Randomized Comparison of Renal Effects, Efficacy, and Safety With Once-Daily Abacavir/Lamivudine Versus Tenofovir/Emtricitabine, Administered With Efavirenz, in Antiretroviral-Naive, HIV-1–Infected Adults: 48-Week Results From the ASSERT Study

Post, Frank A.; Moyle, Graeme; Stellbrink, Hans Jürgen; Domingo, Peré; Podzamczer, Daniel; Fisher, Martin; Norden, Anthony G.W.; Cavassini, Matthias; Rieger, Armin; Khuong-Josses, Marie-Aude; Branco, Teresa; Pearce, Helen; Givens, Naomi; Vavro, Cindy; Lim, Michael

doi:10.1097/qai.0b013e3181dd911e

Cited by 194 publications

(154 citation statements)

References 34 publications

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“…Similarly, Post et. al reported higher urine levels at 48 weeks of retinol-binding protein and b2-microglobulin by 50% (P,0.001) and 24% (P,0.001), respectively, in antiretroviral-naïve individuals randomized to tenofovir/emtricitabine (n=193) compared with abacavir/lamivudine (n=192) (41). Although urine a1m was not measured in that study, retinol-binding protein and b2-microglobulin undergo transport into proximal tubular cells by the same endocytic receptor as urine a1m (31), suggesting that these low molecular mass proteins may provide similar information when measured in urine.…”

Section: Discussionmentioning

confidence: 99%

Association of Urine α1-Microglobulin with Kidney Function Decline and Mortality in HIV-Infected Women

Jotwani

Scherzer

Abraham

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Despite advances in therapy, HIV-infected individuals remain at higher risk for kidney dysfunction than uninfected individuals. It was hypothesized that urine levels of a1-microglobulin, a biomarker of proximal tubular dysfunction, would predict kidney function decline and mortality risk in HIV-infected and uninfected women.Design, setting, participants, & measurements In the Women's Interagency HIV Study, urine a1-microglobulin and creatinine concentrations were measured in 903 HIV-infected and 287 uninfected women using stored urine from 1999 to 2000, when prevalence of tenofovir use was ,1%. Participants were categorized into three categories by level of a1-microglobulin-to-creatinine ratio, and associations with kidney decline and all-cause mortality over 8 years were evaluated.Results Urine a1-microglobulin was detectable in 60% of HIV-infected and 40% of uninfected women (P,0.001). Among HIV-infected women, there were 177 (22%), 61 (7%), and 128 (14%) patients with incident CKD, with 10% annual eGFR decline, and who died, respectively. Compared with HIV-infected women in the lowest a1-microglobulin category, HIV-infected women in the highest a1-microglobulin category had a 2.1-fold risk of incident CKD (95% confidence interval, 1.3 to 3.4), 2.7-fold risk of 10% annual eGFR decline (95% confidence interval, 1.2 to 5.9), and 1.6-fold mortality risk (95% confidence interval, 1.0 to 2.6) in models adjusting for kidney risk factors, baseline eGFR, and albuminuria. Among uninfected women, the highest a1-microglobulin category was associated with 3% (relative risk, 2.2; 95% confidence interval, 1.4 to 3.5) and 5% (relative risk, 2.2; 95% confidence interval, 1.1 to 4.3) annual eGFR decline relative to the lowest a1-microglobulin category.Conclusions Proximal tubular dysfunction, indicated by urine a1-microglobulin, was independently associated with kidney function decline in HIV-infected and uninfected women and mortality risk among HIV-infected women.

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Section: Discussionmentioning

confidence: 99%

Association of Urine α1-Microglobulin with Kidney Function Decline and Mortality in HIV-Infected Women

Jotwani

Scherzer

Abraham

et al. 2015

Clinical Journal of the American Society of Nephrology

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“…A new prodrug of tenofovir, tenofovir alafenamide (TAF or GS-7340), was selected to more efficiently load HIV target cells while lowering circulating levels of TFV, resulting in reduced offtarget exposure (10)(11)(12)(13). The administration of 25 mg of TAF in HIV-infected patients resulted in significantly lower plasma TFV levels (ϳ90%) and higher TFV-DP levels in peripheral blood mononuclear cells (PBMCs) (Ͼ5-fold) than in those patients administered 300 mg of TDF (14)(15)(16).…”

mentioning

confidence: 99%

Implications of Efficient Hepatic Delivery by Tenofovir Alafenamide (GS-7340) for Hepatitis B Virus Therapy

