Tenofovir Research Papers - Academia.edu (original) (raw)

In a double-blind, phase 3 trial, 663 HIV-infected, virologically suppressed adults were randomized to switch to tenofovir alafenamide (TAF; n=333) vs. remain on tenofovir disoproxil fumarate (TDF; n=330), each coformulated with emtricitabine (FTC), while continuing their third agent (boosted protease inhibitor or unboosted third agent). At week 96, 88.6% on FTC/TAF and 89.1% on FTC/TDF had HIV-1 RNA <50 copies/mL (adjusted difference -0.5%; 95%CI [-5.3%, 4.4%]). Proteinuria, albuminuria, proximal renal tubular function, and bone mineral density improved after switching to TAF- from TDF-containing regimens. These longer-term data support FTC/TAF as a safe, well tolerated, and durable nucleotide reverse transcriptase inhibitor backbone.

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- Treatment Outcome, HIV, Clinical Sciences, Adenine

The main objective was to compare the Creatinine Clearance (CLcr) in HIV/AIDS patients on treatment with Tenofovir (TDF) based regimen to those on non- TDF- based regimen (Stavudine (D4T) and Zidovudine (AZT) after 1 year of initiation of therapy. An analytical cross- sectional designed was applied to data on files of 275 HIV/AIDS patients on TDF and 274 HIV/AIDS patients on either D4T or AZT making a total of 549 files. The median age of participants in the study group was 29 years (Q1:19 years, Q3: 35 years) while the median age of participants on D4T or AZT was 20 years (Q1:17 years, Q3: 30 year). CLcr was calculated at baseline and at 1 year of therapy using the Cockcroft- Gault formula from the Serum Creatinine (SCr), weight, age and gender of the patients. There was no significant difference between themedian baseline CLcr in the study group and control group and both were in the normal CLcr range according to Kidney Disease Outcome Quality Initiative (K/ DOQI) criteria; 99.39 mL/min verses 104.58 mL/min, P= 0.0574. It was also found that more patients on TDF developed abnormal creatinine clearance at 1 year from normal baseline kidney function compared to those on either D4T or AZT; 51 vs. 8. In logistics regression it was found that treatment with TDF increased the odds of developing abnormal kidney function to 8.77 times compared to AZT or D4T; P<0.001. Gender was not associated with increased odds of abnormal CLcr while with every unit increase in age, the odds of increased by 1.07, P= 0.001. In conclusion, treatment with TDF increased the odds of developing abnormal CLcr at 1 year of treatment from having normal CLcr at baseline and increase in age was associated with developing abnormal CLcr in treatment with TDF.

- by Journal of Medical Science & Technology jmst
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- HIV/AIDS, Tenofovir

A paper published several years ago suggested that tenofovir disoproxil fumarate (TDF) was superior to entecavir (ETV) for reducing the risk of hepatocellular carcinoma (HCC). Since then, many observational studies have been conducted comparing TDF and ETV. Many studies in Asia demonstrated similar HCC risks between ETV and TDF groups. Similarly, recent studies involving Caucasian and European did not observe any differences in HCC risk between these groups. In this article, we briefly review studies that compared the incidence rates of HCC between ETV and TDF and discuss potential reasons for the discrepant results.

- by Hepatoma Research
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- Hepatitis B, Hepatocellular Carcinoma, Tenofovir

Abstract: A new, accurate and reliable RP-HPLC method has been developed and validated for simultaneous
estimation of Tenofovir disoproxil fumerate (TDF) & Emtricitabine (EMT) in a combined tablet dosage form.
First of all, maximum absorbance was found to be at 270nm and the peak purity was excellent. Injection volume
was selected to be 20μl which gave a good peak area. The column used for study was PHENOMENEX LUNA
C18 chosen. Ambient temperature was found to be suitable for the nature of drug solution. The flow rate was
fixed at 1.0ml/min because of good peak area and satisfactory retention time. Mobile phase of Acetonitrile :
Phosphate pH 3.5 buffers in the ratio of 60:40 was fixed due to good symmetrical peak. The retention times for
TDF & EMT were found to be 2.84 min and 3.55 min respectively. The precision of the System and method
were checked and found to be within limits. This indicates that the method is precise. Linearity study,
correlation coefficient and curve fitting was found to be 0.999. The recovery value of pure drug was found
between 99.4 % to 101.7 %. This indicates that the developed method is accurate, precise and economical and
can be used for the routine analysis of tablets in quality control.

- by Palani Shanmugasundaram
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- Tenofovir Disoproxil Fumarate, Tenofovir

Topical microbicides to stop sexually transmitted diseases, such as herpes simplex virus type 2 (HSV-2), are urgently needed. The emerging field of nanotechnology offers novel suitable tools for addressing this challenge. Our objective was to study, in vitro and in vivo, antiherpetic effect and antiviral mechanisms of several polyanionic carbosilane dendrimers with anti-HIV-1 activity to establish new potential microbicide candidates against sexually transmitted diseases. Plaque reduction assay on Vero cells proved that G2-S16, G1-S4, and G3-S16 are the dendrimers with the highest inhibitory response against HSV-2 infection. We also demonstrated that our dendrimers inhibit viral infection at the first steps of HSV-2 lifecycle: binding/entry-mediated events. G1-S4 and G3-S16 bind directly on the HSV-2, inactivating it, whereas G2-S16 adheres to host cell-surface proteins. Molecular modeling showed that G1-S4 binds better at binding sites on gB surface than G2-S16. Significantly better binding properties of G1-S4 than G2-S16 were found in an important position for affecting transition of gB trimer from G1-S4 prefusion to final postfusion state and in several positions where G1-S4 could interfere with gB/gH-gL interaction. We demonstrated that these polyanionic carbosilan dendrimers have a synergistic activity with acyclovir and tenofovir against HSV-2, in vitro. Topical vaginal or rectal administration of G1-S4 or G2-S16 prevents HSV-2 transmission in BALB/c mice in values close to 100%. This research represents the first demonstration that transmission of HSV-2 can be blocked by vaginal/rectal application of G1-S4 or G2-S16, providing a step forward to prevent HSV-2 transmission in humans.

