Management of heavily treatment‑experienced people with HIV remains challenging due to cumulative drug resistance and limited therapeutic options. We report the case of a cisgender female with HIV‑1 subtype A1 and extensive antiretroviral therapy (ART) resistance who experienced more than a decade of suboptimal viral suppression despite multiple ART regimens. The patient accumulated resistance to all nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), all non‑nucleoside reverse transcriptase inhibitors (NNRTIs), and nearly all protease inhibitors (PIs), with limited remaining treatment options. Following virologic rebound in 2023 and failure of subsequent salvage regimens, lenacapavir was initiated in 2024 in combination with an optimized background regimen of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). The patient rapidly achieved an undetectable viral load and remains virologically suppressed to date.

Chronic hepatitis B remains a major cause of cirrhosis and hepatocellular carcinoma worldwide. We investigated whether histologic hepatic steatosis affects hepatitis B virus deoxyribonucleic acid (HBV DNA) suppression in patients receiving antiviral therapy. This retrospective observational study included 307 adult patients with chronic hepatitis B who received tenofovir or entecavir therapy and underwent pretreatment liver biopsy. Demographic, laboratory, virological, radiological, and histopathological data were retrieved from the electronic medical record system. Laboratory parameters included complete blood count, liver function tests, alpha-fetoprotein, renal function tests, and lipid profile. Histopathological evaluation included fibrosis stage, histologic activity index, and hepatic steatosis percentage. Ultrasonographic findings included hepatic steatosis, liver echotexture, and contour. The primary outcome was HBV DNA suppression at 12 months. Long-term virological response was evaluated as time to first HBV DNA suppression during follow-up (maximum 60 months). A total of 307 patients receiving entecavir or tenofovir were included, of whom 258 (84.0%) achieved HBV DNA suppression at 12 months. Patients without suppression had higher baseline aspartate aminotransferase, histologic activity index, histologic steatosis, and baseline log10 HBV DNA levels (all P < .05). Histologic steatosis ≥5% was more frequent in patients without suppression (42.9% vs 23.6%, P = .005). In multivariable analysis, steatosis ≥5% (odds ratio 0.365, 95% confidence interval [CI] 0.179-0.746; P = .006) and higher baseline log10 HBV DNA (odds ratio 0.842, 95% CI 0.751-0.944; P = .003) were associated with a lower likelihood of 12-month suppression, with similar findings in the parsimonious sensitivity model. Kaplan-Meier analysis showed delayed suppression with steatosis (log-rank P = .016); however, this association was not significant in the conventional adjusted Cox model (hazard ratio 0.900, 95% CI 0.689-1.175; P = .438), and a significant time-dependent interaction indicated non-proportionality (P < .001). Histologic steatosis and higher baseline log10 HBV DNA were associated with a lower likelihood of 12-month HBV DNA suppression. However, an independent longitudinal association with time to suppression was not demonstrated. Residual confounding by unmeasured metabolic factors cannot be excluded.

Combination antiretroviral therapy (cART) has improved human immunodeficiency virus (HIV) management, but long-term use is associated with reproductive dysfunction. This study investigated TLD (Tenofovir, Lamivudine and Dolutegravir)-based cART effects on ovarian function using animal models and exploratory clinical investigations in women living with HIV. In the animal study, female Wistar rats were randomized into control, TLD-based cART (22 mg/kg), and dolutegravir alone (2.5 mg/kg) groups, administered orally for 28 days. Estrous cycle, histology, oxidative stress, reproductive hormones, and ova count were assessed. Both TLD-based cART and dolutegravir significantly prolonged diestrus (p = 0.0083 and p = 0.0007, respectively) and reduced metestrus (p = 0.0057 and p = 0.0083, respectively). Treated groups showed significantly reduced ova counts (p = 0.0002 and 0.0003, respectively). Histology revealed structural alterations of the ovary, including atretic follicles, distorted stroma, and sparse theca cells. Additionally, treated groups showed increased malondialdehyde (p = 0.0421) and decreased glutathione (p = 0.0046) and catalase activities (p = 0.0411), indicating oxidative stress. Serum follicle-stimulating and luteinizing hormones were significantly reduced in both treated groups (FSH: p < 0.0001 and p = 0.0002; LH: p < 0.0001 and p = 0.0108, respectively). In the clinical investigation, serum anti-Müllerian hormone (AMH) levels were evaluated in HIV-positive women (n = 20) receiving TLD-based cART. Ten participants (50%) had AMH in low/very low categories (< 1.0 ng/mL), while 11 (55%) had AMH below the normal reference range (< 1.5 ng/mL). Menstrual interval and dysmenorrhea showed no significant changes. These preliminary findings suggest Dolutegravir and TLD-based cART may negatively affect female reproductive function by altering ovarian structure, hormonal balance, and ovarian reserve, potentially predisposing women living with HIV to fertility complications.

Oral Pre-Exposure Prophylaxis (PrEP) is highly effective for HIV prevention when adherence is optimal, with rare HIV breakthrough infections usually happening within 1-2 years since PrEP start. After 6 years of daily PrEP, routine HIV testing identified seroconversion in a 46-year-old Italian cisgender man. He reported high adherence, confirmed by pharmacy refill history and plasma tenofovir concentration. Genotypic resistance test identified a recombinant HIV-1 strain with M184V and K70E reverse transcriptase mutations. Immediate antiretroviral therapy with FTC/TAF/DRV/c+DTG was initiated, achieving rapid viral suppression. A hair sample was sent for therapeutic drug monitoring and results were consistent with correct daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) before the acquisition of HIV infection. This case represents a rare PrEP failure after the longest reported duration of daily TDF/FTC PrEP with confirmed optimal adherence. It highlights that breakthrough HIV infection can occur even after many years of successful PrEP use, underlying the importance of periodic HIV surveillance.

