A mulher e os ensaios cl nicos no VIH

1. A mulher e os ensaios cl�nicos no VIH This presentation has been produced as part of the Women for Positive Action initiative, supported by Abbott. Women for Positive Action aims to empower, educate and support women with HIV and the healthcare providers who treat them The slides overview the differential responses to therapy and uptake of clinical trials between men and women. The factors behind the under-representation of women in clinical trials and the importance of enrolling and retaining women in clinical trials are discussedThis presentation has been produced as part of the Women for Positive Action initiative, supported by Abbott. Women for Positive Action aims to empower, educate and support women with HIV and the healthcare providers who treat them The slides overview the differential responses to therapy and uptake of clinical trials between men and women. The factors behind the under-representation of women in clinical trials and the importance of enrolling and retaining women in clinical trials are discussed

2. 2 �ndice

3. 3 Introdu��o In 2007 an estimated 33 million people were living with HIV1 The proportion of global HIV cases that are women is about 50%1 Women make up a higher proportion of new diagnoses, meaning the share of infections among women is increasing in several countries2 It is important to note that the number of cases of HIV infection in women are increasing in all parts of the world, albeit at different rates, and not just in the developing world. Most women with HIV are of childbearing potential2 Half of all new infections � over 7000 daily � are occurring among young people, and two-thirds of all new infections are among young women The proportion of women among people newly diagnosed with HIV in Western Europe increased from 25% in 1997 to 38% in 2002: 27.8% of newly registered Canadian HIV cases in 2006 were women3 32�33% of all newly diagnosed HIV/AIDS cases in North America acquired the infection through heterosexual intercourse2 References UNAIDS/ WHO. AIDS epidemic update. 2007;UNAIDS/07.27E / JC1322E UNAIDS. Report on the Global AIDS Epidemic. 2008; UNAIDS/08.25E / JC1510E Public Health Agency of Canada. HIV/AIDS. Epi Updates November 2007 In 2007 an estimated 33 million people were living with HIV1 The proportion of global HIV cases that are women is about 50%1 Women make up a higher proportion of new diagnoses, meaning the share of infections among women is increasing in several countries2 It is important to note that the number of cases of HIV infection in women are increasing in all parts of the world, albeit at different rates, and not just in the developing world. Most women with HIV are of childbearing potential2 Half of all new infections � over 7000 daily � are occurring among young people, and two-thirds of all new infections are among young women The proportion of women among people newly diagnosed with HIV in Western Europe increased from 25% in 1997 to 38% in 2002: 27.8% of newly registered Canadian HIV cases in 2006 were women3 32�33% of all newly diagnosed HIV/AIDS cases in North America acquired the infection through heterosexual intercourse2 References UNAIDS/ WHO. AIDS epidemic update. 2007;UNAIDS/07.27E / JC1322E UNAIDS. Report on the Global AIDS Epidemic. 2008; UNAIDS/08.25E / JC1510E Public Health Agency of Canada. HIV/AIDS. Epi Updates November 2007