- by Marek Maly
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- Biology, Nanomedicine, Nanotechnology, Polymers

Tenofovir is a nucleotide reverse transcriptase inhibitor used as part of antiretroviral regimens. It is well tolerated with relative toxicological effects but recent reports have linked it with renal toxicity which is of clinical concern. This study reviews literary work on tenofovir renal toxicity with more light on case reports. Tenofovir renal toxicity manifests as Fanconi’s syndrome, nephrogenic diabetes insipidus and acute renal failure. Fanconi’s syndrome is characterised by acidosis, protenuria, albuminuria, aminoaciduria, hyperchloremic, metabolic acidosis, hypouricemia, hypophosphatemia and glycosuria. The presence of urine osmolality, polydipsia and polyuria could give credence totenofovir induced nephrogenic diabetes insipidus. In some cases of tenofovir renal toxicity, renal biopsy revealed sclerosed glomeruli with ischemic injury including portal collapse of capillary loops. Histopathological changes in glumeruli include mild mesangial proliferation, increased mesangial matrix and thickened capillary loops. Moderate degenerative tubular changes, loss of tubular mass, interstitial scarring and scattered cellular infiltrates. Pharmacodynamic and pharmacokinetic interactions may occur with the co administration of tenofovir with non steroidal anti-inflammatory drugs, aminoglycosides and some protease inhibitors which may potentiate renal toxicity. Tenofovir renal toxicity is associated with some risk factors including genetic polymorphism as supported by dichotomy in renal toxicity among different race and the association between ABCC2 gene and tenofovir kidney tubular dysfunction. The pharmacology of tenofovir renal toxicity is unclear but it is attributed to the interaction between tenofovir and theorganic anion transporters (hOAT1, and to a lesser extent, OAT3) favoring intracellular accumulation in renal proximal tubule cells. This may lead to ultrastructural mitochondrial abnormalities and decreased mtDNA levels which could stimulate reactive oxygen species production, depletion of antioxidants and antioxidant enzymes. These processes can stimulate the destruction of biomolecules such as DNA, proteins, and lipids, thus causing the deregulation of redox-sensitive metabolic pathways, signaling pathways, and cell death. Despite tenofovir renal toxicity it has achieved notable therapeutic success nevertheless patients on tenofovir containing regimens should be monitored for renal function parameters. Co administration with potential nephrotoxic drugs should be avoided except when benefit outweighs risk.

- by Scientific Research Publishing
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- Pharmacology, Polymorphism, Toxicity, Renal

Background While there has been a rapid global scale-up of antiretroviral therapy programs over the past decade, there are limited data on long-term outcomes from large cohorts in resourceconstrained settings. Our objective in this evaluation was to measure multiple outcomes during first-line antiretroviral therapy in a large treatment program in Nigeria. Methods We conducted a retrospective multi-site program evaluation of adult patients (age !15 years) initiating antiretroviral therapy between June 2004 and February 2012 in Nigeria. The baseline characteristics of patients were described and longitudinal analyses using primary endpoints of immunologic recovery, virologic rebound, treatment failure and longterm adherence patterns were conducted. Results Of 70,002 patients, 65.2% were female and median age was 35 (IQR: 29-41) years; 54.7% were started on a zidovudine-containing and 40% on a tenofovir-containing first-line regimen. Median CD4+ cell counts for the cohort started at 149 cells/mm 3 (IQR: 78-220) and increased over duration of ART. Of the 70,002 patients, 1.8% were reported as having died, 30.1% were lost to follow-up, and 0.1% withdrew from treatment. Overall, of those patients retained and with viral load data, 85.4% achieved viral suppression, with 69.3% achieving suppression by month 6. Of 30,792 patients evaluated for virologic failure, 24.4% met criteria for failure and of 45,130 evaluated for immunologic failure, 34.0% met criteria for immunologic failure, with immunologic criteria poorly predicting virologic failure. In adjusted analyses, older age, ART regimen, lower CD4+ cell count, higher viral load, and inadequate adherence were all predictors of virologic failure. Predictors of immunologic PLOS ONE |

- by PROSPER OKONKWO
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- Medication Adherence, Nigeria, Adolescent, Multidisciplinary

We conducted a longitudinal and cross-sectional analysis of depressive symptomology in iPrEx, a randomized, placebo-controlled trial of daily, oral FTC/TDF HIV pre-exposure prophylaxis (PrEP) in men and transgender women who have sex with men. Depression-related adverse events (AEs) were the most frequently reported severe or life-threatening AEs and were not associated with being randomized to the FTC/TDF arm (152 vs. 144 respectively OR 0.66 95 % CI 0.35-1.25). Center for Epidemiologic Studies Depression scale (CES-D) and a four questions suicidal ideation scale scores did not differ by arm. Participants reporting forced sex at anal sexual debut had higher CES-D scores (coeff: 3.23; 95 % CI 1.24-5.23) and were more likely to have suicidal ideation (OR 2.2; 95 % CI 1.09-4.26). CES-D scores were higher among people reporting non-condom

- by patricia defechereux
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- Depression, Adolescent, Sexual Behavior, Longitudinal Studies

Vitamin D deficiency (VDD) is prevalent among HIV-infected individuals. Vitamin D has been associated with renal and cardiovascular diseases because of its effects on oxidative stress, lipid metabolism and renin-angiotensin-aldosterone system (RAAS). Tenofovir disoproxil fumarate (TDF), a widely used component of antiretroviral regimens for HIV treatment, can induce renal injury. The aim of this study was to investigate the effects of VDD on TDF-induced nephrotoxicity. Wistar rats were divided into four groups: control, receiving a standard diet for 60 days; VDD, receiving a vitamin D-free diet for 60 days; TDF, receiving a standard diet for 60 days with the addition of TDF (50 mg/kg food) for the last 30 days; and VDD+TDF receiving a vitamin D-free diet for 60 days with the addition of TDF for the last 30 days. TDF led to impaired renal function, hyperphosphaturia, hypophosphatemia, hypertension and increased renal vascular resistance due to downregulation of the sodium-phosphorus cotransporter and upregulation of angiotensin II and AT1 receptor. TDF also increased oxidative stress, as evidenced by higher TBARS and lower GSH levels, and induced dyslipidemia. Association of TDF and VDD aggravated renovascular effects and TDF-induced nephrotoxicity due to changes in the redox state and involvement of RAAS.

- by Antonio Seguro
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- Kidney diseases, Oxidative Stress, Multidisciplinary, Hypertension

Pre-exposure prophylaxis (PrEP) with oral tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) prevented HIV acquisition among men and women in several trials and is broadly recommended. In the VOICE and FEM-PrEP trials, however, TDF/FTC-based PrEP did not prevent HIV acquisition among women in eastern and southern Africa. Tenofovir was detected in plasma, reflecting exposure and adherence in recent days, in fewer than one-third of participants. Drug concentrations in hair, which represent cumulative exposure and adherence over weeks to months, have never previously been examined among women on PrEP. We compared tenofovir hair concentrations among women assigned to oral TDF/FTC in the VOICE trial to those among men and transgender women enrolled in 2 open-label PrEP studies, the iPrEx open-label extension (OLE) study and the U.S. PrEP Demonstration Project (PrEP Demo). Tenofovir hair concentrations were detectable in 55% of person-visits in VOICE, 75% of person-visits in iPrEx OL...

- by Nyaradzo Mgodi
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- Medicine, Clinical Sciences, Pre exposure Prophylaxis, Tenofovir

The review describes the European epidemic and the challenges in moving from clinical trials of preexposure prophylaxis (PrEP) to routine practice. Two European trials conducted in gay and other MSM and transgender women reported a high and consistent reduction in HIV incidence using oral PrEP with tenofovir/emtricitabine (TDF/FTC). The incidence of HIV infection in the control group was much higher than anticipated, based on routine surveillance data in MSM, in spite of the highest standard of HIV prevention available. Recent results have highlighted the urgent need to make PrEP available to key populations in Europe as an additional prevention tool. Gilead has not yet submitted an application to use TDF/FTC as PrEP in Europe. Although regulatory approval would accelerate implementation, countries are already dispensing TDF/FTC as postexposure prophylaxis without this. Services for prevention are diverse across countries ranging from free, walk-in services for the diagnosis and tre...