Murakami

Wang

Park

et al. 2015

Antimicrob Agents Chemother

139

129

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Tenofovir alafenamide (TAF) is a prodrug of tenofovir (TFV) currently in clinical evaluation for treatment for HIV and hepatitis B virus (HBV) infections. Since the target tissue for HBV is the liver, the hepatic delivery and metabolism of TAF in primary human hepatocytes in vitro and in dogs in vivo were evaluated here. Incubation of primary human hepatocytes with TAF resulted in high levels of the pharmacologically active metabolite tenofovir diphosphate (TFV-DP), which persisted in the cell with a halflife of >24 h. In addition to passive permeability, studies of transfected cell lines suggest that the hepatic uptake of TAF is also facilitated by the organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3, respectively). In order to inhibit HBV reverse transcriptase, TAF must be converted to the pharmacologically active form, TFV-DP. While cathepsin A is known to be the major enzyme hydrolyzing TAF in cells targeted by HIV, including lymphocytes and macrophages, TAF was primarily hydrolyzed by carboxylesterase 1 (CES1) in primary human hepatocytes, with cathepsin A making a small contribution. Following oral administration of TAF to dogs for 7 days, TAF was rapidly absorbed. The appearance of the major metabolite TFV in plasma was accompanied by a rapid decline in circulating TAF. Consistent with the in vitro data, high and persistent levels of TFV-DP were observed in dog livers. Notably, higher liver TFV-DP levels were observed after administration of TAF than those given TDF. These results support the clinical testing of once-daily low-dose TAF for the treatment of HBV infection. Chronic hepatitis B (CHB) is a major global health problem, and the World Health Organization (WHO) estimates that ϳ240 million people worldwide are chronically infected by hepatitis B virus (HBV) (1) (http://www.who.int/mediacentre /factsheets/fs204/en/). The small-molecule anti-HBV agents currently approved by U.S. Food and Drug Administration (FDA) are all nucleoside/nucleotide analogs targeting HBV reverse transcriptase. Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir (TFV), is a current first-line treatment for CHB (2) and has demonstrated efficacy in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients (3-5). TDF is also widely used as the backbone of current anti-HIV combination regimens (6, 7). For both HIV and HBV, the mechanism of action of TDF is intracellular metabolism to its pharmacologically active form, tenofovir diphosphate (TFV-DP), followed by competition with endogenous 2=-dATP for incorporation by the viral reverse transcriptase and subsequent chain termination of viral DNA replication (8, 9). TFV-DP is an effective inhibitor of HBV reverse transcriptase, with an inhibitor constant (K i ) of 0.18 M in vitro (9).A new prodrug of tenofovir, tenofovir alafenamide (TAF or GS-7340), was selected to more efficiently load HIV target cells while lowering circulating levels of TFV, resulting in reduced offtarget exposure (10-13). The administration of 25 mg of TAF in HIV-i...

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“…18,19 In accordance with other studies comparing abacavir/ lamivudine and tenofovir/emtricitabine, patients taking abacavir/lamivudine showed higher plasma lipids at baseline as compared to patients taking tenofovir/emtricitabine. 13,14,[20][21][22] Although differences were not significant at 48 weeks, it may be of interest that through the study decreases in triglycerides, decreases in total-to-HDL cholesterol, and increases in HDL cholesterol tended to be higher when raltegravir (instead of ritonavir-boosted PIs) was combined with abacavir/lamivudine than with tenofovir/emtricitabine. This was also consistent with a significantly lower proportion of patients showing HDL cholesterol < 40 mg/dl at 48 weeks when treated with abacavir/lamivudine compared to tenofovir/emtricitabine, and a nonsignificant higher decrease in the total-to-HDL cholesterol ratio at 48 weeks in patients treated with abacavir/ lamivudine plus raltegravir relative to patients treated with tenofovir/emtricitabine plus raltegravir.…”

Section: Discussionmentioning

confidence: 93%

Abacavir/Lamivudine Versus Tenofovir/Emtricitabine in Virologically Suppressed Patients Switching from Ritonavir-Boosted Protease Inhibitors to Raltegravir

Martínez

D'albuquerque²,

Pérez³

et al. 2013

AIDS Research and Human Retroviruses

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There are few clinical data on the combination abacavir/lamivudine plus raltegravir. We compared the outcomes of patients from the SPIRAL trial receiving either abacavir/lamivudine or tenofovir/emtricitabine at baseline who had taken at least one dose of either raltegravir or ritonavir-boosted protease inhibitors. For the purpose of this analysis, treatment failure was defined as virological failure (confirmed HIV-1 RNA ‡ 50 copies/ ml) or discontinuation of abacavir/lamivudine or tenofovir/emtricitabine because of adverse events, consent withdrawal, or lost to follow-up. There were 143 (72.59%) patients with tenofovir/emtricitabine and 54 (27.41%) with abacavir/lamivudine. In the raltegravir group, there were three (11.11%) treatment failures with abacavir/ lamivudine and eight (10.96%) with tenofovir/emtricitabine (estimated difference 0.15%; 95% CI -17.90 to 11.6). In the ritonavir-boosted protease inhibitor group, there were four (14.81%) treatment failures with abacavir/ lamivudine and 12 (17.14%) with tenofovir/emtricitabine (estimated difference -2.33%; 95% CI -16.10 to 16.70). Triglycerides decreased and HDL cholesterol increased through the study more pronouncedly with abacavir/lamivudine than with tenofovir/emtricitabine and differences in the total-to-HDL cholesterol ratio between both combinations of nucleoside reverse transcriptase inhibitors (NRTIs) tended to be higher in the raltegravir group, although differences at 48 weeks were not significant. While no patient discontinued abacavir/lamivudine due to adverse events, four (2.80%) patients (all in the ritonavir-boosted protease inhibitor group) discontinued tenofovir/emtricitabine because of adverse events ( p = 0.2744). The results of this analysis do not suggest that outcomes of abacavir/lamivudine are worse than those of tenofovir/emtricitabine when combined with raltegravir in virologically suppressed HIV-infected adults.

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Randomized Comparison of Renal Effects, Efficacy, and Safety With Once-Daily Abacavir/Lamivudine Versus Tenofovir/Emtricitabine, Administered With Efavirenz, in Antiretroviral-Naive, HIV-1–Infected Adults: 48-Week Results From the ASSERT Study

Cited by 194 publications

References 34 publications

Association of Urine α1-Microglobulin with Kidney Function Decline and Mortality in HIV-Infected Women

Association of Urine α1-Microglobulin with Kidney Function Decline and Mortality in HIV-Infected Women

Implications of Efficient Hepatic Delivery by Tenofovir Alafenamide (GS-7340) for Hepatitis B Virus Therapy

Abacavir/Lamivudine Versus Tenofovir/Emtricitabine in Virologically Suppressed Patients Switching from Ritonavir-Boosted Protease Inhibitors to Raltegravir

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