4. A mulher e o VIH - Sinopse

5. 5 Diferen�as de tipo biol�gico entre homens e mulheres: efeitos sobre o VIH Os factores biol�gicos s�o respons�veis por uma susceptibilidade � infec��o por HIV, por parte das mulheres, 2 a 4 vezes superior � dos homens1,2, 3 Tendencialmente, as mulheres s�o diagnosticadas com o VIH mais tarde do que os homens1,2 As cargas v�ricas tendem a ser inferiores nas mulheres, sobretudo se a contagem de CD4 for mais elevada4 O �ndice de decl�nio da contagem de CD4 nas mulheres poder� ser mais r�pido, apesar de apresentarem normalmente uma carga v�rica inferior5,6 Infec��es recorrentes da flora vaginal, DIP aguda e risco acrescido de altera��es cervicais pr�-cancer�genas poder�o ocorrer concomitantemente com a maioria das manifesta��es tamb�m verificadas nos homens Women are physiologically 2-4 times more susceptible to HIV:1,2,3 Women have a more delicate larger mucosal surface area and the female sexual organs are more vulnerable to tears and micro-lesions; a direct transmission route Untreated STIs increase women�s risk of HIV infection Ejaculate is released in greater quantities and contains a higher viral content than vaginal secretions Women tend to present later than men, often diagnosed while pregnant, or as older women seeking treatment for an opportunistic infection Viral loads tend to be lower in women, especially when CD4 count is high4 A meta-analysis several studies of gender effects on viral load showed that HIV-infected women consistently have a 2-6-fold lower viral load than men. Possible biological explanations are variations in viral load and CD4 count throughout the menstrual cycle. These findings are significant as viral loads are used to guide initiation and modification of ART The rate of decline in CD4 count in women may be faster in spite of their generally lower viral load5,6 References WHO. Gender inequalities in HIV. Available at: http://www.who.int/gender/hiv_aids/en/. Accessed January 2008 Stratton SE and Watstein SB. The encyclopedia of HIV and AIDS. 2nd ed. New York: Facts on File. 2003. Pan American Health Organization. Gender and HIV. Women, Health and Development Program Fact Sheets 2008. Available at: http://www.paho.org/English/AD/GE/HIV.htm. Accessed January 2008 Ghandi M et al. Does patient sex affect Human Immunodeficiency Virus levels? Clinical Infectious Diseases 2002;35:313-322 Hubert JB et al. Gender, disease progression and response to HAART. Abstract presented at XIV International AIDS Conference, Barcelona, Spain 2002;ThOrC1448. Patterson K et al. Effects of Age and Sex on Immunological and Virological Responses to Initial HAART. HIV Medicine 2007;8:406-410.Women are physiologically 2-4 times more susceptible to HIV:1,2,3 Women have a more delicate larger mucosal surface area and the female sexual organs are more vulnerable to tears and micro-lesions; a direct transmission route Untreated STIs increase women�s risk of HIV infection Ejaculate is released in greater quantities and contains a higher viral content than vaginal secretions Women tend to present later than men, often diagnosed while pregnant, or as older women seeking treatment for an opportunistic infection Viral loads tend to be lower in women, especially when CD4 count is high4 A meta-analysis several studies of gender effects on viral load showed that HIV-infected women consistently have a 2-6-fold lower viral load than men. Possible biological explanations are variations in viral load and CD4 count throughout the menstrual cycle. These findings are significant as viral loads are used to guide initiation and modification of ART The rate of decline in CD4 count in women may be faster in spite of their generally lower viral load5,6 References WHO. Gender inequalities in HIV. Available at: http://www.who.int/gender/hiv_aids/en/. Accessed January 2008 Stratton SE and Watstein SB. The encyclopedia of HIV and AIDS. 2nd ed. New York: Facts on File. 2003. Pan American Health Organization. Gender and HIV. Women, Health and Development Program Fact Sheets 2008. Available at: http://www.paho.org/English/AD/GE/HIV.htm. Accessed January 2008 Ghandi M et al. Does patient sex affect Human Immunodeficiency Virus levels? Clinical Infectious Diseases 2002;35:313-322 Hubert JB et al. Gender, disease progression and response to HAART. Abstract presented at XIV International AIDS Conference, Barcelona, Spain 2002;ThOrC1448. Patterson K et al. Effects of Age and Sex on Immunological and Virological Responses to Initial HAART. HIV Medicine 2007;8:406-410.

6. 6 Diferen�as de tipo social e cultural afectam o modo como as mulheres gerem o VIH A number of psychosocial factors increase the risk of HIV infection in women: Limited control over the means to practice low-risk sexual behaviour, such as condom use Social standing and inability to negotiate frequency of and nature of sexual interactions Violence may increase a woman�s vulnerability to HIV because: Forced sex may result in tears and lacerations that contribute to virus transmission Violence can prevent women from safe-sex negotiations and access to treatment Fear of violence may prevent women from getting tested for HIV and/or disclosing their HIV status to others References WHO. Gender inequalities in HIV. Available at: http://www.who.int/gender/hiv_aids/en/. Accessed January 2008 Stratton SE and Watstein SB. The encyclopedia of HIV and AIDS. 2nd ed. New York: Facts on File. 2003 Pan American Health Organization. Gender and HIV. Women, Health and Development Program Fact Sheets 2008. Available at: http://www.paho.org/English/AD/GE/HIV.htm. Accessed January 2008 A number of psychosocial factors increase the risk of HIV infection in women: Limited control over the means to practice low-risk sexual behaviour, such as condom use Social standing and inability to negotiate frequency of and nature of sexual interactions Violence may increase a woman�s vulnerability to HIV because: Forced sex may result in tears and lacerations that contribute to virus transmission Violence can prevent women from safe-sex negotiations and access to treatment Fear of violence may prevent women from getting tested for HIV and/or disclosing their HIV status to others References WHO. Gender inequalities in HIV. Available at: http://www.who.int/gender/hiv_aids/en/. Accessed January 2008 Stratton SE and Watstein SB. The encyclopedia of HIV and AIDS. 2nd ed. New York: Facts on File. 2003 Pan American Health Organization. Gender and HIV. Women, Health and Development Program Fact Sheets 2008. Available at: http://www.paho.org/English/AD/GE/HIV.htm. Accessed January 2008

