A Prospective Cohort Study on the effects of Hormonal Contraception on the Natural History of HIV disease among women in Nairobi and Harare

Collaborating institutions: KEMRI, UCSF, UZ, WHO

Background As of 2005, approx 18M women were HIV-

infected worldwide and 80% in sub-Saharan Africa

100M globally use hormonal contraception

Increasing HC use in HIV prevalent areas

Effective contraception, a preventive tool for unintended pregnancies and in reducing proportion of HIV-infected children

Potential Interactions between steroid hormones and HIV

Plausible mechanisms for HIV-HC interactions Direct effects Binds directly to the HIV regulatory protein and

enhances replication hence increasing viral load

Indirect effectsInfluencing both humoral and cell-mediated by either

increasing or decreasing various cytokines

Previous studies

Hunt J et al, 1998 described a direct effect on virus expression via hormone response elements within the HIV-1 promoter.

Marx et al, 1996 described an SIV macaque model and demonstrated increased infectivity with Progesterone treatment (thinning of the vaginal epithelium.

Lavreys L, et al, 2003 found that DMPA use at the time of HIV-1 acquisition and the presence of a GUD during the early phase of infection were associated with higher levels of HIV-1 replication.

Martin H et al, 1998 reported increased HIV-1 acquisition and other STI among women (CSW) using DMPA

Sagar M et al, 2003 reported an association of COC use at the time of HIV-1 infection with increased risk of acquiring multiple HIV-1 genotypes leading to higher viral set points and rapid progression

Justification Previous studies have demonstrated effects

of hormones in animal models and among high risk populations

Currently limited data exists on the effects of HC on HIV progression among women in the general population

Increasing concern among health care providers on the possibility of rapid disease progression among HIV infected women using HC methods

Overall Objective

To determine the effects of hormonal contraception on HIV-1 disease

progression among women in Nairobi and Harare

Specific Objectives

To determine the effects of COC and DMPA on the rate of CD4 decline

To determine the effects of COC and

DMPA on WHO clinical staging

To determine the effects of COC and DMPA on plasma viral load

Methods

Study Design: Prospective Cohort Study (2000-2005)

Study Sites: Nairobi, Kenya and Harare, Zimbabwe

Study Population: HIV-1 infected women aged 18-49yrs presenting to FP facilities with CD4 count >500 cells/µL and on self selected FP method (COC, DMPA, non-Hormonal contraceptive methods) for at least 3 months

Clinical and Laboratory procedures

At enrolment and every 6 month follow up visit: a medical history including social, sexual,

contraceptive and examination performed using a structured questionnaire

Hemogram, RPR, CD4 count, plasma viral load measurement

Annual pap smear test

Data Analysis A Univariate comparison of baseline characteristics was done

by COC, DMPA vs. non-HC methods. Potential confounding was controlled for all multivariate models.

Survival Analysis (univariate comparison of mean change in

CD4 counts by contraceptive method over time).

Linear Mixed Effects Models, multivariate analysis of the rate of CD4 decline by contraceptive method.

Cox Proportional Hazards Models (Multivariate analysis of factors associated with time to advanced HIV disease stages (III and IV).

Considered two scenarios: 1) Analysis of outcomes while excluding non compliant contraceptive users and 2) the intention to treat analysis, included all non-compliant subjects

Results A total of 498 women enrolled beginning

the year 2000 and followed through to 2005

Median follow up of 2 (0-4) years

Mean age of 27.45 (5.3) years

77% were married

Total number of subjects enrolled:498

Nairobi: 302 (60.6%) Harare: 196(39.4%)

Overall number analyzed by contraceptive method and site: 336 (%)

Nairobi: 217 (59.3%) Harare: 149 (40.7%)

COC: 36 (16.6%) COC=54(36.2%)

DMPA: 98 (45.2%) DMPA: 46 (30.9%)

Non-HC: 83(38.2%) Non-HC: 49(32.9%)

Total number excluded from analysis

9 (1.8%) women on Norplant

Nairobi: 7 (1.4%)

Harare: 2 (0.4%)

Overall Outcomes by Contraceptive Method

4 (1.1%) of deathsCOC:0 (0%)DMPA: 3( 75%)Non–HC:1 (25%)

27 (7.4%) with CD4 <200 cells/µL in 4 yearsCOC: 2(7.4%)DMPA: 15(55.6%)Non-HC: 10(37%)

Overall with contraceptive change for both sites127 (25.6%)

DMPA/COC to non-HC: 36 (28.3%)

Non-HC to COC/DMPA: 39 (30.7%)

Vice versa: 14 (11%)

Pregnant: 38 (29.9%)

Fig 1: Patient enrolment and follow up flow chart

Table 1: Sociodemograhic characteristics by contraceptive method among HIV-1 infected women in Nairobi and Harare