Objectives: To study the correlations of genetic variants of tenofovir tubular transporters, plasma tenofovir concentrations and clinical factors with decreased glomerular filtration rate in HIV-infected patients who received tenofovir.

- by Chonlaphat Sukasem
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- Microbiology, Medical Microbiology, HIV, Kidney

A new, simple, accurate and sensitive U.V-Spectrophotometric absorbance correction method has
been developed and validated for simultaneous estimation of Tenofovir disoproxil fumerate (TDF) &
Emtricitabine (EMT) in a combined tablet dosage form. 50% v/v Methanol was used as solvent. The
wavelengths selected for the absorption correction method were 260 nm & 290 nm. The method was found to be
linear between the range of 5-25 μg/ml for TDF and7-35 μg/ml for EMT. The mean percentage recovery was
found in the range of 99.24%-100.42% and 100.03-101.04% for TDF and EMT respectively at three different
levels of standard additions. The precision (intra-day, inter-day) of method were found within limits (RSD
<2%). Thus the proposed method was simple, precise, economic, rapid and accurate and can be successfully
applied for simultaneous determination of TDF and EMT in combined tablet dosage form.
Keywords : Absorbance correction method, Tenofovir disoproxil fumerate, Emtricitabine.

- by Palani Shanmugasundaram
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- Tenofovir Disoproxil Fumarate, Absorbance, Tenofovir, Emtricitabine

Men who have sex with men (MSM) of color are disproportionately affected by HIV in the United States. Pre-exposure prophylaxis (PrEP) using antiretroviral medications is a newer biomedical prevention modality with established efficacy for reducing the risk of acquiring HIV. We conducted formative qualitative research to explore audience reactions and receptivity to message concepts on PrEP as part of the development of prevention messages to promote PrEP awareness among black and Latino MSM in the United States. In 2013, 48 black and 42 Latino (total study sample = 90) mixed HIV serostatus MSM from Chicago, Ft. Lauderdale, and Kansas City participated in either an individual interview or focus group discussion. Men were recruited online and at community-based organizations in each city. We elicited feedback on the comprehensibility, credibility, and relevance of two draft messages on PrEP. The messages included efficacy estimates from iPrEx, a phase III clinical trial to ascertain whether the antiretroviral medication tenofovir/emtricitabine disoproxil fumarate (commercially known as Truvada(®)) could safely and effectively prevent HIV acquisition through sex among MSM and transgender women. With participants&amp;amp;amp;amp;amp;#39; consent, the interviews and focus groups were recorded and transcribed. The data were then summarized and analyzed using a qualitative descriptive approach. The majority of men were unfamiliar with PrEP. It was suggested that additional information about the medication and clinical trials establishing efficacy was needed to enhance the legitimacy and relevancy of the messages. Participants sought to form an opinion of PrEP that was grounded in their own interpretation of the efficacy data. However, confusion about nonadherence among clinical trial subjects and individual versus average risk limited comprehension of these messages. Thematic overlaps suggest that message believability was connected to participants&amp;amp;amp;amp;amp;#39; ability to derive meaning from the PrEP efficacy data. Despite being concerned that other MSM would interpret the messages to mean that condom use was unnecessary while taking PrEP, participants themselves primarily understood PrEP as a supplement rather than a replacement for condoms. Based on their experience with taking antiretroviral medication, HIV-positive men considered condom use a more feasible form of HIV prevention than PrEP. Participants&amp;amp;amp;amp;amp;#39; responses suggest that more information about PrEP and the clinical trial would support the legitimacy of PrEP and the messages as a whole. These details may enhance believability in the concept of PrEP and reinforce confidence in the validity of the efficacy result.

- by Damian J Denson
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- Focus Groups, Qualitative Research, Medicine, Chicago

Objectives As the HIV-infected population ages, the role of cellular senescence and inflammation on co-morbid conditions and pharmacotherapy is increasingly of interest. p16 INK4a expression, a marker for aging and senescence in T-cells, is associated with lower intracellular concentrations of endogenous nucleotides (EN) and nucleos(t)ide reverse transcriptase inhibitors (NRTIs). This study expands on these findings by determining whether inflammation is contributing to the association of p16 INK4a expression with intracellular metabolite (IM) exposure and endogenous nucleotide concentrations. Methods Samples from 73 HIV-infected adults receiving daily tenofovir/emtricitabine (TFV/FTC) with either efavirenz (EFV) or atazanavir/ritonavir (ATV/r) were tested for p16 INK4a expression, and plasma cytokine and intracellular drug concentrations. Associations between p16 INK4a expression and cytokine concentrations were assessed using maximum likelihood methods, and elastic net regression was applied to assess whether cytokines were predictive of intracellular metabolite/endogenous nucleotide exposures. Results Enrolled participants had a median age of 48 years (range 23-73). There were no significant associations between p16 INK4a expression and cytokines. Results of the elastic net

- by Owen Francis
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- Biomarkers, Cytokines, Inflammation, Multidisciplinary

To assess the prevalence of metabolic syndrome (MetS) among patients in rural Lesotho who are taking first-line antiretroviral therapy (ART) containing either zidovudine or tenofovir disoproxil. Cross-sectional survey in 10 facilities in Lesotho among adult (≥16 years) patients on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line ART for ≥6 months. MetS was defined according to the International Diabetes Federation criteria. Among 1166 patients (65.8% female), 22.2% (95% CI: 19.3-25.3) of women and 6.3% (4.1-9.1) of men met the IDF definition of MetS (P < 0.001). In both sexes, there was no significant difference in MetS prevalence between NNRTIs. However, in women taking zidovudine as nucleoside reverse transcriptase inhibitor (NRTI), MetS prevalence was 27.9%, vs. 18.8% in those taking tenofovir. In the multivariate logistic regression allowing for socio-demographic and clinical covariates, ART containing zidovudine was associated with MetS in women (aOR 2...

- by Isaac Ringera
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- Tropical medicine (Health Sciences), Lesotho, Metabolic syndrome, Prevalence

Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naïve individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 - A62V, K65R...

- by Nicole Ngo-Giang-Huong
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- HIV, Mutation, Prevalence, Genotype

Antiretroviral treatment (ART) programs in sub-Saharan Africa have for many years included lamivudine as the sole HBV inhibitor. Long-term outcomes, and the effects of introducing tenofovir as part of ART in these populations, have not been characterized. The study comprised a cross-sectional analysis of 106 HIV-HBV co-infected subjects maintained on lamivudine, and a prospective analysis of 76 lamivudine-experienced subjects who introduced tenofovir. Patients underwent assessment of liver fibrosis by transient elastography (TE) and testing to characterize HIV-1 and HBV replication. After median 45 months of lamivudine, HIV-1 RNA and HBV DNA were detectable in 35/106 (33.0%) and 54/106 (50.9%) subjects respectively, with corresponding drug-resistance rates of 17/106 (16.0%) and 31/106 (29.2%). TE values were median 5.7 kPa (IQR 4.7, 7.2) and independently associated with HBV DNA load, AST levels, and platelet counts; 13/106 (12.3%) subjects had TE measurements >9.4 kPa. Twelve...

