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PubMed2006

Combination of tenofovir and lamivudine versus tenofovir after lamivudine failure for therapy of hepatitis B in HIV-coinfection.

OBJECTIVE: At present sequential monotherapy for chronic hepatitis B with hepatitis B virus (HBV)-polymerase inhibitors is clinical practice. It is unknown to date whether combination therapy with lamivudine plus tenofovir could be superior to sequential therapy with tenofovir after the occurrence of lamivudine resistance. METHODS: We conducted a multicenter, 1: 2 matched pair analysis comparing patients with HBV/HIV-coinfection starting an antiretroviral regimen including tenofovir plus lamivudine with patients who had highly replicative, lamivudine resistant HBe-antigen positive chronic hepatitis B and started with tenofovir as the only active HBV polymerase inhibitor subsequent to lamivudine. RESULTS: At baseline patients on tenofovir plus lamivudine (n = 25) had a median HBV DNA of 5.9 x 10(7) copies/ml compared to 1.37 x 10(8) copies/ml in the tenofovir arm (n = 50; P = 0.32). A sustained undetectable HBV DNA < 1000 copies/ml was achieved in 19/25 (76%) patients on tenofovir plus lamivudine and in 42/50 (84%) on tenofovir (P = 0.53). A loss of HBe-antigen was observed in 9/25 (36%) patients on tenofovir plus lamivudine and in 12/50 (24%) patients on tenofovir (P = 0.29). HBs-antigen loss was found in 1/25 (4%) and 3/50 (6%) patients. CONCLUSIONS: In this cohort of HBV/HIV-coinfected individuals, full HBV DNA suppression was achieved in the majority of patients independent of treatment allocation. Loss of HBe- and HBs-antigen was not different between the two study arms. Over a median treatment period of 116 weeks tenofovir was as effective as tenofovir plus lamivudine. Longer treatment periods may be needed to evaluate potential benefits of first-line combination therapy for chronic hepatitis B.

Adenine↗
PubMed2006

Evaluation of oral tenofovir disoproxil fumarate and topical tenofovir GS-7340 to protect infant macaques against repeated oral challenges with virulent simian immunodeficiency virus.

Simian immunodeficiency virus (SIV) infection of infant macaques is a useful animal model of pediatric HIV infection to evaluate the potential of chemoprophylactic regimens to reduce mother-to-infant transmission of HIV. Previous studies have demonstrated that short-term subcutaneous administration of the reverse transcriptase inhibitor tenofovir was highly effective in protecting newborn macaques against infection after a single high-dose oral inoculation with virulent SIVmac251. In the current study, we mimicked HIV transmission through breast-feeding by repeatedly feeding infant macaques low doses of SIVmac251. Topical administration of a low dose of the second-generation tenofovir prodrug GS-7340 did not have detectable prophylactic efficacy. Oral administration of tenofovir disoproxil fumarate (DF; 10 mg/kg SID) lowered the infection rate at birth, but had lower efficacy against virus infection at 4 weeks of age, most likely because drug levels became suboptimal relative to those obtained with the current tenofovir DF regimen in humans. These prophylactic results further underscore the relevance of the current tenofovir DF prevention trials in pediatric and adult populations.

Adenine↗
PubMed2006

Neuropsychiatric adverse events after switching from an antiretroviral regimen containing efavirenz without tenofovir to an efavirenz regimen containing tenofovir: a report of nine cases.

The combination of tenofovir (TDF) and efavirenz (EFV) has not been associated with any pharmakokinetic interaction or with enhancement of neuropsychiatric disturbances. We report nine cases of neuropsychiatric intolerance occurring early after a switch from an antiretroviral regimen without TDF to an EFV and TDF-containing regimen. Nine HIV-1-infected patients were treated with an EFV-containing regimen for a median duration of 31 months without any EFV-related central nervous system (CNS) effects. They were switched to an EFV-TDF-containing regimen because of lipodystrophy (n=2) and/or the wish to simplify to a once-daily regimen (n=9). Moderate to severe neuropsychiatric events occurred immediately (<48 hours) after TDF initiation in five patients and 2 weeks to 24 months after the switch in the remaining four patients. Treatment modifications occurred in six patients (switch to EFV-nevirapine [n=3], TDF-zidovudine [n=2] or treatment discontinuation [n=1]), leading to a marked improvement of CNS intolerance. Treatment remained unchanged in three patients; two patients experienced chronic persistent sleeping disorders and one patient underwent a spontaneous improvement of symptoms within 2 weeks. EFV plasma concentrations, which were available in two patients before the switch and in four patients after the switch, remained in the therapeutic range. Although the exact mechanism of these symptoms remains hypothetical, neuropsychiatric disorders could be either a consequence of an unexplained interaction between EFV and TDF or an infrequent TDF-related side effect. The incidence of these side effects needs to be evaluated in large databases or pharmacokinetic studies.

Adenine↗
PubMedDate not supplied

[Immunological effectiveness of the nucleoside/nucleotide analog combinations, tenofovir + lamivudine, didanosine + lamivudine and tenofovir + didanosine, in patients with HIV infection and sustained viral suppression].

