Tenofovir alafenamide: An initial experience at Groote Schuur Hospital, Cape Town, South Africa.

BACKGROUND: Hepatitis B virus (HBV) remains endemic in South Africa (SA), with a concomitantly high prevalence of HIV co-infection. Chronic kidney disease in these subpopulations also has a high prevalence. Tenofovir is an important component of management, but the associated risk of nephrotoxicity makes dosing a challenge in patients with impaired kidney function. A new formulation, tenofovir alafenamide fumarate (TAF), with a more favourable renal toxicity profile, is now available. OBJECTIVES: To evaluate our initial experience of TAF use at Groote Schuur Hospital, Cape Town. METHODS: We retrospectively reviewed patients with HBV mono-infection and HIV-HBV co-infection who were initiated on TAF since 2018. We recorded all relevant demographic, serological, virological and biochemical data from patient records. Adherence was documented by pill collection at the pharmacy. RESULTS: A total of 26 patients were included in the evaluation, median (interquartile range (IQR)) age 48 (39 - 51) years, 73% (n=19) male, 27% (n=7) hepatitis B e-antigen-positive, and 46% (n=12) HIV co-infected. The median (IQR) duration of treatment with TAF was 13 (9 - 15) months. The median (IQR) baseline creatinine level was 180 (130 - 227) µmol/L, with significant improvement at 12 months, 122 (94 - 143) µmol/L; p=0.017. Reflecting this change, the estimated glomerular filtration rate improved significantly from baseline to month 12 (42 (25 - 52) and 51 (48 - 68) mL/min/1.73 m2, respectively; p=0.023). Similarly, serum alanine aminotransferase (ALT) normalised from a baseline of 33 (18 - 52) to 18 (15 - 24) U/L at month 12 (p=0.012). HBV DNA viral load also declined, from a baseline of log10 4.04 (2.5 - 7.8) IU/mL to a median of <log10 1.3 IU/mL at month 12. HIV viral load was less than the lower level of quantification at months 6 and 12. CONCLUSIONS: TAF was well tolerated, with stable and significantly improving kidney function throughout a 12-month follow-up period. Serum ALT normalised, mirrored by declining HBV viral load. HIV viral load remained undetectable at 6 and 12 months.

The functionality of African-specific variants in the TGFB1 regulatory region and their potential role in HIVAN.

BACKGROUND: Transcription of transforming growth factor beta-1 (TGF-ß1) is regulated by a polymorphic promoter region containing African-specific single nucleotide polymorphisms (SNPs). Some of these SNPs have higher frequencies among Southern Africans compared to other African populations and their functionality has only been partially studied. Due to the high prevalence of HIV-associated nephropathy (HIVAN) in Africans we hypothesized that functional African TGFB1-promoter SNPs may contribute to HIVAN pathogenesis. METHODS: The functionality of the TGFB1 -1347 C>T variant and African-specific variants (-1287 G>A, -1154 C>T, -387 C>T and -14 G>A) were examined by measuring reporter gene expression in kidney and fibroblast cell lines co-transfected with TGFB1-promoter constructs and an HIV-Tat expression vector. TGF-ß1 immunohistochemical staining was performed on kidney biopsies with HIVAN (n = 18) and compared to control biopsies without HIVAN or tubulointerstitial disease (n = 12) using semi-quantitative and digital image analysis. HIVAN cases were genotyped for TGFB1 -1347 and -387 SNP variants. RESULTS: TGFB1-promoter haplotypes containing the African -387 T-allele resulted in ~ five-fold repression of TGFB1-promoter activity compared to -387 C haplotypes (p ≤ 0.024). HIV-Tat upregulated TGFB1-promoter activity for haplotypes containing -1347 T and -387 T in transfected renal cells (≈ 1.6-fold; p ≤ 0.030) and fibroblasts (≈ 1.3-fold; p ≤ 0.016). The renal interstitium from HIVAN biopsies, compared to HIV-positive and -negative controls, differed in the semi-quantitative TGF-ß1 staining and digital optical density analyses. The TGFB1 -1347 and -387 genotypes in HIVAN cases were similar to population controls. CONCLUSION: African-specific haplotypes lower TGFB1-promoter activity and expression levels and HIV-Tat upregulates TGFB1 promoter activity irrespective of the haplotype.

High prevalence of "non-dipping" blood pressure and vascular stiffness in HIV-infected South Africans on antiretrovirals.

BACKGROUND: HIV-infected individuals are at increased risk of tissue inflammation and accelerated vascular aging ('inflamm-aging'). Abnormal diurnal blood pressure (BP) rhythms such as non-dipping may contribute to an increased risk of cardiovascular and cerebrovascular events in HIV infected individuals. However, little data exists on ambulatory blood pressure (ABP) and measures of vascular stiffness in the black African HIV infected population. METHODS: This is a cross-sectional analysis of otherwise well, HIV infected outpatients on ART for >5 years. Study assessments included: 24hr ABP monitoring, pulse wave velocity (PWV) and central aortic systolic pressure (CASP) using a AtCor Medical Sphygmocor device, fasting lipogram, oral glucose tolerance test, high-sensitivity C-reactive protein (hsCRP) and anthropometric data. Patients completed a questionnaire of autonomic symptoms. CD4+ counts and viral loads were obtained from the National Laboratory results system. RESULTS: Sixty seven black participants were included in the analysis of whom 91% (n = 61) were female with a mean age of 42.2 ± 8.6 years. The median duration on ART was 7.5 years (IQR = 6-10), 84% were virally supressed and the median CD4 count was 529.5cells/mm3 (IQR = 372.0-686.5). The majority (67%) were classified as overweight and 76% had an increased waist circumference, yet only 88% of participants were normotensive. A hsCRP level in the high cardiovascular risk category was found in 68% of participants. The prevalence of non-dipping BP was 65%. Interestingly, there was no association on multivariable analysis between dipping status and traditional risk factors for non-dipping BP, such as: obesity, autonomic dysfunction and older age. CONCLUSION: This relatively young cross-sectional sample of predominantly normotensive, but overweight black women on effective ART >5 years showed: a high prevalence of non-dipping BP, inflammation and vascular stiffness. Causality cannot be inferred but cardiovascular risk reduction should be emphasized in these patients.