Incomplete reversibility of estimated glomerular filtration rate decline following tenofovir disoproxil fumarate exposure.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) has been linked to renal impairment, but the extent to which this impairment is reversible is unclear. We aimed to investigate the reversibility of renal decline during TDF therapy. METHODS: Cox proportional hazards models assessed factors associated with discontinuing TDF in those with an exposure duration of >6 months. In those who discontinued TDF therapy, linear piecewise regression models estimated glomerular filtration rate (eGFR) slopes before initiation of, during, and after discontinuation of TDF therapy. Factors associated with not achieving eGFR recovery 6 months after discontinuing TDF were assessed using multivariable logistic regression. RESULTS: We observed declines in the eGFR during TDF exposure (mean slopes, -15.7 mL/minute/1.73 m(2)/year [95% confidence interval {CI}, -20.5 to -10.9] during the first 3 months and -3.1 mL/minute/1.73 m(2)/year [95% CI, -4.6 to -1.7] thereafter) and evidence of eGFR increases following discontinuation of TDF therapy (mean slopes, 12.5 mL/minute/1.73 m(2)/year [95% CI, 8.9-16.1] during the first 3 months and 0.8 mL/minute/1.73 m(2)/year [95% CI,.1-1.5] thereafter). Following TDF discontinuation, 38.6% of patients with a decline in the eGFR did not experience recovery. A higher eGFR at baseline, a lower eGFR after discontinuation of TDF therapy, and more-prolonged exposure to TDF were associated with an increased risk of incomplete recovery 6 months after discontinuation of TDF therapy. CONCLUSIONS: This study shows that a decline in the eGFR during TDF therapy was not fully reversible in one third of patients and suggests that prolonged TDF exposure at a low eGFR should be avoided

HIV-associated central nervous system diseases in the recent combination antiretroviral therapy era

BACKGROUND AND PURPOSE Data describing the incidence and survival of HIV-related central nervous system diseases (CNS-D) in recent years are sparse. METHODS Between 1996 and 2007, adult subjects without previous CNS-D within a large UK cohort were included (n=30,954). CNS-D were HIV encephalopathy (HIVe), progressive multifocal leucoencephalopathy (PML), cerebral toxoplasmosis (TOXO) and cryptococcal meningitis (CRYP). Associations between demographic, clinical and laboratory parameters with incidence and survival of CNS-D were evaluated using Poisson regression analysis and Kaplan-Meier techniques. RESULTS Six hundred and thirteen new CNS-D occurred in 574 subjects (HIVe:187, PML:113, TOXO:184, CRYP:129). Incidence of all CNS-D declined from 13.1 per 1000 PY in 1996/1997 to 1.0 per 1000 PY in 2006/2007 (P=0.0001). Current CD4+ cell count below 200 cells/ul and plasma HIV RNA above 100,000 copies/ml were independently associated with the development of CNS-D. Calendar year 1996/1997, older age, prior AIDS diagnosis and PML diagnosis were significantly associated with shorter survival. CONCLUSIONS An ongoing decline in the incidence of CNS-D has been observed in very recent years. Mortality following such a diagnosis remains high

Recent trends and patterns in HIV-1 transmitted drug resistance in the United Kingdom.

OBJECTIVES Transmission of drug-resistant HIV-1 has decreased in the UK since the early 2000s. This analysis reports recent trends and characteristics of transmitted drug resistance (TDR) in the UK from 2010 to 2013. METHODS Resistance tests conducted in antiretroviral treatment (ART)-naïve individuals between 2010 and 2013 were analysed for the presence of transmitted drug resistance mutations (TDRMs), defined as any mutations from a modified 2009 World Health Organization surveillance list, or a modified 2013 International Antiviral Society-USA list for integrase tests. Logistic regression was used to examine associations between demographics and the prevalence of TDRMs. RESULTS TDRMs were observed in 1223 (7.5%) of 16 425 individuals; prevalence declined from 8.1% in 2010 to 6.6% in 2013 (P = 0.02). The prevalence of TDRMs was higher among men who have sex with men (MSM) compared with heterosexual men and women (8.7% versus 6.4%, respectively) with a trend for decreasing TDRMs among MSM (P = 0.008) driven by a reduction in nucleoside reverse transcriptase inhibitor (NRTI)-related mutations. The most frequently detected TDRMs were K103N (2.2%), T215 revertants (1.6%), M41L (0.9%) and L90M (0.7%). Predicted phenotypic resistance to first-line ART was highest to the nonnucleoside reverse transcriptase inhibitors (NNRTIs) rilpivirine and efavirenz (6.2% and 3.4%, respectively) but minimal to NRTIs, including tenofovir, and protease inhibitors (PIs). No major integrase TDRMs were detected among 101 individuals tested while ART-naïve. CONCLUSIONS We observed a decrease in TDRMs in recent years. However, this was confined to the MSM population and rates remained stable in those with heterosexually acquired HIV infection. Resistance to currently recommended first-line ART, including integrase inhibitors, remained reassuringly low

A tale of two countries: all-cause mortality among people living with HIV and receiving combination antiretroviral therapy in the UK and Canada

OBJECTIVES: We sought to compare all-cause mortality of people living with HIV and accessing care in Canada and the UK. METHODS: Individuals from the Canadian Observational Cohort (CANOC) collaboration and UK Collaborative HIV Cohort (UK CHIC) study who were aged ≥ 18 years, had initiated antiretroviral therapy (ART) for the first time between 2000 and 2012 and who had acquired HIV through sexual transmission were included in the analysis. Cox regression was used to investigate the difference in mortality risk between the two cohort collaborations, accounting for loss to follow-up as a competing risk. RESULTS: A total of 19 960 participants were included in the analysis (CANOC, 4137; UK CHIC, 15 823). CANOC participants were more likely to be older [median age 39 years (interquartile range (IQR): 33, 46 years) vs. 36 years (IQR: 31, 43 years) for UK CHIC participants], to be male (86 vs. 73%, respectively), and to report men who have sex with men (MSM) sexual transmission risk (72 vs. 56%, respectively) (all P < 0.001). Overall, 762 deaths occurred during 98 798 person-years (PY) of follow-up, giving a crude mortality rate of 7.7 per 1000 PY [95% confidence interval (CI): 7.1, 8.3 per 1000 PY]. The crude mortality rates were 8.6 (95% CI: 7.4, 10.0) and 7.5 (95% CI: 6.9, 8.1) per 1000 PY among CANOC and UK CHIC study participants, respectively. No statistically significant difference in mortality risk was observed between the cohort collaborations in Cox regression accounting for loss to follow-up as a competing risk (adjusted hazard ratio 0.86; 95% CI: 0.72-1.03). CONCLUSIONS: Despite differences in national HIV care provision and treatment guidelines, mortality risk did not differ between CANOC and UK CHIC study participants who acquired HIV through sexual transmission