Providing Care for HIV-Infected Women

Amneris E. Luque, MDSMH AIDS Center Medical

Director

AIDS Incidence* for Women and Percentage of AIDS Cases:

US, January 1986-June 1999

*Adjusted for reporting delay.

Percen

t of A

ll Cases

Cas

es o

f A

IDS

in

Wo

men

1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999

Half-Year of Diagnosis*

0

2000

4000

6000

8000

0

5

10

15

25

30

20

AIDS Cases and Rates inAdult/Adolescent US Women:

by Race/Ethnicity, 1999

*Includes 21 women of unknown race/ethnicity.

Rate perRace/Ethnicity N (%) 100,000

White, not Hispanic 1924 (18) 2

Black, not Hispanic 6784 (63) 49

Hispanic 1948 (18) 15

Asian/Pacific Islander 63 (1) 1

American Indian/ Alaska Native 40 (<1) 5

Total* 10,780 (100) 9.3

AIDS in US Women:Rate per 100,000, by State, 1999

US rate: 9.3N=10,780

10+

5 9.9_<5

Rate per 100,000

<5 cases*

3.0

2.12.5

1.9

1.61.7

1.2

3.6

1.3

2.0

2.0

2.7

2.1

1.81.2

2.5

2.10.9

3.4

9.1

11.0

5.9

30.0

15.0

13.4

23.2

6.3

6.7

7.4

5.51.8

9.2

7.4

0.9 1.54.7

4.6

5.2

1.6PR 21.3 VI 30.1

14.8

21.0

1.2

7.213.019.614.1

93.4

MANH

RICTNJDEMDDC

**

*

*

HIV in Women

• Initially acquired through IVDU

• 1991-Heterosexual contact with IVDU or bisexual partner

• 1995- Heterosexual partner not in a high risk group

Risk Factors for Increased Heterosexual Transmission of HIV

• Presence of ANY other STD in HIV negative partner

• Anatomic factors

• Sexual practices

Risk Factors for Increased Heterosexual Transmission of HIV

• HIV disease stage in HIV+ partner

• Certain HIV clades

• Use of hormonal contraceptives

HIV in Women

• Disease characteristics

• Impact of pregnancy on HIV disease

• Impact of HIV disease on fetal outcome

Demographics of HIV-infected Women in US

• Age 15-44 years

• Majority are from racial/ethnic minority groups

• 64% live in households with incomes < 10K/year • 23% live alone, 2% live in facilities 1% are

homeless

Access to Health Care in HIV-infected Women

• Several studies have shown that women are less likely to receive ARV and to be admitted for AIDS related conditions than men

• Family and child care obligations may preclude

access to care

• HCW less familiar with HIV disease in women

Is HIV Different in Women?

• The Viral load debate– Early in infection lower viral loads than

men at similar CD4 counts

– Survival and disease progression appear to be similar to men

– Further studies are needed

Initial Manifestations of HIV infection in Women

• The most common is recurrent candida vaginitis (37%)

• Generalized lymphadenopathy (15%)

• Bacterial pneumonia (13%)

Other Gynecological Infections

• PID tends to be more severe

• HSV infections are common

• Bacterial vaginosis more frequent than in HIV-

• Syphilis

Menstrual Abnormalities

• Amenorrhea– Lower CD4 count– Low serum albumin– Heroin use

• Other menstrual irregularities– Not clearly different from HIV-– Report of menorrhagia in 4 women on

RIT

Toxicity of ARV in Women

• Women more likely to experience nausea and perioral paresthesias with RIT

• More abdominal pain with NFV

• Higher incidence of rash with DLV

Toxicity of ARV in Women

• Higher incidence of hepatotoxicity with NVP

• Different patterns of fat redistribution with ARVT

– More frequent increase in abdominal girth

– More frequent increase in breast size

Toxicity of ARV in Women

• Steatosis and death with use of stavudine plus didanosine during pregnancy.

Interactions Between ARV and Ethinyl Estradiol

ARV Effect on EE Recommendation

Nevirapine EE AUC 19% Do not use

Efavirenz EE AUC 37% Usual doses

Indinavir No interaction Usual doses

Nelfinavir Levels EE Do not use

Amprenavir No interaction Usual doses

Ritonavir Levels EE Do not use

AIDS-defining illnesses in women

• Similar spectrum than in men

• Two exceptions:

– Kaposi’s sarcoma– Cervical cancer

Cervical Cancer in HIV-infected Women

• More aggressive disease

• 40-60% more likely to have

relapses

HPV in HIV-Infected Women Study

Amneris E. Luque, Lisa M. Demeter, Heng Li and Richard C. Reichman

Study DesignStudy Design

• HIV-infected women obtaining their care at the University of Rochester’s AIDS Center.

• Longitudinal study of HPV infection in HIV-infected women.

• 204 non-pregnant women with documented HIV infection gave informed consent

Study Design

• Subjects who were menstruating at the time of the study visit or had a history of hysterectomy were excluded (n=16)

• All participating subjects underwent :– Standardized history and physical

examination – Gynecological questionnaire– Pelvic examination

Study DesignStudy Design

– Pelvic examination:

• PAP Smear: Cervex-Brush®

• Cervical cultures for N. gonorrheae and C. trachomatis

• Cervical sampling for wet mount preparation.