7. Resposta � terap�utica: diferen�as entre homens e mulheres

8. 8 Diferen�as de g�nero das interven��es terap�uticas A pr�tica cl�nica constata diferen�as de g�nero, devido a uma s�rie de factores

9. 9 Factores farmacocin�ticos na mulher There have been variable data reporting gender differences in disease outcome in women versus men with HIV Due to weight and fat distribution differences, standard doses for men may not be equivalent in women Administration of concomitant medications can affect the pharmacokinetic profile � the extent of the differences and the type of concomitant medication may differ between men and women. For example, hormonal contraceptives or hormone replacement therapies may alter the metabolic action of some drugs A 20% increase in the AUC has been reported for women taking nevirapine (an NRTI) vs men, although the clinical significance of this finding is not clear. Body size and metabolic differences are possible determining factors of differences in pharmacokinetics between men and women. However, psychosocial, behavioural and attitudinal differences such as accessing treatment or delays in initiating therapy until pregnant explain most differences between men and women with HIV References Bacon MC et al. The Women�s Interagency HIV Study: an Observational Cohort Brings Clinical Studies to the Bench. Clinical and Diagnostic Laboratory Immunology 2005;12:1013-1019. UK Collaborative HIV Cohort Steering Committee. The creation of a large UK-based multicentre cohort of HIV-infected individuals: The UK Collaborative HIV Cohort (UK CHIC) Study. HIV Medicine 2004;5:115-124 Rezza G et al. Plasma Viral Load Concentrations in Women and Men From Different Exposure Categories and With Known Duration of HIV Infection. JAIDS 2000;25:56-62. Moore AI et al. Gender differences in response to HAART. JAIDS 2003;1(3):188 Fletcher CV et al. Sex-Based Differences in Saquinavir Pharmacology and Virologic Response in AIDS Clinical Trials Group Study. Journal of Infectious Diseases 2004;189:1176-1184 Patterson K et al. Effects of age and sex on immunological and virological responses to initial highly active antiretroviral therapy. HIV Medicine 2007;8:406-410There have been variable data reporting gender differences in disease outcome in women versus men with HIV Due to weight and fat distribution differences, standard doses for men may not be equivalent in women Administration of concomitant medications can affect the pharmacokinetic profile � the extent of the differences and the type of concomitant medication may differ between men and women. For example, hormonal contraceptives or hormone replacement therapies may alter the metabolic action of some drugs A 20% increase in the AUC has been reported for women taking nevirapine (an NRTI) vs men, although the clinical significance of this finding is not clear. Body size and metabolic differences are possible determining factors of differences in pharmacokinetics between men and women. However, psychosocial, behavioural and attitudinal differences such as accessing treatment or delays in initiating therapy until pregnant explain most differences between men and women with HIV References Bacon MC et al. The Women�s Interagency HIV Study: an Observational Cohort Brings Clinical Studies to the Bench. Clinical and Diagnostic Laboratory Immunology 2005;12:1013-1019. UK Collaborative HIV Cohort Steering Committee. The creation of a large UK-based multicentre cohort of HIV-infected individuals: The UK Collaborative HIV Cohort (UK CHIC) Study. HIV Medicine 2004;5:115-124 Rezza G et al. Plasma Viral Load Concentrations in Women and Men From Different Exposure Categories and With Known Duration of HIV Infection. JAIDS 2000;25:56-62. Moore AI et al. Gender differences in response to HAART. JAIDS 2003;1(3):188 Fletcher CV et al. Sex-Based Differences in Saquinavir Pharmacology and Virologic Response in AIDS Clinical Trials Group Study. Journal of Infectious Diseases 2004;189:1176-1184 Patterson K et al. Effects of age and sex on immunological and virological responses to initial highly active antiretroviral therapy. HIV Medicine 2007;8:406-410

