sexual dysfunction in HIV-infected women can be due to a number of factors Psychogenic factors: Anxiety and depression Guilt or shame Drug abuse Grief reactions Socio-cultural and economic problems Sexual and physical abuse Relationship issues and stigma related to fear of infecting others Sexual issues Fertility issues Body image Pregnancy-related concerns Lipodystrophy (change in body shape) Organic factors: Neurological e.g. cortical, spinal, autonomic and sensory nerve related Endocrine problems e.g. oestrogen, testosterone, thyroid related Cardiovascular disease e.g. atherosclerosis, hypertension, dyslipidaemia Treatment related e.g. HAART, antidepressants, other medications Infective causes e.g. advanced HIV disease, genital herpes, candidiasis Reference Bell C et al. HIV-associated female sexual dysfunction–clinical experience and literature review. Int J STD AIDS 2006; 17: Endocrine problems Pregnancy Fear of infecting others Socio-cultural Sexual/ physical abuse Other issues e.g. surgery, radiotherapy Infective causes Lack 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 women Viral load higher in women Study N Moore (VI)* 1173 Sterling (1999) 71 Evans 42 Sterling (2001) 202 Moore (V)* Farzadegan 527 Anastos (IV)* 2859 Rezza 415 Lyles 149 Moroni 2011 Anastos (III)* Moore (IV)* Katenstein 391 Junghans (H)* 1337 Junghans (IDU)* Anastos (II)* Moore (III)* Bush 40 Anastos (I)* Moore (II)* Moore (I)* Kalish 494 750 675 600 525 450 375 300 225 150 75 Women have lower numbers of circulating HIV-RNA copies than men, particularly at higher CD4 cell count CD4 count This 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 use Possible biological explanations are: variations in VL over menstrual cycle oestrogen-mediated down-regulation of TNF-α dose-dependent inhibition of CCR5 expression in activated CD4s by progesterone These 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-W Gandhi 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 and 49 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 affected by 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/l per 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/l for 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 the curves tended to converge slightly close to death 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. Prins M, AIDS 1999

20 The rate of CD4 cell count decline did not differ
significantly by sex Tabella: 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, 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 This 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. Reference Patterson 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 HAART Lack 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 pregnancy Specific guidelines for women are currently in development: Treating Women with HIV in the UK 2010, J Anderson & MA Johnson 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:

25 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 Study n Proportion of women 2NN 1216 37% GS-903 602 26% Abbott M98-863 653 20% ACTG5095 1147 19% ACTG384 980 18% GS-934 509 14% DMP-006 450 Abbott M0-730 All 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 age Give 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. Reference Derived from a slide of John Bartlett, CROI 2006 Physician panel – personal communication Derived from a slide of John Bartlett, CROI 2006

26 Women are under-represented in ARV-naive comparison trials
Trial design Proportion female (%) Citation KLEAN1 LPV/r bid vs FPV/r bid 22 Eron et al. Lancet 2006;368:476 GEMINI2 LPV/r bid vs SQV/r bid 20 Walmsley et al. EACS Spain, 2007, abstract PS1/4 ACTG A50733 LPV/r bid self-administered (SA) vs LPV/r qd SA vs LPV/r qd Mildvan et al. CROI, USA, 2007, abstract 138. ARTEMIS4 LPV/r bid or qd vs DRV/r qd 30 De Jesus et al. ICAAC, USA, 2007, abstract LBA H-718b M LPV/r bid vs LPV/r qd Gathe et al. CROI, USA, 4–6 Feb 2008, Abstract 775 CASTLE6 LPV/r bid vs ATV/r qd 31 Molina 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 patients1 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) 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 race2 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 1. 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 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) 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 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 ITT-TLOVR-non-VF censored ITT-TLOVR Currier 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 arm FDA review of registrational trials from 2000–20081,2 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 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 rationale Strong social rationale 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) 50% of the HIV population are women Understanding and addressing the barriers to inclusion Ensuring that women have equal access to successful treatment 31 Women 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;16:2175–82 Antiretroviral adherence among HIV-infected women is poor: ranged from 64% (month 1) to 45% (month 6) in a study of 161 women Observational studies show that women experience greater toxic effects with all classes of antiretroviral drugs Among 2179 women (59.4% of the population) in the UK CHIC study, treatment discontinuation was higher than in men Barber et al. HIVMed 2009;10Suppl2:PE10.4/1 Ofotokun. Top HIV Infect 2005;13:79 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 With 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 toxicity Women 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
Pharmacokinetics Bioavailability Distribution Metabolism Elimination 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 There 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. Reference Fletcher CV et al. JID 2004; 189: Patterson K et al. HIV Med. 2004; 8: 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;

34 Difference in ARV concentrations based on gender
NVP Female Vdss/F ↑; T1/2 ↓; ↔ oral cl (4) EFV ↔ (1) SQV Female AUC ↑ 56%; Cmax 26% (2,4) RTV Female AUC ↑ 22% (13) NFV ↔ (3) APV ↔ (4) LPV ↔ (4, 6,) IDV Female AUC ↓ 13% (4) TPV Female AUC ↑ (7) DRV Female AUC ↑ 16.8% (4,5) ATV Vdss/F = weight adjusted volume of distribution Per PI –increase volume minus decreased T1/2=no gender differ References 1. Ribaudo H, et al. 11th CROI, San Francisco 2004, #132 & Pfister M et al. AAC 2003; 47:130-7 2. Fletcher CV JID 2004 ;189: 3. Jackson KA et al. AAC 2000;44:1832-7 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 (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 home1 Lipodystrophy and poor body image can have negative effects on adherence2–4 Medication effects on the body and body image are commonly listed reasons for non-adherence among women with HIV5 Depression tends to be more common in women and is also linked to poor adherence6 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.

36 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 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 HIV-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. References Lima 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-D Lima 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 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

39 GRUPPO WFPA ITALIA Coordinatori
Adriana Ammassari INMI L Spallanzani Roma Antonella d’Arminio Monforte Clinica Malattie Infettive H San Paolo Milano Membri Enza Anzalone Divisione Malattie Infettive Osp. Civile “UmbertoI” Frosinone Teresa Bini Clinica Malattie Infettive H San Paolo Milano Antonella Castagna Clinica Malattie Infettive HSR Milano Anna Maria Cattelan Divisione Malattie Infettive H Rovigo Antonella Cingolani Clinica Malattie Infettive UCSC Roma Gabriella D’Ettorre Clinica Malattie Infettive Policlinico Umberto I Roma Fiorella Di Sora Divisione Malattie Infettive AO “S. Giovanni-Addolorata” Roma Miriam Gargiulo Divisione Malattie Infettive H Cotugno Napoli Cristina Gervasoni Clinica Malattie Infettive H L Sacco Milano Nicoletta Ladisa Clinica Malattie Infettive Università Bari Giuseppina Liuzzi INMI L Spallanzani Roma Rita Murri Clinica Malattie Infettive UCSC Roma Cristina Mussini Clinica Malattie Infettive Università Modena Paola Nasta Clinica Malattie Infettive Università Brescia Tiziana Quirino Divisione Malattie Infettive H Busto Arsizio (VA) Raffaella Rosso Clinica Malattie Infettive Università Genova Annalisa Saraceno Clinica Malattie Infettive Università Foggia Maria Paola Trotta INMI L Spallanzani Roma Francesca Vichi Divisione Malattie Infettive Firenze

40 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 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 trasversale A 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-positive Criteri di inclusione: infezione da HIV documentata età >18 anni assenza di analfabetismo comprensione della lingua italiana consenso 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 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

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