• Cervical sampling for HPV DNA.

Virological StudiesVirological Studies• HIV-1 RNA Roche’s Amplicor® Assay

• HPV DNA DIGENE® Hybrid Capture Assay

• Low risk HPV: (LR HPV): HPV 6, 11, 42, 43, 44• High risk HPV: (HR HPV): HPV 16, 18, 31, 33,

35, 45, 51, 52, 57

• HPV Serology: ELISA, using VLP

Results-Cross Sectional Study

• HIV-1 RNA levels > 10,000 are associated with presence of oncogenic HPV and abnormal Pap smears

Luque AE, Demeter LM and Reichman RC. JID 179:1405-9, 1999

Results-Cross Sectional Study

• Abnormal Pap smears were associated with HIV-1 RNA > 10,000 copies/ml P = 0.0016

• Oncogenic HPV was strongly associated with abnormalities in Pap smear

P = < 0.001

Luque AE, Demeter LM and Reichman RC. JID 179:1405-9, 1999

HPV inn HIV-infected Women

• Pap smear results (n=191)– 123 (64%) normal– 31 (16%) ASCUS– 25 (13%) LGSIL– 7 (4%) HGSIL– 3 (2%) dysplasia nos

HPV in HIV-infected Women

• ARVT– At baseline:

• 104 (51%) were on ARV• 37 (18%) were on 2 NRTI• 61 (30%) were on 2 NRTI + PI• 6 (3%) were on 2NRTI + NNRTI

Pap Smears and Cervical HPV DNA Results in 108 Women at Enrollment and F/U Visits According to

ARVTInitial Visit ARVT No ARVT Follow-up Visit ARVT No ARVT Median CD4count(cells/ml) 357 422 429 270MedianHIV-1 RNA(copies/ml) 1,056 11,968 572 33,667Normal Papsmear 50 (69%) 22 (31%) 58 (76%)* 18 (24%)AbnormalPap smear 18 (51%) 17 (49%) 16 (53%) 14 (47%)HPV DNA - 42 (63%) 25 (37%) 46 (77%)** 14 (23%)HPV DNA + 24 (62%) 15 (38%) 16 (50%) 16 (50%)

Pap Smear Results at F/U Visit,According to ART in 34 Women With Abnormal Pap Smears at Enrollment

87%87%

53%53%

13%13%

47%47%

0

20

40

60

80

100

Normal Abnormal

ARTNo ART

P<.03

Luque. 8th CROI; 2001; Chicago. Abstract 724.

HPV DNA in Cervical Samples at F/U Visit, According to ART, in 53 Women With

HPV DNA– at Enrollment

22%22%

80%80%78%78%

20%20%

0

20

40

60

80

HPV DNA+ HPV DNA–

ARTNo ART

P<.01

Luque. 8th CROI; 2001; Chicago. Abstract 724.

Conclusions

• In this study women receiving ARVT were more likely to have a normal Pap smear than women not receiving ARVT

• Among women who had an abnormal Pap smear at enrollment, those on no ARV were more likely to continue to have an abnormal Pap smear at the F/U visit than those on ARV P = 0.03, OR: 0.17, 95% CI: 0.03-0.97

Conclusions

• Women receiving ARVT were less likely to have HPV DNA detected on their cervical samples at the first F/U visit than women not receiving ARV. P = <0.01, OR: 0.07, 95% CI; 0.013-0.416

• These differences remained significant after adjusting for HIV-1 plasma level and CD4 counts

Influence of Pregnancy on HIV Infection

• 32 women (SHCS) compared to 416 controls

• Recurrent bacterial pneumonia only AIDS

defining illness that was SS

• Inconsistent acceleration of disease progression

Weisser M, Rudin C, et al. J Acqu Imm Def Hum Ret 1998;17:404-410

Vertical transmission

• Intrauterine

• Peripartum

• Postpartum

Vertical Transmission

• Intrauterine

– HIV in fetal organs (PCR)

– HIV detected as early as 10th weeks gestation

– Placental infection

– Corioamnionitis

Vertical Transmission

• Peripartum

– HIV in cervico-vaginal secretions

– Discordant infections in twins

– Less genetic diversity in viral strains of the newborn compared to maternal strains

Vertical Transmission

• Intrauterine

• Peripartum

• Postpartum– Breast milk

Risk Factors in Vertical Transmission

• High maternal plasma and genital tract virus load

• Advanced maternal clinical HIV-1 disease stage

• Reduced maternal immunocompetence

Risk Factors in Vertical Transmission

• Vaginal delivery

• Lengthy interval between rupture of amniotic membrane and delivery

• Prematurity and low birth weight

Prevention of Vertical Transmission

ACTG 076

• ZDV 500 mg/day starting at week 14-34

• ZDV during labor 2mg/Kg over one hour followed by ZDV 1mg/Kg until delivery

• ZDV to the newborn 2 mg/Kg q 6 h for 6 weeks starting 8-12 h after birth

DHHS Recommendations

• To inform the results of ACTG 076 to all HCW and all HIV + patients

• To inform HIV + patients that the risk of transmission is reduced but not eliminated

