Top Infectious Disease News of the Week—August 11, 2019

#5: Study to Evaluate Experimental Adjuvants for Seasonal Influenza Vaccine

The National Institutes of Health (NIH) has announced the launch of an early-stage clinical trial to evaluate the safety and efficacy of 2 licensed seasonal influenza vaccines, administered with or without novel adjuvants.

Although seasonal influenza vaccines have been available for decades, effectiveness varies depending on how well the vaccine matches the seasonal strain circulating in a given year. When an adjuvant is added to a vaccine, individuals are more likely to produce a stronger immune response, which may provide better protection.

The phase 1 trial will enroll 240 healthy adults between 18 to 45 years at 8 Vaccine and Treatment Evaluation Units, which comprise a network of clinical trial sites funded by the NIH’s National Institute of Allergy and Infectious Diseases. The trial is expected to last approximately 18 months.

Read about seasonal adjuvant research.

#4: Antiretroviral Safety in Pregnancy: Focus on Dolutegravir, Integrase Inhibitors, and Neural Tube Defects

The reduction in morbidity and mortality with combina­tion antiretroviral therapy (cART) in the past 2 decades has positively changed the outlook for pregnancy and extended life expectancy in mothers with HIV. Women being treated effectively with cART during pregnancy has reduced vertical transmission to 1% or less in the United States and Europe and close to zero when virologically suppressed prior to conception and throughout the pregnancy.^1-3 Women with HIV have the same reproductive desires as women without HIV infection.⁴ Therefore, in order to lower the risk of unplanned pregnancies and mother-to-child-transmission (MTCT), it is important to routinely discuss reproductive plans with women of childbearing potential.⁵

Among women with HIV who are pregnant or planning to conceive, important considerations include the thera­peutic efficacy of the individual antiretrovirals (ARVs) in pregnancy, teratogenicity, and potential for poor tolera­bility.⁵ Information that patients can use to make deci­sions about the safe use of medications in pregnancy is based on results from preliminary animal studies, preg­nancy registries, clinical trials, and reported experience. The Antiretroviral Pregnancy Registry (APR) represents a prospective, observational study of pregnancy outcomes related to ARV exposure in utero.⁶ Pregnancy cases are evaluated with the intention of identifying teratogenicity signals with exposure. In order to ascertain the risk of birth defects with a given ARV medication, the APR requires use of the individual therapy in at least 200 preg­nancies.⁶ Studies have generally found similar rates of birth defects from ARV exposure during the first and later trimesters, indicating that early ARV use is not associ­ated with an increased risk of birth defects.⁷ ARV medica­tion safety in pregnancy based on current information is provided in more detail in Table 1.⁸

Read about ART safety in pregnancy.

#3: FDA Approves Treatment for Resistant Forms of Tuberculosis

The US Food and Drug Administration (FDA) has announced the approval of pretomanid tablets in combination with bedaquiline and linezolid for the treatment of highly treatment-resistant tuberculosis. The novel compound, pretomanid, was developed by the TB Alliance.

The approval was granted under the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD pathway) as a 3-drug, 6-month, all-oral regimen for individuals with extensively-drug resistant (XDR) or multidrug-resistant (MDR) tuberculosis who are treatment intolerant or non-responsive to treatment. Pretomanid is only the third new anti-TB drug approved for use by FDA in more than 40 years.

According to a statement issued by the TB Alliance the 3-drug regimen, referred to as the BPaL regimen, was studied in the Nix-TB trial across 3 sites in South Africa. The study enrolled 109 individuals with XDR-TB or treatment-intolerant or non-responsive MDR-TB.

Read about the approval of pretomanid tablets.

#2: Ebola Clinical Trial Halted in DRC

A clinical trial evaluating 4 experimental therapeutics for Ebola virus disease has been halted after an independent data and safety monitoring board determined 2 of the therapies were linked with better rates of survival.

The PAmoja TuLinde Maisha (PALM [together save lives]) clinical trial was launched on November 20, 2018 as part of the response to an ongoing Ebola outbreak in the Democratic Republic of the Congo (DRC).

The randomized, multicenter, controlled trial was designed to evaluate the safety and efficacy of 3 antibody-based investigational agents for the treatment of Ebola: REGN-EB3, ZMapp, and mAb114, and 1 small molecule antiviral remdesivir.

Read about the halting of the Ebola clinical trial.

#1: Preclinical Trial of TDF Vaginal Ring for PrEP Ends Early

A preclinical trial of a tenofovir disoproxil fumarate (TDF) intravaginal ring for HIV pre-exposure prophylaxis ended early after 8 of 12 women unexpectedly developed vaginal ulcers.

The National Institutes of Health-funded study, published in The Lancet, included 17 sexually active women, 12 of whom received intravaginal rings with TDF. None of the 5 women in the placebo group experienced vaginal ulcers.

The study came after preclinical macaque models and a small 2-week phase 1 clinical trial in which the vaginal ring was shown to be safe.

“The mechanisms by which the drug ring (and not the placebo ring) led to this unanticipated finding are not yet fully understood,” corresponding author Betsy Herold, MD, director of the Translational Prevention Research Center at Albert Einstein College of Medicine, told Contagion^®. “We did observe increases in inflammatory markers in women using the TDF compared [with] placebo ring by examining, for example, gene expression in biopsy tissue. The findings suggest that sustained levels of intracellular TFV-diphosphate (the active form of the drug in cells) and/or other metabolites released by the TDF but not placebo ring induce inflammation and may disrupt epithelial repair, which in the setting of microabrasions associated with ring use and/or sex, may predispose to ulceration. The ulcers were NOT predicted by the preclinical or earlier 2-week clinical study.”

All ulcers resolved after the rings were removed. Only 2 participants in the TDF group completed the 3-month study with continuous ring use and monthly ring changes. Ulcers were detected an average of 32 days after TDF ring use began, with 8 participants discontinuing use early as a result. Rings were electively removed from the other 2 participants in the TDF group at 20 and 23 days.

“Because other products that deliver related drugs (tenofovir itself or another prodrug called tenofovir alafenamide) are in preclinical or clinical trials, it is critical that we determine the mechanism by which this TDF ring led to this unexpected outcome as it has implications for these other products,” Herold told Contagion^®. “We are currently conducting intensive safety studies in other animal models including sheep to try and identify the precise mechanisms.”

Read about the end of the preclinical trial of the TDF vaginal ring.