Wastewater treatment performance is commonly evaluated based on contaminant removal, although environmental protection ultimately depends on reducing the cumulative ecological risk imposed by complex pharmaceutical mixtures. Here, we investigated the barrier-specific attenuation of estrogens, antidepressants, and antiretrovirals in a full-scale lagoon treatment system coupled to a pilot-scale constructed wetland by integrating repeated-measures ANOVA, barrier-specific log removal values (LRV), deterministic ecological risk assessment, and probabilistic mixture modeling using species sensitivity distributions (SSDs), and multisubstance potentially affected fraction (msPAF). Mean influent concentrations were 31.07 μg L[-1] for lamivudine and 322.75, 119.52, and 33.73 ng L[-1] for estrone, 17β-estradiol, and estriol, respectively. Pharmaceutical attenuation differed markedly among treatment barriers, with limited removal under anaerobic conditions and substantially greater attenuation during oxidative treatment and tertiary polishing. The constructed wetland provided the greatest incremental ecological protection, accounting for approximately 91.4% of the total cumulative deterministic ecological risk attenuation. Deterministic ecological risk identified efavirenz as the dominant contributor to cumulative long-term ecological risk, accounting for approximately 99.9% of the cumulative long-term deterministic risk throughout the wastewater treatment train. The short-term probabilistic mixture risk declined progressively from 0.651 in the influent to 0.602 after secondary treatment and was modeled as zero following tertiary wetland polishing. These findings demonstrate that wastewater treatment performance is more appropriately evaluated through barrier-specific ecological risk attenuation than concentration removal alone and highlight nature-based tertiary treatment as a highly effective strategy for mitigating pharmaceutical risks before environmental discharge.

A 66-year-old Chinese man with chronic hepatitis B treated with tenofovir disoproxil fumarate, a history of liver transplantation approximately 17 months earlier, hypertension, and atrial fibrillation treated with apixaban presented with progressive weakness, weight loss, and inability to ambulate. His only anti-rejection agent was tacrolimus. One month earlier, he had been hospitalized for multifocal pneumonia and treated with intravenous piperacillin-tazobactam for seven days after outpatient cefdinir failed. He was discharged without antibiotics. Bronchoscopy showed no endobronchial lesions or mucosal abnormalities. The initial routine microbiologic results were negative, but mycobacterial cultures remained in prolonged incubation. After discharge but before his subsequent readmission, a sputum culture from the prior hospitalization identified Mycobacterium fortuitum. On readmission, he had profound hyponatremia with a serum sodium concentration of 105 mmol/L, requiring intensive care and hypertonic saline. Imaging showed progressive right upper lobe consolidation concerning for infection or malignancy. Several days into the readmission, a biopsy of a technically accessible right lower lobe nodule showed inflammation without malignancy or caseating granulomas. Shortly thereafter, a bronchoalveolar lavage culture obtained during the prior hospitalization identified Mycobacterium tuberculosis after prolonged incubation. Tissue culture from the lung biopsy later identified Nocardia beijingensis. Given the patient's immunosuppression and progressive pulmonary abnormalities, all three isolates were treated as potentially pathogenic with imipenem, trimethoprim-sulfamethoxazole, moxifloxacin, isoniazid, pyrazinamide, and a rifamycin, with tacrolimus adjustment for drug interactions. The relative contribution of each organism could not be established with certainty. This case highlights the diagnostic and therapeutic complexity of concurrent pulmonary organism detection in a transplant recipient.

Antiretroviral pre-exposure prophylaxis (PrEP) is less effective in women than expected, partly because drug exposure within the female genital tract is variable and may be influenced by the vaginal microbiome. We developed an integrated pharmacometrics and machine learning framework to evaluate associations between vaginal microbiome composition and cervical antiretroviral exposure in women with human immunodeficiency virus (HIV) receiving tenofovir (TFV)-, lamivudine (3TC)-, or emtricitabine (FTC)-containing regimens. Pharmacokinetic and microbiome data were obtained from two single-center studies in Uganda and the United States. Published population pharmacokinetic models were used to estimate individual parameters by maximum a posteriori Bayesian estimation and to simulate plasma and cervical tissue exposure metrics under sexual-activity-driven dosing that were not studied in these trials. Microbiome diversity was assessed using alpha and beta diversity analyses. Associations between microbial genera and cervical drug exposure were evaluated using correlation analysis, differential abundance testing, and three machine learning approaches: LASSO, random forest, and XGBoost. Overall vaginal microbiome diversity was not associated with cervical exposure to TFV, 3TC, or FTC. In contrast, specific taxa-level associations with cervical drug exposure were identified. For TFV, Gemella was positively associated with cervical TFV-diphosphate exposure, whereas Megasphaera and Falsiporphyromonas were negatively associated across multiple models. For 3TC, Dialister, Prevotella, Atopobium, Streptobacillus, and Gardnerella were repeatedly identified. For FTC, Bifidobacteriaceae was consistently selected, with Lachnospiraceae and Prevotellaceae also implicated. This pharmacometrics-machine learning framework identified specific vaginal taxa associated with cervical antiretroviral exposure, supporting the future development of microbiome-based biomarkers and precision PrEP strategies for women.