- by Richard O Phillips
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- Ghana, Treatment Outcome, HIV, Biological Sciences

Background: Nucleos(t)ide analogue (NA) treatment causes selection pressure for hepatitis B virus strains carrying mutations conferring NA resistance. Drug-resistance mutations occur in the reverse transcriptase (RT) region of the HBV polymerase gene and spontaneously arise during viral replication. These mutations can also alter the HBs protein and in some cases reduce binding to HBs antibodies. The spread of NAresistant HBV may impact the efficacy of antiviral treatment and hepatitis B immunization programs. In this study, we used direct sequencing to assess the occurrence of HBV carrying known mutations that confer NA resistance in the largest cohort of treatment-naïve patients with chronic hepatitis B (CHB) to date.

- by Dimas Kliemann and +1
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- Brazil, Mutation, Genotype, Retrospective Studies

A qualitative assessment of Kenyan men who have sex with men taking daily and intermittent oral HIV preexposure prophylaxis (PrEP) found stigma, sex work, mobility, and alcohol impacted adherence. We analyzed quantitative data from the same cohort to explore different definitions of intermittent adherence. Volunteers were randomized to daily emtricitabine/tenofovir or placebo, or intermittent (prescription: Mondays/Fridays/after sex, maximum 1 dose/day) emtricitabine/tenofovir or placebo (2:1:2:1), and followed for 4 months. By electronic monitoring, median adherence for daily dosing was 80 %. Median adherence for intermittent dosing was 71 % per a ''relaxed'' definition (accounting for off-prescription dosing) and 40 % per a ''strict'' definition (limited to the prescription). Factors associated with lower adherence included travel, transactional sex, and longer follow-up; higher adherence was associated with daily dosing and an income. The definition of intermittent dosing strongly affects interpretation of adherence. These findings suggest interventions should address challenges of mobility, sex work, and long-term PrEP.

Background. Our objective was to assess the therapeutic noninferiority of dual therapy with darunavir/ritonavir and lamivudine compared to triple therapy with darunavir/ritonavir plus 2 nucleos(t)ides for maintenance of human immunodeficiency virus type 1 (HIV-1) suppression. Methods. This was a multicenter, open-label, noninferiority trial (margin 12%). Patients with HIV-1 RNA <50 copies/mL for 6 months or longer on triple therapy with darunavir/ritonavir and 2 nucleos(t)ides (tenofovir disoproxil fumarate and emtricitabine or abacavir and lamivudine) and with no resistance were randomized to continue therapy (n = 128) or switch to darunavir/ritonavir and lamivudine (n = 129). The primary endpoint was the proportion of participants with HIV-RNA <50 copies/mL after 48 weeks of follow-up according to the snapshot algorithm. Results. A total of 249 participants received study drugs (intention-to-treat exposed). The proportion of participants with HIV-RNA <50 copies/mL in the dual-and triple-therapy arms was 88.9% (112/126) and 92.7% (114/123; difference,-3.8%; 95% confidence interval,-11.0 to 3.4), respectively. Four participants in the dual-therapy arm and 2 in the triple-therapy arm developed protocol-defined virological failure. Switching to dual therapy was associated with a significant increase in total, low-density lipoprotein, and high-density lipoprotein (HDL) cholesterol, but not in the total-to-HDL cholesterol ratio. Serious adverse events and study drug discontinuations due to adverse events occurred in 4.8% vs 4.9%P = .97) and in 0.8% (1/126) vs 1.6% P = .55) in dual therapy vs triple therapy, respectively. Conclusions. Dual therapy with darunavir/ritonavir and lamivudine demonstrated noninferior therapeutic efficacy and similar tolerability compared to triple therapy. Clinical Trials Registration. NCT02159599.

- by Antonio Rivero
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- Medicine, HIV, Biological Sciences, Medication Therapy Management

Hepatitis B virus (HBV) reactivation in patients with resolved HBV infection (HBsAg negative, antiHBc positive) is uncommon, but potentially fatal. The role of HBV prophylaxis in this setting is uncertain. The aim of this study was to compare the efficacy of tenofovir disoproxil fumarate (TDF) prophylaxis versus close monitoring in antiHBc-positive, HBsAg-negative patients under treatment with rituximab (RTX)-based regimens for hematologic malignancy. PREBLIN is a phase IV, randomized, prospective, open-label, multicenter, parallel-group trial conducted in 17 hospitals throughout Spain. Anti-HBc-positive, HBsAg-negative patients with undetectable HBV DNA were randomized to receive TDF 300 mg once daily (Group I) or observation (Group II). The primary endpoint was the percentage of patients showing HBV reactivation during 18 months following initiation of RTX treatment. Patients with detectable HBV DNA (Group III) received the same dose of TDF and were analyzed together with Group I ...

- by Pilar Magdalena Cun Castillo
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- Leukemia, Multidisciplinary, Hepatitis B, PLoS one

Background Antiretroviral preexposure prophylaxis has been shown to reduce the risk of human immunodeficiency virus type 1 (HIV-1) infection in some studies, but conflicting results have been reported among studies, probably due to challenges of adherence to a daily regimen. Methods We conducted a double-blind, randomized trial of antiretroviral therapy for preexposure HIV-1 prophylaxis among men who have unprotected anal sex with men. Participants were randomly assigned to take a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) or placebo before and after sexual activity. All participants received risk-reduction counseling and condoms and were regularly tested for HIV-1 and HIV-2 and other sexually transmitted infections. Results Of the 414 participants who underwent randomization, 400 who did not have HIV infection were enrolled (199 in the TDF-FTC group and 201 in the placebo group). All participants were followed for a median of 9.3 months (interquartil...

