Journal Club

In this feature, a panel of IDSA members identifies and critiques important new studies in the current literature that have a significant impact on the practice of infectious diseases medicine.

• Prednisone Reduces the Risk of TB-Associated IRIS in HIV-Infected Patients
• Probiotics for Acute Gastroenteritis in Children: Throw in the Towel or Back to the Drawing Board?
• Two-Drug Therapy for Treatment-Naïve Adults with HIV-1 Infection

Click here for the previous edition of Journal Club. For a review of other recent research in the infectious diseases literature, see “In the Literature,”  by Stanley Deresinski, MD, FIDSA, in each issue of Clinical Infectious Diseases.

Prednisone Reduces the Risk of TB-Associated IRIS in HIV-Infected Patients

Reviewed by Daniel Mendoza, MD, PhD

Early initiation of antiretroviral therapy (ART) in HIV-infected patients who have tuberculosis (TB) reduces mortality. However, ART increases the risk of TB-associated immune reconstitution inflammatory syndrome (IRIS). There is a lack of knowledge about strategies to prevent TB-associated IRIS.

Meintjes et al. conducted a randomized, double-blind, placebo-controlled trial (PredART) to determine whether prednisone reduces the incidence of TB-associated IRIS in South Africa and recently reported their results in the New England Journal of Medicine. They enrolled HIV-infected patients with high risk for developing TB-associated IRIS. They included patients with CD4⁺ T cell counts of 100 cells or fewer per microliter who were on anti-TB treatment for less than 30 days and were going to start ART. Patients with hepatitis B infection and uncontrolled diabetes were excluded. The groups received prednisone (40 mg for 2 weeks followed by 20 mg for 2 weeks) or placebo. Prednisone or placebo was started within 48 hours after initiating ART. The primary outcome was the intention-to-treat incidence of TB-associated IRIS within 12 weeks after initiating ART.

One hundred twenty patients were assigned to each group. The ART regimen was tenofovir, emtricitabine (or lamivudine) and efavirenz in 233 patients (97.1 percent). Nine patients (7.5 percent) in each group withdrew or failed to complete follow-up. TB-associated IRIS was diagnosed in 39 patients (32.5 percent) in the prednisone group and 56 patients (46.7 percent) in the placebo group (relative risk, 0.70; 95 percent confidence interval [CI], 0.51 to 0.96; P = 0.03). Open-label glucocorticoids were prescribed to treat TB-associated IRIS in 16 patients (13.3 percent) in the prednisone group and in 34 (28.3 percent) in the placebo group (relative risk, 0.47; 95 percent CI, 0.27 to 0.81). There were five deaths in the prednisone group and four in the placebo group (P = not significant). Severe infections developed in 11 patients in the prednisone group and in 18 patients in the placebo group (P = 0.23). One case of Kaposi’s sarcoma occurred in the placebo group.

The PredART trial indicates that starting prednisone within 48 hours of initiating ART lowers the risk of TB-associated IRIS in HIV-infected patients 30 percent more than with placebo, without increasing the risk of adverse events. Clinicians should consider using a 4-week course of prednisone to prevent TB-associated IRIS.

(Meintjes et al. N Engl J Med. 2018; 379:1915-1925.)

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Probiotics for Acute Gastroenteritis in Children: Throw in the Towel or Back to the Drawing Board?

Reviewed by A. Krishna Rao, MD, MS

Acute gastroenteritis (AGE) accounts for 1.7 million visits to the emergency department (ED) each year in the U.S. Treatment focuses on close monitoring and symptom management, as few treatments can modify the disease course. The evidence for use of probiotics in AGE is poor and based on studies that are small and often have methodologic limitations. Despite this, probiotics constitute a multibillion-dollar industry, are being taken by patients to treat intestinal infections, and are even represented in guidelinesfor treatment of diarrhea.

Two recent studies published in the New England Journal of Medicine, one conducted in Canada and the other in the U.S., fail to support the use of probiotics in AGE. Both shared many features including robust study design/assessment and 90 percent statistical power. They were multicenter, randomized, and placebo-controlled, recruiting from six Canadian and 10 U.S. EDs. Subjects age 3–48 months with diarrhea (≥ 3 watery stools/24 hours) for up to 3 (Canada) or 7 (U.S.) days were recruited. Exclusion criteria were similar and focused on risk of bacteremia (indwelling vascular access catheters, structural heart disease, or immunocompromised) and chronic GI disorders. The primary outcome was moderate to severe AGE on the Vesikari scale (score ≥ 9 points), a validated metric designed for outpatients. The interventions included Lactobacillus rhamnosus R0011 and L. helveticus R0052 in a 95:5 ratio (Canada) or L. rhamnosus GG (Chr. Hansen) (U.S.) twice daily for 5 days.

