Metronidazole Treatment Failure and Persistent BV Lead to Increased Frequencies of Activated T- and Dendritic-Cell Subsets.

Metronidazole (MDZ) treatment failure and bacterial vaginosis (BV) recurrence rates are high among African women. This cohort study identified genital immune parameters associated with treatment response by comparing vaginal microbiota and immune cell frequencies in endocervical cytobrushes obtained from 32 South African women with symptomatic BV pre- and post-metronidazole treatment. Cervical T- and dendritic-cell subsets were phenotyped using multiparameter flow cytometry and the composition of vaginal microbial communities was characterized using 16S rRNA gene sequencing. MDZ treatment led to a modest decrease in the relative abundance of BV-associated bacteria, but colonization with Lactobacillus species (other than L. iners) was rare. At 6 and 12 weeks, MDZ-treated women had a significant increase in the frequencies of CCR5+ CD4+ T cells and plasmacytoid dendritic cells compared to the pre-treatment timepoint. In addition, MDZ non-responders had significantly higher frequencies of activated CD4 T cells and monocytes compared to MDZ responders. We conclude that MDZ treatment failure was characterized by an increased expression of activated T- and dendritic-cell subsets that may enhance HIV susceptibility. These data suggest the need to further assess the long-term impact of MDZ treatment on mucosal immune response and the vaginal microbiota.

High-risk human papillomavirus prevalence among South African women diagnosed with other STIs and BV.

INTRODUCTION: Human papillomavirus (HPV) infection is a leading cause of cervical cancer. Although this relies on infection and persistence of HPV in epithelial cells, often occurring in the context of other sexually transmitted infections (STIs) and bacterial vaginosis (BV), data on the relationships between these and their relative effects on epithelial barrier integrity in women remain sparse. This study describes the epidemiology of HPV combined with STI and/or BV prevalence and the relative impact on matrix metalloproteinases (MMPs) among South African women. METHODS: Roche Linear Array was used for HPV genotyping in menstrual cup pellets of 243 HIV-negative women participating in the CAPRISA 083 cohort study. Vulvovaginal swabs were tested for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis using Xpert® CT/NG assay and lateral flow assay, and Gram staining was performed to diagnose BV using Nugent scoring criteria. Concentrations of 5 MMPs were measured in menstrual cup supernatants by multiplexed ELISA. Fisher's exact tests, Mann-Whitney U tests, and multivariable regression models determined associations between HPV infection, STI and/or BV, and MMP concentrations. RESULTS: HPV was prevalent in 34% of women (83/243; median 23 years, interquartile range (IQR) 21-27 years). Low-risk (lr) (71%, 59/83) and high-risk (hr)-HPV infections (54.2%, 45/83) were common. Hr-HPV was frequently detected in STI and/or BV-positive women compared to women without STIs or BV (p = 0.029). In multivariable analysis, BV was associated with increased odds of hr-HPV detection (OR: 2.64, 95%CI: 1.02-6.87, p = 0.046). Furthermore, Gardasil®9 vaccine-type strains were more frequently detected in women diagnosed with STI and/or BV (55.2%, 32/58 vs 24%, 6/25; p = 0.009). Among STI and/or BV-positive women, HPV detection was significantly associated with increased MMP-10 concentrations (b = 0.55, 95% CI 0.79-1.01; p = 0.022). CONCLUSION: Most women with hr-HPV had another STI and/or BV, emphasizing an urgent need for STI and BV screening and intensive scale-up of cervical cancer screening and HPV vaccination programmes. Furthermore, the study highlights the need for more extensive research to confirm and understand the relationship between HPV infection and barrier integrity.

NPHS2 V260E Is a Frequent Cause of Steroid-Resistant Nephrotic Syndrome in Black South African Children.

INTRODUCTION: In South Africa (SA), steroid-resistant nephrotic syndrome (SRNS) is more frequent in black than in Indian children. METHODS: Seeking a genetic basis for this disparity, we enrolled 33 Indian and 31 black children with steroid-sensitive nephrotic syndrome (SSNS) and SRNS from KwaZulu-Natal, SA; SRNS children underwent kidney biopsy. We sequenced NPHS2 and genotyped APOL1 in 15 SSNS and 64 SRNS unrelated patients and 104 controls and replicated results in 18 black patients with steroid-resistant focal segmental glomerulosclerosis (SR-FSGS). Known FSGS genes (n = 21) were sequenced in a subset of patients. RESULTS: Homozygosity for NPHS2 V260E was found in 8 of 30 black children with SRNS (27%); all 260E/E carriers had SR-FSGS. Combining SR-FSGS patients from the 2 groups, 14 of 42 (33%) were homozygous for V260E. One black control was heterozygous for V260E; no Indian patients or controls were carriers. Haplotype analysis indicated that homozygosity for V260E was not explained by cryptic consanguinity. Children with NPHS2 260E/E developed SRNS at earlier age than noncarriers (34 vs. 78 months, P = 0.01), and none achieved partial or complete remission (0% vs. 47%, P = 0.002). APOL1 variants did not associate with NS. Sequencing FSGS genes identified a CD2AP predicted pathogenic variant in the heterozygous state in 1 Indian case with SR-FSGS. CONCLUSION: NPHS2 260E/E was present in one-third of black FSGS patients, was absent in black controls and Indian patients, and affected patients were unresponsive to therapy. Genotyping V260E in black children from South Africa with NS will identify a substantial group with SR-FSGS, potentially sparing these children biopsy and ineffective steroid treatment.