Sophie Jose

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 m2/year [95% confidence interval {CI}, −20.5 to −10.9] during the first 3 months and −3.1 mL/minute/1.73 m2/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 m2/year [95% CI, 8.9–16.1] during the first 3 months and 0.8 mL/minute/1.73 m2/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.

Risk factors for recurrent primary sclerosing cholangitis after liver transplantation

BACKGROUND & AIMS The association between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) is well recognised. However, the relationship between IBD and recurrent PSC (rPSC) is less well understood. We assessed the prevalence of rPSC and analysed the factors associated with rPSC post-liver transplantation and its influence on graft and patient survival. METHODS This is a UK multicentre observational cohort study across six of the seven national liver transplant units. All patients undergoing a first liver transplant for PSC between January 1 1990 and December 31 2010 were included. Prospectively collected liver transplant data was obtained from NHSBT and colitis data was retrospectively collected from individual units. RESULTS There were 679 (8.8%) first transplants for PSC. 347 patients (61.4%) had IBD, of which 306 (88.2%) had ulcerative colitis (UC). 81 (14.3%) patients developed rPSC and 37 (48.7%) of them developed graft failure from rPSC. Presence of UC post-liver transplant (HR=2.40, 95% CI 1.44-4.02) and younger age (HR=0.78, 95% CI 0.66-0.93) were the only factors significantly associated with rPSC. rPSC was associated with over a 4-fold increase in the risk of death (HR=4.71, 95% CI 3.39, 6.56) with 1, 5, and 10-year graft survival rates of 98%, 84%, and 56% respectively compared to 95%, 88%, and 72% in patients who did not develop rPSC. CONCLUSION The presence of UC post-liver transplant is associated with a significantly increased risk of rPSC. Furthermore, the presence of rPSC increases the rate of graft failure and death, with higher re-transplantation rates.

Predicted savings to the UK National Health Service from switching to generic antiretrovirals, 2014-2018.

In other disease areas, generic drugs are normally used after patent expiry. Patents on zidovudine, lamivudine, nevirapine and efavirenz have already expired. Patents will expire for abacavir in late 2014, lopinavir/r in 2016, and tenofovir, darunavir and atazanavir in 2017. However, patents on single‐tablet regimens do not expire until after 2026.

Effects of age on antiretroviral plasma drug concentration in HIV-infected subjects undergoing routine therapeutic drug monitoring

OBJECTIVES The pharmacokinetic and pharmacodynamic effects of antiretroviral therapy may differ in older compared with younger subjects with HIV infection. We aimed to assess factors associated with plasma antiretroviral drug exposure, including age, within a large HIV-infected cohort undergoing therapeutic drug monitoring (TDM). METHODS Data from the Liverpool TDM Registry were linked with the UK Collaborative HIV Cohort (CHIC) Study. All TDM of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) was included and in order to account for different antiretroviral drugs the plasma concentrations were standardized by group measurements according to drug, dosing and timing of TDM. Regression modelling was used to evaluate associations of drug exposure with age and clinical parameters, including hepatic transaminase results and time to antiretroviral treatment modification. RESULTS Data from 3589 TDM samples were available from 2447 subjects. The greatest numbers of plasma concentrations were assessed for lopinavir (22.4%), efavirenz (18.5%), atazanavir (17.0%) and saquinavir (11.6%). As age increased, median standardized NNRTI concentrations remained constant, whereas PI concentrations increased (correlation coefficient 0.04, P = 0.033). In a regression analysis stratified by antiretroviral drug class, standardized plasma concentrations were significantly associated with age for PIs (0.05 increase in standard deviation of drug concentration with each 10 year increase in age, P = 0.044), but not for NNRTIs or other clinical parameters, including hepatic transaminase results or time to antiretroviral treatment modification. CONCLUSIONS With increasing age, statistically significant rises in plasma PI exposure, but not NNRTI exposure, were observed. The clinical relevance of this observation merits further investigation.

Comparative effectiveness of immediate antiretroviral therapy versus CD4-based initiation in HIV-positive individuals in high-income countries: observational cohort study

BACKGROUND Recommendations have differed nationally and internationally with respect to the best time to start antiretroviral therapy (ART). We compared effectiveness of three strategies for initiation of ART in high-income countries for HIV-positive individuals who do not have AIDS: immediate initiation, initiation at a CD4 count less than 500 cells per μL, and initiation at a CD4 count less than 350 cells per μL. METHODS We used data from the HIV-CAUSAL Collaboration of cohort studies in Europe and the USA. We included 55,826 individuals aged 18 years or older who were diagnosed with HIV-1 infection between January, 2000, and September, 2013, had not started ART, did not have AIDS, and had CD4 count and HIV-RNA viral load measurements within 6 months of HIV diagnosis. We estimated relative risks of death and of death or AIDS-defining illness, mean survival time, the proportion of individuals in need of ART, and the proportion of individuals with HIV-RNA viral load less than 50 copies per mL, as would have been recorded under each ART initiation strategy after 7 years of HIV diagnosis. We used the parametric g-formula to adjust for baseline and time-varying confounders. FINDINGS Median CD4 count at diagnosis of HIV infection was 376 cells per μL (IQR 222-551). Compared with immediate initiation, the estimated relative risk of death was 1·02 (95% CI 1·01-1·02) when ART was started at a CD4 count less than 500 cells per μL, and 1·06 (1·04-1·08) with initiation at a CD4 count less than 350 cells per μL. Corresponding estimates for death or AIDS-defining illness were 1·06 (1·06-1·07) and 1·20 (1·17-1·23), respectively. Compared with immediate initiation, the mean survival time at 7 years with a strategy of initiation at a CD4 count less than 500 cells per μL was 2 days shorter (95% CI 1-2) and at a CD4 count less than 350 cells per μL was 5 days shorter (4-6). 7 years after diagnosis of HIV, 100%, 98·7% (95% CI 98·6-98·7), and 92·6% (92·2-92·9) of individuals would have been in need of ART with immediate initiation, initiation at a CD4 count less than 500 cells per μL, and initiation at a CD4 count less than 350 cells per μL, respectively. Corresponding proportions of individuals with HIV-RNA viral load less than 50 copies per mL at 7 years were 87·3% (87·3-88·6), 87·4% (87·4-88·6), and 83·8% (83·6-84·9). INTERPRETATION The benefits of immediate initiation of ART, such as prolonged survival and AIDS-free survival and increased virological suppression, were small in this high-income setting with relatively low CD4 count at HIV diagnosis. The estimated beneficial effect on AIDS is less than in recently reported randomised trials. Increasing rates of HIV testing might be as important as a policy of early initiation of ART. FUNDING National Institutes of Health.

The Human Immunodeficiency Virus Continuum of Care in European Union Countries in 2013: Data and Challenges

Summary Definitions for a 4-stage continuum of HIV care were standardized and applied to HIV surveillance and national cohort data in 11 European Union countries. These countries are nearing the UNAIDS 90-90-90 target, although reducing the proportion undiagnosed remains challenging.

Renal tubular disease in the era of combination antiretroviral therapy.

Objectives:To describe the spectrum of renal tubular disease (RTD) in HIV-positive patients and its association with exposure to antiretroviral therapy (ART). Design:Review of 265 consecutive renal biopsies from HIV-positive patients attending eight clinics in the United Kingdom between 2000 and 2012. Methods:We described the clinical characteristics of patients with RTD and compared current/recent exposure (at the time of, or up to 3 months prior to the date of biopsy) to potentially nephrotoxic ART [tenofovir (TDF), atazanavir (ATV), indinavir (IDV) and lopinavir/ritonavir (LPV/r)]. We also analysed the incidence of RTD in the UK CHIC cohort. Kruskall–Wallis, analysis of variance and Fishers exact tests were used to evaluate between-group differences. Results:Of the 60 RTD cases, 54 (90%) were included in the analyses. RTD comprised of three distinct patterns: acute tubular injury (ATI, n = 22), tubulo-interstitial nephritis (TIN, n = 20) and interstitial fibrosis and tubular atrophy (IFTA, n = 12). Compared with TIN and IFTA, ATI cases were less likely to be of black ethnicity (10 vs. 42–55%; P = 0.006), more likely to be on ART (100 vs. 55–68%; P = 0.001), with HIV-RNA below 200 copies/ml (100 vs. 54–58%; P < 0.001), and more likely to have current/recent exposure to TDF (P < 0.001). We did not find evidence for an association between exposure to TDF, ATV/r or LPV/r and either TIN or IFTA. Conclusion:RTD was present in approximately 20% of renal biopsies and comprised three distinct injury patterns with considerable clinical overlap. ATI was associated with TDF exposure, although the overall incidence of biopsy-defined ATI was low.

End-stage Kidney Disease and Kidney Transplantation in Hiv-positive Patients: An Observational Cohort Study

Abstract:End-stage kidney disease (ESKD) is a major complication of HIV infection. We observed a 3.8-fold increase in ESKD prevalence among black patients in the UK CHIC cohort during the 12-year study period. As of 2005, 107 patients had an ESKD diagnosis, 69 of whom (64%) were considered suitable for kidney transplantation (KT) and 34 (32%) had received a KT. Survival was similar for KT recipients and those awaiting KT (85% and 89% at 5 years, respectively; P = 0.53). Our results endorse the use of KT to manage ESKD in HIV-positive patients.

No association between vitamin D deficiency and parathyroid hormone, bone density and bone turnover in a large cohort of HIV-infected men on tenofovir.

Combination antiretroviral therapy (cART) may affect vitamin D [25(OH)D], parathyroid hormone (PTH), bone mineral density (BMD) and bone turnover (BT). Reduced BMD and secondary hyperparathyroidism have been reported with tenofovir (TDF). We investigated the associations between TDF and bone markers, especially in 25(OH)D‐deficient patients.

Sexual and reproductive health in a UK cohort of young adults perinatally infected with HIV

Objectives To assess sexual health and behaviour outcomes of young adults with perinatally acquired HIV-1 (PaHIV), and audit sexual health interventions against published standards of care. Methods Retrospective case note audit of 16–25-year-olds with PaHIV attending a dedicated transition clinic from January 2005 to 2011. Results Fifty-two young adults, 31 women, median age 20 years. 41 were sexually active; median age of coitarche 16 years. Median number of lifetime partners was 3.5, and five reported non-consensual sex. All had a sexually transmitted infection (STI) screen; 6 were diagnosed with an STI, genital warts (human papilloma virus) most frequently. The median interval from coitarche to first STI screen was 2 years. The pregnancy incidence was 103 per 1000 person years. 18/25 (72%) sexually active women had a cervical smear, four had colposcopy. All patients had hepatitis B virus (HBV) serology. 47 had not been vaccinated against HBV prior to transition. 23 completed HBV vaccination of which 11 had surface antibody >100 IU/ml at 1 year. Conclusions The majority of our cohort was sexually active while still under the care of paediatric health services. Cervical screening and hepatitis B vaccination rates fell short of audit standards. Vaccination for hepatitis B should be considered prior to transfer of care to adult HIV services.