10. A mulher e os ensaios cl�nicos

11. 11 O conhecimento de que dispomos � limitado

12. 12 Estudos relativamente escassos e poucas mulheres inscritas em ensaios de VIH This literature study, conducted in 2007, included data which met the following criteria: written in English, involved human subjects, involved adults and reported data on sex differences in the viroimmunological and clinical parameters during HAART. Reference Nicastri EN et al. Sex issues in HIV-1-infected persons during highly active antiretroviral therapy: a systematic review. Journal of Antimicrobial Chemotherapy 2007;60:724-732This literature study, conducted in 2007, included data which met the following criteria: written in English, involved human subjects, involved adults and reported data on sex differences in the viroimmunological and clinical parameters during HAART. Reference Nicastri EN et al. Sex issues in HIV-1-infected persons during highly active antiretroviral therapy: a systematic review. Journal of Antimicrobial Chemotherapy 2007;60:724-732

13. 13 Estudos relativamente escassos com percentagem de mulheres superior a 50%: exemplos recentes Reference Nicastri EN et al. Sex issues in HIV-1-infected persons during highly active antiretroviral therapy: a systematic review. Journal of Antimicrobial Chemotherapy 2007;60:724-732 Reference Nicastri EN et al. Sex issues in HIV-1-infected persons during highly active antiretroviral therapy: a systematic review. Journal of Antimicrobial Chemotherapy 2007;60:724-732

14. 14 Diferen�as entre homens e mulheres: in�cio da HAART O tempo m�dio de in�cio da HAART nas mulheres foi superior ao dos homens; 28 vs 17 semanas (a partir da data de inscri��o no estudo)1 As mulheres tinham uma probabilidade duas vezes superior de apresentar dificuldades na toma aberta de medica��o em casa do que os homens homossexuais/bisexuais2 As mulheres com dificuldades de toma de medica��o em casa apresentavam uma probabilidade consideravelmente inferior de estar a seguir uma HAART2 O sexo feminino � um indicador aut�nomo de n�o seguimento de uma HAART3,4 A study investigating ART-na�ve patients (2323 men and 1335 women) found that the median time to commencing ART from enrollment to the study was 28 weeks for women and 17 weeks for men (P = 0.0003 by logrank test). However, when adjusted for CD4 count and viral load at the point of enrollment this difference was no longer statistically significant1 A survey of 2864 people receiving treatment for HIV found that women had twice the odds of having difficulties in openly taking medication at home than homo/bisexual men2 women having difficulties taking medication openly at home had a substantially lower probability of being on HAART (0.59 compared to 0.78) even after adjusting for confounding factors2 Female sex is an independent predictor of not receiving HAART3,4 References Murri R et al. Access to antiretroviral treatment, incidence of sustained therapy interruptions, and risk of clinical events according to sex: evidence from the I.Co.N.A. Study. JAIDS 2003;34:184�90 Sayles JN, Wong MD, Cunningham WE. The inability to take medications openly at home: does it help explain gender disparities in HAART use? Journal of Women�s Health 2006;15:173�81 McNaghten AD et al. Adult/Adolescent Spectrum of HIV Disease Group. Differences in prescription of antiretroviral therapy in a large cohort of HIV-infected patients. JAIDS 2003;32:499�505 Giordano TP, White AC Jr, Sajja P et al. Factors associated with the use of highly active antiretroviral therapy in patients newly entering care in an urban clinic. JAIDS 2003;32:399�405A study investigating ART-na�ve patients (2323 men and 1335 women) found that the median time to commencing ART from enrollment to the study was 28 weeks for women and 17 weeks for men (P = 0.0003 by logrank test). However, when adjusted for CD4 count and viral load at the point of enrollment this difference was no longer statistically significant1 A survey of 2864 people receiving treatment for HIV found that women had twice the odds of having difficulties in openly taking medication at home than homo/bisexual men2 women having difficulties taking medication openly at home had a substantially lower probability of being on HAART (0.59 compared to 0.78) even after adjusting for confounding factors2 Female sex is an independent predictor of not receiving HAART3,4 References Murri R et al. Access to antiretroviral treatment, incidence of sustained therapy interruptions, and risk of clinical events according to sex: evidence from the I.Co.N.A. Study. JAIDS 2003;34:184�90 Sayles JN, Wong MD, Cunningham WE. The inability to take medications openly at home: does it help explain gender disparities in HAART use? Journal of Women�s Health 2006;15:173�81 McNaghten AD et al. Adult/Adolescent Spectrum of HIV Disease Group. Differences in prescription of antiretroviral therapy in a large cohort of HIV-infected patients. JAIDS 2003;32:499�505 Giordano TP, White AC Jr, Sajja P et al. Factors associated with the use of highly active antiretroviral therapy in patients newly entering care in an urban clinic. JAIDS 2003;32:399�405

