CONCLUSION

• Serum NET AUC 0 to 72 hours is significantly increased among HIV+ women taking PI therapy as compared to controls.

• In vivo PI therapy in conjunction with POP inhibits NET metabolism with significantly increased serum levels of NET

• Increased serum NET levels provide therapeutic contraceptive efficacy.• Compared to COC, POP require less restrictive screening, have wider distribution

potential and can provide an additional safe type of contraception for women with HIV.• This is the first trial to describe NET POP pharmacokinetics in HIV+ women taking PI• Data supports increased utilization of POP in HIV+ women taking PI.• This should alter current POP medical eligibility recommendations for women taking ARV.

REFERENCES

1. US Dept. Of Health. Guidance for Industry Drug Interaction Studies (2006)2. US Dept of Health, Guidelines for the Use of Antiretroviral (2011) 3. U.S. Medical Eligibility Criteria for Contraception use, 2010. CDC, MMWR. 2010; 59 (RR04): 1-85.

OBJECTIVETo Compare area under the time-concentration curve (AUC) of serum norethindrone (NET) 0

to 72 hours following oral administration of 0.35 mg NET in HIV+ women taking PI (study group) with NET AUC in women taking anti-retovirals (ARV) without protease inhibitors PI (control group).

Secondary objectives: to compare minimum plasma concentration, maximum plasma concentration, time to Cmax, and half-life of NET in both groups

BACKGROUND HIV+ women are a high-risk population in need of safe and effective contraception. ARV agents are used to treat HIV. ARV regimens often contain PI. PIs alter hepatic enzyme systems including CYP 3A41

PI may alter the bioavailability of concurrently administered medications Small trials demonstrated an interaction between combined oral contraceptives (COC) and

ARV with PI2 Plasma ethinyl estradiol levels are decreasedThere have been several trials noting no significant change in NET levels

CDC categorize PI + progestin-only pills (POP) as Class 3 based on trials with COC3

Limits POP use in HIV+ womenNo published pharmacokinetic (PK) trials of POP in HIV+ women taking ARV with PI

DESIGNThis two-arm, open-label, prospective , steady state trial was conducted to characterize PK of oral NET in HIV+ women taking ARV with and without PI.Study group: women taking ARV with PIControl group: women taking ARVs, without PI. In previous COC trials the various ARVs do

not alter NET levels.

EFFECT OF PROTEASE INHIBITORS ON PHARMACOKINETICS OF ORAL NORETHINDRONE CONTRACEPTION IN HIV+ WOMEN

Jessica Atrio, Frank Stanczyk, Alice Stek, Andrea Kovacs, Laura Sech, Penina Segall-Gutierrez, Daniel Mishell

Department of Obstetrics & Gynecology, Keck School of Medicine, Los Angeles, CA

METHODS

  PI* No PI* P-value

N 16 17

Age at enrollment* (IQR) 39.9 (35.9-42.3) 38 (33.4-41.3) 0.60

Nulliparous (%) 3 (9.1) 0 (0) 0.10

Parity (IQR) 2.5 (1-4) 3.0 (2-4) 0.30

Intake CD4 (cells/mm3) (IQR) 618.5 (398.0-883.5) 669 (479-749) 0.65

Opportunistic infections** (%) 5 (31.1) 4 (23.5) 0.71

BMI *** (IQR) 26.8 (25.5-33.8) 29 (24.1-32.8) 0.90

Current smoker (%) 3 (18.8) 2 (11.8) 0.66

Table 1. Demographic Characteristics

*PI protease inhibitor **Opportunistic infections diagnosed in the past ***Body mass index = kg/ m2

21 days oral NET 0.35 mg was ingested to obtain steady state NET levels.10 serum samples were collected for 72 hours after NET ingestion to obtain PK measurements.Data are presented as medians and interquartile range (IQR) for continuous data and n (%) for categorical data. Differences between the groups were compared using Wilcoxon rank sum test for continuous data and Fisher's exact test for categorical data. Calculation of NET geometric mean ratio of AUC0-72 by trapezoidal approximation.Log-transformed control and PI group AUCs were compared with Student’s T-test.

Figure 1: Screening, enrollment and study completion

Funding for this research was awarded by the Society of Family Planning and the USC CTSI

RESULTS

Both groups were similar at baseline with regard to age, parity, ethnicity and other characteristics (Table 2). Participants took multiple medications as per the standard of care.  Other than the PI study group the other ARV medications have demonstrated no interaction in previous trials.  The study group included women taking PI therapy: atazanavir & ritonavir (N=14), atazanavir (1), darunavir & ritonavir (3), lopinavir & ritonavir (2).  The control group was taking other non-interacting medications including, etravirine, rilpivirine, tenofovir, emtricitabine and raltegravir.  4 women in the control group were on no ARV medications.

NET AUC was significantly higher among women taking PI: 37.8 ng*h/ml compared to controls: : 25.2 ng*h/mL (p=0.004). The ratio of PI to controls was 1.50 (90% CI: 1.21 – 1.86) P value = 0.004

Table 2. Pharmacokinetic Characteristics of Serum Norethindrone (NET) after Oral NET 0.35 mg Ingestion with and without Protease Inhibitor

* Study group took protease inhibitor (PI) therapy, control group took no PI**Geometric mean & geometric mean ratio***Area under curve 0 to 72 hours after oral NET ingestion

Figure 2. Violin Plot of Norethindrone Area under the Curve by Group

The width of violin area corresponds to the mass of the data. A traditional box and whisker plot is centered within each violin, where the filled circle is the median, the lower and upper bounds of the box are the 25th and 75th percentiles (i.e. the interquartile range [IQR]), the dashed “whiskers” indicate the range of the data within 1.5 IQR of the box boundaries, and the open circle is an outlier outside this range. Exclusion of this outlier did not change the results significantly (data not shown).