HORMONAL CONTRACEPTIVES IN WOMEN TREATED WITH ANTIRETROVIRAL THERAPIES Kavita Nanda, MD, MHS 3rd International Workshop on HIV & Women

January 14, 2013

Background

• ~16 million women HIV-infected worldwide • Most in southern Africa • ~ 3 million women in sub-Saharan Africa are

receiving ART • most of reproductive age

Hormonal contraceptive and HIV prevalence

Source: UN World Contraceptive Use, 2011

Adult HIV Prevalence

5% — <10.0%

10% — <20.0%

1% — <5.0%

20% — 28.0%

0% — 0.9%

Hormonal Contraceptive Prevalence

10 — 20% 20 — 35%

> 35%

<10%

Sources: UNAIDS, 2011

Diet

Pharmacokinetics

Time

Conc

entr

atio

n

Adapted from Back

Liver-Cytochrome P 450 System

• Involved in metabolism of many drugs • Many different enzymes • Main one for contraceptive metabolism is CYP 3A4

– also active in intestine

Liver-Cytochrome P 450 System

• Substrate: metabolized by enzyme

• Inhibitor: inhibits metabolism of substrate

• Inducer: induces metabolism of substrate – may be delayed

Liver-Other enzymes

• Phase 2 reactions – conjugation – glucuronidation – Sulfation, methylation, etc.

• Multiple different enzymes – uridine diphosphate glucuronyl transferase (UGT)

causes glucuronidation – relevant to both COC and ARV metabolism

P-glycoprotein

• Transporter; controls drug uptake, distribution and elimination

• Inhibiting or inducing its activity can lead to alterations in drug exposure

• Substrates for CYP3A4 may be substrates for P-glycoprotein • Drugs that inhibit or induce CYP3A4 may affect P-glycoprotein • P-gp may modulate expression of CYP3A4 • Difficult to determine by which specific mechanism drug

interactions occur

Bailey D G , Dresser G K CMAJ 2004;170:1531-1532

Metabolism by CYP3A4 and/or transport by P-glycoprotein (P-gp) in enterocytes of the small intestine and then hepatocytes of the liver

Contraceptive metabolism

• Combined methods contain ethinyl estradiol (EE) and a progestin

• After contraceptives taken orally, absorbed from intestinal lumen into mesenteric capillaries

• May be subject to conjugation/hydroxylation in gut • Liver hydroxylation of EE catalyzed by hepatic

enzymes CYP3A4 and CYP2C9, and glucuronidation by UGT

Contraceptive metabolism

• EE pK varies within and between individuals – variability can even exceed differences between

low dose and high- dose COCs • Contraceptive progestins also have large inter- and

intrasubject variability • Contraceptive threshold difficult to define • COCs with as low as 15 mcg EE are effective

Contraceptive effects on other drugs

• EE has been shown in vitro to inhibit certain CYP enzymes

• EE may also increase glucuronidation of drugs by inducing UGT enzymes

• Different progestins have varying effects on liver enzymes

• Not clear whether contraceptive hormones are substrates of transporters or if they can affect transporter affinity for other drugs

Antiretroviral Therapies

• Non-nucleoside reverse transcriptase inhibitors (NNRTIs) – e.g. nevirapine, efavirenz

• Nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs) – e.g. zidovudine, tenofovir

• Protease inhibitors (PIs) – e.g. ritonavir

• Fusion/entry/integrase inhibitors • Many antiretrovirals (ARVs) metabolized by CYP3A4

ARV Metabolism

• NRTIs generally do not affect hepatic enzymes and have limited drug interactions

• NNRTIs – Efavirenz: can induce or inhibit CYP3A4 (most often acts as

an inducer and can also induce others) – Nevirapine is an inducer of CYP3A4 – Etravirine is a substrate and inducer of CYP3A4, and can

inhibit 2C9 and 2C19 – Some NNRTIs also substrates for P-glycoprotein

ARV Metabolism

• PIs – ritonavir is potent inhibitor of CYP3A4, other isoenzymes – ritonavir can induce CYP1A2 – saquinavir is least potent inhibitor of CYP3A4 – atazanavir, fos-amprenavir, nelfinavir, indinavir are

moderate inhibitors of CYP3A4 – tipranavir induces CYP3A4 – some PIs also substrates for P-glycoprotein

