Management of HIV Infection in Women

Management of HIV Infection in Women
Professor Margaret Johnson Royal Free Hospital, London, UK Romania, January 2012 Management of HIV Infection in Women

In the UK in 20101 34% (22,220) of the people with diagnosed HIV were women This has quadrupled since 2000 34% (2,230) new diagnoses of HIV were in women 95% of women living with HIV acquired the infection heterosexually Health Protection Agency. HIV in the United Kingdom: 2010 Report. 2010: London. 1. Health Protection Agency. HIV in the United Kingdom: 2010 Report. 2010, London

Royal Free Clinic Population
1992 2001 2009 Clinic population under care 325 1284 2447 Rate of Death• 10.7 1.3 0.5 New AIDS 29.8 4.6 2.2 Hospitalisation 41.1 10.1 5.1 % with CD4<200 41 14 6 On ART 39 64 85 VL<400# 88 97 VL <50# 79 91 Median CD4 290 443 539 Per 100 person year # 24 weeks ART

Royal Free Clinic Population (new diagnosis)
1992 1997 2001 2005 2007 2009 N 73 117 136 129 113 95 %CD4 <200 25 30 32 29 27 % AIDS or death in 6 months 15 20 22 19

Characteristics of women (>15yrs) with HIV in the UK
61% of women are diagnosed with a CD4 cell count <350 per mm3 Median CD4 count at HIV diagnosis 324 cells/mm3 in pregnant women 262 cells/mm3 in unpregnant women 1 woman in 10 is at least 50 years old, twice as many as in 2000 Health Protection Agency. Personal communication 2010

Late1 and very late2 diagnosis of HIV infection by prevention and age group
1 Diagnosed with a CD4 cell count <350 per mm3 (within 91days of diagnosis) 2 Diagnosed with a CD4 cell count <200 per mm3 (within 91days of diagnosis) Health Protection Agency Centre for Infections. HIV in the UK, CD4 Surveillance. Accessed November 2011

Potential places to test women for HIV
Beyond antenatal care: additional places to consider HIV testing for women Potential places to test women for HIV General practice Family planning HIV testing for couples seeking fertility assistance Sexually transmitted infection clinics Termination of pregnancy (TOP) clinics Gynaecology Cervical and breast screening programmes Paediatrics Plastic surgery Dental practices Community-based testing services Prison health services Note: There are only limited published data on testing programmes in most of these settings

HIV testing in termination of pregnancy service
Antenatal clinic Genitourinary medicine TOP Number, n 3,166 2,045 699 Number HIV positive, (%) 10 (0.5) 4 (0.2) 2 (0.6) Baseline CD4 285 417 561 VOLUNTARY NAMED HIV TESTING AMONGST WOMEN UNDERGOING TERMINATION OF PREGNANCY (TOP) IS FEASIBLE AND ACCEPTABLE HIV Med 2008; 9(Suppl. 1):25 (abstract no. P58) G Crowe and F Chhibber Princess Alexandra Hospital, Harlow, UK BACKGROUND: The prevalence of HIV among women undergoing TOP has been shown to be increasing in seven inner London TOP services where unlinked anonymous testing of women has been carried out since The same survey has shown that the equivalent rate in women attending Antenatal clinics in London is around half that in TOP facilities. To date, however, it has not been shown that named voluntary HIV testing is feasible or acceptable to women undergoing TOP. Since 2003 we have offered HIV testing as an opt out test in our TOP service. Here we present the first 5 years of this data. METHODS: The TOP service is run jointly by the Department of Sexual Health and the Women's Health Department. Every woman requesting TOP is offered a sexual health screen and serology for syphilis and HIV. Those found to be HIV positive are referred to the HIV clinic for follow-up. RESULTS:Over the 5 years from January 2003 to December 2007, 1618 women underwent TOP. Of these, 59 (3.6%) declined an HIV test. Of the remaining 1559 tests, 12 were positive (0.77%). Ten of the 12 were black African women, one was Thai and one was a British caucasian with no identifiable risk factors for HIV. Seven of the 12 were diagnosed at TOP, while five were already known to be HIV positive. One of these five TOPs was requested as a direct result of HIV disease (patient unwell with a low CD4 count and about to start antiretroviral therapy). The reasons for the other four TOPs were not directly related to HIV. CONCLUSIONS: HIV testing at TOP is feasible and acceptable with over 96% of women accepting a test. Consideration should be given to testing for HIV in women attending TOP services nationally Creighton S, Reeves I. BHIVA 2009 HIV Med. 2008; 9(Suppl. 1):25(P58)

Adjusted cumulative risk
CASCADE: Slower disease progression following HIV seroconversion in women n=3,414 women; n=3,509 men Progression to AIDS Progression to death Pre-1997 1997 onward Adjusted cumulative risk 95% CI Men 1.00 Women 0.99 0.86,1.14 0.76 0.63,0.90 0.89 0.76,1.05 0.68 0.56,0.82 *p value 0.90 0.002 0.17 <0.001 †p value 0.016 0.024 *Effect of sex within calendar period; †effect of sex across calendar periods Jarrin I, et aI. Am J Epidemiol 2008;168:532–40

Life expectancy Why do HIV +ve individuals on HAART not have a normal life expectancy? Why are women more disadvantaged than men?

Life expectancy General population HIV -ve Men Women Delta
A 20yr old will live to (years) 76 80 4 A 35yr old will live to (years) 77 81 HIV +ve at HAART initiation A 20yr old will live to (years; adjusted) 63 64 1 A 35yr old will live to (years; adjusted) 67 68 ART-CC, Lancet 2000;372:293‒99

Life expectancy Patients aged >20yrs starting ART from 1996 to 2008, with >3 drugs and CD4 <350 cells/mm3 (N=17,661; 25% female) Over 91,203 person-years, 1,248 (7%) patients died Men Women Life expectancy UK CHIC UK general population At age 20 years 39.5 57.8 50.2 61.6 At age 35 years 30.1 43.5 37.7 46.9 May M et al. BMJ. 2011; 343:d6016

COHERE: Time with CD4 ≥500 cells/mm3
Allows men, but not women, to reach similar mortality rates to general population Time spent CD4 ≥500 cells/mm3 Current CD4 After 1 year MALE After 2 consecutive years FEMALE After 3 consecutive years After 4 consecutive years After 5 consecutive years 1 2 3 Mortality ratio Adapted from Lewden C et al. 17th CROI, Poster 527. Abstract L-166

Who delivers? HIV specialist clinicians
HIV specifics Clinicians in other specialities e.g. obstetrics and gynecology, mental health and others Primary care Voluntary sector Peer Support Local Authorities

The package HIV Diagnosis: Impact for women
Family life and relationships Prevention of onward transmission Sex-specific conditions In the interests of time and for the purposes of today’s discussion we have pulled out three themes that inform the treatment and clinical care of women with HIV ARV management

Rates of heterosexual transmission of HIV
The likelihood of HIV transmission to women in serodiscordant couples has been reported to be more than twice that of men 3.8 for women and 1.7 for men per 100 person-years were reported in one African study1 A meta-analysis of studies of heterosexual discordant couples observed no incidences of transmission in patients treated with ART and with VL <400 copies/mL2 Male circumcision can decrease the risk of male infection3,4 1. Mugo N, et al. International Microbicides Conference Pittsburgh, Abs 8 2. Attia S, et al. AIDS 2009;23:1397– Baeten JM, et al. J Infect Dis2005;191:546–53 4. Quinn TC, et al. N Engl J Med 2000;342:921–29 18

HIV and life expectancy
HIV +ve individuals do not have normal lifespan even with HAART Chronic inflammation Comorbidities Women particularly disadvantaged Multimorbidity HIV HAART Traditional risk factors

HIV transmission risk1 Higher viral load and STIs increase transmission risk Type of exposure(from an HIV+ source) 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% 1. Adapted from NONOPEP website: RecommendationsNONOCC.htm. Accessed Jan 2012 20

