Evaluating the performance of the GeneXpert HIV-1 qualitative assay as a consecutive test for a new early infant diagnosis algorithm in South Africa.

BACKGROUND: The proportion of HIV-exposed infants and young children infected with HIV in South Africa (SA) has declined markedly over the past decade as a result of the country's comprehensive prevention of mother-to-child transmission programme. This decrease has in turn reduced the positive predictive value (PPV) of diagnostic assays, necessitating review of early infant diagnosis (EID) algorithms to ensure improved accuracy. OBJECTIVES: To evaluate the performance of the GeneXpert HIV-1 qualitative assay (Xpert EID) as a consecutive test for infants with an 'HIV-detected' polymerase chain reaction screening test at birth. METHODS: We retrospectively analysed a longitudinal cohort of HIV-exposed infants on whom birth testing was performed, using whole-blood ethylenediaminetetra-acetic acid samples, from four tertiary sites in Gauteng Province between June 2014 and December 2019. Birth samples from all infants with a Cobas AmpliPrep/Cobas TaqMan HIV-1 Qualitative Test v2.0 (CAP/CTM v2.0) HIV-detected screening test, a concurrent Xpert EID test and a subsequent confirmatory CAP/CTM v2.0 test on a separate specimen were included. Performance of the Xpert EID in predicting final HIV status was determined as proportions with 95% confidence intervals (CIs). A comparison of indeterminate CAP/CTM v2.0 results, as per National Health Laboratory Service resulting practice, with discordant CAP/CTM v2.0 v. Xpert EID results was performed. RESULTS: Of 150 infants who met the inclusion criteria, 6 (3.9%) had an Xpert EID result discordant with final HIV status: 5 (3.3%) were false negatives and 1 (0.7%) was false positive. As a consecutive test, the Xpert EID yielded a sensitivity of 96.5% (95% CI 92 - 98.9), specificity of 85.7% (95% CI 42.1 - 99.6), PPV of 99.3% (95% CI 95.7 - 99.9), negative predictive value of 54.5% (95% CI 32.5 - 74.9) and overall accuracy of 96.1% (95% CI 91.5 - 98.5). Using discordant CAP/CTM v2.0/Xpert EID results as criteria to verify indeterminate results instead of current practice would have reduced the number of indeterminate screening results by 42.1%, from 18 (12.6%) to 11 (7.2%), without increasing the false-positive rate. CONCLUSIONS: Addition of the Xpert EID as a consecutive test for specimens with an HIV-detected PCR screening result has the potential to improve the PPV and reduce the indeterminate rate, thereby reducing diagnostic challenges and time to final status, in SA's EID programme.

The next generation: Pregnancy in adolescents and women living with perinatally acquired HIV in South Africa.

BACKGROUND: An increasing number of girls living with perinatally acquired HIV (PHIV) are reaching adolescence and adulthood and becoming pregnant. Youth living with PHIV (YLPHIV) may have HIV-associated infections/complications, long-term exposure to antiretroviral treatment (ART), drug resistance and increased psychosocial challenges, which may adversely affect pregnancy outcomes. There is a lack of published studies on pregnancy in YLPHIV in sub-Saharan Africa. Objectives. To describe characteristics of pregnant South African (SA) YLPHIV and their pregnancy outcomes. METHODS: We retrospectively identified pregnancies in YLPHIV, who were diagnosed with HIV when they were <12 years old and before their first pregnancy (as a proxy for perinatal route of infection), from routinely collected data in Western Cape Province, SA (2007 - 2018). We combined these with pregnancies from a Johannesburg cohort of YLPHIV. Results. We identified 258 pregnancies among 232 females living with likely PHIV; 38.8% of pregnancies occurred in YLPHIV ≤16 years old, 39.1% at age 17 - 19 years and 22.1% at age ≥20 years. In recent years, a steady increase in the number of pregnancies in YLPHIV was noted; more than two-thirds occurred during 2016 - 2018. ART was commenced prior to pregnancy in 84.9% of YLPHIV, during pregnancy in 6.6% and was not commenced by pregnancy end date in 8.5%. Of the pregnancies in young women with documented outcomes (88.8%; n=229), 80.3% were live births, 14.4% terminations, 3.1% miscarriages and 2.2% stillbirths. Mother-to-child transmission of HIV occurred in 2.2% of infants, 75.3% were uninfected when last tested and 22.6% had unknown HIV status. Among YLPHIV with CD4 counts available within 12 months of pregnancy end date (n=202), 20.3% had a CD4 count <200 cells/µL, 43.1% CD4 count 200 - 499 cells/µL and 36.6% CD4 count ≥500 cells/µL. Among those with a viral load (VL) available within 12 months of pregnancy end date (n=219), 66.7% had a VL <400 copies/mL, 5.0% VL 400 - 999 copies/mL and 28.3% VL ≥1 000 copies/mL. Of 186 neonates, 20.4% were preterm deliveries (<37 weeks' gestation). Among neonates with known birthweight (n=176), the mean birthweight was 2 900 g (95% confidence interval (CI) 2 747 - 2 935 g) and 20.5% had a low birthweight (<2 500 g). One congenital malformation (musculoskeletal) and 2 neonatal deaths were recorded. CONCLUSIONS: In recent years, the number of pregnancies in YLPHIV has increased. A considerable proportion of pregnancies occurred in YLPHIV ≤16 years old. A high proportion of pregnancies was electively terminated. The prevalence of elevated VL and poor immunological status among pregnant YLPHIV is concerning.