• Fusion inhibitors and integrase inhibitors not

metabolized by these systems

Drug Interactions

• Pharmacokinetic interactions – action of one drug on the

absorption, metabolism, binding, or excretion of another

• Pharmacodynamic interactions: direct interactions of combined drugs at site of activity – additive toxicity – synergistic activity – antagonistic activity

Pharmacokinetic interactions between ARVs and hormonal contraceptives

• EE levels breakthrough bleeding, efficacy

• Progestin levels efficacy

• EE levels toxicity

• ARV levels resistance, disease progression

• ARV levels toxicity

Potential pharmacodynamic interactions

• COC+ARV cardiovascular risks

• DMPA+ARV bone demineralization

Key Questions

• Are hormonal contraceptives effective and safe in

women taking ARVs?

• Are ARVs effective and safe in women taking various hormonal contraceptives?

Available data

• Very few published peer-reviewed studies • Information included from:

– package inserts – meeting abstracts – FDA website – manufacturer clinical trials registries

COCs

COCs

• Studies small, non-randomized, open-label, and many evaluate only single dose of COC

• Much data not published, unable to evaluate study quality

• No adequately powered studies designed to evaluate contraceptive effectiveness

ARV and HC effectiveness

• Retrospective chart review • 2053 women enrolled in US ARV clinic • 11 women apparently conceived while using

hormonal contraceptive (DMPA=1 or COCs=10) • 86(4.2%) of the 2053 women given COCs • Women on nelfinavir more likely to experience COC

failure • No failures with ritonavir

Clark 2004

ARVs and HC effectiveness

• Evaluation of pregnancy incidence in MTCT-Plus Initiative, 7 African countries

• 90% received NVP based ART • 39% of women (n = 1,755) reported contraceptive use at baseline:

– barrier (17%), injectable (15%), OCs(4%), IUD (1%) • 589 incident pregnancies in 4,531 women (7.8/100 PY)

– pregnancy rate higher in women receiving ART (9.0/100 PY) compared to women not on ART (6.5/100 PY) (HR 1.74; 95% CI, 1.19–2.54).

– non-barrier contraceptive use associated with reduced incidence of pregnancy; driven by injectables

• Injectable pregnancy rates 1.10 before ART and 1.97 after ART • OC pregnancy rates 3.11 before ART and 5.38 after ART • May reflect discontinuation/nonadherence of OCs or drug

interactions

Myer 2012

HC and ARV effectiveness

• Women’s Interagency HIV Study • 77 hormonal contraceptive users matched with 77 nonusers • All women beginning ARVs

– 79% protease inhibitor and no NNRTIs – no difference in regimens between hormonal

contraceptive users and nonusers • No significant differences in CD4+ and HIV viral load by

hormone use after ARV initiation • Time-dependent hormonal contraceptive use not associated

with changes in CD4+ or undetectable viral load after HAART initiation.

Chu 2005

HC and ARV effectiveness

• Prospective data from REACH cohort • Compared response to ART in adolescent females using

hormonal contraception (HC, type not specified) to the response among those not using hormonal contraception VL and CD4+ T cell counts every 3 months

• VL of ART users decreased over time in both HC users and non-users

• Decrease slightly lower (1.2×10−3, 95%CI: 6.2×10−5–2.4×10−3 copies/ml log VL per day, p-value = 0.03) among HC users

• Did not look at progression or treatment failure

Johnson 2011

Pharmacokinetic Data

COCs + NNRTIs

ARV EE PK Progestin PK COC effectiveness/ toxicity ARV PK

ARV effectiveness/ toxicity

Nevirapine ↓20%* ↓29%* ↔

↓19%* NET ↓18%* NET ↑29% LNG

0/18 ovulations 0/9 ovulations

↔ ↑17%

Efavirenz

↑37% * ↓10%

↓64% NGM

0/28 ovulations 3/16 ovulations

↔ ↓22%; in 3/16 EFV <1.0 mg/l, (therapeutic threshold)

