- Isoniazid Preventive Therapy for HIV-Infected Pregnant Women: Start During Pregnancy or Postpartum?
- Cryptococcal Mortality in the Modern ART Era
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.
Reviewed by Dr. Michael T. Melia
Isoniazid preventive therapy (IPT) has been shown to prevent active tuberculosis (TB) in people with HIV, but pregnant women have been excluded from trials of this treatment approach. Investigators have recently filled this gap.
In the prospective, double-blind, placebo-controlled, non-inferiority TB APPRISE trial conducted at 13 sites in eight high-TB prevalence countries and recently published in The New England Journal of Medicine, 956 pregnant adult women were randomized to receive 28 weeks of isoniazid 300 mg daily during pregnancy (immediate group) or at week 12 after delivery (deferred group). Diagnosed latent TB infection was not required. The primary outcome was a composite safety outcome of maternal adverse events of grade 3 or higher at least possibly related to the study drug or permanent discontinuation of the study drug owing to toxicity through 48 weeks after delivery.
Over 90 percent of the study participants were black African. One-third were between 14 and 24 weeks gestation at study entry, and 30 percent had a positive interferon-gamma release assay for TB. The median CD4 count was 493 cells/mm3, and nearly two-thirds of the subjects had an undetectable HIV RNA. All but one woman were receiving combination antiretroviral therapy; 85 percent were receiving an efavirenz-based regimen.
In the intention-to-treat population, a primary outcome event occurred in 72 women (15.1 percent) in the immediate group and 73 (15.2 percent) in the deferred group, meeting the criterion for non-inferiority. Among 926 deliveries, a greater percentage of women in the immediate than the deferred group had a composite adverse pregnancy effect (23.6 percent vs 17.0 percent; 95 percent confidence interval [CI], 0.8 to 11.9; P = 0.01). The incidence rate of maternal tuberculosis was 0.60 and 0.59 per 100 person-years, respectively (95 percent CI, -0.94 to 0.96); there was one probable case of TB in an infant in the deferred group. Of the four women who died of liver failure, two had received IPT, and all four were receiving efavirenz-tenofovir-emtricitabine at death.
TB APPRISE demonstrates the importance of including pregnant women in clinical trials. More women in each group experienced maternal treatment-related serious adverse events than expected based on a review of seven trials of IPT with liver function monitoring in non-pregnant adults, highlighting the potential role for increased monitoring among this population. Possible explanations for this outcome include contributions from efavirenz itself or an interaction between isoniazid and efavirenz associated with increased efavirenz levels. The new finding of increased rates of adverse pregnancy outcomes in the immediate group provides a reason to favor deferred therapy in this population; further study of this issue is needed, as are additional studies of other regimens used to treat latent TB infection in pregnant women.
Reviewed by Dr. Lauren Richey, MPH, FIDSA
Cryptococcal infection remains an important opportunistic infection for people living with HIV (PLWH). Ninety day mortality estimates are 13-19 percent, but little is known about long-term mortality and risk factors for mortality in the modern era.
A recent study in the Journal of Acquired Immune Deficiency Syndromes included all PLWH diagnosed with cryptococcosis at Barnes-Jewish Hospital in St. Louis from 2002 to mid-2017. Cryptococcal infection was defined by a positive serum or cerebrospinal fluid antigen or positive culture. The patients were split into three groups; survivors, early mortality (within 90 days of cryptococcal diagnosis), and late mortality (90 days after diagnosis). The cohort was also split into the premodern antiretroviral therapy (ART) era (prior to 2008) and modern ART era (2008 to 2017).
Overall, 105 PLWH met the criteria and mortality was 47.6 percent; early mortality was 16.2 percent and late mortality was 31.4 percent. The central nervous system was the most common site of infection (68 percent). There were no significant differences in the median opening pressures or antigen titers between survivors, early-mortality, and late-mortality groups. CD4 count, viral loads, and prescription of ART prior to cryptococcal diagnosis were not different between the survivors and the late-mortality group, however survivors were more likely to be virally suppressed at last observation (62 percent vs 24 percent , P < 0.001). The survivors were more likely to have a new diagnosis of HIV at the time of cryptococcal diagnosis (P = 0.003) and to have private insurance (P = 0.008) compared to late-mortality individuals. There were significantly fewer survivors in the premodern era compared to the modern ART era (34 percent vs 74 percent, P < 0.001.) Early mortality was similar; the difference was driven by late mortality (48 percent vs 12 percent, P < 0.001.)
While infections with Cryptococcus carry a high mortality, even after 90 days, mortality is less in the modern era of ART. Lower late-mortality was seen in patients with private insurance, which is likely a surrogate for a higher socioeconomic status. The causes of the late mortality are not known but could reflect neurologic or psychiatric sequelae of the infection, or may reflect persistence of previous barriers to care that led the patient to have poor adherence to ART in the past.