- by Gabriel Girard
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- Medication Adherence, HIV, Sexual Behavior, Risk factors

BACKGROUND Randomized-trial data on the risks and benefits of antiretroviral therapy (ART) as compared with zidovudine and single-dose nevirapine to prevent transmission of the human immunodeficiency virus (HIV) in HIV-infected pregnant women with high CD4 counts are lacking. METHODS We randomly assigned HIV-infected women at 14 or more weeks of gestation with CD4 counts of at least 350 cells per cubic millimeter to zidovudine and single-dose nevirapine plus a 1-to-2-week postpartum "tail" of tenofovir and emtricitabine (zidovudine alone); zidovudine, lamivudine, and lopinavir-ritonavir (zidovudine-based ART); or tenofovir, emtricitabine, and lopinavir-ritonavir (tenofovir-based ART). The primary outcomes were HIV transmission at 1 week of age in the infant and maternal and infant safety. RESULTS The median CD4 count was 530 cells per cubic millimeter among 3490 primarily black African HIV-infected women enrolled at a median of 26 weeks of gestation (interquartile range, 21 to 30). The rate of transmission was significantly lower with ART than with zidovudine alone (0.5% in the combined ART groups vs. 1.8%; difference, −1.3 percentage points; repeated confidence interval, −2.1 to −0.4). However, the rate of maternal grade 2 to 4 adverse events was significantly higher with zidovudine-based ART than with zidovudine alone (21.1% vs. 17.3%, P = 0.008), and the rate of grade 2 to 4 abnormal blood chemical values was higher with tenofovir-based ART than with zidovudine alone (2.9% vs. 0.8%, P = 0.03). Adverse events did not differ significantly between the ART groups (P>0.99). A birth weight of less than 2500 g was more frequent with zidovudine-based ART than with zidovudine alone (23.0% vs. 12.0%, P<0.001) and was more frequent with tenofovir-based ART than with zidovudine alone (16.9% vs. 8.9%, P = 0.004); preterm delivery before 37 weeks was more frequent with zidovudine-based ART than with zidovudine alone (20.5% vs. 13.1%, P<0.001). Tenofovir-based ART was associated with higher rates than zidovudine-based ART of very preterm delivery before 34 weeks (6.0% vs. 2.6%, P = 0.04) and early infant death (4.4% vs. 0.6%, P = 0.001), but there were no significant differences between tenofovir-based ART and zidovudine alone (P = 0.10 and P = 0.43). The rate of HIVfree survival was highest among infants whose mothers received zidovudine-based ART. CONCLUSIONS Antenatal ART resulted in significantly lower rates of early HIV transmission than zidovudine alone but a higher risk of adverse maternal and neonatal outcomes.

- by Gerhard Theron
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- Pregnancy, Young Adult, Infant, African Americans

Tenofovir (TFV), a nucleotide reverse transcriptase inhibitor, requires two phosphorylation steps to form a competitive inhibitor of HIV reverse transcriptase. Adenylate kinase 2 (AK2) has been previously demonstrated to phosphorylate tenofovir to tenofovir-monophosphate, while creatine kinase, muscle (CKM), pyruvate kinase, muscle (PKM) and pyruvate kinase, liver and red blood cell (PKLR) each have been found to phosphorylate tenofovir-monophosphate to the pharmacologically active tenofovir-diphosphate. In the present study, genomic DNA isolated from dried blood spots collected from 505 participants from Bangkok, Thailand; Cape Town, South Africa; and New York City, USA were examined for variants in AK2, CKM, PKM, and PKLR using next-generation sequencing. The bioinformatics tools SIFT and PolyPhen predicted that 19 of the 505 individuals (3.7% frequency) carried variants in at least one kinase that would result in a decrease or loss of enzymatic activity. To functionally test thes...

- by Sharon Mannheimer
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- Thailand, Multidisciplinary, HIV, South Africa

The use of nonhuman primate (NHP) models to study persistent residual virus and viral eradication strategies in combination antiretroviral therapy (cART)-treated individuals requires regimens that effectively suppress SIV replication to clinically relevant levels in macaques. We developed and evaluated two novel cART regimens in SIVmac239-infected rhesus macaques: (1) a ''triple regimen'' containing the nucleo(s/t)ide reverse transcriptase inhibitors emtricitabine (FTC) and tenofovir disoproxil fumarate [TDF, prodrug of tenofovir (TFV, PMPA)] with the integrase strand transfer inhibitor dolutegravir (DTG) (n = 3), or (2) a ''quad regimen'' containing the same three drugs plus the protease inhibitor darunavir (DRV) (n = 3), with each regimen coformulated for convenient administration by a single daily subcutaneous injection. Plasma drug concentrations were consistent across animals within the triple and quad regimen-treated groups, although DTG levels were lower in the quad regimen animals. Time to achieve plasma viral loads stably <30 viral RNA copies/ml ranged from 12 to 20 weeks of treatment between animals, and viral loads <30 viral RNA copies/ml plasma were maintained through 40 weeks of follow-up on cART. Notably, although we show virologic suppression and development of viral resistance in a separate cohort of SIV-infected animals treated with oral DRV monotherapy, the addition of DRV in the quad regimen did not confer an apparent virologic benefit during early treatment, hence the quad regimen-treated animals were switched to the triple regimen after 4 weeks. This coformulated triple cART regimen can be safely, conveniently, and sustainably administered to durably suppress SIV replication to clinically relevant levels in rhesus macaques.

Background: This study aimed to determine the effect of tenofovir disoproxil fumarate (TDF) on bone metabolism and bone mass in HIV-infected adolescents. Methods: This was a sub-study of a cross-sectional multicentre bone health trial that enrolled perinatally HIV-infected Thai and Indonesian adolescents (10-18 years) with viral suppression on antiretroviral therapy. Participants were classified into two groups as TDF users and non-users. Bone metabolism-related markers (25-hydroxyvitamin D [25-OHD], intact parathyroid hormone [iPTH], bone turnover biomarkers), and lumbar spine dual-energy X-ray absorptiometry were assessed. Bone mineral density (BMD)/bone mineral apparent density (BMAD) Z-scores were calculated. Results: Of 394 adolescents, 136 (34.5%) and 258 (65.5%) were TDF users and non-users, respectively. Among TDF users, median age (IQR) was 16.1 (14.7-17.4) years and TDF treatment duration (IQR) was 2.3 (1.4-3.1) years. Among TDF non-users, median age (IQR) was 14.3 (12.6-16.4) years. BMD and BMAD Z-scores comparing TDF users with non-users were-0.8 and-0.6 (P=0.27), and-0.3 and-0.2 (P=0.58), respectively. The association between TDF use and iPTH elevation was intensified in adolescents with suboptimal vitamin D levels (25-OHD <30 ng/ml; P=0.001). TDF administration was positively associated with bone resorption marker (P=0.04) and negatively associated with bone formation marker (P=0.04). With data up to 4 years, neither association between TDF use and bone mass loss (BMD: P=0.09; BMAD: P=0.22), nor variation of bone mass Z-scores by TDF treatment duration (BMD: P=0.34; BMAD: P=0.58) was demonstrated. Conclusions: Recent TDF administration was correlated with PTH elevation and bone turnover dysregulation but not with bone mass reduction in our cohort. A study with extended follow-up to ascertain TDF-associated bone mass deterioration is warranted.