1 SAE: suicide attempt post- treatment in pt. with hx of depression

Etravirine ↑22% ↔ NET 0/30 ovulations ↑** Possible ↑ rash**

Rilpivirine ↑14% ↓11% NET 0/18 ovulations ↔** No SAEs

*single dose of COC ** compared with historical controls

COCs + Boosted PIs

ARV EE PK Progestin PK

COC effectiveness/ toxicity ARV PK

ARV effectiveness/ toxicity

Ritonavir ↓41% *

Darunavir/r ↓ 44% ↓ 14% ↔ darunavir ritonavir

Fosamprenavir/r ↓37% ↓34% NET ↔ amprenavir

↑ ritonavir ↑ LFTs

Lopinavir/r ↓42% ↓55%*

* ↓17% NET

Atazanavir/r ↓19% ↑85% NGM ↑20% atazanavir No SAEs

Tipranavir/r ↓50% ↑ skin, musc AEs

* single dose of 50 mcg EE COC **single dose of 35 mcg EE COC

COCs + non-boosted PIs

ARV EE PK Progestin PK

COC effectiveness/ toxicity ARV PK

ARV effectiveness/ toxicity

Nelfinavir ↓47% ↓18% NET

Saquinavir ↔

Amprenavir ↔ ↑18% NET ↓ 22%

Atazanavir ↑48% ↑110% NET

Indinavir ↑24% ↑26% NET

COCs + Other ARVs

ARV EE PK Progestin PK

COC effectiveness/ toxicity ARV PK

ARV effectiveness/ toxicity

Tenofovir ↔ ↔ NGM ↔

Zidovudine ↔ No change in viral load or CD4+

Raltegravir ↔ ↑ 14% NGM No serious AEs

Maraviroc ↔ ↔ LNG ↔ No serious AEs

Quad (elvitegravir +cobicistat + FTC +TDF)

↓25% ↑ 100% NGM 0/15 ovulations ↔ More nausea and headache with combined treatment

Dolutegravir ↔ ↔ NGM ↔

DMPA

ACTG 5093

• HIV+ women on ARVs containing nelfinavir, efavirenz or nevirapine vs. controls

• No difference in DMPA levels between groups

• Nevirapine AUC slightly higher after DMPA

• No changes in efavirenz, nelfinavir levels

• No ovulations • No grade 3 or 4 related AEs

Cohn. Clin Pharm Ther. 2007

FHI study

• HIV+ women in Brazil • ARV containing

Combivir+efavirenz vs. controls

• No difference in DMPA levels between groups

• 1 ovulation in control group at 12 weeks

• No serious AEs

Nanda. Fert Ster. in press

ARV and HC effectiveness

• 740 adults (74% women) beginning efavirenz ARV regimen

• All women participating agreed to use contraception, with CPR 80% at 6 months – 65% injectable progestin; 35% COCs

• 7 pregnancies – incidence=2.6/100 person-years

• Unclear if women using contraception at time they conceived

Danel 2005

COC/DMPA effects on Zidovudine

• Zidovudine pharmacokinetics in 18 men and 20 women treated with zidovudine

• Repeat zidovudine levels following 2 months of starting contraceptive therapy – 8 women started COCs and 6 DMPA

• No change in zidovudine levels after contraceptive use

• Contraceptives did not affect plasma or cervical HIV viral load

Aweeka. AIDS 2006

DMPA and ARV effectiveness

• 418 female Ugandan ARV initiators • 12% of women using injectable contraceptives at ARV

initiation • Composite virologic failure (failure to achieve virologic

suppression, switch to second line therapy, or death within 12 months) at 12 months similar among women using and not using injectable contraceptives at ARV initiation

• Adherence to ARVs increased with time since initiation, and did not differ between injectable contraceptive users and non-users.

Polis 2012

Other methods

Contraceptive patch and ARVs

• Prospective non-randomized trial • 8 women on LPV/r; 24 controls • All received contraceptive patch • EE AUC ↓45% with LPV/r • NGMN AUC ↑83% • LPV/r AUC ↓19% (NS) • 0/32 ovulations • No SAEs; 1 grade-3 AE (generalized aches and pains)

possibly related to treatment in LPV/r arm

Vogler et al. 2010

ECPs and ARV

• Prospective, single-arm, equivalence study • 21 healthy women, treated with:

– LNG 0.75 mg – EFV 600 mg qd for 14 days, followed by another dose of LNG

0.75mg • With EFV, LNG AUC ↓56% • No grade 3 or 4 related AEs

Carten et al, 2012

LNG-IUS and ARVs

• Prospective study of 12 HIV-infected women; – 10/12 on ARVs – LNG levels in same range as in healthy historical controls – LNG levels similar in 10 women using ARVs and 2 without ARVs – 0 pregnancies – Among women using ARVs, 10% of lavage specimens with detectable HIV RNA

before and after LNG-IUS • Retrospective review of 6 HIV-positive women with LNG-IUS.