15. 15 Diferen�as entre homens e mulheres: ades�o a HAART e interrup��o do tratamento Os resultados apurados relativamente � ades�o s�o pouco claros, e alguns estudos n�o detectaram diferen�as entre os sexos1 Contudo, alguns estudos apuraram que as mulheres registam um �ndice de ades�o inferior ao dos homens (18% vs 25%)2 � mais prov�vel o diagn�stico de depress�o nas mulheres do que nos homens (34% vs 29%)2 � mais prov�vel que as mulheres venham a interromper o tratamento do que os homens do mesmo grupo de exposi��o 35.8% vs 24.4% entre toxicodependentes 22.1% vs 13.3% entre heterossexuais3 A literature review showed no difference in adherence between the sexes1 However, there are individual reports of differences: A retrospective cohort study reported that women are less adherent (18% vs 25%) and more likely to be diagnosed with depression (34% vs 29%)2 Women are more likely to have an interruption than men in the same exposure group (35.8% vs 24.4% among drug users; 22.1% vs 13.3% among heterosexuals)3 Women with HIV are known to be particularly vulnerable to experiencing depressive symptoms, and persistent depression has been associated with reduced adherence to HAART and significantly poorer survival rates. The relationship of gender, depression, medical care, and mental health care with 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 were. This correlates to other evidence which indicates that women are less likely to receive care from an HIV specialty provider, or receive antiretroviral therapy4 References Ammassari A et al. Relationship between HAART adherence and adipose tissue alterations. JAIDS 2002;31:S140�4 Turner BJ et al. Relationship of gender, depression, and health care delivery with antiretroviral adherence in HIV �infected drug users. Journal of General Internal Medicine 2003;18:248-257 Touloumi et al. CASCADE Collaboration. Highly active antiretroviral therapy interruption: predictors and virological and immunologic consequences. Journal of Antimicrobial Chemotherapy 2007;60:724-732 Shapiro MF et al. Variations in the care of HIV infected adults in the United States: results from the HIV Cost and Services Utilisation Study. Journal of the American Medical Association 1999;281:2305-15 A literature review showed no difference in adherence between the sexes1 However, there are individual reports of differences: A retrospective cohort study reported that women are less adherent (18% vs 25%) and more likely to be diagnosed with depression (34% vs 29%)2 Women are more likely to have an interruption than men in the same exposure group (35.8% vs 24.4% among drug users; 22.1% vs 13.3% among heterosexuals)3 Women with HIV are known to be particularly vulnerable to experiencing depressive symptoms, and persistent depression has been associated with reduced adherence to HAART and significantly poorer survival rates. The relationship of gender, depression, medical care, and mental health care with 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 were. This correlates to other evidence which indicates that women are less likely to receive care from an HIV specialty provider, or receive antiretroviral therapy4 References Ammassari A et al. Relationship between HAART adherence and adipose tissue alterations. JAIDS 2002;31:S140�4 Turner BJ et al. Relationship of gender, depression, and health care delivery with antiretroviral adherence in HIV �infected drug users. Journal of General Internal Medicine 2003;18:248-257 Touloumi et al. CASCADE Collaboration. Highly active antiretroviral therapy interruption: predictors and virological and immunologic consequences. Journal of Antimicrobial Chemotherapy 2007;60:724-732 Shapiro MF et al. Variations in the care of HIV infected adults in the United States: results from the HIV Cost and Services Utilisation Study. Journal of the American Medical Association 1999;281:2305-15

