This month, we feature a case from the Substance Use Warmline, our new clinician-to-clinician telephone consultation service focusing on substance use evaluation and management for primary care clinicians. This case, Opioid Use and HIV Management During Pregnancy, was authored by Joanna Eveland, MS, MD, with contributions from Lealah Pollock, MD, James Gasper, PharmD, and Cristina Gruta, PharmD.

Case Summary
A primary care physician called the CCC Substance Use Warmline regarding management of a 30 year-old HIV-positive pregnant woman at 10 weeks of gestation who is on maintenance opioid agonist therapy with sublingual buprenorphine/naloxone for treatment of opioid use disorder. The patient is G1 P0, otherwise healthy and not on other medications. She was diagnosed with HIV during this pregnancy on routine prenatal screening. She is antiretroviral (ARV) treatment-naïve with a CD4 count of 400 cells/mm3 and an HIV viral load of 2000 copies/ml. Her baseline HIV genotype shows pan-sensitive virus. She feels well, with no morning sickness.

The caller’s questions for the CCC consultant were:
1. What is the best management of this patient’s opioid use disorder during this pregnancy?
2. What is the best management of this patient’s HIV infection during this pregnancy?
3. Are there any drug-drug interactions to be concerned about between buprenorphine and ARVs?

CCC Consultant Response
Management of Opioid Use Disorder During Pregnancy
Maintenance opioid agonist therapy has been used successfully in pregnant women for over four decades. Opioid agonist therapy during pregnancy improves both maternal and fetal outcomes and promotes engagement in care. Untreated opioid use disorder during pregnancy is associated with fetal growth restriction, placental abruption, preterm labor, stillbirth and spontaneous abortion. These effects are thought to be due to the cumulative effects of opioid withdrawal both on placental function and directly on the fetus. Other treatment strategies, such as withdrawal management, abstinence and opioid antagonist therapy are not recommended during pregnancy as they increase fetal risk.

While the standard of care has historically been methadone maintenance therapy, increasing evidence supports office-based buprenorphine as a safe and effective alternative. In 2012, the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study found similar clinical outcomes for pregnant women treated with methadone and buprenorphine. Infants born to women who used buprenorphine required fewer hospital treatment days and lower doses of morphine for neonatal abstinence syndrome than women who received methadone. However, women who received buprenorphine were more likely to drop out of the study. It has been hypothesized that this higher dropout rate was due to a treatment protocol utilizing relatively low doses of buprenorphine.

With physiologic changes during the second and third trimester, methadone doses often need to be increased and patients may need twice daily dosing due to a shortening of the half-life of the drug. While usually less affected, patients on buprenorphine should also be evaluated for increased craving and split doses should be considered.

In this case, we recommended that the patient should continue on office-based opioid agonist therapy, but should be transitioned from the buprenorphine/naloxone co-formulation to the buprenorphine mono-product. This recommendation is based on limited safety data for the opioid antagonist naloxone and a theoretical risk of precipitated withdrawal with this drug.

Management of HIV infection During Pregnancy
As with treatment of this patient’s opioid use disorder, treatment of HIV during pregnancy will improve both maternal and fetal health. Expansion of perinatal ARV treatment for HIV+ pregnant women has proved to be a public health victory, with risk of mother-to-child HIV transmission declining from greater than 25% without treatment to less than 1% if the mother is virally suppressed.

As earlier viral suppression is associated with a lower risk of transmission, we recommended that this patient start ARV therapy immediately. As treatment recommendations are updated frequently, providers should review the DHHS Perinatal HIV Guidelines before beginning ARVs to confirm which regimens are preferred versus alternative. In this case, we recommended tenofovir/emtricitabine with ritonavir-boosted atazanavir.

Although abacavir/lamivudine could be considered instead of the tenofovir/emtricitabine nucleoside reverse transcriptase inhibitor (NRTI) “backbone”, a negative HLA-B*5701 result must first be confirmed before abacavir initiation. Zidovudine/lamivudine is another option instead of tenofovir/emtricitabine, but it requires twice daily dosing and has increased potential for toxicity.