Women’s vulnerability to HIV
Biological factors1,2 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 Structural factors1,3 Gender norms and inequalities (control over avoiding risk behaviour and nature of sexual interactions) Violence3 Forced sex may cause damage May prevent women from safe-sex negotiations, being tested, disclosing HIV status and receiving treatment 1. Pan American Health Organization. Gender and HIV. Available from: Accessed March Larkin J, et al. MedscapeWomens Health 1996: 1(11):1. 3. WHO. Gender inequalities and HIV. Available from: Accessed March 2011. 21

Aspiration: timely diagnosis
Reduce late presentation in women Identify barriers and opportunities for HIV testing for women Expand HIV testing into existing women's services Enhance the visibility of women who are not pregnant or who are older Late presentation The antenatal programme has been hugely successful in engaging pregnant women in diagnosis and care but fewer opportunities exist for women who are not pregnant and amongst these in particular are older women 1. BHIVA. National HIV Testing Guidelines NICE. HIV Testing Guidelines 2011

Need for improved testing in women
There is a need to improve HIV testing: across Europe, 15–38% of HIV-infected individuals present late* – increasing risk of mortality and morbidity1 Similar proportions of women present late across European countries2–4 Women are not being reached by existing testing strategies 35 33 25 Women presenting late (%) J Acquir Immune Defic Syndr. * Definition of late presentation varied depending on the study and included CD4+ counts < 50, 200 or 350/μl; short (specified) time periods from HIV diagnosis to AIDS diagnosis; or HIV diagnosis concurrent with AIDS 2 3 4 number of women = 780 58 391 1. Adler et al. AIDS Care 2009;21:284– Health Protection Agency. HIV in the UK: 2010 Report. 3. Girardi et al. J AIDS 2004;36:951– Sobrino-Vegas et al. Current HIV Research 2009;7: 23

Potential places to test women for HIV
Beyond antenatal care: additional places to consider HIV testing for women Potential places to test women for HIV General practice Family planning HIV testing for couples seeking fertility assistance Sexually transmitted infection clinics Termination of pregnancy (TOP) clinics Gynaecology Cervical and breast screening programmes Paediatrics Plastic surgery Dental practices Community-based testing services Prison health services Note: There are only limited published data on testing programmes in most of these settings

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. ECDC and WHO HIV/AIDS Surveillance Report in Europe. 2007 Joint United Nations Programme on HIV/AIDS (UNAIDS), United Nations Population Fund (UNFPA), UNIFEMWomen and HIV/AIDS: Confronting the crisis. 2004

Tests offered at time of indicator condition
Of the 362 indicator conditions for which testing was offered, the test was: positive in 305 (84.3%) declined in 27 (7.5%) – 14 of these were STIs. negative in 30 (8.3%) (ie patient subsequently seroconverted) – 23 were STIs and 5 were hepatitis B/C. Data relates to conditions, not patients. Patients could have more than one condition so the test might be not offered with one condition, and then subsequently offered with a different one. In some cases there was substantial delay between a patient presenting with an indicator condition and being offered a test. This was still counted as an offer. BHIVA Audit & Standards Sub-Committee. HIV testing and diagnosis. 2008

Physician barriers to HIV testing
HIV testing was offered to 4,111 age-eligible patients in emergency units or acute care units within the UK Rayment et al. HINTS Study Group. Available at

Patient AR 24 yr old HIV-positive woman CD4 370,VL89,000
Partner HIV -ve BMI 21

What are the problems she faces?
Disclosure Losing her job Contraception - Pregnancy Starting Treatment Anxiety and Depression Anaemia Trip around the world Am I going to die?

For women newly diagnosed with HIV
Engaging in HIV care with a comprehensive multidisciplinary team which includes peer support Identification of each woman’s coping strategies and support networks Undertaking appropriate baseline assessment and investigations Supporting women through disclosure

The HIV factor.... The impact of HIV on: Contraceptive options
Existing relationships Formation of new relationships Sero-different relationships Contraceptive options Fertility and getting pregnant The management of pregnancy Wilson TE, Jean-Louis G, Schwartz R, Golub ET, Cohen MH, Maki P, et al. HIV infection and women's sexual functioning. J Acquir Immune Defic Syndr 2010,54: Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011,365: Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C, Mansoor LE, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010,329: Vernazza PL, Graf I, Sonnenberg-Schwan U, Geit M, Meurer A. Pre-exposure prophylaxis and timed intercourse for HIV-discordant couples willing to conceive a child. AIDS 2011. Linas BS, Minkoff H, Cohen MH, Karim R, Cohan D, Wright RL, et al. Relative time to pregnancy among HIV-infected and uninfected women in the Women's Interagency HIV Study, AIDS 2011,25: Cliffe S, Townsend CL, Cortina-Borja M, Newell ML. Fertility intentions of HIV-infected women in the United Kingdom. AIDS Care 2011,23: Ezeanochie M, Olagbuji B, Ande A, Oboro V. Fertility preferences, condom use, and concerns among HIV-positive women in serodiscordant relationships in the era of antiretroviral therapy. Int J Gynaecol Obstet 2009,107:97-98. Townsend CL, Cortina-Borja M, Peckham CS, de Ruiter A, Lyall H, Tookey PA. Low rates of mother-to-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, AIDS 2008,22: de Ruiter A, Mercey D, Anderson J, Chakraborty R, Clayden P, Foster G, et al. British HIV Association and Children's HIV Association guidelines for the management of HIV infection in pregnant women HIV Med 2008,9:

After the test: telling others
Disclosure – difficulties and dilemmas for women Telling men Telling children Reckless transmission Vyavaharkar M, Moneyham L, Corwin S, Tavakoli A, Saunders R, Annang L. HIV-disclosure, social support, and depression among HIV-infected African American women living in the rural south-eastern United States. AIDS Educ Prev 2011,23:78-90 Vyavaharkar M et al. AIDS Educ Prev. 2011; 23:78–90

Disclosure 2‒67% women do not disclose to anyone1–4
Positive outcomes of disclosure reported5 Less anxiety Fewer symptoms of depression Increased social support, acceptance No need to hide treatment Easier to plan for future, discuss prevention Not associated with break up of relationship5 Important to identify those at risk of violence2 1.Gielen AC et al. Women’s Health. 1997; 25:19–31 2.Kilmarx P et al. Sexually Transmitted Diseases. 1998; 25:28–37. 3.Simoni J et al. AIDS and Behaviour :147–58 3.Lester P et al. JAIDS and HR. 1995; 10:341–9 4.WHO. Gender Dimensions of HIV Status Disclosure to Sexual Partners: Rates, Barriers and Outcomes. 2004

Current treatment guidelines: when to start ART?
Clinical category CD4 cells/mm3 EACS1 DHHS2 IAS3 AIDS-defining symptoms Any value Treat Asymptomatic < 200 200–350 350–500 Individual basis‡ > 500 Individual basis* 50% panel: treat 50% panel: optional‡ Individual basis† ‡ Treat in specific circumstances, including pregnancy, coinfection, HIV-AN or other deficiency, VL > 105 copies/mL, CD4 decline > cells/mm3 per year, age > 50 years, high cardiovascular risk or malignancy *Generally defer treatment; closer follow up if VL > 105 copies/mL † ART should be considered unless patient is an elite controller (HIV-1 RNA 50 copies/mL) or has stable CD4 cell count and low-level viremia in the absence of ART 1. EACS Guidelines Available at Accessed April DHHS Guidelines Available at Accessed April 2011 3. Thompson MA et al., JAMA 2010;304:321–333

EACS recommendations for initiation of ART in HIV-positive persons
Current CD4 count 350‒500 >500 Asymptomatic HIV infection Consider Defer Symptomatic HIV disease (BorC) Recommend Primary HIV infection HIV associated renal disease HIV associated neurocognitive impairment Hodgkin’s lymphoma HPV associated cancers Other non AIDS defining cancer Autoimmune disease History CVD or CVD risk >20% Hep B requiring Hep B treatment HBV not requiring Hep B treatment Consider/Recommend HCV for which HCV treatment given HCV for which treatment not feasible

