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Interactions between highly active antiretroviral therapy and over-the-counter agents: a cautionary note
  1. Jerome Federspiel12,
  2. Melanie J Bukhari2,
  3. Matthew M Hamill34
  1. 1 Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, North Carolina, USA
  2. 2 Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
  3. 3 Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
  4. 4 Sexual Health, Berkshire Healthcare NHS Foundation Trust, Slough, UK
  1. Correspondence to Dr Jerome Federspiel; jfederspiel{at}gmail.com

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In conjunction with BMJ Case Reports, DTB will feature occasional drug-related cases that are likely to be of interest to readers. These will include cases that involve recently marketed drugs for which there is limited knowledge of adverse effects and cases that highlight unusual reactions to drugs that have been marketed for several years.

SUMMARY

Highly active antiretroviral therapy (HAART) has dramatically lowered rates of mother-to-child HIV transmission among patients with access to treatment. Barriers to complete viral suppression increase rates of transmission, even with only low levels of viral replication. Here, we present the case of a pregnant patient who developed a detectable viral load in pregnancy, thought to be related to calcium supplement consumption or emesis while using a dolutegravir-based HAART regimen. Ultimately, with adjustments, the patient again reached an undetectable viral load and had an uncomplicated perinatal and neonatal outcome. We discuss new data on the use of dolutegravir in pregnancy and precautions for maintaining viral suppression while on antiretroviral therapy in pregnancy.

Background

The advent of, and access to, highly active antiretroviral therapy (HAART) has revolutionised HIV care and restored near-normal life expectancy. The use of optimal active antiretroviral therapy (ART) can reduce mother-to-child transmission (MTCT) rate from 15%–30% to less than 0.5%.1 2 Optimal therapy requires initiation of ART prior to pregnancy, adherence throughout pregnancy, abstaining from breastfeeding and an undetectable viral load near time of delivery; even a modest elevation in viral load (50–399 copies per mL (cpm), compared with <50) is associated with a 22-fold increase in the rate of transmission.2 Here, we describe a patient who developed an elevated HIV viral load in pregnancy, thought to be related to either calcium carbonate ingestion or emesis.

Case presentation

A 35-year-old patient, gravida 8 and para 4, presented at 10 weeks gestation for prenatal care. She was diagnosed with HIV 4 years previously. Her medical history was notable for tobacco, marijuana and alcohol use; depression; treated secondary syphilis; and herpes simplex virus-2 genital infection. CD4 count at time of diagnosis was 141 cu/mm, with viral load greater than 500 000 cpm. No antiretroviral resistance was identified, and she was human leucocyte antegin-B*5701 negative. After counselling, she was initiated on ART consisting ritanovir-boosted darunavir/abacavir/lamivudine and sulfamethoxazole/trimethoprim for pneumocystis prophylaxis. Her viral load became undetectable (<20 cpm at our institution) after 9 months of therapy. She requested to change to a single-pill regimen and transitioned to abacavir/dolutegravir/lamivudine 18 months after ART initiation. Her viral load had been undetectable for longer than 2 years prior to pregnancy, and CD4 count was 869 cu/mm at approximate time of conception.

Repeat viral load testing at time of obstetrical care intake remained undetectable; CD4 count was 702 cu/mm. She had a normal fetal anatomy screen at 20 weeks gestation. Her pregnancy was notable for repair of patellar and femoral fractures following a motor vehicle accident, after which she was placed on enoxaparin for venous thromboembolism prophylaxis but was otherwise uncomplicated. Her next viral load, at 29 weeks gestation, was 67 cpm. This was repeated at 30 weeks and increased to 72 cpm. She reported perfect adherence to ART but occasional emesis after taking it. She also reported taking her ART with her prenatal vitamin and additional supplementary calcium carbonate. She was prescribed antiemetics and counselled to take ART 6 hours after her prenatal vitamins/calcium. Her next viral load obtained 6 days later was 32 cpm; within 3 weeks, her vital load was undetectable, and it remained so for the remainder of her pregnancy.

Outcome and follow-up

She was admitted at 37 weeks for induction for gestational hypertension and had a vaginal delivery of a male neonate, whose initial HIV viral load was undetectable and who received routine postpartum treatment with azidothymidine (AZT) after a brief course of AZT, lamivudine and nevirapine. Subsequent HIV testing remained negative for the newborn.