16. 16 Diferen�as entre homens e mulheres: epis�dios adversos durante a HAART In an observational study in HIV patients receiving stavudine (d4t) treatment in South Africa, all 14 cases of lactic acidosis were in females, with a mortality rate of 29%1 In Canada, a large population-based study confirmed the significantly greater risk of developing lactic acidosis in women compared with men2 There is conflicting data over whether Nevirapine poses a greater risk for liver toxicity in women3 The nucleoside drug classes (still widely used in the developing world) are associated with a number of adverse events that are greater in women vs men: AZT-associated anaemia and d4T-associated hyperlactataemia and lipodystrophy References Geddes R et al. A high incidence of nucleoside reverse transcriptase inhibitor (NRTI)-induced lactic acidosis in HIV-infected patients in a South African context. South African Medical Journal 2006;96:722�4. Boulassel MR et al. Gender and long-term metabolic toxicities from antiretroviral therapy in HIV-1 infected persons. Journals of Medical Virology 2006;78:1158�63. De Lazzari E at al. Risk of hepatotoxicity in virologically suppressed HIV patients switching to nevirapine according to gender and CD4 count. 46th ICAAC, San Francisco 2006;Abstract H-1064 In an observational study in HIV patients receiving stavudine (d4t) treatment in South Africa, all 14 cases of lactic acidosis were in females, with a mortality rate of 29%1 In Canada, a large population-based study confirmed the significantly greater risk of developing lactic acidosis in women compared with men2 There is conflicting data over whether Nevirapine poses a greater risk for liver toxicity in women3 The nucleoside drug classes (still widely used in the developing world) are associated with a number of adverse events that are greater in women vs men: AZT-associated anaemia and d4T-associated hyperlactataemia and lipodystrophy References Geddes R et al. A high incidence of nucleoside reverse transcriptase inhibitor (NRTI)-induced lactic acidosis in HIV-infected patients in a South African context. South African Medical Journal 2006;96:722�4. Boulassel MR et al. Gender and long-term metabolic toxicities from antiretroviral therapy in HIV-1 infected persons. Journals of Medical Virology 2006;78:1158�63. De Lazzari E at al. Risk of hepatotoxicity in virologically suppressed HIV patients switching to nevirapine according to gender and CD4 count. 46th ICAAC, San Francisco 2006;Abstract H-1064

17. A import�ncia da mulher nos ensaios cl�nicos

18. 18 As mulheres utilizam mais recursos farmac�uticos, mas est�o pouco representadas em ensaios cl�nicos

19. 19 Representa��o reduzida de mulheres em ensaios cl�nicos de novas TAR Women are under-represented in the majority of clinical studies, such that effective gender comparisons are not possible References Derived from a slide of John Bartlett, CROI 2006Women are under-represented in the majority of clinical studies, such that effective gender comparisons are not possible References Derived from a slide of John Bartlett, CROI 2006

20. Directrizes para a inclus�o de mulheres em estudos cl�nicos 20

21. 21 A import�ncia da mulher nos ensaios cl�nicos

22. 22 A gravidez passou a ser uma realidade de vida das mulheres seropositivas References Stratton SE and Watstein SB. The encyclopedia of HIV and AIDS. 2nd ed. New York: Facts on File. 2003 Finer LB et al. Disparities in Rates of Unintended Pregnancy In the United States, 1994 and 2001. Perspectives on Sexual and Reproductive Health, 2006,38(2):90�96 Koenig LJ et al. Young, seropositive, and pregnant: epidemiologic and psychosocial perspectives on pregnant adolescents with human immunodeficiency virus infection. American Journal of Obstetrics and Gynecology 2007;S123-S131 References Stratton SE and Watstein SB. The encyclopedia of HIV and AIDS. 2nd ed. New York: Facts on File. 2003 Finer LB et al. Disparities in Rates of Unintended Pregnancy In the United States, 1994 and 2001. Perspectives on Sexual and Reproductive Health, 2006,38(2):90�96 Koenig LJ et al. Young, seropositive, and pregnant: epidemiologic and psychosocial perspectives on pregnant adolescents with human immunodeficiency virus infection. American Journal of Obstetrics and Gynecology 2007;S123-S131

