Dolutegravir plus Tenofovir to Treat HIV: How did the efficacy of the dolutegravir regimens compare to the standard-care regimen in the ADVANCE trial? Adrenal Crisis: What are some of the events that may trigger an adrenal crisis?

NEW CURBSIDE CONSULT Listen to the latest episodes of the Curbside Consults podcast, The Evolution of Opioid Prescription Habits and Approaches to Opioid Prescribing with Dr. Scott Hadland and the related Statistical Review — Observational Studies with Dr. David Harrington. This series complements the foundational information in Rotation Prep on NEJM Resident 360 by taking a deep dive into key clinical topics with expert clinicians and educators. Subscribe on iTunes.

Teaching Topic Dolutegravir plus Tenofovir to Treat HIV ORIGINAL ARTICLE Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV W.D.F. Venter and Others           In the ADVANCE trial, Venter et al. compared treatment with dolutegravir combined with either of two tenofovir prodrugs to the first-line standard-of-care regimen used in the majority of patients with human immunodeficiency virus (HIV) infection in low- and middle-income countries. Clinical Pearls   What limitations are associated with the regimen of tenofovir disoproxil fumarate, lamivudine (or emtricitabine), plus efavirenz as first-line treatment for HIV infection? A first-line regimen of tenofovir disoproxil fumarate (TDF) with either lamivudine (3TC) or emtricitabine (FTC) plus efavirenz (EFV) for the treatment of HIV infection is recommended by the World Health Organization because it can be safely used in pregnancy and during tuberculosis treatment. However, the regimen has a low resistance barrier, and there are relatively high incidences of toxic effects among some patients. Other antiretroviral agents are recommended in high-income countries.   What new drugs are under consideration for inclusion in first-line HIV regimens? Two drugs under consideration for inclusion in new regimens are dolutegravir (DTG), to replace EFV, and tenofovir alafenamide fumarate (TAF), to replace TDF, both prodrugs of tenofovir. DTG has potency, resistance, and side-effect benefits over EFV, and there are widespread plans to rapidly expand its use in low- and middle-income countries. However, associations of DTG with teratogenic effects (specifically, neural-tube defects), neuropsychiatric symptoms, and weight gain have aroused concern, as has the complexity of twice-daily administration with rifampin-containing tuberculosis treatment. TAF has similar efficacy to that of TDF, with fewer effects on markers of renal or bone toxicity, but lacks data in low- and middle-income countries and in patients who are receiving rifamycins for tuberculosis therapy and in those who are pregnant. Morning Report Questions Q. How did the efficacy of the dolutegravir regimens compare to the standard-care regimen in the ADVANCE trial? A. The ADVANCE trial compared a triple-therapy combination of emtricitabine (FTC) and DTG plus either of two tenofovir prodrugs — TAF (TAF-based group) or TDF (TDF-based group) — against the local standard-of-care regimen of TDF–FTC–efavirenz (standard-care group). The primary end point was the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter at week 48. In the primary efficacy analysis, the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter was 84% in the TAF-based group, 85% in the TDF-based group, and 79% in the standard-care group. Both DTG-containing regimens showed noninferior efficacy to the standard-care regimen. There was no significant difference in efficacy between groups in the three pairwise comparisons, at the prespecified significance level of 0.017. After virologic failure, no resistance to integrase inhibitors was observed in patients receiving the DTG-containing regimens. Q. Which regimen in the ADVANCE trial was associated with the highest absolute weight gain? A. At week 48, absolute weight gain and the percentage of patients in whom obesity emerged during treatment were highest in the TAF-based group (6 kg, 14% new obesity), but the values in the TDF-based group (3 kg, 7% new obesity) were also higher than those in the standard-care group (1 kg, 6% new obesity). Weight gain was significantly higher in female patients than in male patients across all three groups, with no clear plateau in the increase. Regression analysis showed that obesity that emerged during treatment at week 48 was associated with a lower CD4 count, a higher viral load, and older age.