As the third drug in the combination, we chose the HIV protease inhibitor (PI) ritonavir-boosted atazanavir as it has the advantages of good safety data in pregnancy, once daily dosing, and a high barrier to development of ARV resistance. Many experts recommend increasing atazanavir dosing from 300 to 400 mg/day in the second and third trimesters to ensure adequate drug levels. Other preferred agents that could be given instead of boosted atazanavir include: 1) twice-daily boosted darunavir, 2) twice-daily raltegravir (an integrase inhibitor), or 3) once-daily efavirenz (a non-nucleoside reverse transcriptase inhibitor). Efavirenz should be initiated only after 8 weeks of gestation due to concern for potential neural tube defects (seen in animal, not human studies). An advantage of efavirenz is that it is available as a single-tablet, once-daily regimen co-formulated with tenofovir/emtricitabine.

After starting ARV therapy, HIV viral load should be monitored monthly until RNA levels are undetectable, and then at least every 3 months during pregnancy. HIV RNA levels should be assessed at approximately 34 to 36 weeks’ gestation to inform decisions about mode of delivery. Finally, early communication with the labor and delivery team and/or infant’s care provider should be attempted in order to optimally coordinate intrapartum and postpartum care for the mother and her exposed infant.

Drug Interactions Between ARVs and Buprenorphine
Opioid agonist therapy has the added benefit for this patient of improving HIV treatment outcomes and engagement in care. However, there are important drug-drug interactions to consider between ARVs and buprenorphine.

There are case reports of patients on ritonavir-boosted atazanavir who experienced symptoms of opioid excess with initiation of buprenorphine. The potential mechanism may be CYP3A4 inhibition by PIs leading to increased levels of buprenorphine and its metabolites. Similar elevations in levels of the buprenorphine metabolite norbuprenorphine have been observed with darunavir. However, dose adjustment does not appear to be required for co-administration with lopinavir/ritonavir.

This patient may require a reduction in her buprenorphine dosing after starting atazanavir/ritonavir and should be closely monitored for evidence of over-sedation. Alternatively, instead of boosted atazanavir, she could take either an efavirenz or raltegravir-based regimen. Although no dose adjustments are recommended when co-administering efavirenz and buprenorphine, there is a noted 50% decline in AUC of buprenorphine and 70% decrease of norbuprenorphine. As such, it’s recommended that clinicians monitor for signs of opioid withdrawal with this combination.

There are no significant interactions with buprenorphine when co-administered with integrase inhibitors such as raltegravir. Buprenorphine does not appear to impact ARV drug levels. Interactions between methadone and ARVs are significantly more complicated, and another reason to continue this patient on buprenorphine rather than transitioning to methadone.

Conclusion
Pharmacotherapy for both opioid use disorder and HIV infection is an evidence-based strategy for improving health outcomes for HIV-positive women during pregnancy.

References:
1. Center for Substance Abuse Treatment. Medication-assisted treatment for opioid addiction during pregnancy. SAHMSA/CSAT treatment improvement protocols. Rockville (MD): Substance Abuse and Mental Health Services Administration; 2008.
2. ACOG Committee Opinion No. 524: Opioid abuse, dependence, and addiction in pregnancy. Obstet Gynecol 2012 May;119(5):1070-6,
3. ASAM National Practice Guideline for the Use of Medications in the Treatment of Opioid Use Disorder, 2015
4. DHHS Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States, 2015
5. Antiretroviral Interactions with Narcotics. Table Prepared by: Michelle Foisy, Pharm.D., Northern Alberta Program, Edmonton, Alberta. Updated by Michelle Foisy, Pharm.D., Alice Tseng, Pharm.D., Toronto General Hospital. September 2014

Because CCC consultations are based on information provided by the caller or clinician accessing the online consultation center, without the benefit of a direct evaluation or examination of the patient, consultations are intended to be used as a guide. They do not constitute medical advice and are not to serve as a substitute for medical judgment. This Case of the Month includes consultation based on the most up-to-date evidence at the time of its publication. To learn about current recommendations, please call one of our clinical consultation lines.