23. 23 Uma parcela significativa de gravidezes entre mulheres seropositivas n�o � planeada Entre 334 mulheres submetidas a TARV, menos de metade referiu ter planeado a sua actual gravidez O regime de TARV na concep��o normalmente � apenas adequado a mulheres n�o gr�vidas Foram prescritos muitos regimes diferentes a mulheres em idade de concep��o, entre os quais: regimes com base em ddI+d4T (9.6%) regimes com base em EFV (13.5%) Uma vez gr�vidas, as doentes submetidas a EFV ou ddI tiveram muitas vezes de alterar a TARV (OU 13.2 P<0.001; 1.8 P=0.033, respectivamente) Os m�dicos dever�o ter em conta  o potencial de concep��o deste grupo de doentes, ao iniciar a TARV Women with HIV infection, like other women, may wish to plan pregnancy to start a family, control the size of their family, or avoid pregnancy Anticipating for the possibility of pregnancy, whether planned or unplanned, is an important component of care Health professionals should enable women to make reproductive choices by counselling, education and provision of contraception at the time of HIV diagnosis and during follow up With access to optimal management, becoming pregnant and giving birth to a healthy, HIV negative baby is possible for the vast majority of women of childbearing age References Floridia M et al. Short communication: Antiretroviral therapy at conception in pregnant women with HIV in Italy: wide range of variability and frequent exposure to contraindicated drugs. Antiviral Therapy 2006;11:941-946Women with HIV infection, like other women, may wish to plan pregnancy to start a family, control the size of their family, or avoid pregnancy Anticipating for the possibility of pregnancy, whether planned or unplanned, is an important component of care Health professionals should enable women to make reproductive choices by counselling, education and provision of contraception at the time of HIV diagnosis and during follow up With access to optimal management, becoming pregnant and giving birth to a healthy, HIV negative baby is possible for the vast majority of women of childbearing age References Floridia M et al. Short communication: Antiretroviral therapy at conception in pregnant women with HIV in Italy: wide range of variability and frequent exposure to contraindicated drugs. Antiviral Therapy 2006;11:941-946

24. Inscrever e manter as mulheres em ensaios cl�nicos

25. 25 Factores de tipo social, log�stico e cient�fico afectam a participa��o das mulheres em ensaios Os obst�culos n�o s�o bem compreendidos ou definidos Thalidomide and diethylstilbestrol (DES) were used in the 1950s and 60s Since then, all women between the time of first menstruation until menopause were defined as �potentially pregnant� A policy of exclusion prohibited all such women from pharmaceutical research for fear of causing foetal harm Thalidomide and diethylstilbestrol (DES) were used in the 1950s and 60s Since then, all women between the time of first menstruation until menopause were defined as �potentially pregnant� A policy of exclusion prohibited all such women from pharmaceutical research for fear of causing foetal harm

26. 26 Equil�brio das implica��es �ticas Exposi��o no primeiro trimestre da gravidez levanta uma s�rie de considera��es �ticas

27. 27 Compreens�o das motiva��es e dos obst�culos � participa��o em ensaios

28. 28 Informar as mulheres e prever obst�culos e motiva��es para a participa��o em ensaios Any attempt to put pressure on an individual to take part in research is unethical Patients must make their own fully-informed decisions, knowing all the potential risks and benefits of enrolling in the study Information and support should anticipate issues that are likely to impact women e.g. additional clinic visits and impact on work and family life Any attempt to put pressure on an individual to take part in research is unethical Patients must make their own fully-informed decisions, knowing all the potential risks and benefits of enrolling in the study Information and support should anticipate issues that are likely to impact women e.g. additional clinic visits and impact on work and family life

29. 29 Os protocolos de estudo poder�o ser mais ben�ficos para as mulheres? Altera��o de requisitos de concep��o Inclus�o de fase aberta / seguimento para mulheres que engravidem Absten��o de uso de linguagem �cr�tica� como, por exemplo, as mulheres n�o �desistem� devido � gravidez, mas s�o convertidas para outra fase do protocolo Desenvolvimento de redes de centros que prestem assist�ncia a um grande volume de mulheres Disponibilizar encaminhamento, centros e investigadores que prestem orienta��o sobre como tornar as consultas e os estudos mais acess�veis e ben�ficas para as mulheres Cuidados infantis Despesas de transporte Confidencialidade

30. 30 O que acontece se uma mulher engravida enquanto integra um ensaio cl�nico?

31. Alternativas aos ensaios cl�nicos

32. 32 Ensaios controlados e randomizados Os ECR proporcionam o n�vel mais elevado de prova quando se trata de dar resposta a quest�es espec�ficas do foro cl�nico com relev�ncia estat�stica Possuem as suas limita��es: integram normalmente um universo de indiv�duos menos diversificado do que existe normalmente na pr�tica cl�nica di�ria (por exemplo, menos mulheres, doentes com menos complica��es) nem sempre reflectem os cen�rios cl�nicos habituais em que a maioria das pessoas recebe tratamento muitas vezes dispendiosos e morosos bons para dar resposta a quest�es espec�ficas, mas n�o para gerar hip�teses novas ou para explorar quest�es mais alargadas

33. 33 Alternativas aos ensaios controlados e randomizados Post-hoc analyses, retrospective studies and chart reviews are ways to study data that has already been collected or looking at completed studies in a new way. Case-control studies look at patients who already have HIV or their condition and look back to see if there are characteristics of these patients that differ from a control group. If the evidence found from these alternatives to randomized controlled trials is convincing enough, then resources can be allocated to more comprehensive studies. Regulatory authorities, drug manufacturers and clinicians are increasingly recognising the benefits of data from registries and observational studies, while still accepting their limitations.Post-hoc analyses, retrospective studies and chart reviews are ways to study data that has already been collected or looking at completed studies in a new way. Case-control studies look at patients who already have HIV or their condition and look back to see if there are characteristics of these patients that differ from a control group. If the evidence found from these alternatives to randomized controlled trials is convincing enough, then resources can be allocated to more comprehensive studies. Regulatory authorities, drug manufacturers and clinicians are increasingly recognising the benefits of data from registries and observational studies, while still accepting their limitations.

34. 34 Registos de doentes Randomized Controlled Trials (RCTs) are considered the �gold standard� when testing the efficacy and effectiveness of healthcare interventions. They involve splitting the trial participants into a randomly allocated intervention group and a control group. The outcomes of these two groups are then compared to measure the effectiveness of the intervention. If done correctly this form of clinical trial compares like for like and therefore eliminates the effects of confounding factors on the data. Randomized Controlled Trials (RCTs) are considered the �gold standard� when testing the efficacy and effectiveness of healthcare interventions. They involve splitting the trial participants into a randomly allocated intervention group and a control group. The outcomes of these two groups are then compared to measure the effectiveness of the intervention. If done correctly this form of clinical trial compares like for like and therefore eliminates the effects of confounding factors on the data.

35. 35 Registos de mulheres seropositivas Exemplo: Antiretroviral Pregnancy Registry (APR) www.apregistry.com Estudo internacional prospectivo de registo de exposi��o, criado em 1989 Recolhe dados sobre resultados de nascimentos, em particular, anomalias � nascen�a na sequ�ncia da exposi��o a terap�utica anti-retrov�rica durante a gravidez Os registos s�o ben�ficos sobretudo perante um grande volume de doentes Os registos apresentam v�rias limita��es, nomeadamente: O relat�rio passivo poder� traduzir-se em representa��o excessiva das anomalias Poder� ser dif�cil determinar que f�rmaco est� na raiz do problema, em caso de prescri��o de um combinado

36. Estudos de caso

37. 37 Estudo de caso 1: uma potencial candidata a inscri��o em ensaio cl�nico Informa��o padr�o acerca do que implica um ensaio cl�nico, para que a mulher possa tomar uma decis�o cabalmente informada Informa��o acerca de cuidados infantis, como proceder caso n�o possa comparecer a uma consulta, etc. Crit�rios de inclus�o de contraceptivos, o que isso significa e como proceder caso venha a engravidar Implica��es para a crian�a que vai nascer Implica��es para a pr�pria Implica��es para o ensaio cl�nico Pormenores acerca de onde poder� obter mais informa��es e aconselhamento, caso necess�rio

38. 38 Estudo de caso 2: potencial desistente de ensaio cl�nico Os problemas e necessidades espec�ficos dela, evitando dar qualquer impress�o de culpabiliza��o ou desilus�o pela desist�ncia Explorar de que modo o centro ou o patrocinador poder� prestar apoio para que esta consiga comparecer �s consultas Presta��o de informa��o e de apoio, utilizando linguagem que seja relevante para ela e para as suas necessidades An�lise das op��es de continuidade da terap�utica por parte dela, caso abandone o estudo Reassegur�-la de que apesar de muitos doentes n�o completarem a dura��o total do estudo, a participa��o dos mesmos continua a ser v�lida

39. 39 Estudo de caso 3: gravidez durante um ensaio cl�nico Dar resposta a quest�es acerca dos efeitos que o f�rmaco experimental poder� ter na gravidez dela Analisar as op��es de continuidade do ensaio, por exemplo, por meio de convers�o para uma fase aberta do protocolo, caso admiss�vel Seguimento durante e ap�s a gravidez Op��es de continuidade da terap�utica Evitar dar qualquer impress�o de culpabiliza��o ou desilus�o pela desist�ncia Reassegur�-la de que apesar de muitos doentes n�o completarem a dura��o total do estudo, a participa��o dos mesmos continua a ser v�lida

40. Obrigado pela aten��o H� perguntas?