- by Nia Kurniati
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- Microbiology, Medical Microbiology, Biomarkers, Adolescent

seroclearance (i.e., 'complete cure') remain very low. 2,3 Two categories of therapeutic agents are currently available for the treatment of CHB: (1) immunomodulatory agents (interferonalpha and pegylated interferon-alpha), and (2) oral nucleos(t)ide analogues (NAs) (lamivudine, adefovir, telbivudine, entecavir, and tenofovir). The response rate to interferons remains low, particularly International Journal of Infectious Diseases 28 (2014) [153][154][155][156][157][158][159] Objective: To compare responses to tenofovir (TDF) and entecavir (ETV) therapy. Methods: This was a multicenter retrospective study including treatment-naïve patients with chronic hepatitis B (CHB) who received TDF or ETV. The primary end-points were undetectable HBV-DNA at 48 weeks and serological and biochemical responses. Results: Out of 195 CHB patients, 90 (46%) received TDF and 105 (54%) received ETV; 72% were male, their mean age was 43 AE 12 years, and the mean duration of treatment was 30.2 AE 15.7 months. Hepatitis B e antigen (HBeAg) seropositivity was 32% in the TDF group and 34% in the ETV group. HBeAg seroconversion rates in HBeAg-positive patients were 24% in the TDF group and 39% in the ETV group; the difference was not significant (p = 0.2). The mean time to alanine aminotransferase (ALT) normalization and rates of ALT normalization at 3, 6, 12, 18, and 24 months were similar in the two groups (p > 0.05). The mean time to undetectable HBV-DNA levels in the TDF and ETV groups was 11.5 AE 8.9 and 12.9 AE 10.8 months, respectively (p = 0.32). A significantly greater decline in HBV-DNA levels at 12 and 18 months was observed in the TDF group (p = 0.02 and p = 0.03, respectively). Seven (7%) patients on ETV therapy had virological breakthrough (p = 0.01). Only one patient in each group had hepatitis B surface antigen (HBsAg) clearance. None of the patients developed decompensation or hepatocellular carcinoma during treatment. Conclusions: The two drugs appear to have similar efficacy in CHB patients. However, 7% of patients on ETV therapy had virological breakthrough, while none of the patients on TDF therapy did.

- by Ertugrul Guclu
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- Microbiology, Medical Microbiology, Infectious Diseases, Retrospective Studies

Oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) has been evaluated as pre-exposure prophylaxis (PrEP). We describe the accuracy of self-reported adherence to FTC/TDF and pill counts when compared to drug concentrations in the FEM-PrEP trial. Using drug concentrations of plasma tenofovir (TFV) and intracellular tenofovir diphosphate (TFVdp) among a random sub-sample of 150 participants assigned to FTC/TDF, we estimated the positive predictive value (PPV) of four adherence measures. We also assessed factors associated with misreporting of adherence using multiple drug-concentration thresholds and explored pill use and misreporting using semi-structured interviews (SSIs). Reporting use of C1 pill in the previous 7 days had the highest PPV, while pill-count data consistent with missing B1 day had the lowest PPV. However, all four measures demonstrated poor PPV. Reported use of oral contraceptives (OR 2.26; p = 0.014) and weeks of time in the study (OR 1.02; p \ 0.001) were significantly associated with misreporting adherence. Although most SSI participants said they did not misreport adherence, participant-dependent adherence measures were clearly unreliable in the FEM-PrEP trial. Pharmacokinetic monitoring remains the measure of choice until more reliable participant-dependent measures are developed.

- by Lut Van Damme
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- Medication Adherence, Qualitative Research, Treatment Outcome, Kenya

Tenofovir disoproxil fumarate (TDF) is effective against chronic hepatitis B (CHB) infection and its use is increasing rapidly worldwide. However, it has been established that TDF is associated with renal toxicity in human immunodeficiency virus-infected patients, while severe or symptomatic TDF-associated nephrotoxicity has rarely been reported in patients with CHB. Here we present two patients with TDF-associated nephrotoxicity who were being treated for CHB infection. The first patient was found to have clinical manifestations of proximal renal tubular dysfunction and histopathologic evidence of acute tubular necrosis at 5 months after starting TDF treatment. The second patient developed acute kidney injury at 17 days after commencing TDF, and he was found to have membranoproliferative glomerulonephritis with acute tubular injury. The renal function improved in both patients after discontinuing TDF. We discuss the risk factors for TDF-associated renal toxicity and present recommendations for monitoring renal function during TDF therapy.

WHO recommends that stavudine is phased out of antiretroviral therapy (ART) programmes and replaced with tenofovir (TDF) for first-line treatment. In this context, the Integrated HIV Care Program, Myanmar, evaluated patients for ART failure using HIV RNA viral load (VL) before making the change. We aimed to determine prevalence and determinants of ART failure in those on first-line treatment. Patients retained on stavudine-based or zidovudine-based ART for >12 months with no clinical/immunological evidence of failure were offered VL testing from August 2012. Plasma samples were tested using real time PCR. Those with detectable VL>250 copies/ml on the first test were provided with adherence counseling and three months later a second test was performed with >1000 copies/ml indicating ART failure. We calculated the prevalence of ART failure and adjusted relative risks (aRR) to identify associated factors using log binomial regression. Of 4934 patients tested, 4324 (87%) had an...

- by Nay Thiha
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- Adolescent, Medicine, Multidisciplinary, HIV

To demonstrate the non-inferiority (15% non-inferiority limit) of monotherapy with tenofovir disoproxil fumarate (TDF) vs the combination of lamivudine (LAM) plus adefovir dipivoxil (ADV) in the maintenance of virologic response in patients with chronic hepatitis B (CHB) and prior failure with LAM. This study was a Phase IV prospective, randomized, open, controlled study with 2 parallel groups (TDF and LAM+ADV) of adult patients with hepatitis B e antigen (HBeAg)-negative CHB, prior failure with LAM, on treatment with LAM+ADV for at least 6 mo, without prior resistance to ADV and with an undetectable viral load at the start of the study, in 14 Spanish hospitals. The follow-up time for each patient was 48 wk after randomization, with quarterly visits in which the viral load, biochemical and serological parameters, adverse effects, adherence to treatment and consumption of hospital resources were analysed. Forty-six patients were evaluated [median age: 55.4 years (30.2-75.2); 84.8% ma...

- by Francisco Jorquera
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- Prospective studies, Hospital costs, Clinical Sciences, Aged

Tenofovir alafenamide (TAF) is a novel tenofovir prodrug with improved renal and bone safety compared with TDF-containing regimens. We report the 48 week safety and efficacy of a once-daily single tablet regimen of elvitegravir 150 mg (E), cobicistat 150 mg (C), emtricitabine 200 mg (F), and TAF 10 mg (E/C/F/TAF) in HIV-1-infected patients with mild to moderate renal impairment. We enrolled virologically suppressed HIV-infected subjects with estimated creatinine clearance (CrCl) 30-69 mL/min in a single-arm, open-label study to switch regimens to E/C/F/TAF. The primary endpoint was the change from baseline in glomerular filtration rate estimated using various formulae. This study is registered with ClinicalTrials.gov, number NCT01818596. We enrolled and treated 242 patients with mean age 58 years, 18% Black, 39% hypertension, 14% diabetes. Through Week 48, no significant change in estimated CrCl was observed. Two patients (0.8%) discontinued study drug for decreased creatinine clear...

