Cobicistat as a Pharmacoenhancer in Pregnancy and Postpartum: Progress to Date and Next Steps

Combination antiretroviral therapy with fixed-dose drug combinations (FDCs) that allow for once-daily, single-tablet regimens for the management of HIV infection, are now available. Many of these FDCs include cobicistat, a pharmacoenhancer that inhibits cytochrome P450 (CYP) metabolism of protease and integrase inhibitors, enhancing and prolonging their plasma concentrations. Pregnant women were excluded from the drug development programs for these FDCs. Only recently, years after these products were first approved for use in nonpregnant adults, data from postmarketing studies has come forward, describing the pharmacokinetics of these products in pregnancy. These studies have demonstrated that cobicistat is not an effective pharmacoenhancer in pregnancy, and the US Food and Drug Administration (FDA) has recently revised labeling for these products to recommend that they should not be used in pregnancy.¹

Cobicistat (Tybost) was developed as an alternative antiretroviral pharmacoenhancer to ritonavir. Ritonavir is a potent inhibitor of the CYP enzymes CYP3A4, CYP2D6, CYP2C19, CYP2C8, and CYP2C9, as well as a known inducer of CYP1A2, CYP2B6, and uridine 5′-diphospho-glucuronosyltransferase.² Ritonavir also inhibits P-glycoprotein, breast cancer resistance protein, organic anion transporters and multidrug and toxin extrusion cellular transport mechanisms in the liver, gastrointestinal tract, and kidneys.² Ritonavir has poor water solubility and tolerability, making coformulation difficult. Cobicistat is a potent inhibitor of CYP3A4 and a weak inhibitor of CYP2D6, organic anion transporting polypeptides (OATP1B1, OATP1B3), and P-glycoprotein.² Cobicistat is well tolerated and easily coformulated with other antiretrovirals, and a 150-mg once-daily dose of cobicistat has a pharmacokinetic (PK) boosting effect comparable with ritonavir 100 mg once daily.

The FDA approval of cobicistat was primarily based on 2 PK studies, along with clinical efficacy data from phase III trials of atazanavir/cobicistat³ and darunavir coadministered with ritonavir. Cobicistat was granted FDA approval in August 2012 as part of a coformulation that also includes elvitegravir, tenofovir, and emtricitabine for use as initial therapy for adults with HIV-1 infection.^4,5 However, on June 27, 2012, Gilead submitted the New Drug Application to the FDA for cobicistat as a free-standing agent with either atazanavir or darunavir. The New Drug Application for the safety and efficacy of cobicistat was supported by 48-week data from a crucial phase III study (Study 114) in which cobicistat met its primary objective of noninferiority to ritonavir when both agents were administered with a background regimen of atazanavir sulfate plus Truvada (emtricitabine and tenofovir disoproxil fumarate).³ In Study 114, 692 participants were randomized in a one-to-one ratio to receive either atazanavir 300 mg plus cobicistat 150 mg once daily or atazanavir 300 mg plus ritonavir 100 mg once daily. All subjects received simultaneous treatment with 300 mg of tenofovir diphosphate fumarate and 200 mg of emtricitabine once daily administered as single tablet (Truvada). Randomization was stratified by screening HIV-1 RNA level (≤100,000 copies/mL or >100,000 copies/mL).³ The results show that cobicistat was noninferior to ritonavir at week 48. Both regimens achieved high rates of virologic success, and safety and tolerability profiles of the 2 regimens were comparable.³ The New Drug Application was also supported by PK data demonstrating that cobicistat boosts serum levels of atazanavir and darunavir similar to ritonavir.^6-8

On April 29, 2013, Gilead announced that it had received Complete Response Letters from the FDA (dated April 26, 2013) for its new drug application for cobicistat for use as part of HIV treatment regimens. The FDA stated that it could not approve the application in its current form at the time due to deficiencies in documentation and validation of certain quality testing procedures and methods. In April 2014, the FDA accepted Gilead’s refiling (refiled to the FDA on March 28, 2014) for cobicistat, and approved cobicistat for use as a free-standing agent in combination with either atazanavir or darunavir for treatment of HIV-1 infections, with subsequent FDA approval on September 24, 2014.⁹ In 2015, fixed-dose combinations of cobicistat plus atazanavir and cobicistat plus darunavir were approved. However, pregnant women were excluded from these drug approval processes for cobicistat.

