Human monkeypox virus infection in women and non-binary individuals during the 2022 outbreaks: a global case series.

BACKGROUND: Between May and November, 2022, global outbreaks of human monkeypox virus infection have been reported in more than 78 000 people worldwide, predominantly in men who have sex with men. We describe the epidemiological and clinical characteristics of monkeypox virus infection in cisgender (cis) and transgender (trans) women and non-binary individuals assigned female sex at birth to improve identification and understanding of risk factors. METHODS: International collaborators in geographical locations with high numbers of diagnoses of monkeypox virus infection were approached and invited to contribute data on women and non-binary individuals with confirmed monkeypox virus infection. Contributing centres completed deidentified structured case-report spreadsheets, adapted and developed by participating clinicians, to include variables of interest relevant to women and non-binary individuals assigned female at birth. We describe the epidemiology and clinical course observed in the reported infections. FINDINGS: Collaborators reported data for a total of 136 individuals with monkeypox virus infection who presented between May 11 and Oct 4, 2022, across 15 countries. Overall median age was 34 years (IQR 28-40; range 19-84). The cohort comprised 62 trans women, 69 cis women, and five non-binary individuals (who were, because of small numbers, grouped with cis women to form a category of people assigned female at birth for the purpose of comparison). 121 (89%) of 136 individuals reported sex with men. 37 (27%) of all individuals were living with HIV, with a higher proportion among trans women (31 [50%] of 62) than among cis women and non-binary individuals (six [8%] of 74). Sexual transmission was suspected in 55 (89%) trans women (with the remainder having an unknown route of transmission) and 45 (61%) cis women and non-binary individuals; non-sexual routes of transmission (including household and occupational exposures) were reported only in cis women and non-binary individuals. 25 (34%) of 74 cis women and non-binary individuals submitted to the case series were initially misdiagnosed. Overall, among individuals with available data, rash was described in 124 (93%) of 134 individuals and described as anogenital in 95 (74%) of 129 and as vesiculopustular in 105 (87%) of 121. Median number of lesions was ten (IQR 5-24; range 1-200). Mucosal lesions involving the vagina, anus, or oropharynx or eye occurred in 65 (55%) of 119 individuals with available data. Vaginal and anal sex were associated with lesions at those sites. Monkeypox virus DNA was detected by PCR from vaginal swab samples in all 14 samples tested. 17 (13%) individuals were hospitalised, predominantly for bacterial superinfection of lesions and pain management. 33 (24%) individuals were treated with tecovirimat and six (4%) received post-exposure vaccinations. No deaths were reported. INTERPRETATION: The clinical features of monkeypox in women and non-binary individuals were similar to those described in men, including the presence of anal and genital lesions with prominent mucosal involvement. Anatomically, anogenital lesions were reflective of sexual practices: vulvovaginal lesions predominated in cis women and non-binary individuals and anorectal features predominated in trans women. The prevalence of HIV co-infection in the cohort was high. FUNDING: None.

Cytokine expression in the colonic mucosa of human immunodeficiency virus-infected individuals before and during 9 months of antiretroviral therapy.

High-level human immunodeficiency virus (HIV) replication and the rapid breakdown of the mucosal immune system are the hallmarks of HIV infection in the gut. Cytokine dysregulation may be related to both phenomena. Using real-time PCR we quantified the colonic mucosal mRNA expression of selected proinflammatory and regulatory (gamma interferon [IFN-gamma], tumor necrosis factor alpha [TNF-alpha], and interleukin-2 [IL-2], IL-4, IL-6, and IL-10) and HIV-inhibitory (IL-16, CCL3, and CCL5) cytokines for 10 HIV-infected patients before and during 9 months of highly active antiretroviral therapy (HAART). HIV RNA and T-cell dynamics were measured in the colonic mucosa and the blood. Seven HIV-negative individuals served as controls. The mucosal mRNA expression of TNF-alpha, IFN-gamma, IL-4, IL-6, and IL-10 was significantly higher in HIV-infected patients than in control patients and remained elevated during 9 months of HAART despite the decline in blood and mucosal HIV RNA levels and an increase in the level of CD4(+) T lymphocytes. The mRNA levels of CCL3 and CCL5, both of which were elevated before treatment, returned to nearly normal during therapy. Despite reductions in levels of mucosal HIV RNA and the restoration of mucosal CD4(+) T lymphocytes, antiretroviral therapy failed to restore the normal colonic immunologic environment.