Characteristic COCN= 90 (24.7%)

DMPAN= 144 (39.2%)

Non-HCN= 132 (36.2%)

P-value

Study site:KenyaZimbabwe

36(40.0%)54(60.0%)

98(68.1%)46(31.9%)

83(62.9%)49(37.1%) 0.000

Mean age (sd) yrs 27.5 (5.31) 26.2(4.5) 29.9 (6.56) 0.000

EducationNonePrimary Secondary College

0 (0%)38(42.2%)51(56.7%)1(1.1%)

1 (0.7%)66 (46.2%)75 (52.4%)1 (0.7%)

4 (3.0%)44 (33.3%)66 (50.0%)18 (13.6%)

0.000

Marital StatusSingle (never married)Married (cohabiting)Regular partn(not cohabiting)Divorced/separated/widowed

0(0%)84(93.3%)4 (4.4%)2 (2.2%)

2 (1.4%)126 (87.5%)9 (6.3%)7 (4.9%)

12 (9.2%)66 (50.4%)21 (16.0%)32 (24.4%)

0.000

Current smoker 2 (2.2%) 3 (2.1%) 11(8.3%) 0.028

Currrent alcoholic drinks 23(25.6%) 25(17.4%) 47(35.6%) 0.003

Table 1 continued: Sexual history by contraceptive method

Characteristic COC DMPA Non-HC P-value

Mean (sd) age of sexual debut (yrs)

17.8 (2.54) 16.87(2.44) 17.7(2.94) 0.02

No of lifetime sexual partnersOne2-34-1011 and more

37 (41.1%)39 (43.3%)13 (14.4%) 1 (1.1%)

38(26.4%)69(47.9%)35(24.3%) 2(1.4%)

31(23.5%)53(40.2%)34(25.8%)14(10.6%)

0.000

Condom use with regular partner

NeverLess than halfMore than halfalways

60 (68.2%)7 (8.0%)9 (10.2%)12(13.6%)

95 (78.5%)10 (8.3%)5 (4.1%)11 (9.1%)

13 (17.6%) 3 (4.1%) 4 (5.4%) 54(73.0%)

0.000

Currently having other sexual partners

2(2.2%) 3(2.1%) 20(15.2%) 0.000

Table 1 continued: Sexual, reproductive history and Clinical parameters by contraceptive method

Characteristic COC DMPA Non-HC P-value

Ever exchanged sex for money or gifts

2(2.2%) 4(2.8%) 20(15.2%) 0.000

Lifetime number of sexual partners:

One2-34-1011 or more

37 (41.1%)39 (43.3%)13 (14.4%)1 (1.1%)

38 (26.4%)69 (47.9%)35 (24.3%)2 (1.4%)

31(23.5%)53 (40.2%)34 (25.8%)14 (10.6%)

0.000

Reproductive historyCurrently breastfeedingMedian (range) number of births

24 (26.7%) 2 (1-5)

57 (39.6%) 2 (1-6)

16 (12.2%) 2 (0-8)

0.000

CD4 count, median (range) 639 (502 -1457) 684 (505-1383) 630 (500-1689) 0.343

Baseline WHO clinical stagesWHO stage IWHO stage II

80 (88.9%)10 (11.1%)

126 (87.5%)18 (12.5%)

117(90.0%)13 (10.0%)

0.807

Table 2: Multivariate analysis of the association of contraceptive use on CD4 count decline among HIV-1 infected women in Nairobi and Harare

Characteristic Estimate (95% CI)

P-value

Study siteKenyaZimbabwe

0.015 (-0.066, 0.096)ref

0.719-

Age (mean, SD) years -0.001 (-0.008, 0.006) 0.749

Contraceptive methodCOCDMPANon-HC

-0.266 (-0.612, 0.081)-0.145 (-0.426, 0.137)ref

0.1330.313-

Baseline CD4 count 0.001 (0.000, 0.002) 0.024

WHO Disease Staging Stage IStage IIAdvanced stage

0.464 (-0.223, 1.152)0.198 (-0.511, 0.908)ref

0.1850.584-

Age of sexual debut -0.017 (-0.032, -0.003) 0.019

Table 3: Multivariate analysis of the association of contraceptive use with time to advanced WHO clinical stages among HIV-1 infected women in Nairobi and Harare

Covariate Adjusted HR (95%CI)

P-value

Study siteKenyaZimbabwe

0.30 (0.11, 0.82)ref

.018-

Age (years) 1.12 (1.03, 1.21) .006

Contraceptive methodCOCDMPANon-HC

0.91 (0.25, 3.27)0.56 (0.19, 1.64)ref

0.8830.290-

Initial CD4 count 0.994 (0.990, 0.999) 0.021

Education level

NonePrimarySecondaryPost Secondary

1.84(0.12, 27.63)0.12 (0.02, 0.88)0.32 (0.05, 1.87)ref

0.6580.0380.205-

Table 3 continued….: Multivariate analysis of the association of contraceptive use with time to advanced disease