Cobicistat has been approved as a single-agent product and as a component of FDCs. It is available coformulated with the integrase inhibitor elvitegravir in 2 fixed-dose combinations, as elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (Stribild) and elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate (Genvoya). Cobicistat is coformulated with the protease inhibitors darunavir as darunavir/cobicistat/emtricitabine/tenofovir alafenamide (Symtuza) and darunavir/cobicistat (Prezcobix), and atazanavir as atazanavir/cobicistat (Evotaz). Despite the approval of these FDCs by the FDA in 2012 (Stribild), 2015 (Genvoya, Prezcobix, and Evotaz) and 2018 (Symtuza), pregnant women were excluded from the drug development programs for all of these drugs. Their original FDA labels (with the exception of Symtuza) include the instruction to “use during pregnancy only if the potential benefit justifies the potential risk.”

Excluding women in drug trials has a historical and ethical context. Significant efforts by the National Institutes of Health in the early 1990s led to a significant increase in the percentage of women participating in research trials.¹⁰ As a result, a great amount of pertinent information was obtained describing diseases and their treatment as they relate to women—information that was previously unavailable. Although significant changes in research methodology and practice have caused an increase in the number of women included in drug trials, knowledge gaps still remain because of a continued lack of including pregnant women in premarketing clinical drug trials.^11,12 There are 2 major reasons for the lag in the inclusion of pregnant women in clinical trials: designating pregnant women as a “vulnerable” population and the perceived legal risk if the fetus or mother has an adverse outcome.¹¹

Recently completed postmarketing studies have shown that use of these FDCs in pregnancy results in very low plasma concentrations of cobicistat and of darunavir or elvitegravir.^13,14 Data from the darunavir/cobicistat arm of TMC114HIV3015, a phase IIIb PK trial of antiretrovirals during pregnancy, demonstrated that compared with postpartum, the mean area under the curve during the second and third trimesters was 56% and 50% lower for darunavir and 63% and 49% lower for cobicistat, respectively.¹³ The IMPAACT network P1026s cohort studies show similar reductions in plasma exposures with elvitegravir/cobicistat and darunavir/cobicistat in pregnancy.¹⁴ As a result, the FDA revised its labeling of these products to say that they should not be initiated during pregnancy and that an alternative regimen should be recommended for individuals who become pregnant during therapy with these FDCs.¹ While no data are available describing drug exposures with the use of atazanavir/cobicistat in pregnancy, it is likely that drug exposures of both drugs will also be low in pregnancy, and the label for the atazanavir/cobicistat combination (Evotaz) has been similarly modified.¹

The FDA label changes do not address all the complex issues confronting care providers of women living with HIV who become pregnant while receiving one of these cobicistat FDCs. Discontinuation or alteration of antiretroviral therapy can lead to an increase in viral load, leading to an increased risk of viral resistance, decline in immune status and breakthrough infection, disease progression, and HIV transmission to the fetus. A study of risk factors for detectable HIV viral load in 662 pregnancies demonstrated that treatment changes in pregnancy significantly increased the risk of incomplete viral suppression at the end of pregnancy.¹⁵ The 2017 US Perinatal Guidelines recommend that in cases where women are already on a well-tolerated HIV regimen that suppresses viral load to undetectable levels, they may continue on the same regimen throughout their pregnancies with more frequent virologic monitoring.¹⁶

Several of the newer FDCs include tenofovir alafenamide fumarate, a newer tenofovir prodrug. Tenofovir alafenamide fumarate was approved in 2015 for use as 25 mg unboosted, 10 mg boosted with cobicistat in FDCs and 25 mg boosted with ritonavir or cobicistat as separate products. Although these tenofovir alafenamide fumarate-containing products have been available since 2015, the first pregnancy PK and safety data for tenofovir alafenamide fumarate were presented in 2018.¹⁴ These data suggest that the tenofovir alafenamide fumarate exposures are adequate when tenofovir alafenamide fumarate 25 mg without boosting and 10 mg with cobicistat are used in pregnancy. Cobicistat boosts tenofovir alafenamide fumarate plasma exposures by inhibiting efflux transporters in gut enterocytes, enhancing bioavailability. Cobicistat boosts protease and integrase inhibitors by blocking CYP3A4 metabolism in the liver, which is dependent on plasma cobicistat concentrations that are reduced in pregnancy. This difference in mechanism likely explains the difference in effectiveness of cobicistat boosting of tenofovir alafenamide fumarate in pregnancy compared to protease inhibitors and integrase inhibitors. Since tenofovir alafenamide fumarate 10 mg with cobicistat is available only in FDCs with either darunavir or elvitegravir, the ability of cobicistat to effectively boost tenofovir alafenamide fumarate 10 mg during pregnancy is not of clinical significance, as use of these FDCs in pregnancy is not recommended due their low exposures of darunavir or elvitegravir.