Saquinavir, nelfinavir and M8 pharmacokinetics following combined saquinavir, ritonavir and nelfinavir administration.

OBJECTIVES: This study evaluated the steady-state pharmacokinetic interaction between ritonavir-boosted saquinavir and nelfinavir. METHODS: Open label, multiple-dose, two parallel-groups, single crossover study conducted in 24 HIV-infected patients (12 in each group). Patients in the nelfinavir group added saquinavir/ritonavir, 1000/100 mg twice daily to their ongoing stable treatment regimen consisting of nelfinavir, 1250 mg twice daily and two nucleoside reverse transcriptase inhibitors (NRTIs). Patients in the saquinavir group added nelfinavir, 1250 mg twice daily to their ongoing stable treatment regimen consisting of saquinavir/ritonavir, 1000/100 mg twice daily and two NRTIs. Pharmacokinetic assessments were performed before and 7 days after the start of combined treatment with nelfinavir/saquinavir/ritonavir. Blood samples were collected before and 1, 2, 3, 4, 6, 8, 10 and 12 h after dosing for measurement of nelfinavir, the nelfinavir metabolite M8 and saquinavir using liquid chromatography tandem mass spectrometry (LC-MS/MS). RESULTS: The addition of saquinavir/ritonavir to the nelfinavir-containing regimen resulted in significant increases in the M8 pharmacokinetic parameters AUC(0-12), Cmax and C12; geometric mean ratios (90% confidence intervals) of 2.25 ng.h/mL (1.47-3.44), 1.74 ng/mL (1.25-2.40) and 4.21 ng/mL (2.10-8.47), respectively. The intra-individual changes in nelfinavir and saquinavir concentrations were highly variable. Statistical analysis could not discard a relevant interaction but includes the possibility that some parameters may be halved, others more than doubled. At the same time the analysis failed to show any directed change. CONCLUSIONS: The co-administration of nelfinavir and saquinavir/ritonavir leads to unpredictable changes in concentrations of both drugs. It is unclear whether the increased concentrations of M8 are associated with a clinical benefit.

Pharmacokinetics of enfuvirtide in patients treated in typical routine clinical settings.

Therapeutic drug monitoring (TDM) is gaining importance for improving the success of antiretroviral treatment in human immunodeficiency virus-infected patients. However, enfuvirtide (ENF) concentrations are not regularly determined. The objective of this work was to study the pharmacokinetics (PK) of ENF in patients treated in routine clinical settings, to develop a population PK model describing the concentration-time profile, and to establish PK reference values. A liquid chromatography-tandem mass spectrometry method was developed and applied to serum samples submitted for TDM. A two-compartment model with linear absorption and elimination was fitted to 329 concentrations from 131 patients. The PK model was used for simulations resulting in percentile curves for ENF levels for the full dosing interval. The model predicted that a median concentration of 1,968 ng/ml would be reached 12 h after administration of 90 mg of ENF, and 23% and 58% of patients are expected to have concentrations below 1,000 ng/ml and 2,200 ng/ml, respectively. Both values have been proposed as cutoffs for virological efficacy. The median maximum concentration of drug in serum (Cmax) of 3,943 ng/ml, predicted for 3 h after drug administration, is lower than the Cmax reported previously. We found an enormous interpatient variability at every time point, with concentration spectrums covering >1 log and 52% and 123% interindividual variabilities in the typical clearance and volume of distribution, respectively, in contrast to preexisting PK data. In summary, ENF levels are lower and more variable than expected. Many patients may achieve insufficient concentrations. Further covariate analysis in the population PK model might help to identify factors influencing the variability in ENF concentrations.