Is there a preferred first line regimen for women
Safe among women with CD4 >350 cells/mm3 No interactions with hormonal contraception Safe in pregnancy Not associated with weight gain or increases in body fat Associated with few adverse events

Aspiring to... effective ARV therapy
EFFICACY Equivalent efficacy between sexes in RCTS but numbers are small1 There is substantial variability within the data EFFECTIVENESS Tolerability differences2 Discontinuation and switch rates higher in women3,4 Struble K. Meta-analysis of efficacy outcomes for treatment-naïve and treatment-experienced HIV-infected women in randomized controlled clinical rrials: 2000 to th Conference on Retroviruses and Opportunistic Infections, February 8–11, 2009 Metanalysis of 48-week efficacy data in FDA registration trials, 2000–2008 17,826 subjects 38 RCTs on 14 agents No clinically or statistically significant gender differences in week 48 efficacy outcomes regardless of treatment history, or drug class BUT Not enough women! Currier Barber Grace Study. Currier J et al. Ann Intern Med 2010; 153:349−357 1.Struble K.16th Conference on Retroviruses and Opportunistic Infections, February 8–11, Ofotokun. Top HIV Infect. 2005;13:79 3. Barber TJ et al. Antiviral Ther (in press) Currier et al. Ann Intern Med. 2010;153:349–57 37

EACS Treatment Guidelines 2011

Initial combination regimen for antiretroviral-naïve adult patients
Select one drug in column A and one NRTI combination in column B (*) A B REMARKS Recommended (**) NNRTI: EFV (i) NVP (ii) ABC/3TC (vi) TDF/FTC TDF/FTC co-formulated ABC/3TC co-formulated EFV/TDF/FTC co-formulated Ritonavir-boosted PI: ATV/r (iii) DRV/r (iii) LPV/r (iv) ATV/r: 300/100 mg qd DRV/r: 800/100 mg qd LPV/r: 400/100 mg bid or 800/200 mg qd ITI: RAL RAL: 400 mg bid Alternative SQV/r FPV/r MVC (v) ZDV/3TC Dd/3TC or FTC (vii) SQV/r: start with 500/100 mg then change to 1000/100 mg bid after one week FPV/r: 700/100 mg bid or 1400/200 mg qd ZDV/3TC co-formulated * Generic HIV drugs are becoming more available and can be used as long as they replace the same drug and do not break recommended fixed dose combinations. ** Only drugs currently licensed for initiation of therapy by the European EMA are taken into consideration.

Number of female patients (%)
Representation of women in randomised controlled trials in naïve patients Trial Trial design Number of female patients (%) Citation ACTG 5142 EFV vs LPV/r 151 (20%) Riddler SA, et al. N Engl J Med 2008;358:2095−106 ARTEMIS LPV/r vs DRV/r 209 (30%) Ortiz R, et al. AIDS 2008, 22:1389–1397 CASTLE LPV/r vs ATV/r 277 (31%) Molina JM, et al. Lancet 2008; 372(9639):646–55 STARTMRK EFV vs RAL 105 (19%) Lennox JL, et al. Lancet 2009; 374(9692):796–806 MERIT EFV vs MVC 206 (29%) Cooper DA et al. JID 2010; 201:803–813 ACTG 5202 EFV vs ATV/r TDF/FTC vs ABC/3TC 322 (17%) Daar ES, et al. Ann Intern Med 2011 Feb 14. [Epub ahead of print] 40

FDA meta-analysis: Similar efficacy of HAART in women versus men
FDA review of trials from 2000–2008 Results 22,411 HIV+ subjects in 43 RCTs for 16 ARVs; 20% women No significant gender differences in treatment response at week 48, discontinuations for AEs, lost to follow-up or death Higher rate of discontinuations for virological failure in males (8.15%) than females (4.25%) Soon G, et al. 50th ICAAC Abstract H-1812

FDA meta-analysis: Similar efficacy of HAART in women versus men
Total -100% -50% 0% % % Favours male (n=6) Soon G, et al. 50th ICAAC Abstract H-1812

Efficacy and Safety analysis of LPV/r in HIV-infected women
Meta-analysis of seven randomized clinical trials VL <50; similar between women and men through 48 weeks Men Women Naïve 74.2% 68.9% Experienced 57% 52.4% Intention to treat; non-completers = failures No gender differences in CD4 increases, treatment related moderate/severe AE’s. Increased rates of discontinuation in ARV naïve women but similar in experienced women

Virological outcome RPV versus EFV in combination with TDF/FTC (TLOVR)
Women Men RPV EFV Responders 75% 73% 77% 78%

ACTG 5202: Association of race/ethnicity and sex with outcomes
Female (n=322) Male (n=1535) Virological failure events Number at risk Virological failures by gender and treatment group Study not specifically powered for gender/race comparisons Black race was associated with increased risk of VF, possibly related to lower adherence and higher rate of third drug tolerability endpoints Smith K, et al. CROI Poster 536

ACTG 5202: Association of race/ethnicity and sex with outcomes
Multivariate analyses HR (95% CI) P value With ABC/3TC Female versus male, EFV 0.52 (0.26‒1.04) 0.006 Female versus male, ATV/r 1.72 (0.99‒2.98) With TDF/FTC 0.86 (0.41‒1.80) 0.03 2.35 (1.30‒4.26) Smith K, et al. CROI Poster 536 Smith K, et al. CROI Poster 536

DRV/r 600/100 mg BD + investigator-selected OBRb
GRACE study design GRACE n=287 women n=142 men Study criteria ≥18 years of age Viral load ≥1000 copies/mL Previous therapy consisting of a PI- or NNRTI-based HAART regimen of ≥12 weeksa No prior use of DRV/r, ETR, ENF or TPV 4-week follow up 48 weeks DRV/r 600/100 mg BD + investigator-selected OBRb 287 women; 142 men a Patients were allowed to enter the study on treatment interruption of ≥4 weeks b Investigator-selected NRTIs and NNRTIs were allowed; ENF, TPV, or agents from novel classes were not allowed Race Women Men Black, n (%) 191 (66.6) 73 (51.4) Hispanic/Latino, n (%) 60 (20.9) 36 (25.4) White, n (%) 34 (11.8) 31 (21.8) Other, n (%) 2 (0.7) 2 (1.4) Currier J, et al. Ann Intern Med. 2010;153:349–57

Patients with HIV-1 RNA <50 copies/mL, %
GRACE: Virological response not significantly different in women versus men at 48 weeks 100 Women (ITT-LOVR), Men (ITT-LOVR) Women (TLOVR-non-VF) Men (TLOVR-non-VF) 90 80 73.5% 70 73.0% 60 58.5% Patients with HIV-1 RNA <50 copies/mL, % 50 50.9% 40 30 20 10 8 16 24 32 40 48 Time, weeks Women (ITT-LOVR), N 287 287 287 287 287 287 287 Women (TLOVR-non-VF), n 266 252 244 236 222 212 200 Men (ITT-LOVR), N 142 142 142 142 142 142 142 Men (TLOVR-non-VF), n 136 132 131 128 122 117 113 The 95% CI crossed zero for both ITT and non-VF censored analyses; The 95% CI only included 15% in the ITT–TLOVR analysis Currier J, et al. Ann Intern Med. 2010;153:349–57 48

ARVs, women and adverse events
Different adverse event profiles between women and men1,2 Rates similar but the events differ1 Women with nausea, men with diarrhea3 Discontinuation rates are consistently higher in women compared to men clinical trials3‒7 Discontinuation in randomised controlled trials due to pregnancy 1. Tedaldi E et al. JAIDS. 2008; 47:441–8; 2. Ofotokun I. Top HIV Infect. 2005; 13:79–83; 3. Squires K et al. J Antimicrob Chemother. 2011; 66:363–70; 4.Murri R et al. JAIDS. 2003; 34:184–90; 5. Spire B et al. AIDS Care. 2004; 16:558–64; 6. Currier J et al. Ann Intern Med. 2010; 153:349–57; 7. Pirkle CM et al. HIV Med. 2009; 10:152–6 49 49

UK cohort: clinical outcomes
Adjusted relative hazard (men vs. women): 0.72 [0.63, 0.83] Time to first treatment modification Women were more likely than men to discontinue treatment for reasons other than virologic failure Barber TJ et al. Antivir Ther. 2011; 16(6):805–14.