One approach to overcoming the failure of cobicistat to effectively boost darunavir and elvitegravir in pregnancy would be to add a stand-alone cobicistat dose (Tybost) to the cobicistat-containing FDCs. While cobicistat exposure is markedly reduced during pregnancy, higher-than-standard doses (ie, 150 mg) have never been studied in pregnant women. Although cobicistat may increase serum creatinine levels (possibly via inhibition of proximal renal tubular cell transporters) and thus reduce estimated glomerular filtration rate, it does not appear to significantly affect actual glomerular filtration rate. A recently published phase IIIb multicenter trial on the safety of cobicistat-containing regimens in HIV-1–infected patients with end-stage renal disease on dialysis demonstrated that at 48 weeks, switching to the single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide was well tolerated.¹⁷ The authors concluded that this regimen might provide a tolerable and convenient option for ongoing treatment of HIV-1 infection in adults with end-stage renal disease on chronic hemodialysis. Cobicistat was generally well tolerated in the initial drug approval studies (including postmarketing studies in pregnant women), with a tolerability profile similar to that of ritonavir.^3-5,14 While there are no studies to support increased doses of cobicistat in pregnancy, it is likely to be well tolerated during pregnancy due to the physiologic changes in pregnancy that alter the absorption, distribution, metabolism, and excretion of drugs, notably increased renal plasma flow, increased glomerular filtration rate, and increased creatinine clearance. However, it is unknown whether increased dosing during pregnancy will result in increased plasma cobicistat exposure and pharmacoenhancement of CYP3A4-metabolized antiretrovirals. The potential of cobicistat to decrease renal function should be considered when interpreting changes in estimated creatinine clearance in pregnant patients initiating combination therapies of cobicistat with tenofovir or atazanavir.⁹

While the recent changes to the labels for cobicistat-containing FDCs are welcome, they have come 3 to 6 years after these products were first approved for use in adults in the United States. This gap between initial licensure of a drug and availability of essential pregnancy-specific PK and safety data is a chronic failure of standard drug development programs. Acquisition of pregnancy data is not required for licensure for most new drugs, and drug development programs in the United States generally exclude pregnant women. As a result, these cobicistat-containing FDCs, which provide potent, convenient, and well-tolerated alternatives to previous therapies in nonpregnant adults, were widely prescribed to pregnant women living with HIV for 3 to 6 years before data became available in pregnancy.

We need to identify strategies to address knowledge and research gaps regarding drug use during pregnancy, including the historical and ethical issues surrounding the inclusion of pregnant women in drug trials. Strategies to initiate pregnancy-specific drug trials at an earlier stage in drug development would involve an increase in the amount of adaptive drug trials during pregnancy. Two such adaptive trial approaches include the “staggered” and “embedded” trial strategies, as described by Baylis.¹⁸ With the staggered adaptive clinical drug trial strategy, pregnant mothers and their fetuses would not be exposed to any drugs that were unsuccessful in phase I and II drug trials, while with the embedding adaptive clinical drug trial strategy it would be feasible for pregnant mothers to enroll in bigger randomized clinical drug trials involving nonpregnant adults but with increased safety monitoring.