- by Ploenchan Chetchotisakd
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- Adolescent, Bone Density, Quinolones, Clinical Sciences

BACKGROUND/AIMS Several guidelines recommend the use of tenofovir or entecavir as the first-line treatment for hepatitis B due to the lower resistance rates of these drugs than lamivudine, although lamivudine may still be preferred because of its low adverse effect profile and cost. It is important to know which patients might benefit from lamivudine as the first-line treatment. We aimed to assess the success rates of lamivudine, entecavir, and tenofovir, as well as the resistance rates, frequencies of HBsAg clearance, and risk factors for lamivudine resistance. MATERIALS AND METHODS A total of 191 patients with chronic HBeAg-negative hepatitis who were treated with lamivudine, entecavir, or tenofovir were included. Predictors of resistance to lamivudine were analyzed. RESULTS The cumulative first-, second-, third-, fourth-, and fifth-year rates of virologic breakthrough during extended lamivudine therapy were 24%, 30%, 38%, 46%, and 54%, respectively. The rate of undetectable DNA a...

- by Sebati Özdemir
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- Treatment Outcome, Regression Analysis, Risk factors, Time Factors

Background: Tenofovir (TDF) based regimen was reported to have better immunological outcomes. Unfortunately, there is limited information regarding the immunologic outcome associated with this regimen in Ethiopia, as its routine... more

- by Teshale Ayele
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- Immunology, Treatment Outcome, Ethiopia, HIV

An open-label randomized trial (DAYANA) was conducted in sub-Saharan settings to evaluate four different regimens containing tenofovir disoproxil fumarate as first-line treatment for HIV infection. The objectives of the present substudy were to assess the relationship between trough concentrations of tenofovir in plasma collected after 24 h (C24) and estimated glomerular filtration rates (eGFR) calculated by the different formulae that are available. The criteria for eligibility were those of the DAYANA trial, recruiting naive patients. The four tenofovir regimens were: Group 1, tenofovir/emtricitabine/nevirapine; Group 2, tenofovir/lopinavir/ritonavir; Group 3, tenofovir/emtricitabine/zidovudine; and Group 4, tenofovir/emtricitabine/efavirenz. The C24 of tenofovir was determined using LC-MS/MS. The eGFR was calculated using the Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulae. The median C24 of te...

- by Sinata Koulla-shiro
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- Microbiology, Medical Microbiology, Adolescent, HIV

- by Dr.Syifa Mustika,Sp.PD-KGEH
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- Electron Microscopy, Acute kidney injury, Risk factors, Aged

HIV infection is associated with increased risk of renal dysfunction, including tubular dysfunction (TD) related to antiretroviral therapy (ART). Tenofovir disoproxil fumarate (TDF) is becoming available for ART in sub-Saharan Africa, although data on its long-term safety there is limited. We aimed to study the prevalence of HIV-associated renal dysfunction in Ghana and explore associations between proteinuria or TD and potential risk factors, including TDF use. A single-centre cross-sectional observational study of patients taking ART was undertaken. Creatinine clearance (CrCl) was calculated and proteinuria detected with dipsticks. Spot urinary albumin and protein:creatinine ratios (uACR/uPCR) were measured and further evidence of TD (defined as having two or more characteristic features) sought. Logistic regression analysis identified factors associated with proteinuria or TD. In 330 patients, of whom 101 were taking TDF (median 20 months), the prevalence of CrCl < 60ml/min/1....

- by Fred Sarfo
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- Kidney diseases, Ghana, Risk assessment, Causality

- by PROSPER OKONKWO
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- Medication Adherence, Nigeria, Adolescent, Multidisciplinary

The use of tenofovir disoproxil fumarate (TDF) is supposed to be increased in a resource-limited setting due to the changing of the guidelines. TDF-associated renal function declines among HIV-infected patients were defined by an increase of serum creatinine (SCr) >1.5 times, a 25% decrease in calculated creatinine clearance (CCrCl), or an estimated glomerular filtration rate (eGFR) from the baseline. Of all, 99% were antiretroviral treatment (ART)-experienced patients. At the 30th month, 19 (5.3%), 53 (14.9%), and 63 (17.7%) patients had renal function decline as defined by the above criteria with an incidence of 4.5, 12.5, and 14.6/100 person-year. A proportion of patients with a renal function decline detected by CCrCl or eGFR criteria was not different (P ¼ .301), whereas, it differed from that detected by SCr criteria (P < .001). In conclusion, we encourage either CCrCl or eGFR calculations in monitoring renal function decline among HIV-infected patients receiving TDF in resource-limited settings.

- by Chureeratana Bowonwatanuwong
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- Resource Limitation, Hiv Infection, Serum Creatinine, Renal Function

In developed countries, remarkable advances in antiretroviral therapy have transformed HIV infection into a chronic condition. As a result, HIV-associated nephropathy, the classic HIV-driven kidney lesion among individuals of African descent, has largely disappeared in these regions. However, HIV-positive blacks continue to have much higher rates of ESRD than HIV-positive whites, which could be attributed to the APOL1 renal risk variants. Additionally, HIV-positive individuals face adverse consequences beyond HIV itself, including traditional risk factors for CKD and nephrotoxic effects of antiretroviral therapy. Concerns for nephrotoxicity also extend to HIV-negative individuals using tenofovir disoproxil fumarate-based pre-exposure prophylaxis for the prevention of HIV infection. Therefore, CKD remains an important comorbid condition in the HIV-positive population and an emerging concern among HIV-negative persons receiving pre-exposure prophylaxis. With the improved longevity of ...

- by Mohamed Atta
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- Kidney transplantation, Apolipoproteins, Risk factors, Clinical Sciences

The efficacy of pre-exposure prophylaxis (PrEP) in preventing sexual acquisition of human immunodeficiency virus (HIV) is well established. Little is known about the feasibility of PrEP implementation in middle-income settings with concentrated epidemics among men who have sex with men (MSM) and transgender women (TGW). PrEP Brasil is a prospective, multicentre, open-label demonstration project assessing PrEP delivery in the context of the Brazilian Public Health System. HIV-uninfected MSM and TGW in 3 referral centres in Rio de Janeiro and São Paulo were evaluated for eligibility and offered 48 weeks of daily emtricitabine/tenofovir for PrEP. Concentrations of tenofovir diphosphate in dried blood spot samples (DBS) at week 4 after enrolment (early adherence) were measured. Predictors of drug levels were assessed using ordinal logistic regression models considering the DBS drug level as a 3 level variable (<350 fmol/punch, ≥350-699 fmol/punch and ≥700 fmol/punch). 1,270 individua...

- by José Madruga
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- Medication Adherence, Brazil, Adolescent, Prospective studies

Trials to assess microbicide safety require strict adherence to prescribed regimens. If adherence is suboptimal, safety cannot be adequately assessed. MTN-017 was a phase 2, randomized sequence, open-label, expanded safety and acceptability crossover study comparing 1) daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), 2) daily use of reduced-glycerin 1% tenofovir (RG-TFV) gel applied rectally, and 3) RG-TFV gel applied before and after receptive anal intercourse (RAI)-if participants had no RAI in a week, they were asked to use two doses of gel within 24 hours. Product use was assessed by mixed methods including unused product return count, text messaging reports, and qualitative plasma TFV pharmacokinetic (PK) results. Convergence interviews engaged participants in determining the most accurate number of doses used based on product count and text messaging reports. Client-centered adherence counseling was also used. Participants (N = 187) were men who have sex with ...