Hermes el al 2nd International Workshop HIV & Women Bethesda Jan 2012
A Meta-Analysis Evaluating the Effects of Body Mass Index on Efficacy, Safety and Tolerability of LPV/r in Women from 7 Randomised Clinical Trials through 48 weeks of Treatment Hermes el al 2nd International Workshop HIV & Women Bethesda Jan 2012

Subjects meeting meta-analysis criteria
Total Subjects N= 2022 Total Women W = 492 Women with BMI data N=485 BMI <25 n=258 25 < BMI <30 N=130 BMI >30 N=97

Disposition of women at Week 48 by body mass index
Reason for discontinuation BMI <25 (n=258) 25< BMI <30 (n=130) BMI >30 (n=97) Any reason, n (%) 55 (21.3) 34 (26.2) 21 (21.6) AE/HIV event 15 (5.8) 11 (8.5) 6 (6.2) Withdrew consent 11 (4.3) 2 (1.5) 1 (1.0) Host to follow up 8 (6.2) 8 (8.2) Non adherence 10 (38) 7 (5.4) 4 (4.1) Virological failure 3 (1.2) 5 (3.8) Death 1 (0.4) 3 (2.3) Other 7 (27) 2 (2.1)

Moderate or severe AEs in women by body mass index
Variable BMI <25 (n= 258) 25< BMI <30 (n= 130) BMI >30 (n= 97) Any AE n (%) 76 (29.5) 38 (29.2) 40 (41.2) Abdo Pain 2 (0.8) 7 (7.2) Diarrhoea 24 (9.3) 14 (10.8) 22 (22.7) Nausea 21 (8.1) 9 (6.9) 11 (11.3) Vomiting 10 (3.9) 6 (4.6) 9 (9.3)

Antiretrovirals and outcomes
Do women fare better than men? Yes and No1 What are the factors that affect outcomes for women? Access Adherence Adverse effects May, M., et al., Impact of late diagnosis and treatment on life expectancy in people with HIV-1: UK Collaborative HIV Cohort (UK CHIC) Study. BMJ, : p. d6016. Cohort study demonstrting the impcat of ARVs on life expcetancy of men and women in the UK Barber, T.J., et al., Outcomes in the first year after initiation of first-line HAART among heterosexual men and women in the UK CHIC Study.AntivirTher, (6): p May, M et al. BMJ 2011; 343: d6016.

Are virological suppression rates in women as good as men?
CDC Medical Monitoring Project in US Proportion virologically suppressed on antiviral therapy Women 71% (95% CI: 68‒75) Men who have sex with men 81% (95% CI: 79‒84) Men who have sex with women 75% (95% CI: 71‒79) CDC MMWR, Dec 2, 2011

Patient AR Plans to get pregnant in the next few months
Using condoms and not intending to use hormonal contraception

When would you start treatment?
CD4 drops below 350 Immediately CD4 drops below 200 Wait until pregnant, start end first trimester

What HAART should be considered?
EFV based ATV/r based LPV/r RAL

DHHS Guidelines October 2011 Update
Preferred regimens Alternative regimens Third agent NRTI backbone Rating Efavirenz Truvda AI Darunavir/r Truvada Atazanavir/r Raltegravir Lopinavir/r* Combivir* Third agent NRTI backbone Rating Efavirenz Kivexa BI Rilpiverine Truvada BIII Atazanvir/r Darunavir/r Fosamprenavir/r TVD / KVX Lopinavir/r Raltegravir *Pregnancy only Rating of Recommendations: A = Strong; B = Moderate; C = Optional Rating of Evidence: I = data from randomized controlled trials; II = data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = expert opinion Preferred Regimens (Regimens with optimal and durable efficacy, favorable tolerability and toxicity profile, and ease of use)The preferred regimens for nonpregnant patients are arranged by chronological order of FDA approval of components other than nucleosides and, thus, by duration of clinical experience. Alternative Regimens (Regimens that are effective and tolerable but have potential disadvantages compared with preferred regimens. An alternative regimen may be the preferred regimen for some patients.) DHSS. Panel on Antiretroviral Guidelines for Adults and Adolescents. 2011

Communication gap Women Living Positive survey:
48% who had been pregnant / would consider pregnancy had never been asked by their HCP if they had/were considering having children 57% who had been / were currently pregnant had not had preconception discussions with HIV provider regarding treatment options Similar findings in Toronto, Canada Squires KE etal AIDS Pat Care STDs 2011; 25(5) Loyalty 2nd Womens Workshop

Unintended pregnancy rates in HIV infected women
Cross sectional study of HIV women in Ontario Age 18‒52 Oct 2007–April 2009 416/504 had been pregnant 56% identified their last pregnancy as unintended Loutfy et al, submitted

Patient AR Cervical cytology CIN 1
Hep B: HBsAg –ve; HBsAb –ve; HBcAb -ve Given Hep B vaccine

Loutfy M, 2nd Womens Workshop, Jan 2011
PAP testing in Toronto Latest PAP test HIV +ve HIV –ve Tested >1yr ago 69.3% 55.3% Tested >3yrs ago 7.1% 5.9% Never tested 10.2% 20.9% Loutfy M, 2nd Womens Workshop, Jan 2011

Hep B Vaccination Toronto
HIV +ve HIV -ve P value Reported being vaccinated 66.1% 43.3% <0.0001 One dose 21.7% 23.3% NS Two doses 36.7% Three doses 41.7% 40.0% Loutfy M, 2nd Womens Workshop, Jan 2011

Should this patient be given the HPV vaccine?
Yes No Don’t know

Cervical dysplasia and cancer
15–40% with evidence of dysplasia, 10–11x greater than HIV -ve women declining CD4 counts Dysplasia and cancer associated with more extensive cervical involvement and to involve other sites (vagina, vulva, perianal region) Overall HIV infected women have higher burden of HPV-related disease compared with HIV -ve women

HPV prevalence in HIV-infected versus HIV -ve individuals
women HIV -ve Number 767 390 Any HPV 64% 27% >2 HPV 37.8% 19.6%

Prevalence of vaccine HPV types in HIV-infected individuals
Although the majority of HIV infected women have a higher prevalence of vaccine HPV subtype 6, 11, 16 and 18; the majority do not Unlikely to have all vaccine types Benefit at least of some vaccine types Significance of the higher titres induced by the vaccine? HPV vaccine needs to be tested in HIV patients

Challenges associated with ageing in women with HIV
This slide presentation has been produced as part of the Women for Positive Action initiative Women for Positive Action aims to empower, educate and support women with HIV and the healthcare providers who treat them The slides overview the challenges and co-morbidities associated with ageing that face women living with HIV The Women for Positive Action educational slide kits are intended for use by healthcare professionals, community representatives and patients who want to create or participate in learning opportunities related to improving the care of women living with HIV If you have any questions about WFPA and sponsorship please the WFPA secretariat: These files are provided by the Women for Positive Action initiative. By requesting these materials, you are agreeing to use them as provided. However, if you choose to significantly adapt or edit these slides, change the meaning or context of the information, or use them for a purpose other than that outlined above, you accept responsibility for the content of your presentation and agree to use a different slide template Accuracy of Information and Disclaimer We do our best to ensure that all information and material on the slides is accurate as of 01 October 2010 ,and if you find anything that is inaccurate let us know and we will correct it as soon as practicable We provide use of these resources free of charge and do so on the basis that we have no liability for their use Women for Positive Action is supported by a grant from Abbott Challenges associated with ageing in women with HIV