Another strategy would be to be to accrue data in pregnant women during the conduct of a clinical trial.^19,20 For example, in the setting of a phase II or III clinical trial where a new medication is being compared to a current standard of care, collecting efficacy and safety data may be beneficial.¹⁹ The inclusion of pregnant women in a phase III doubleblind safety and efficacy study of long-acting injectable cabotegravir compared to a combination of daily oral tenofovir disoproxil fumarate 300 mg plus emtricitabine 200 mg as part of the HIV Prevention Trials Network (HPTN-084) is a good example.²¹ This trial was originally designed for nonpregnant women, but recently included women who got pregnant while on either cabotegravir or tenofovir disoproxil fumarate 300 mg plus emtricitabine 200 mg when used for preexposure prophylaxis.²¹ In other situations, there may be maternal and fetal benefits from involvement in clinical trials. For example, pregnant women may need access to experimental therapies in the setting of a clinical trial if there are no other approved treatment options available. In this situation, the drug treatment is offered only through a clinical trial that enrolls pregnant women based on ethical principles and clinical need. The Pediatric AIDS Clinical Trials Group 076²² is an excellent example. The rise of the AIDS epidemic in the 1980s and the critical need to curb mother-to-child transmission of HIV compelled researchers to include pregnant women in HIV/AIDS clinical trials. One of the only few drugs available at that time—zidovudine, a nucleoside reverse transcriptase inhibitor—had been approved for use in adults, but concerns existed that in-utero exposure could harm the fetus. Despite these reservations, the HIV community advocated for a study design beginning in pregnancy to decrease the risk of vertical HIV transmission. This resulted in the Pediatric AIDS Clinical Trials Group 076, a National Institute of Allergy and Infectious Diseases–sponsored trial from 1990 to 1994, which turned out to be one of the initial successful trials in HIV-infected pregnant women based on ethical principles and clinical need.²²

Encouraging the use of mechanistic modeling (eg, physiologically based pharmacokinetic modeling [PBPK] in pregnancy) or quantitative systems pharmacology modeling initiatives to better understand the gestation-specific changes in the physiology of pregnant women and its impact on drug development is important. PBPK models integrate the knowledge of changes in various elements related to pharmacokinetics and consider the gestational time-dependent parameters to optimize the design and conduct of PK studies in pregnant women. To promote the use of PBPK modeling of HIV drugs during pregnancy, the FDA; Center for Drug Evaluation and Research; Office of New Drugs; Office of Drug Evaluation III; and the University of California, San Diego recently encouraged PBPK modeling in HIV pharmacology in pregnancy through the Oak Ridge Institute for Science and Education Fellowship,²³ with the goal of leveraging the unique and extensive PK database generated in pregnant women with HIV treated with various medications to improve our understanding of the PK changes and safety issues associated with pregnancy.²³ This PK database generated over the years from HIV-infected pregnant women on antiretrovirals will be used to develop a PBPK model applied to pregnancy in pregnant women living with HIV. The results will allow for optimization in the design and conduct of PK studies in pregnant women treated with antiretroviral drugs (eg, more precise selection of periods of gestation to be studied, more informed decisions about necessary sample sizes and initial doses to study in pregnant women). The progress made so far in using PBPK models during pregnancy rely on establishing databases on the system-related (biological, anatomic, and physiological) and drug-related (physiochemical, affinity to enzymes and transporters) parameters in pregnant women.^24,25

To address ethical risks, reclassifying pregnant women from being a vulnerable population to being a scientifically complex population as suggested by the 2010 workshop by the National Institutes of Health Office of Research on Women’s Health will help this ethical debate.¹¹ One of the reasons that pregnant women have been systematically excluded from research is their perceived status as vulnerable. However, pregnant women are scientifically complex, including physiologic and ethical complexity. This ethical complexity stems out of the need to balance the maternal and fetal risks versus benefits during pregnancy. Maternal and fetal interests usually align, as appropriate care of the woman is necessary for the health of the fetus, but these interests may diverge in the setting of clinical drug trials, especially research that is not focused on concerns of pregnancy or fetal health. It is also worthy to note that there has been a renewed government interest in increasing drug trials during pregnancy through the Task Force on Research Specific to Pregnant and Lactating Women, established as part of the 21st Century Cures Act.²⁶

This experience with cobicistat demonstrates that as long as pregnant women are excluded from drug development programs prior to licensure, they will receive potentially inadequate treatment for years until postmarketing pregnancy PK and safety data become available. Continued emphasis on recruitment of pregnant women into clinical trials must be encouraged. The potential for pregnancy should not automatically exclude a woman from participating in a clinical drug trial.