Covariate HR (95% CI) P-valuePsychosocial characteristics

Had support from friends

Had support from other groups

Let others know of their HIV status

1.56 (0.58, 4.22)

1.57 (0.55, 4.49)

0.28 (0.10, 0.78)

0.378

0.400

0.015

Body weight 0.95 (0.91, 0.99) 0.010

Sexual and social behavior

Age of sexual debutTaking alcoholic beveragesExchanged sex for gifts

0.98 (0.81, 1.18)1.86 (0.62, 0.77)0.21 (0.06, 0.77)

0.8040.2710.019

Fig 2: Kaplan Meier Curves for survival to advanced WHO clinical stages by contraceptive method

Time in years

543210

1.1

1.0

.9

.8

.7

Method

Non-hormonal

DMPA

COC

Slopes of mean CD4 count by hormonal contraceptive method

Follow-up visit (in yrs))

4.003.503.002.502.001.501.00.50.00

100

0

-100

-200

-300

Method

Combined pills

DMPA

Non-hormonal

Mean change in CD4 count by contraceptive method

Follow-up visit (in yrs))

4.003.503.002.502.001.501.00.50.00

100

0

-100

-200

-300

Method

Combined pills

DMPA

Non-hormonal

Follow-up visit (in yrs))

4.003.503.002.502.001.501.00.50.00

Me

an

ch

an

ge

in C

D4

100

0

-100

-200

-300

Method

Kaplan Meier curves on time to WHO advanced disease stages (intent-to-treat analysis)

Time to advanced disease (yrs)

543210

1.02

1.00

.98

.96

.94

.92

.90

.88

Method

non-hormonal

dmpa

combined oral pills

Time in years

543210

1.1

1.0

.9

.8

.7

Method

Non-hormonal

DMPA

COC

Comparison of analyses of the effect of contraceptive on CD4 count decline: intent-to treat analysis vs. per exposure analysis

Intent-to-treat Analysis

Characteristic

Estimate cells/µL/yr (95%CI)

P-value

WHO clinical stages

III

Advanced stage

0.268(0.0173, 0.362)0.215(0.111,0.320)-ref

<0.001

<0.001

Per exposure Analysis

Characteristic

Estimate cells/µL(95%CI)

P-value

WHO clinical stages

III

Advanced stage

0.464(-0.223, 1.152)

0.198(-0.511, 0.908)-ref

0.185

0.584

Comparison of Multivariate analysis on the effect of HC on time to advanced WHO clinical stages: intent-to-treat vs. per exposure analysis

Intent-to-treat analysis Per exposure analysis

Characteristic

HR (95%CI) P-value

Characteristic HR (95%CI) P-value

Country

Kenya

Zimbabwe

0.69 (0.29, 1.69)

Ref

0.427

Country

Kenya

Zimbabwe

0.30 (0.11, 0.82)

Ref

0.018

Ever exchanged sex for gifts

0.310 (0.095, 1.011)

0.052 Ever exchanged sex for gifts

0.21 (0.06, 0.77) 0.019

Pending Analysis

Effects of HC on Plasma viral load Effects of COC vs. DMPA on CD4

decline

Study Limitations

Switching from one contraceptive method to another

Stringent inclusion criteria thereby missing women who were likely faster progressors

Follow up period shorter to attain study endpoints

Discussion Differences in baseline CD4 counts and time

to advanced WHO stages by country CD4 decline compared to other natural

history studies Non-HC group risky sexual and social

behavior Why findings differ from those among high

risk populations: issues of residual confounding in terms of sexual practice or STI

Discussion

Factors significantly associated with CD4 decline, faster progression to advanced WHO clinical stages:

Baseline CD4 count, age of sexual debut, age and body weight

Summary

Findings suggest that COC and DMPA have no effects on HIV-1 progression among women attending FP facilities in Nairobi and Harare

Baseline CD4 and age of sexual debut were associated with the rate of CD4 decline.

Older age and body weight were associated with faster progression to advanced WHO clinical stages

Summary

These findings will contribute to findings that HIV-1 infected women using either COC or DMPA are not at increased risk of rapid disease progression compared to their counterparts using non hormonal contraceptive methods

Acknowledgements Dr. Craig Cohen (UCSF) Dr. Tsungai Chipato (UZ) Tim Farley (WHO) Estie Hudes (CAPS, UCSF) Research teams (Kenya and Zimbabwe) Study participants Collaborating institutions (UCSF,KEMRI,

UZ) and funding orgs (WHO, CFAR)