Discussion

In this report, we summarise several learning points related to the care of patients on ART in pregnancy, particularly those on dolutegravir-based therapy, and we illustrate our suggested approach to management (figure 1). ART regimens containing integrase strand transfer inhibitors, such as doutegravir, have excellent tolerability, rapid viral suppression, high resistance barrier and convenient dosing. Dolutegravir-based ART is recommended in US guidelines as the preferred initial regimen for most patients. However, enthusiasm was tempered by announcement in May 2018 of preliminary data from an observational birth surveillance study in Botswana, in which patients who became pregnant while taking dolutegravir-based ART had higher than expected rates of births affected by neural tube defects (NTD) (4/426, 0.9%) compared with the background risk of 0.1%.3 Based on these findings, US guidelines recommend avoiding initiating dolutegravir in the first trimester (up to 14 weeks gestation) or in those contemplating pregnancy (or sexually active and not using contraception). Initiation or continuation of dolutegravir in patients who present in the second trimester or later was considered reasonable.4 For patients presenting in the first trimester, guidelines recommended counselling about balancing NTD risks from continuing therapy compared with the risks of viral rebound and transmission from ART changes. Subsequently updated surveillance data continued to suggest a higher rate of NTD among dolutegravir-exposed pregnancies, although with a smaller difference in risk (3/1000 vs 1/1000) than previously reported.5 6 Based on these updated data, the US guidelines were updated and now recommend the use of dolutegravir as a preferred agent for initiation of ART in pregnancy and recommend its continuation in patients who present for care in pregnancy with well-controlled HIV infection on a dolutegravir-based regimen, regardless of gestational age. Dolutegravir is considered an alternative agent for non-pregnant patients contemplating conception, with other long-established ART regimens being the preferred preconception therapies.7

Figure 1

Suggested flow to manage art use during pregnancy. ART, antiretroviral therapy; VL, Viral Load.

Despite long-standing suppression and reported excellent adherence, this patient developed detectable viremia during her pregnancy. Two potential mechanisms for incomplete viral suppression were (1) emesis after consuming ART and (2) consumption of ART with prenatal vitamins and calcium carbonate. Concomitant administration of dolutegravir with divalent cations under fasting conditions (including calcium and iron supplements, both commonly found in prenatal vitamins) can reduce dolutegravir concentrations by as much as 57%.8 The manufacturer recommends taking dolutegravir 2 hours before or 6 hours after consuming divalent cations or dolutegravir and supplement with a full meal.9 This case highlights the importance of unexpected, idiosyncratic drug–drug interactions with ART and the need for careful evaluation of all home medications, even those as putatively harmless as vitamins and indigestion remedies (see https://www.hiv-druginteractions.org/). This patient’s last visit prior to pregnancy was days prior to dolutegravir-related safety concern publications, and she conceived shortly thereafter. She first reported her pregnancy at approximately 9 weeks, well after the end of neural tube closure (6 weeks gestation). Thus, incremental risk of continued dolutegravir exposure was likely minimal. The case illustrates the need for collaboration between providers and the requirement to ascertain a full supplement/medication history at every visit to decrease the risk of virological breakthrough and HIV MTCT.

Learning points

  • Antepartum and intrapartum utilisation of antiretroviral therapy has dramatically reduced mother-to-child transmission of HIV.

  • While current-generation antiretroviral therapy agents are generally less toxic, more convenient and more effective in suppressing viral load than their predecessors, significant drug–drug interactions still exist that could alter the in vivo effectiveness of these agents. Notably, dolutegravir exhibits a significant interaction with divalent cations, such as calcium. It is important to assess for use of over-the-counter medications and vitamins in patients on antiretroviral therapy.

  • While there were previously significant safety concerns about the safety of dolutegravir in pregnancy with respect to neural tube defects, contemporary evidence suggests that the risk, if extant, is small. For this reason, newer guidelines recommend the use of dolutegravir in pregnancy as a preferred agent and consider it a reasonable alternative agent in women contemplating conception.

Ethics statements

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References

Footnotes

  • Contributors Drs MJB and MMH originated the idea for the manuscript. Dr JF drafted the manuscript. Drs MJB and MMH reviewed the draft manuscript for important intellectual contributions.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.