Proportion of new HIV/AIDS cases in older people
However, the efficacy of ART is not the sole reason for the ageing HIV population The rate of HIV infection and new diagnoses among older people is increasing1‒3 In Europe, the proportion of women aged ≥50 years accounting for new HIV/AIDS cases rose from approximately 6% in 2002 to almost 10% in 20061 In the UK, women represent a quarter of all true rates of infection in the population aged ≥50 years are currently unknown due to poor testing rates5 diagnoses in people over the age of 504 However, the efficacy of ART is not the sole reason for the ageing HIV population. Rather, the rate of infections and new diagnoses among older people may also be increasing,1-3 although data on HIV and sexual behaviour in older people is limited In Western Europe, the proportion of women aged 50 years or over accounting for new HIV/AIDS cases has risen from approximately 6% in 2002 to almost 10% in 20061 This trend is matched in Central and Eastern Europe, with an increasing proportion of all diagnoses represented by women over the age of 501 In the UK, women represent a quarter of all diagnoses in people over the age of 504 True rates of infection in the population aged ≥50 yrs are currently unknown due to poor testing rates; most likely due to older people and their healthcare providers not considering them a sexually active, at-risk group5,6 References Simone MJ et al. Geriatrics 2008;63(12):6-12 Dougan S et al. Epidemiol Infect 2004;132(6): Smith R et al. HIV Medicine 2010;11(S1):O3 Pratt G et al. Age and ageing 2010;39: Kearney F et al. Age and ageing 2010;39(5): Simone MJ et al. Geriatrics 2008;63(12):6-12; 3. Dougan S et al. Epidemiol Infect 2004;132(6): ; 4. Smith R et al. HIV Medicine 2010;11(S1):O3; 5. Pratt G et al. Age and ageing 2010;39:

HIV in older women Sexual activity of older individuals is hardly researched Erectile dysfunction drugs extend the sex life of older individuals Older people less likely to practice safer sex Thinning of the vaginal mucosa Increasing HSV-2 antibodies with age Shorter time from diagnosis to onset of AIDS (age-related faster progression to AIDS, late diagnosis) Screening of older women uncommon

Immunosenescence and HIV
T-cell compartment most disrupted Thymus involution Naïve and memory T-cells Decreased numbers and functionality Memory cells Proinflammatory cytokines Early mortality in the elderly More rapid progression to AIDS in HIV Effros et al 2008 CID 47:

Consequences of ageing as a woman with HIV
Conditions with increased incidence in women living with HIV: Hormonal changes Cardiovascular events Non-AIDS-defining infections Renal disease Non-AIDS-defining cancers/malignancy Muscular and skeletal changes Non-AIDS-dementias, neurocognitive changes, mood and CNS disorders Women living with HIV face all the challenges that the general population faces when growing older PLUS: The consequences of living longer with HIV As they age, women living with HIV face all the challenges that the general population face when growing older, as well as the additional consequences of living longer with HIV, and longer exposure to HIV treatment regimens1 Longer treatment exposure may have an impact on adherence to treatment; although people of a younger age are less likely to adhere with their HIV treatment, a study by Glass et al reported that a longer time with HIV and receiving treatment may also result in a reduction in adherence2 Sometimes it may not be obvious whether health issues are due to the normal ageing process or due to HIV and its treatment, but while mortality from HIV-associated factors among people living with HIV has decreased, mortality and morbidity from non-AIDS- defining conditions has increased.1 Approximately half of people with HIV who are being treated with antiretroviral therapy now die as a result of non-AIDS defining conditions3 Non-AIDS-defining conditions that have increased in incidence in women living with HIV include:4 non-AIDS-defining infections, renal disease, non-AIDS-defining cancers/malignancy, muscular and skeletal changes, hormonal changes, cardiovascular events, non-AIDS-dementias, neurocognitive changes, mood and CNS disorders There is therefore a growing need to address the challenges women face as they live longer with HIV References Luther VP et al. Clin Geriatr Med 2007;23(3): Glass TR et al. AIDS 2009;Epub ART Cohort Collaboration Clin Infect Dis 2010;50(10): Santoro N et al. Maturitas 2009;64: The consequences of longer exposure to HIV treatment regimens

Onset of early menopause in women with HIV
Women living with HIV may be at an increased risk of an earlier onset of menopause compared with HIV-negative women; one study amongst 571 women (median age, 43 years), of whom 53% had HIV, demonstrated that HIV infection was a significant independent predictor of menopause. Among menopausal women, 26% of HIV-infected women compared with 10% of uninfected women experienced onset of menopause at <40 years of age (P=0.04)1 Women living with HIV were 73% more likely to experience early onset of menopause, compared with HIV uninfected women (adjusted OR, 1.734; 95% CI, 1.075–2.795)1 Symptoms of the menopause may also be more severe in women with HIV, particularly vasomotor, psychological symptoms, and vaginal dryness and dsypareunia2,3 In addition, for women living with HIV, the proportion of women experiencing onset of menopause increased as the CD4+ count decreased (P=0.01)1 Earlier onset of menopause may impact the underlying risk for CVD, dyslipidemia, diabetes and osteopenia in women living with HIV3-7 References Schoenbaum EE et al. Clin Infect Dis 2005;41: Ferreira CE et al. Gynecol Endocrinol 2007;23(4): Santoro N et al. Maturitas 2009;64: Dobs A et al. J Acquir Immune Defic Syndr 2002;31(Suppl 2):S70-77 Grunfeld C et al. Am J Med 1989;86:27-31 Justman JE et al. JAIDS 2003;32: Vescini F et al. J Acquir Immune Defic Syndr 2003;33: n=303 n=268 Women living with HIV were 73% more likely to experience early onset of menopause, compared with HIV-uninfected women (P=0.024) Schoenbaum et al (2005) Clin Infect Dis

Potential contributors to early onset of menopause in women with HIV
Lower CD4+ count has been associated with early menopause onset Immunosuppression Smoking Socioeconomic status Markers of low socioeconomic status (e.g. lower level of education, unemployment and poverty) have been associated with early menopause onset Menopause can occur up to 1–2 years earlier in smokers, compared with non-smokers Other potential contributors to early onset of menopause in women living with HIV may include: An increased proportion of smokers among patients with HIV;1 menopause can occur up to 1–2 years earlier in smokers, compared with non-smokers2-4 Many patients with HIV are from lower socioeconomic situations;5 markers of low socioeconomic status, including a lower level of education and unemployment, have been associated with earlier age at the onset of menopause4,6,7 Among women living with HIV, immunosuppression can be a predictor for early onset of menopause; of 302 women living with HIV (aged years), CD4+ count <200 cells/mm3 was associated with early menopause onset compared with CD4+ count or >500 cells/mm3 (adjusted OR, and 0.191, respectively; P=0.015 and P<0.0001, respectively)8 References Thompson SC et al. AIDS Care 1996;8(1):5-14 Willett W et al. Am J Epidemiol 1983;117: Cooper GS et al. Epidemiology 1999;10: Luoto R et al. Am J Epidemiol 1994;139(1):64-76 Gold EB et al. Am J Epidemiol 2001;153(9): Standford JL et al. J Chronic Dis 1987;40(11): Schoenbaum EE et al. Clinical Infectious Diseases 2005;41:

Managing the menopause in women with HIV
Strategies to offset effects associated with menopause include: Healthy lifestyle choices Smoking cessation Adherence to effective ART HRT Symptom management Alternative therapies Healthy lifestyle choices, smoking cessation and adherence to effective ART medication can be recommended to enhance women's health and offset any effects that can be associated with menopause Alternatives to HRT for hot flushes include using a selective seratonin reuptake inhibitor (SSRI) antidepressant Some women use alternative / herbal therapies, including soy products, black cohosh (Cimicifugaracemosa) or evening primrose (Oenotherabiennis), which contain oestrogen-like compounds known as phytoestrogens, to alleviate hot flashes, bloating, and mood swings It is essential, however, for a woman living with HIV to consult with her own healthcare professional before beginning a supplement regimen, as some herbal and dietary supplements can interact with ARV medications and other drugs Ageing women are entitled to live fulfilled sexual lives. Topical oestrogen creams or lubricants during sexual intercourse can help vaginal dryness and thinning. An oestrogen-releasing silicone ring (Estring) that can be inserted in the vagina and worn for three months at a time to alleviate the symptoms of vaginal atrophy. Local administration of oestrogen is not associated with the same risks as systemic HRT References Monroe A. BETA 2007:39-44