Both studies met recruitment goals, completed follow-up in > 90 percent of subjects, had ~80 percent or higher adherence to treatment, and were balanced between intervention/placebo arms.  Norovirus and rotavirus were the most commonly detected pathogens. The difference between arms in the primary outcome was small and not statistically significant: 26.1 percent versus 24.7 percent for probiotic versus placebo (odds ratio 1.06 [0.77-1.46]), P = 0.72) in Canada and 11.8 percent versus 12.6 percent (relative risk 0.96 [0.68-1.35], P = 0.83) in the U.S. There were no differences in secondary outcomes (e.g., frequency/duration of diarrhea, vomiting, or unscheduled health care visits) or subgroups (e.g., age, duration of symptoms prior to enrollment, or antibiotic use prior to enrollment).

These data suggest that probiotics do not work for AGE in children. However, there are many probiotic strains and AGE is a collection of many distinct infections. Effects of probiotics in studies are strain and disease specific. Also, there is evidence that only some individuals have a “permissive” microbiome allowing for robust colonization. The present studies did not examine the microbiome of participant stool following the 5-day course to assess for persistent colonization.

So how can we make progress in developing effective probiotic therapeutics? Firstly, focusing on specific strains is critical: A rational, bench-to-bedside approach could be pursued. Secondly, while there was prior evidence for the strains used in the present studies, AGE is a heterogeneous condition caused by many specific infections, and the best evidence for these probiotic strains was in norovirus infection. Thus, focusing on a specific infection is warranted. Finally, precision-health approaches that account for “permissive” microbiomes can be used to pre-screen patients prior to administration of probiotics. Rather than giving up on probiotics for AGE, investigators could go back to the drawing board, take a rational approach to probiotic trial design, and utilize insights from recent studies.

(Freedman et al. N Engl J Med. 2018;379:2015-2026.)

(Schnadower et al. N Engl J Med. 2018;379:2002-2014.)

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Two-Drug Therapy for Treatment-Naïve Adults with HIV-1 Infection

Reviewed by Michael T. Melia, MD

Two-drug antiretroviral therapy regimens are attractive for many reasons, including the potential for lower toxicity and lower cost. Prior studies of two-drug regimens, however, met with mixed results. A recent study in Lancetprovides additional data for the efficacy of this approach.

The GEMINI-1 and -2 studies were identical, multicenter, double-blind, industry-funded phase III trials of treatment-naïve adult patients with HIV-1 infection. Most patients were young (90 percent < 50 years), 85 percent were male, and 68 percent were white. Patients were randomized 1:1 to receive either dolutegravir (DTG) + lamivudine (3TC) or DTG + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). Patients with baseline viral loads ≤ 500,000 copies/mL were included. Patients with baseline major resistance mutations to nucleoside reverse transcriptase inhibitors (NRTI), non-NRTI, or protease inhibitors were excluded.

In the pooled analysis of the intention-to-treat population at 48 weeks, 91 percent (655/716) of patients receiving DTG + 3TC achieved plasma HIV-1 RNA of < 50 copies/mL, compared with 93 percent (669/717) of patients receiving DTG + TDF/FTC (adjusted treatment difference -1.7 percent, 95 percent confidence interval -4.4 to 1.1). Of the 8 percent of patients with baseline CD4 cell counts ≤ 200/μL, more achieved plasma HIV-1 RNA of < 50 copies/mL with DTG + TDF/FTC than with DTG + 3TC, although most non-response was unrelated to efficacy or treatment failure. None of the 10 patients who experienced virological withdrawal developed NRTI or integrase strand transfer inhibitor resistance mutations. Aside from expected greater renal and bone turnover biomarkers in patients receiving TDF, there were no significant differences in side effects.

For treatment-naïve patients with viral loads ≤ 500,000 copies/mL and without baseline drug resistance, DTG + 3TG is an attractive option. Additional data regarding its durability and its effectiveness among patients with CD4 cell counts ≤ 200/μL (as well as higher viral loads) will help determine its place in the armamentarium of regimens for treatment-naïve patients.

(Cahn et al. Lancet. 2019;393(10167):143-155.)

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