Global Solutions for Infectious Diseases

While higher pyrazinamide and isoniazid exposures and slow NAT2 acetylator status were each associated with increased hepatotoxicity, only pyrazinamide exposure was associated when considering pharmacokinetic variables together. Rifampin exposure was not associated with hepatotoxicity, supporting further evaluation of doses up to 20 mg/kg/day in a larger trial.

Even with antiretroviral therapy, people with HIV often face residual immune activation and chronic systemic inflammation, heightening their risk for early-onset comorbidities such as cardiovascular disease. In a study of 492 men who have sex with men, suboptimal ART adherence, measured by undetectable urine tenofovir, was directly associated with elevated C-reactive protein, even after adjusting for viral suppression and stimulant use. These findings highlight the importance of adherence monitoring to reduce inflammation-related chronic health outcomes.

Abstract Certain bacterial infections, such as those involving prosthetics, can require antimicrobial therapy over months to years, potentially increasing the burden of antimicrobial resistance. Here we longitudinally track the antimicrobial resistome in mice during continuous antibiotic dosing over 21 months. The burden of antibiotic resistance genes (ARGs) initially increases, but, surprisingly, declines in later months, approaching levels observed in untreated animals. ARG burden is regulated by taxonomy and declines as ARG-harboring taxa that initially bloom are replaced by commensals. Furthermore, we find that the dynamics of antibiotic-induced ARG burden are influenced by age-related differences in microbial taxonomy and can be removed by fecal microbiota transplantation. We show that commensals may regulate the resistome by limiting the growth of ARG-harboring taxa, thereby providing antimicrobial expansion resistance.

Background:Sputum collection for tuberculosis (TB) diagnosis poses challenges for children, people living with HIV, and those who struggle with sputum production. Tongue swab-based molecular testing offers a promising non-invasive alternative, but person-centered research on acceptability is limited.Methods:We conducted a pragmatic survey across eight countries (Vietnam, Philippines, South Africa, Nigeria, Zambia, India, Uganda, Peru) among people with presumptive TB attending primary care facilities. Participants provided both tongue swab and sputum samples, then completed a 5–10 minute survey about their collection preferences.Results:From October 2023 to July 2024, 1,297 participants were enrolled (median age 43 years, 45% female, 13% HIV-positive). Overall, 61% (95% CI: 58–64%) preferred tongue swab collection compared to 22% (95% CI: 20–25%) who preferred sputum collection and 17% (95% CI: 15–19%) with no preference. Preference for tongue swab was consistent across demographic and clinical subgroups, with country-level variation ranging from 47% in South Africa to 74% in Zambia and Nigeria.Conclusion:Strong preference for tongue swab over sputum collection among individuals with presumptive TB supports this diagnostic innovation’s potential to overcome barriers to timely TB testing, particularly for populations struggling with sputum production.

Interleukin (IL)-23 is a validated therapeutic target in inflammatory bowel disease. While antibodies targeting IL23 demonstrate clinical efficacy, they face challenges such as high costs, safety risks, and the necessity of parenteral administration. Here, we present a workflow to simultaneously enhance the affinity and protease stability of an inhibitory anti-IL23R VHH for oral use. Cocrystal structure analysis reveals that the anti-IL23R VHH employs both CDR and framework residues to achieve picomolar affinity for IL23R. The engineered VHH remains stable for over 8 h in intestinal fluid and 24 h in fecal samples. Oral administration of this VHH achieves deep pathway inhibition in a murine colitis model. Furthermore, a single pill provides sustained IL23R inhibition in nonhuman primate blood for over 24 h. With high potency, gut stability, high production yield, and favorable drug-like properties, oral VHHs offer a promising approach for inflammatory bowel diseases.

The CDC recommends doxycycline postexposure prophylaxis (doxyPEP) for MSM with a bacterial sexually transmitted infection (bSTI) in the past year. This study explored determinants of doxyPEP awareness and uptake, and associations with HIV care outcomes, among US MSM with HIV. Cross-sectional study. From October 2023 to October 2024, we enrolled 827 MSM with HIV from 46 states, Washington, DC, and Puerto Rico via a popular geospatial networking app. Adjusted multivariable logistic regression examined determinants of doxyPEP awareness/use and associations with HIV treatment adherence, viral suppression, and care engagement. Among 827 participants, 13% were currently taking doxyPEP, 46% were aware of doxyPEP but not prescribed it, and 41% had not heard of it. Of 360 participants Centers for Disease Control and Prevention (CDC)-eligible for doxyPEP, 20% were prescribed it, 49% had heard of it but were not on it, and 31% were unaware, 95% of whom expressed interest. Neither awareness nor use of doxyPEP was associated with HIV care outcomes. Both awareness and uptake of doxyPEP were higher among participants with a recent bSTI [adjusted odds ratio (aOR) = 1.15, 95% confidence interval (CI): 1.06-1.25; aOR = 1.11, 95% CI: 1.05-1.17, respectively) and lower in the United States. Midwest, Mountain, and South regions [inverse-variance weighted average (IVW-Avg) aOR = 0.81, 95% CI: 0.76-0.86; IVW-Avg aOR = 0.86, 95% CI: 0.82-0.90, respectively] relative to Pacific states. High doxyPEP interest underscores unmet demand in integrated HIV/sexual healthcare. Sociodemographic and geographic disparities in doxyPEP implementation necessitate targeted interventions for MSM with HIV to optimize impact on the bSTI epidemic.

Current trials toward an HIV cure involve combination strategies aimed at achieving durable antiretroviral treatment (ART)-free viral control or HIV elimination, many relying on analytical treatment interruptions (ATIs) to evaluate efficacy. Given the physical, psychosocial, and interpersonal risks associated with ATIs, it is critical to monitor participants' experiences so that support can be provided when needed. While qualitative approaches have been used in similar settings, we designed and implemented a series of short, closed-ended participant surveys in the University of California, San Francisco-amfAR trial, a single-arm multi-intervention HIV cure-related trial with an extended ATI. Surveys were administered at relevant trial timepoints to capture participants' (n = 10) perspectives and experiences. These included their understanding of the trial, motivations, expectations, perceived risks, benefits, and burdens of trial participation, as well as their perspectives on restarting ART and partner protections. We describe these data using descriptive statistics and summarize lessons learned from implementing quantitative surveys in this complex trial. Our data indicate that all respondents understood the scientific goals and requirements of participating in the trial. Most were motivated to help advance research but many expressed anxiety about participating. During the trial, respondents had limited side effects, discomfort, and trial burnout. Those who completed surveys at ART restart reported mixed (positive and negative) feelings and challenges (e.g., missed doses) when restarting ART. Participants offered various methods for partner protection during ATIs and at ART restart. Many respondents expressed future willingness to participate in a similar HIV cure trial. While the number of respondents was small, these findings are consistent with concerns identified in guidance regarding these types of trials as well as qualitative findings from earlier studies. Moreover, we demonstrated that it is feasible to implement quantitative evaluations of participants' experiences. Such approaches should be implemented in future HIV cure trials to optimize human-centered research implementation.