Due to its worldwide prevalence, osteoporosis is a serious public health concern. Currently it is estimated that over 200 million people worldwide suffer from this condition1 Approximately 30% of all post-menopausal women have osteoporosis in the US and in Europe. At least 40% of these women2 will sustain one or more fragility fractures in their remaining lifetime. Ageing of populations worldwide will be responsible for a major increase of the incidence of osteoporosis in post-menopausal women3 By 2050, the worldwide incidence of hip fracture in women is projected to increase by 240%.4 The estimated number of hip fractures worldwide will rise from 1.66 million in 1990 to 6.26 million in 2050, even if age-adjusted incidence rates remain stable5 Fractures resulting from osteoporosis cause suffering and disability, with great impact on a person’s quality of life, including: chronic pain, reduced mobility, disability, an increasing degree of dependence, and increased mortality6 References Cooper C et al. Osteoporos Int 1992;2(6): Melton III LJ et al. J Bone Miner Res 1992;7: Reginster JY et al. Bone 2006;38: S4-S9 Gullberg B et al. Osteoporosis Int 1997;7: Sambrook P et al. Lancet 2006;367: Osteoporosis

Risk factors for decreased bone mineral density in women
Female sex Decreased physical activity White race Smoking Family history Alcohol Increasing age Decreased bone acquisition Amenorrhoea /premature menopause Classic Secondary Chronic diseases (e.g. hyperthyroidism, hyperparathyroidism, liver disease, rheumatological conditions, eating disorders, etc.) Hypogonadism Renal dysfunction Malnutrition/low BMI Medications (e.g. corticosteroids, anticonvulsants, anticoagulants) What are the risk factors for decreased bone mineral density in HIV-infected patients? The complexity of evaluating possible risk factors in the HIV-infected individual is illustrated. Risks for the development of bone pathology in patients with HIV may be classic or secondary, in addition to those associated with HIV infection and long-term HAART. HIV infection-related, HAART-related and other secondary risk factors may overlap. Reference Glesby MJ. Clin Infect Dis 2003; 37(Suppl 2):S91-S95. HIV-infection related Cytokines (e.g. TNFa, IL6) Decreased muscle mass Decreased fat mass Fat deposition in marrow HAART-related Nucleoside analogues /mitochondrial dysfunction Protease inhibitors Lipodystrophy Adapted from Glesby MJ. Clin Infect Dis. 2003; 37(Suppl 2):S91–S95 79

Meta-analysis: HIV and osteoporosis
Being HIV+ conferred increased risk for osteoporosis compared with HIV- (n=654, mean age 38.1) 6.4 fold increased risk for reduced BMD (95% CI: 3.7‒11.3) Meta Analysis: Bone Jun;38(6):893-7. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. Brown TT, Qaqish RB. Abstract INTRODUCTION: Prevalence estimates of osteopenia and osteoporosis (reduced bone mineral density; BMD) in HIV-infected patients and the role of antiretroviral therapy (ART) varies in the literature. METHODS: We conducted a meta-analytical review of cross-sectional studies published in English to determine the pooled odds ratios (OR) of reduced BMD and osteoporosis in the following groups: HIV-positive versus HIV-negative; ART-treated versus ART-naive; protease inhibitor (PI)-treated versus PI-untreated. We searched the MEDLINE, PubMed, and EMBASE databases for eligible references between January 1966 and November Random effects models were used to generate pooled OR estimates and confidence intervals. RESULTS: Of 37 articles identified, 20 met the inclusion criteria. Of the 884 HIV-infected patients, 67% had reduced BMD, of whom 15% had osteoporosis, yielding a pooled OR of 6.4 and 3.7, respectively, compared with HIV-uninfected controls (n = 654) using 11 studies with available data. Compared with ART-naive patients (n = 202, 10 studies), ART-treated individuals (n = 824) had a 2.5-fold increased odds of prevalent reduced BMD. The risk of prevalent osteoporosis (seven studies) was similarly elevated in ART-treated individuals. Compared with non-PI-treated HIV patients (n = 410, 14 studies), PI-treated patients (n = 791) had increased odds of reduced BMD and osteoporosis (12 studies). Few studies adjusted for important covariates such as HIV disease severity or treatment duration. CONCLUSION: The prevalence of osteoporosis in HIV-infected individuals is more than three times greater compared with HIV-uninfected controls. ART-exposed and PI-exposed individuals had a higher prevalence of reduced BMD and osteoporosis compared with their respective controls. The influence of other disease and treatment variables on these estimates could not be determined. Brown TT, Qaqish RB. Bone 2006

Meta-analysis: Bone loss and ARV
ART-treated compared with non-treated had odds ratio of 2.5 for reduced BMD, 2.4 for osteoporosis AIDS Nov 14;20(17): Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. Brown TT, Qaqish RB. Abstract INTRODUCTION: Prevalence estimates of osteopenia and osteoporosis (reduced bone mineral density; BMD) in HIV-infected patients and the role of antiretroviral therapy (ART) varies in the literature. METHODS: We conducted a meta-analytical review of cross-sectional studies published in English to determine the pooled odds ratios (OR) of reduced BMD and osteoporosis in the following groups: HIV-positive versus HIV-negative; ART-treated versus ART-naive; protease inhibitor (PI)-treated versus PI-untreated. We searched the MEDLINE, PubMed, and EMBASE databases for eligible references between January 1966 and November Random effects models were used to generate pooled OR estimates and confidence intervals. RESULTS: Of 37 articles identified, 20 met the inclusion criteria. Of the 884 HIV-infected patients, 67% had reduced BMD, of whom 15% had osteoporosis, yielding a pooled OR of 6.4 and 3.7, respectively, compared with HIV-uninfected controls (n = 654) using 11 studies with available data. Compared with ART-naive patients (n = 202, 10 studies), ART-treated individuals (n = 824) had a 2.5-fold increased odds of prevalent reduced BMD. The risk of prevalent osteoporosis (seven studies) was similarly elevated in ART-treated individuals. Compared with non-PI-treated HIV patients (n = 410, 14 studies), PI-treated patients (n = 791) had increased odds of reduced BMD and osteoporosis (12 studies). Few studies adjusted for important covariates such as HIV disease severity or treatment duration. CONCLUSION: The prevalence of osteoporosis in HIV-infected individuals is more than three times greater compared with HIV-uninfected controls. ART-exposed and PI-exposed individuals had a higher prevalence of reduced BMD and osteoporosis compared with their respective controls. The influence of other disease and treatment variables on these estimates could not be determined. AIDS Jul 31;23(12): Continuous antiretroviral therapy decreases bone mineral density. Grund B, Peng G, Gibert CL, Hoy JF, Isaksson RL, Shlay JC, Martinez E, Reiss P, Visnegarwala F, Carr AD; INSIGHT SMART Body Composition Substudy Group. Collaborators (61)Acosta EA, Arduino RC, Riso-Patron JD, Machado C, Okhuysen PC, Rodriguez-Barradas MC, Insignares MT, White AC, Antoniskis D, Beers D, Gilbert D, Godbey J, Johnson G, Korthuis T, Leggett J, McVeigh M, Mueller M, O'Hearn M, Sampson J, Anderson J, Barnes K, Cain A, Cooper D, Eu B, French M, Hoy J, Medland N, Moore R, Price S, Roth N, Sarangapany J, Smith D, Tee BK, Caras S, Contreras R, Corser J, Johnson L, Raghavan S, Seedhom HM, Larrousse M, Vidal S, Brennan R, Bruzzese V, Chiang A, Childress C, Clark C, Dodson P, Genther K, Higginson R, Kaatz J, McKee J, Nixon D, Settle J, Watson V, Zeh J, Vecino I, Weis SE, Adams SL, Pabolvich S Sr, Scott CZ, Walker JY. OBJECTIVES: To assess the effects of antiretroviral therapy (ART) on bone mineral density (BMD) DESIGN: Randomized comparison of continuous ART (viral suppression group; VS) with intermittent ART (drug conservation group; DC) SETTING: Outpatient clinics in the United States, Australia, and Spain. PARTICIPANTS: Participants in the Strategies for Management of Antiretroviral Therapy (SMART) Body Composition substudy. MAIN OUTCOME MEASURES: Annual hip and spine BMD by dual-energy radiographic absorptiometry (DXA) and spine BMD by quantitative computed tomography (qCT). METHODS: Comparisons were by intention-to-treat analysis, using longitudinal models for change in BMD. Risk factors for BMD loss were evaluated. RESULTS: The 214 participants (median 44 years, 19% female participants, 73% on ART; median T-scores -0.5 total hip, -0.7 spine DXA, -0.9 spine qCT; 98 randomized to VS and 116 to DC) were followed for a mean 2.4 years. With continuous ART, BMD declined per year by 0.8% (hip), 0.4% (spine DXA), and 2.4% (spine qCT). BMD declined significantly less with intermittent ART. Estimated DC minus VS group differences in mean BMD change through follow-up were 1.4% [hip; 95% confidence interval (CI) ; P = 0.002], 1.3% (spine DXA; 95% CI , P = 0.03), and 3.0% (spine qCT; 95% CI , P = 0.007). No consistent drug-specific association with BMD decline was found. In the parent study, 10 of 2753 participants in the VS group and two of 2720 in the DC group reported serious fractures (hazard ratio 4.9; 95% CI ; P = 0.04). CONCLUSION: Continuous ART is associated with decline in BMD and possibly more fractures relative to intermittent, CD4 cell count-guided ART. Conde D, Silva, E, Amaral W, et al. HIV, reproductive aging, and health implications in women: a literature review. Menopause. 2009;16 (1): Brown TT, Qaqish RB. Bone 2006