• Caution not to use ZDV before week 14 of pregnancy

ZDV during Pregnancy

• ZDV crosses the placenta

• ZDV is well tolerated by the newborn

• Macrocytic anemia most common adverse effect

Abbreviated ZDV Prophylaxis and Perinatal Transmission

121-32.763 (26.6)237 (25)No ZDV

0.69 (0.35-1.36)

7.7-34.37 (18.4038 (4)>3d after birth

0.35 (0.19-0.65)

4.1-17.58 (9.3)86 (9.2)Within 48 h after birth

0.38 (0.18-0.81)

3.3-21.85 (10)50(5.3)Intra-partum

0.23 (0.16-0.34)

4.1-8.926 (6)423(45)Prenatal

95% CIN (%)

Relative Risk

Positive PCRNo. of Infants

Time of ZDV

Wade N, Birkhead G et al NEJM 1998: 339-1409-14

Recommendations

• Offer ZDV intrapartum to HIV+ women who did not take prenatal ZDV

• Initiate testing for identification of HIV+ women during labor-48h after delivery using rapid testing to implement prophylaxis

Study ARV Dosage HIV-1 TR

Antepartum Intrapartum Postpartum

US PACTG 076

1994

ZDV 100 x 5d @ week 14-36

ZDV 2 mg /Kg x1, 1mg/kg/hr till delivery

ZDV 2 mg/kg po q 6h x 6 w

ZDV 8.3% P 25%( 67.5%)

Thailand 1999

ZDV 300 mg BID@week 36

ZDV 300 mg @ OL, q 3h till delivery

None ZDV 9.2% P 18.6%( 51%)

Ivory Coast 1999

ZDV 300 mg BID@ week 36

ZDV 300 mg BID @ OL, q3h till delivery

None ZDV 15.7% P 25%( 37%) BF

Uganda 1999

None ZDV 600 mg @ OL, 300 mg q3h till del. orNVP 200 mg @ OL

ZDV 4 mg/Kg BID x 7d or NVP 2 g/Kg

ZDV 25% NVP 13%

( 47%NVP)

Vertical Transmission HIVNET-012

• 311 women in Uganda received single dose NVP (200 mg PO) at onset of labor

• Infants received NVP within 72h

• Compared to ZDV • NVP 47% more effective than ZDV in decreasing

Vertical transmission

Guay LA, Musoke P, Fleming T et al Lancet 199;354:795-802

Vertical TransmissionHIVNET-012

• NVP resistance mutation in

– 19% of women @ 6-8 weeks

– 46% of infants

• K103 most common mutation in women and Y181C most common in infants

Eshelman S, et al Abstract 516. 8th CROI Feb 4-8, 2001. Chicago

Role of NVP in Preventing Vertical Transmission in US

• PACTG 316– Randomized, multicenter phase 3 trial– NVP 200 mg during labor + 2 mg/kg x1 to

the newborn in the first 72 h c/t placebo– Most patients were receiving other ARV

• 41% were on 3 ARV with PI• 28% were on ZDV + 3TC• 21-24% on ZDV only• 2% only received NVP

Role of NVP in Preventing Vertical Transmission in US

PACTG 316-Conclusions

• HIV transmission rate was low (1.5%)

• Prenatal ARV were effective (50% had undetectable VL)

Dorenbaum A, et al Abstract LB7. 8th CROI Feb 4-8, 2001.. Chicago

Vertical TransmissionPACTG 316

– Addition of NVP to standard US regimen does not influence transmission rates

• ZDV 23%

• ZDV + 3TC 28%

• PI containing regimen 41%

Dorenbaum A, et al Abstract LB7. 8th CROI Feb 4-8, 2001.. Chicago

Risk Factors for HIV Transmission Through BF

• Younger maternal age• Lower parity• Seroconversion during lactation• Duration of breastfeeding• Clinical and subclinical mastitis, breast

abscess

Correlates of Early vs Late Infant HIV Infection

• Early infection (< 2m of age)– Genital ulcers– CD4 < 200– Prematurity– Breast Feeding– Bleeding nipples– Viral load ( plasma and genital)

John GC et al. JID 2001: 183: 206-12

Correlates of Early vs Late Infant HIV Infection

• Late infection ( > 2m of age)– Maternal plasma HIV RNA ( > 43K)– Mastitis– Breast abscess

John GC et al. JID 2001: 183: 206-12

The Role of C-Section in Preventing Vertical

Transmission• 15 prospective studies (5 European and 1 US)• Restricted to 8533 mother-child pairs

– Known indication for C-section– Known HIV status in children

• 4675 pairs did not receive ZDV• Logistic regression model in 7840 pairs

showed that elective C section associated to lower risk of transmission

The International Perinatal HIV group.NEJM 1999: 340:977-87

Recommendations

• Address access to care

• Assess gynecological issues as in non HIV infected women

• Screen and treat cervical dysplasia and other STDs

Recommendations

• Screen and treat for depression and drug use

• Screen for domestic violence • Be aware that ARV may have different

toxicity profile in women

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