- by Carmen Zorrilla
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- Medication Adherence, Adolescent, Multidisciplinary, Young Adult

Daily pre-exposure prophylaxis (PrEP) with oral emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) decreases the risk of HIV acquisition. Initiation of TDF decreases bone mineral density (BMD) in HIV-infected people. We report the effect of FTC/TDF on BMD in HIV-seronegative men who have sex with men and transgender women. Dual-energy X-ray absorptiometry was performed at baseline and 24-week intervals in a substudy of iPrEx, a randomized, double-blind, placebo-controlled trial of FTC/TDF PrEP. Plasma and intracellular tenofovir concentrations were measured in participants randomized to FTC/TDF. In 498 participants (247 FTC/TDF, 251 placebo), BMD in those randomized to FTC/TDF decreased modestly but statistically significantly by 24 weeks in the spine (net difference -0.91 [-1.44 to -0.38]%, P=0.001) and hip (-0.61 [-0.96 to -0.27]%, P=0.001). Changes within each subsequent 24-week interval were not statistically significant. Changes in BMD by week 24 correlated inversely ...

- by Pedro Gonzales
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- Adolescent, Biological Sciences, Chemoprevention, Plasma
- by Glenn Swartz
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- HIV, Mice, Pre exposure Prophylaxis, Proportional Hazards Models

- by Moti Ramgopal
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- Bone Density, Quinolones, Clinical Sciences, Combination drug therapy

Chronic HIV treatment with antiretroviral drugs has been associated with adverse health outcomes. Mitochondrial toxicity exhibited by nucleoside reverse transcriptase inhibitors (NRTIs) is pinpointed as a molecular mechanism of toxicity. This study evaluated the effect of NRTIs: Zidovudine (AZT, 7.1 μM), Stavudine (d4T, 4 μM) and Tenofovir (TFV, 1.2 μM), on mitochondrial (mt) stress response, mtDNA integrity and oxidative stress response in human hepatoma cells at 24 and 120 h. Markers for mt function, mt biogenesis, oxidative stress parameters, and antioxidant response were evaluated by spectrophotometry, luminometry, flow cytometry, qPCR and western blots. We found that AZT and d4T reduced mtDNA integrity (120 h, AZT: 76.1%; d4T:36.1%, P < 0.05) and remained unchanged with TFV. All three NRTIs, however, reduced ATP levels (AZT: 38%; d4T: 56.4%; TFV: 27.4%, P = 0.01) and mt membrane potential at 120 h (P < 0.005). Oxidative damage and reactive oxygen species (ROS) were increased by TFV and AZT at 24 h, and by d4T at 120 h (P < 0.05). Antioxidant response molecules and mt biogenesis markers were elevated by all NRTIs, with TFV causing the most significant increase (P < 0.05). Data from this study suggest that AZT, d4T and TFV alter mt function. TFV, however, achieves this independently of mtDNA depletion. Furthermore, AZT exerts toxicity soon after exposure as noted from changes at 24 h and d4T exerts greater toxicity over prolonged exposure (120 h).

- by Anil Chuturgoon
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- Oxidative Stress, Mitochondria, Mitochondrial DNA, Reactive Oxygen Species

Several guidelines recommend the use of tenofovir or entecavir as the first-line treatment for hepatitis B due to the lower resistance rates of these drugs than lamivudine, although lamivudine may still be preferred because of its low adverse effect profile and cost. It is important to know which patients might benefit from lamivudine as the first-line treatment. We aimed to assess the success rates of lamivudine, entecavir, and tenofovir, as well as the resistance rates, frequencies of HBsAg clearance, and risk factors for lamivudine resistance. A total of 191 patients with chronic HBeAg-negative hepatitis who were treated with lamivudine, entecavir, or tenofovir were included. Predictors of resistance to lamivudine were analyzed. The cumulative first-, second-, third-, fourth-, and fifth-year rates of virologic breakthrough during extended lamivudine therapy were 24%, 30%, 38%, 46%, and 54%, respectively. The rate of undetectable DNA at the 60th month of those who took lamivudine ...

- by Sebati Özdemir
- •
- Treatment Outcome, Regression Analysis, Risk factors, Time Factors

Introduction: Several risk factors including stavudine and age have been strongly associated with polyneuropathy. However, conflicting data exist on height as an independent risk factor in polyneuropathy. The objective of this study is to exclude height as an independent polyneuropathy risk factor in a cohort of human immunodeficiency virus (HIV)-infected Kenyan sex workers. Methods: This was an analysis of prospectively collected data of treatment-naive subjects initiating either stavudine or tenofovir diphosphate fumarate or zidovudine-based antiretroviral therapy (ART) regimens from January 2008 to August 2012. Polyneuropathy was characterised as burning sensation, numbness, or dysesthesia. The study used arithmetic means of weight (kg) and height (cm) measured in duplicates using calibrated scales. Results: After exclusion of duplicate data sets and un-confirmed cases of polyneuropathy, the study identified 212 patients without polyneuropathy, 14 pre-ART and 94 post-ART related polyneuropathy cases. Polyneuropathy cases were older but did not differ in demographic, clinical and laboratory parameters at baseline. There was a significant difference in first-line ART regimens with more patients on tenofovir disoproxil fumarate in the post-ART group (p=0.017). Conclusion: Polyneuropathy is a common disorder among HIV-infected Kenyan sex workers. These data cannot support the postulated increased risk by height after matching for gender and ART duration. Though stavudine is associated with polyneuropathy, in this study many patients previously not exposed to stavudine developed polyneuropathy. This suggests the involvement of unknown risk factors such as genetic and metabolite differences in the development of polyneuropathy.

- by Frank Ndakala
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- Kenya, Sex Workers, Risk factors, Prevalence

The study aim was to evaluate the impact on Liver and Kidney toxicity of the single tablet regimen Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate (EVG/COBI/FTC/TDF) on Antiretroviral Therapy (ART) experienced or naïve patients. Patients initiating EVG/COBI/FTC/TDF were enrolled in the SCOLTA project, a multicenter observational study reporting grade 3-4 Adverse Events in subjects beginning new antiretroviral drug regimens. In this analysis, patients were evaluated at T0 (baseline), T1 (six months) and at T2 (twelve months). A total of 329 patients were enrolled, and 280 (85.1%) of these had at least one follow-up visit. Median observation time was 11 months (IQR 7.0-15.5). Two hundred and two patients (72.1%) were ART experienced and 78 (27.9%) ART naive. Prevalence of HCV-co-infection was 21.4%. At T1, we observed a significant decline in estimated glomerular filtration rate (eGFR), both in experienced and naive patients (mean change from T0-7.5 ± 12.8 ml/min, ...

- by Giuseppe De Socio
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- Multidisciplinary, HIV, Safety, Quinolones