Increased fractures in HIV+ women
Fracture prevalence in women /100 persons Healthcare registry study: 8,525 HIV-infected patients 2,208,792 non HIV-infected patients Overall comparison p=0.002 HIV+ HIV- 30-39 40-49 50-59 60-69 70-79 Years 7 6 5 4 3 2 1 J Clin Endocrinol Metab Sep;93(9): Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system. Triant VA, Brown TT, Lee H, Grinspoon SK. Abstract CONTEXT: Reduced bone mineral density has been demonstrated among HIV-infected patients, but fracture prevalence is unknown. OBJECTIVE: The objective of the study was to compare fracture prevalence in HIV-infected and non-HIV-infected patients. DESIGN: This was a population-based study. SETTING: The study was conducted at a large U.S. health care system. PATIENTS: A total of 8525 HIV-infected and 2,208,792 non-HIV-infected patients with at least one inpatient or outpatient encounter between October 1, 1996, and March 21, 2008, was compared. MAIN OUTCOME MEASURE: Fracture prevalence using specific International Classification of Diseases, Ninth Revision, Clinical Modification fracture codes was measured. RESULTS: The overall fracture prevalence was 2.87 vs patients with fractures per 100 persons in HIV-infected, compared with non-HIV-infected patients (P < ). Among females, the overall fracture prevalence was 2.49 vs per 100 persons in HIV-infected vs. non-HIV-infected patients (P = 0.002). HIV-infected females had a higher prevalence of vertebral (0.81 vs. 0.45; P = 0.01) and wrist (1.31 vs. 0.83; P = 0.01) fractures per 100 persons, compared with non-HIV-infected females but had a similar prevalence of hip fractures (0.47 vs. 0.56; P = 0.53). Among males, the fracture prevalence per 100 persons was higher in HIV-infected vs. non-HIV-infected patients for any fracture (3.08 vs. 1.83; P < ), vertebral fractures (1.03 vs. 0.49; P < ), hip fractures (0.79 vs. 0.45; P = 0.001), and wrist fractures (1.46 vs. 0.99; P = 0.001). Fracture prevalence was higher relative to non-HIV-infected patients among African-American and Caucasian females and Caucasian males. CONCLUSIONS: Fracture prevalence is increased in HIV-infected compared with non-HIV-infected patients. Triant VA, Brown TT et al. J Clin Endocrinol Metab 2008 82

Managing bone disease Consider: Traditional risk factors
Exclude vitamin D deficiency FRAX scoring DEXA every 2–5 years Bisphosphonates Consultation with endocrinologist or rheumatologist FRAX calculation tool available at McComsey GA, et al. Clin Infect Dis 2010;51:937–46

Cancer is a leading cause of death worldwide and accounted for 7
Cancer is a leading cause of death worldwide and accounted for 7.4 million deaths (or around 13% of all deaths) in 20041 The most frequent types of cancer among women worldwide (in order of the number of global deaths) are breast, lung, stomach, colorectal and cervical1 More than 70% of all cancer deaths occurred in low and middle income countries. Deaths from cancer worldwide are projected to continue rising, with an estimated 12 million deaths in 20301 In the general population, breast cancer is the most common cancer among women, excluding non-melanoma skin cancers. About 1.3 million women will be diagnosed with breast cancer annually worldwide and about 465,000 will die from the disease 2 In general, breast cancer rates have risen about 30% in the past 25 years in western countries, due in part to increased screening which detects the cancer in earlier stages. However, breast cancer death rates have been dropping steadily since 1990, because of earlier detection and better treatments 2 The lifetime probability of developing breast cancer in developed countries is about 4.8%, (the probability is about 13% for any type of cancer). In developing countries, the lifetime probability of developing breast cancer is about 1.8%2 References American Cancer Society. Global Cancer Facts & Figures 2007 Cancer

Increased risk for cancer among women living with HIV
Ratio of observed to expected cancer casesa AIDS-defining cancers Kaposi's sarcoma 178.49 Non-Hodgkins Lymphoma 48.97 Invasive cervical cancer 9.20 Non-AIDS-defining cancers Cancer of the lung 7.95 Oesophagus 7.69 Multiple myeloma 7.37 Oral cavity and pharynx 6.55 Hodgkin’s disease 5.65 Leukaemias 4.52 Rectal/anal cancers 3.23 Among AIDS-defining cancers, women living with HIV/AIDS are at an increased risk for Kaposi's sarcoma, lymphomas, and invasive cervical cancer,1 although the inclusion of cervical cancer in this list is controversial2 One study of women with HIV/AIDS in the US showed that the standardised incidence ratio (SIR; ratio of observed to expected cancer cases) of these cancers was for Kaposi's sarcoma, for non-Hodgkin's lymphoma, and 9.20 for invasive cervical cancer3 The overall SIR for all non-AIDS-defining cancers in the same study was 2.20, with elevated rates found for cancers of the lung (7.95), oesophagus (7.69), multiple myeloma (7.37), oral cavity and pharynx (6.55), Hodgkin's disease (5.65), leukaemias (4.52), and rectal/anal cancers (3.23) References Centers for Disease Control and Prevention. Bower M et al. J Clin Oncol 2006;24(16): Fordyce EJ et al. AIDS Public Policy J 2000;15(3-4):95-104 aStandardised incidence ratio (SIR) Fordyce EJ et al (2000) AIDS Public Policy