– 2 on ARVs, and 4 not on ARVs. – No pregnancies or AEs

• Case-control study of 15 HIV-positive women using LNG-IUS and 25 HIV-positive women not using LNG-IUS – 73% LNG-IUS users and 76% controls on ARVs at end of followup – no pregnancies and no differences in CD4 or HIV viral load

Heikinheimo et al, Lehtovirta et al, Heikinheimo et al d. 2006; 21

ENG Implant and ARVs

• 6 case reports of women becoming pregnant while using Implanon and EFV based ART concurrently, including 3 ectopic pregnancies (2 in same woman) – most after 2 years

• Only cohort study: – Implanon inserted in 79 HIV-infected women with comorbidities

and a history of poor adherence to other contraceptive methods – followed up every 6 months for 3 years – at insertion, 47 (59.5%) women receiving ARVs, increased to 56

(71%) by end of study – 0 pregnancies – 2 women died: 1 of AIDS and 1 of cardiac arrest

(cardiomyopathy at baseline); both deaths considered unrelated to Implanon

Kreitchmann 2012

LNG Implant and ARV effectiveness

• 60 women using ARVs who wanted to use a levonorgestrel contraceptive implant

• 36 women on ARVs not using hormonal contraception recruited as controls

• Implant users and controls had similar age, baseline CD4, and marital status

• Higher proportion of implant users had high parity • CD4 counts over time similar for women in the implant group and

women in control group – CD4 counts for both groups rose slightly over time

• No participants died • 6 participants (2 implant users and 4 controls) diagnosed with

opportunistic infections. • 0 pregnancies

Liku 2011

Summary

DMPA

• DMPA effectiveness likely not affected by ARVs and vice versa

• No clinical outcomes studies • Combined toxicity long-term not evaluated

– bone demineralization • Grace period not studied

COCs

• Small suboptimal studies suggest pharmacokinetics of single dose COCs may be altered by some single ARVs – both decreases or increases in EE and progestin seen – ARVs used in combination; ARVs themselves interact

• Most data unpublished, cannot evaluate study quality or generalizability

• Few data on ARV levels • Limited data on clinical outcomes • No long-term data

WHO/CDC MEC Guidelines

CONDITION COC/POP/ patch/ring

Combined injectable

DMPA NET-EN

LNG/ENG Implants

I = Initiation, C = Continuation

ANTIRETROVIRAL THERAPY

a) NRTIs

1 1 DMPA=1 NET-EN=1

1

b) NNRTIS

2* 2* DMPA=1 NET-EN=2*

2*

C) BOOSTED PIS 3* 3* DMPA=1 NET-EN=2*

2*

*…if a woman on antiretroviral treatment decides to initiate or continue hormonal contraceptive use, consistent use of condoms recommended for both preventing HIV transmission and to compensate for any possible reduction in effectiveness of the hormonal contraceptive. When a COC is chosen, a minimum of 30 μg EE should be used.

HHS Guidelines

• Data limited; clinical implications of findings unclear • Magnitudes of change in drug levels that may reduce contraceptive

efficacy or increase adverse effects unknown • Concerns about pharmacokinetic interactions between hormonal

contraceptives and ARVs should not prevent clinicians from prescribing hormonal contraceptives for women on ART

• When women wish to use hormonal contraceptives and drug interactions with ARVs are known, additional or alternative contraceptive methods may be recommended

• Condoms recommended to prevent transmission of HIV and protect against other STIS

Summary of Issues

• PK studies can be used to make some recommendations; linking evidence from PK studies to clinical effect is difficult

• What level of increased (or decreased) concentration is important?

• Contraceptive threshold difficult to determine for many methods

• Women with HIV on long-term therapy – often taking ARVs and other drugs that may interact

with hormonal contraception

Conclusion

• Adequately powered studies of clinical outcomes to make evidence-based recommendations for COCs+ARVs are needed – in the absence of data, interactions that lead to

changes in levels <30% probably ok • DMPA maintains adequate contraceptive protection

with concomitant ARV use • More data needed regarding concomitant use of

ARVs and LARC methods (IUDs, implants) • Given high effectiveness, LARC methods or DMPA

should be first-line if drug interactions are the main concern