[Necrobiosis lipoidica. Variants on a theme]. / Necrobiosis lipoidica. Kasuistische Vielfalt einer Diagnose.

A 69-year-old patient presented with different skin lesions all of which belonged to group of necrobiosis lipoidica. The initial histologic diagnosis was actinic granuloma O'Brien. A subsequent biopsy was interpreted as granulomatous necrobiosis lipoidica. The history of these necrobiotic variants is reviewed and exemplarily depicted with this case. Necrobiosis lipoidica is part of the spectrum of granulomatous skin disorders. Although its etiology is unclear, an association with diabetes mellitus is often discussed. Multiple therapeutic options exist, but standardized guidelines for treatment are missing.

Nephrogenic systemic fibrosis following exposure to gadolinium-containing contrast agent.

Nephrogenic systemic fibrosis (NSF) is a disease recently described in patients with kidney failure. It is characterized by scleroderma-like thickening of the skin, subcutaneous edema and ensuing joint contractures leading to profound disability. Furthermore, involvement of internal organs has been described. Whereas the pathogenesis is not known to date, recent reports have linked NSF to high doses of gadolinium-containing contrast agents given at magnetic resonance angiography (MRA). We describe a patient with severe NSF. The patient had received erythropoietin and had undergone vascular interventions which are suspected risk factors for this disease. Notably, the disease developed shortly after the application of gadolinium at an MRA, giving support to the recently published hypothesis that gadolinium-containing contrast agents are among the causative factors. We provide a short overview and hope to raise overall awareness towards this entity and the use of MRA contrast agents in renal patients.

Concordant upregulation of type II-TGF-beta-receptor, the cyclin-dependent kinases inhibitor P27Kip1 and cyclin E in human atherosclerotic tissue: implications for lesion cellularity.

Atherosclerosis is a 'response-to-injury' process associated with chronic inflammation, tissue repair and a considerable cell turnover. These growth-related processes are controlled by the 'cell cycle clock' which is composed of cyclin-dependent kinases (Cdks), their activating subunits, the cyclins, and by inhibitors of Cdks (Ckis). P27 is a Cki which associates with cyclin A-Cdk2, cyclin D-Cdk4 and with cyclin E (CE)-Cdk2 complexes thereby abrogating their catalytic activity leading to potent inhibition of late G1 to S-phase transition. Furthermore, TGF-beta1 mRNA and immunoreactivity are locally increased in atherosclerotic lesions. Since TGF-beta1 growth suppressive function in the late G1 phase may be mediated by p27, blocking the catalytic activity of CE-Cdk2 complexes, via the stimulation of TGF-beta-RI and TGF-beta-RII, we investigated the topographical association between TGF-beta-RI, TGF-beta-RII, P27Kip1 and CE by immunohistochemistry in coronary artery segments without atherosclerosis and carotid atheromatous plaques of 11 patients undergoing carotid endarterectomy. P27-immunoreactivity was present in 11/11 atherosclerotic (92.7 +/- 3.3% of the cells) and 5/5 control (80.9 +/- 3.7% of the cells; P < 0.002 versus control) specimens and localized to nuclei of macrophages (CD68-positive), vascular smooth muscle cells (alpha-actin positive), T-lymphocytes (CD3-positive) as well as to the nuclei of endothelial cells. In the atherosclerotic tissue, TGF-beta-RI and TGF-beta-RII-immunoreactivity was present in 11/11 specimens and localized to inflammatory cells and to cells with VSMC-like-morphology. TGF-beta-RI-immunoreactivity was present in 87.4 +/- 5.3% (controls 75.3 +/- 7.48%; n.s.) and TGF-beta-RII-immunoreactivity was present in 83.7 +/- 6.8% (controls 39.5 +/- 7.3%; P < 0.002) of the cells. Double immunolabeling, and investigation of serial sections revealed co-expression of TGF-beta-RI and TGF-beta-RII in virtually all cells positive for P27. In the atherosclerotic specimens, CE-immunoreactivity was present in all specimens in macrophages (CD68-positive), vascular smooth muscle cells (alpha-actin positive) and in endothelial cells in 12.58 +/- 13.58% of the nuclei whereas in the controls CE staining was restricted to 0.19 +/- 0.43% of the cells (P < 0.001). Importantly, as shown by immunofluorescent double-labeling, we found cells expressing P27 that were simultaneously positive for CE. In summary, the present study provides evidence that TGF-beta1 present in human atherosclerotic tissue may mediate its growth suppressive activity also by p27, blocking the activity of CE-Cdk2 complexes. Quantitative analysis revealed that TGF-beta-RII, p27 and CE are concordantly upregulated in the atherosclerotic tissue with chronic inflammation, supporting the view that TGF-beta1, p27 and CE may play an important role in the processes associated with chronic inflammation and cell turnover in advanced human atherosclerotic plaques. Taken together, these results provide a possible link between the chronic inflammation associated with advanced atherosclerosis, the effects of extracellular growth factors and cell cycle control.