Cardiovascular disease
In 2005, roughly half of the 17.2 million victims of heart disease and stroke, the world's biggest cause of mortality, were women1 Heart disease and stroke kill more women each year than cancer, tuberculosis, HIV/AIDS and malaria combined2 Women are more likely than men to be under-diagnosed and under-treated3,4 As life expectancy continues to increase and economies become more industrialised, the burden of CVD on women and the global economy will continue to increase5 References World Health Organization. Preventing chronic diseases: A vital investment. Geneva, 2005 World Health Organization. World health report 2004: Changing history. Geneva, 2004 Willingham SA et al. Heart 2005;91(2): Doyle F et al. Euro J Cardiovasc Prev Rehabil 2005;12(4): Di Cecco R et al. BMC Fam Pract 2002;3(8):Epub Cardiovascular disease

Cardiovascular disease among women living with HIV
Women living with HIV may be at increased risk of CVD Several other major factors increase risk of CVD Increasing age Male gender (a women's risk increases after menopause) Heredity (Including race) Factors that can NOT be changed Smoking Blood pressure and cholesterol Physical activity Obesity and overweight Diabetes Factors that CAN be changed or controlled by treatment or lifestyle modification Women living with HIV may be at increased risk of CVD1-3 HIV infection, as an inflammatory condition, confers its own CVD risk Furthermore, ART contributes to an increase in CVD risk4 Several other factors may increase the risk of CVD including traditional risk factors such as family history, smoking and hypertension5 Among patients with HIV, traditional risk factors for CVD such as age and smoking play a similar role in increasing the risk of CVD as they do in non-infected individuals Comparing 403 HIV-subjects without CVD with 96 age- and gender-matched HIV-negative control subjects, the average 10-year risk for acute coronary events was 7.0 and 6.3%, respectively (P=0.32) The 10-year estimated risk for cardiovascular mortality was 1.23 and 0.83%, respectively (P=0.01) The main contributor to the increased CVD risk was the high proportion of smokers among the HIV subjects6 References Mangili A et al. Clin Infect Dis 2006;43(11): Santoro N et al. Maturitas 2009;64: French A et al. J Acquir Immune Defic Syndr 2009;51: Filardi PP et al. Cardiovasc Haematol Disord Drug Targets 2008;8: Lavy AR et al. Lipids Health Dis 2005;4:4 De Socio GV et al. Scand J Infect Dis 2007;39(9):

Increased risk of myocardial infraction in women with HIV
Large data registry 3,851 HIV-infected patients 1,044,589 non HIV-infected patients HIV+ HIV- Triant VA et al. J Clin Endocrinol Metab. 2007; 92:2506–12

Cardiovascular disease risk and exposure to ART
Incidence of myocardial infarction (MI) has been shown to increase with longer exposure to combination ART DAD Study: incidence of MI in HIV+ compared to patients not exposed to ART Exposure (yr) None <1 1-2 2-3 3-4 >4 8 7 6 5 4 3 2 1 Incidence per 1000 Person-Yr In a prospective observational study, 23,468 patients from 11 previously established cohorts were enrolled from December 1999 to April 2001, with follow-up data collected until February 2002 Over a period of 36,199 person years, 126 patients had a myocardial infarction The incidence of myocardial infarction increased with longer exposure to combination ART (adjusted relative rate per year of exposure, 1.26 [95% CI, 1.12‒1.41]; P<0.001). References The DAD Study Group. N Engl J Med 2003;349: P<0.001 for trend The DAD Study Group (2003) N Engl J Med

SMART: Higher CVD incidence with interruption versus continuous HAART
CD4-guided drug conservation strategy was associated with significantly greater disease progression or death, compared with continuous viral suppression RR 2.5 (95% CI: 1.8‒3.6; P<0.001) Parameter No. of patients with events RR (95% CI) 1.5 1.4 2.5 Severe complications 114 CVD, liver, or renal deaths 31 Risk of complications Nonfatal CVD events 63 Nonfatal hepatic events 14 Nonfatal renal events 7 0.1 1.0 10.0 El-Sadr W, et al. CROI Abstract 106 LB.

Neurocognitive Disorders, Depression and Anxiety

Cognitive function and women with HIV
Patients with HIV appear to be at higher risk of age related cognitive decline, mild cognitive impairment or dementia1 A small number of studies have reported a significantly higher prevalence of neurocognitive impairment among women with HIV compared to HIV controls, regardless of symptom status and with or without AIDS diagnosis2 In a small study of matched HIV+ men (n=45) and women (n=30), the women performed significantly worse than men on measures of motor skill and probabilistic learning3 More gender-specific data in the HIV+ population is required 1. Fan M, et al. Menopause Int 2008;14:163–8; 2. Maki PM, et al. Neuropsychol Rev 2009;19:204–14 3. Martin E, et al. J Clin Exp Neuropsychol2011;33:112–20

Cranium study 35.5% female positive screen for anxiety and 17.9% depressive symptoms Depressive symptoms were significantly more common when compared with male HIV-infected patients however this difference seen only in ART naïve population (20.8 vs 10.6%) Prevalence of depressive symptoms in women in the study is 2x as in the general population in Europe Van Wyk 2nd International Workshop on HIV & Women Jan 2012

HIV and depression Most common psychiatric disorder in HIV+ patients
2‒3x more common than general population Potential consequences Decreased adherence Decreased quality of life Increased likelihood of ART discontinuation Substance abuse

Depression and anxiety in women with HIV
Depression and anxiety are common among women with HIV1 Rates of depression in people living with HIV and AIDS are 5‒10 times greater than the general population Older people with HIV may have lower depressive symptoms and use of mental health services compared to younger people, possibly due to greater support While some studies have shown that depression and anxiety can decrease with age,1 depression and anxiety are common among women living with HIV1 Rates of depression in people living with HIV and AIDS are 5–10 times greater than the general population2 ARTs that affect the mood can make these conditions worse The rate of major depressive disorder has been shown to be as much as four times higher in women living with HIV versus HIV-negative women, with the former group also exhibiting higher depressive and anxiety symptoms3 One study, however, noted lower depressive symptomology and use of mental health services in patients with HIV aged 55 years or over compared with patients aged 54 years or under, which was linked to higher subjective support in the older age group4 References Streiner DL et al. Can J Psychiatry 2006;51(3): Pence BW. J Antimicrob Chemother 2009;63(4): Morrison MF et al. Am J Psychiatry 2002;159(5): Mavandadi S et al. J Acquir Immune Defic Syndr 2009;51(1):91-98 Streiner DL et al. Can J Psychiatry 2006;51(3):

Peer support Including peer support within clinical care may provide significant advantages for women Information provided by peers is seen as particularly credible and influential Benefits include increased feelings of empowerment, being better informed and enhanced self esteem van Uden-Kraan, N. Online Peer Support for patients with Somatic Diseases

What's needed? Diagnosis Access Evidence Resources Who, where and when
Health care, social care, peer support Evidence Guidelines, audit, research Resources Human, structural, political, financial

Proportion of women presenting late in Europe
Data from different years, and resources. Definition of late presentation is heterogenous1‒5 In France and Italy, the definition of late presentation was AIDS or CD4 < 200 cells/µL at enrollment In Spain the definition of late presentation was AIDS < 1 month after diagnosis In the UK the definition of late presentation was CD4 < 200 cells/µL within 3 months of diagnosis In Germany the definition of late presentation was 2 months or less between diagnosis and start of HAART and CD4< 100 cells/mm3 and/or AIDS-defining disease. 1. HPA. HIV in the United Kingdom: 2008 Report. 2. Lanoy et al. Antiviral Therapy 2007;12: Girardi et al. JAIDS 2004;36: Castilla et al. AIDS 2002;16: van Lunzen et al. IAS 2009, abstract MOPEB061. 1. Health Protection Agency. HIV in the UK: 2010 Report. 2. Lanoy et al. Antiviral Therapy 2007;12: Girardi et al. JAIDS 2004;36: Castilla et al. AIDS 2002;16: van Lunzen et al. IAS 2009, abstract MOPEB061.

Management of HIV Infection in Women

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Management of HIV Infection in Women

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Presentation on theme: "Management of HIV Infection in Women"— Presentation transcript:

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