Teaching Topic Adrenal Crisis REVIEW ARTICLE Adrenal Crisis R.L. Rushworth, D.J. Torpy, and H. Falhammar    Adrenal crisis appears to be increasing in frequency, despite the availability of effective preventive strategies. Clinical Pearls   What is the definition of an adrenal crisis in an adult? Given the lack of a research-based classification and in recognition of the physiological changes that distinguish an adrenal crisis from a milder episode of hypoadrenalism, pragmatic definitions of adrenal crisis have generally been adopted. An adrenal crisis in an adult is defined as an acute deterioration in health status associated with absolute hypotension (systolic blood pressure <100 mm Hg) or relative hypotension (systolic blood pressure ≥20 mm Hg lower than usual), with features that resolve within 1 to 2 hours after parenteral glucocorticoid administration (i.e., a marked resolution of hypotension within 1 hour and improvement in clinical symptoms over a period of 2 hours). Concomitant features in patients of all ages include acute abdominal symptoms; delirium, obtundation, or both; and hyponatremia, hyperkalemia, hypoglycemia, and pyrexia.   What are some of the risk factors for adrenal crisis among patients with hypoadrenalism? Susceptibility to adrenal crises varies among patients with hypoadrenalism. Risk factors include older age, a history of prior adrenal crises, the presence of autoimmune polyglandular syndromes, type 1 diabetes mellitus, and nonendocrine coexisting conditions such as asthma and cardiac disease. However, the mechanism of action of these various factors in adrenal crisis is unclear and may be specific to coexisting conditions. In addition, unknown factors may potentiate the risk of adrenal crisis, since some patients have numerous episodes, whereas others have few, if any, episodes. Morning Report Questions Q. What are some of the events that may trigger an adrenal crisis? A. Infections, which act as inflammatory stressors, commonly precipitate adrenal crises. Gastroenteritis is frequently cited as a precipitant and can be particularly hazardous, since vomiting and diarrhea impair the absorption of oral medication and may also exacerbate dehydration. Other pathophysiological states may precipitate an adrenal crisis if the body cannot mount an increase in endogenous cortisol and if the amount of replacement therapy is not increased. Such conditions include serious injury and major surgery, but situations that generally are associated with the need for milder cortisol increases (exercise and emotional upset) have been reported as crisis precipitants in up to 10% of episodes, according to the results of patient surveys in which no specific precipitant was identified. Adrenal crises have been reported in association with the release of acute-phase cytokines and other substances after certain relatively minor medical procedures such as vaccinations and zoledronic acid infusion. Some types of immunotherapy or chemotherapy may precipitate adrenal crises. Q. What are some of the key strategies to prevent adrenal crisis? A. Key strategies that can prevent adrenal crisis include an individualized prescription and plan for the use of supplementary glucocorticoid administration for physiological stress; use of parenteral hydrocortisone, preferably at home, when oral glucocorticoids cannot be taken; and the provision of devices, such as a MedicAlert bracelet or necklace, that can warn caregivers of the risk of adrenal crisis when patients cannot communicate verbally. Patients and their family members should be taught how to perform intramuscular injection of hydrocortisone and should be provided with vials, needles, and syringes. Parenteral administration of hydrocortisone at home may prevent progression of an early adrenal crisis. However, injectable hydrocortisone is not offered to, or may not be obtained by, all patients. Barriers to hydrocortisone use by patients include reluctance to inject the drug intramuscularly, impaired dexterity, and advanced age.

Archive of Teaching Topics »

QUOTE OF THE WEEK “This cardiovascular outcomes trial met its primary objective of ruling out an 80% excess cardiovascular risk with oral semaglutide, confirming noninferiority to placebo for the primary outcome (hazard ratio, 0.79; 95% CI, 0.57 to 1.11). This finding is consistent with those of other published cardiovascular outcomes trials of GLP-1 [glucagon-like peptide-1] receptor agonists, all of which confirmed the absence of excess cardiovascular risk.” M. Husain and Others, Original Article,  “Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes”