Tenofovir is an acyclic nucleotide analogue reverse-transcriptase inhibitor structurally similar to the nephrotoxic drugs adefovir and cidofovir. Tenofovir is widely used to treat HIV infection and approved for treatment of hepatitis B virus. Despite initial cell culture and clinical trials results supporting the renal safety of tenofovir, its clinical use is associated with a low, albeit significant, risk of kidney injury. Proximal tubular cell secretion of tenofovir explains the accumulation of the drug in these mitochondria-rich cells. Tenofovir nephrotoxicity is characterized by proximal tubular cell dysfunction that may be associated with acute kidney injury or chronic kidney disease. Withdrawal of the drug leads to improvement of analytical parameters that may be partial. Understanding the risk factors for nephrotoxicity and regular monitoring of proximal tubular dysfunction and serum creatinine in high-risk patients is required to minimize nephrotoxicity. Newer, structurally similar molecular derivatives that do not accumulate in proximal tubules are under study.

https://downloads.hindawi.com/journals/art/2011/354908.pdf

Tenofovir Nephrotoxicity: 2011 Update

In the US, an estimated 1 million people are infected with HIV, although one-third of this population are unaware of their diagnosis. While HIV infection is commonly thought to affect younger adults, there are an increasing number of patients over 50 years of age living with the condition. UNAIDS and WHO estimate that of the 40 million people living with HIV/AIDS in the world, approximately 2.8 million are 50 years and older. With the introduction of highly active antiretroviral therapy (HAART) in the mid-1990s, survival following HIV diagnosis has risen dramatically and HIV infection has evolved from an acute disease process to being managed as a chronic medical condition. As treated HIV-infected patients live longer and the number of new HIV diagnoses in older patients rise, clinicians need to be aware of these trends and become familiar with the management of HIV infection in the older patient. This article is intended for the general clinician, including geriatricians, and will review epidemiologic data and HIV treatment as well as provide a discussion on medical management issues affecting the older HIV-infected patient.

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HIV infection in the elderly

Tenofovir disoproxil fumarate (TDF), the first nucleotidic inhibitor of HIV reverse transcription, became available in 2001. It has been extensively used worldwide and is now the most prescribed antiretroviral (ARV) drug. Its high antiviral activity and favorable metabolic profile are responsible for its success. Furthermore, TDF has been associated with other ARVs to form new combined antiretroviral treatments in only one tablet once-a-day, which increases treatment adherence. Fears of potential nephrotoxicity that tenofovir would have in common with two other drugs from the same family (adefovir, used to treat hepatitis B, and cidofovir, used to treat cytomegalovirus infections) were alleviated by the early clinical trials. Yet, in 2001, the first case of TDF-induced acute nephrotoxicity was published. Numerous cases have been published since then, and it is now established that TDF presents a tubular toxicity risk. Some facilitating factors have been identified, such as co-prescription of didanosine or boosted protease inhibitor, preexisting CKD, low body weight, and associated diabetes mellitus. Conversely, whether TDF is nephrotoxic in the long term is a highly debated question. Some studies suggest a decreased GFR when TDF is prescribed for a long period, while others indicate that TDF is safe for the kidneys even after many years of use. Here we review the differences in patient characteristics, study designs, and measured outcomes that can possibly explain these conflicting findings. We conclude with rational recommendation for appropriate TDF prescription.

/pdf/tenofovir-effect-on-the-kidneys-of-hiv-infected-patients-a-3bg6d08dkd.pdf

Tenofovir Effect on the Kidneys of HIV-Infected Patients: A Double-Edged Sword?

Background 
Cardio-metabolic risk factors are of increasing concern in HIV-infected individuals, particularly with the advent of antiretroviral therapy (ART) and the subsequent rise in longevity. However, the prevalence of cardio-metabolic abnormalities in this population and the differential contribution, if any, of HIV specific factors to their distribution, are poorly understood. Therefore, we conducted a systematic review and meta-analysis to estimate the global prevalence of metabolic syndrome (MS) in HIV-infected populations, its variation by the different diagnostic criteria, severity of HIV infection, ART used and other major predictive characteristics.


Methods 
We performed a comprehensive search on major databases for original research articles published between 1998 and 2015. The pooled overall prevalence as well as by specific groups and subgroups were computed using random effects models.


Results 
A total of 65 studies across five continents comprising 55094 HIV-infected participants aged 17–73 years (median age 41 years) were included in the final meta-analysis. The overall prevalence of MS according to the following criteria were: ATPIII-2001:16.7% (95%CI: 14.6–18.8), IDF-2005: 18% (95%CI: 14.0–22.4), ATPIII-2004-2005: 24.6% (95%CI: 20.6–28.8), Modified ATPIII-2005: 27.9% (95%CI: 6.7–56.5), JIS-2009: 29.6% (95%CI: 22.9–36.8), and EGIR: 31.3% (95%CI: 26.8–36.0). By some MS criteria, the prevalence was significantly higher in women than in men (IDF-2005: 23.2% vs. 13.4, p = 0.030), in ART compared to non-ART users (ATPIII-2001: 18.4% vs. 11.8%, p = 0.001), and varied significantly by participant age, duration of HIV diagnosis, severity of infection, non-nucleoside reverse transcriptase inhibitors (NNRTIs) use and date of study publication. Across criteria, there were significant differences in MS prevalence by sub-groups such as in men, the Americas, older publications, regional studies, younger adults, smokers, ART-naive participants, NNRTIs users, participants with shorter duration of diagnosed infection and across the spectrum of HIV severity. Substantial heterogeneities across and within criteria were not fully explained by major study characteristics, while evidence of publication bias was marginal.


Conclusions 
The similar range of MS prevalence in the HIV-infected and general populations highlights the common drivers of this condition. Thus, cardio-metabolic assessments need to be routinely included in the holistic management of the HIV-infected individual. Management strategies recommended for MS in the general population will likely provide similar benefits in the HIV-infected.

/pdf/a-meta-analysis-of-the-metabolic-syndrome-prevalence-in-the-3hlplhofl1.pdf

A Meta-Analysis of the Metabolic Syndrome Prevalence in the Global HIV-Infected Population

Importance of the field: Tenofovir (TFV) is a nucleotide analogue widely used for the treatment of HIV infection. Despite its proven efficacy and safety, cases of kidney tubular dysfunction have increasingly been reported and concern exists about the risk of nephrotoxicity associated with the long-term use of TFV.Areas covered in this review: Evidences about the renal toxicity associated with TFV use as well as predictors are examined. The most relevant publications assessing TFV safety and those which have reported cases of tubular dysfunction were identified and carefully revised.What the reader will gain: Renal damage of clinical significance caused by TFV is uncommon in the short-mid-term. It occurs more frequently in subjects with underlying kidney conditions. TFV primarily results in kidney tubular dysfunction and less frequently in glomerular abnormalities. Kidney damage may progress over time under long-term TFV exposure but is reversible in most cases on drug discontinuation.Take home message: Se...

Renal toxicity associated with tenofovir use

Objective: To compare the prevalence of metabolic syndrome (MS) in HIV-positive patients with that from a sample of a general Italian population. Design: Cross-sectional study. Methods: A total of 1263 HIV-infected patients 18 years of age or older were recruited in 18 centers for infectious diseases in northern and central Italy. Controls were 2051 subjects aged 25 to 74 years representative of the residents of Monza, a town in Milan province, who were enrolled in the Pressioni Arteriose Monitorate E Loro Associazioni study. Results: The prevalence of MS in the HIV group was 20.8%, whereas in the control group, it was only 15.8%, with the difference being statistically significant. The age- and gender-adjusted risk of having MS in HIV-infected patients was twice as great as that in controls. Compared with controls, HIV-infected patients had a greater prevalence of the impaired fasting glucose, increased plasma triglycerides, and reduced high-density lipoprotein cholesterol components. MS prevalence was similar in treated and never-treated HIV-infected patients, and so were the various MS components. Conclusions: The risk of MS is greater in HIV-infected patients compared with the general population because of a greater prevalence of lipid and glucose abnormalities. The prevalence of MS and its components is similar in treated and untreated HIV-positive patients.

HIV and metabolic syndrome: a comparison with the general population.

Tenofovir renal safety in HIV-infected patients: results from the SCOLTA Project.

In this study we evaluated the efficacy of boosted and
unboosted ATV in different regimens in a cohort of HIV-1
infected patients.

/pdf/long-term-efficacy-of-boosted-and-unboosted-atazanavir-381pyho5su.pdf

Long-term efficacy of boosted and unboosted atazanavir-containing regimens: results from the SCOLTA Project

Tossicità renale in pazienti con infezione da HIV in trattamento con HAART contenente tenofovir Renal toxicity in HIV-infected patients receiving HAART includine tenofovir

Elena Rosella

Papers

HIV and metabolic syndrome: a comparison with the general population.

Tenofovir renal safety in HIV-infected patients: results from the SCOLTA Project.

Long-term efficacy of boosted and unboosted atazanavir-containing regimens: results from the SCOLTA Project

Tossicità renale in pazienti con infezione da HIV in trattamento con HAART contenente tenofovir Renal toxicity in HIV-infected patients receiving HAART includine tenofovir