BACKGROUND: Several recent studies have shown that the combination of ddI plus TDF can produce an unexpected drop in CD4 cell counts, even after correcting the ddI dose. OBJECTIVE: Comparative study of the immunological effectiveness of various once-daily NRTI backbones (ddI plus TDF, ddI plus 3TC or TDF plus 3TC) in antiretroviral-experienced HIV-infected patients achieving viral suppression (PCR, HIV-RNA < 50 copies/microl). METHODS: Prospective cohort study of 48 weeks' duration following viral load suppression with any of the NRTI combinations studied. The main outcome variable was the increase in CD4+ lymphocyte count from the time that viral load was undetectable or treatment was changed for simplification or toxicity (baseline) up to 48 weeks of follow-up. Differences between the assigned therapies were compared. The variables included in analysis were age, sex, risk group, HCV infection, clinical categories of HIV (CDC criteria), lowest CD4 cell count, reason for change of NRTI backbone, type of antiretroviral treatment (PI, NNRTI, or 3 NRTI) and duration of suppressed viral load. RESULTS. Regimens including ddI plus TDF showed significant decreases in CD4 cell counts with adjustments by type of HAART, reason for change, and duration of suppressed viral load. In patients treated with TDF + 3TC, CD4 count increased by 160 cel/microl (95% CI, 53-266) more than in patients treated with TDF + ddI; and in patients receiving ddI + 3TC, CD4+ count increased by 138 cel/microl (95% CI, 25-266) more than in patients receiving TDF + ddI. CONCLUSIONS: The ddI plus TDF backbone seems unadvisable because of the lower associated CD4 cell counts, and because it is poorer than the other options from the immunological standpoint.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Tenofovir disoproxil fumarate: clinical pharmacology and pharmacokinetics.

Tenofovir disoproxil fumarate (tenofovir DF) is an oral prodrug of tenofovir, a nucleotide (nucleoside monophosphate) analogue with activity against retroviruses, including HIV-1, HIV-2 and hepadnaviruses. Following absorption, tenofovir DF is rapidly converted to tenofovir, which is metabolised intracellularly to its active anabolite tenofovir diphosphate, which is a competitive inhibitor of HIV-1 reverse transcriptase and terminates the growing DNA chain. Tenofovir exerts antiviral effects in a variety of cell types, including resting cells. Tenofovir exhibits longer serum (17 hours) and intracellular (> or =60 hours) half-lives than those of nucleoside analogues, which supports a flexible once-daily administration schedule. The pharmacokinetics of tenofovir are dose-proportional and similar in healthy volunteers and HIV-infected individuals. The oral bioavailability of tenofovir is enhanced by administration with a high-fat meal, but is similar at steady state when administered with or without a typical meal. Tenofovir is not a substrate, inducer or inhibitor of human cytochrome P450 enzymes in vitro or in vivo. Tenofovir DF has been studied with 15 other antiretroviral and other concomitant medications frequently used in the HIV-1-infected population. With the exception of didanosine and atazanavir, which require dosage modifications, no clinically significant drug interactions have been observed with tenofovir DF. The recommended oral dosage of tenofovir DF in adults is 300 mg/day. Tenofovir is eliminated by renal elimination, including tubular secretion; dose-interval adjustments are necessary for tenofovir DF in patients with significant renal impairment. No dosage adjustment of tenofovir DF is necessary in patients with liver disease.

Adenine↗
PubMed2006

Pharmacokinetics and dosing recommendations of tenofovir disoproxil fumarate in hepatic or renal impairment.

BACKGROUND: Tenofovir disoproxil fumarate is the prodrug of the acyclic nucleotide reverse transcriptase inhibitor tenofovir that is indicated for use in the treatment of HIV. Tenofovir is eliminated as unchanged drug in the urine, with a significant component of active tubular secretion. The aim of this study was to evaluate the pharmacokinetics of tenofovir in subjects with renal or hepatic impairment, both of which are common in HIV-infected individuals. PATIENTS AND METHODS: HIV seronegative and otherwise healthy subjects with varying degrees of renal or hepatic function were recruited, and tenofovir pharmacokinetics were evaluated over 48 hours (hepatic impairment study) and 96 hours (renal impairment study) following a single tenofovir disoproxil fumarate 300 mg dose. Subjects with hepatic dysfunction were categorised based upon Child-Pugh-Turcotte score, and subjects with renal impairment were categorised based upon their calculated creatinine clearance (CL(CR)) using the Cockcroft-Gault method. RESULTS: As expected for a renally eliminated drug, subjects with and without hepatic impairment displayed similar tenofovir systemic exposures without evidence of substantial alterations in drug disposition, and therefore no dosage adjustments were warranted in these patients. In contrast, in subjects with renal impairment, two distinct groups were observed: (i) subjects with CL(CR)>/=50 mL/min in whom tenofovir pharmacokinetics were similar to subjects with normal renal function; and (ii) subjects with CL(CR) <50 mL/min (moderate or severe impairment) in which tenofovir renal clearance was substantially reduced and thus drug exposures increased. Subjects with end-stage renal disease (ESRD) demonstrated no extrarenal route of tenofovir elimination. Simulations of once-daily or modified dosing regimens demonstrated the need for tenofovir disoproxil fumarate dose-interval adjustment to prevent unnecessary drug accumulation. In patients with ESRD, high-flux haemodialysis efficiently removed tenofovir, with an elimination rate of 134 mL/min and an extraction coefficient of 54%. CONCLUSION: No tenofovir disoproxil fumarate dose adjustment is warranted in the setting of hepatic impairment. Tenofovir disoproxil fumarate 300 mg every 48 hours in individuals with moderate renal impairment and twice weekly corresponding to every 72-96 hours in those with severe renal impairment is recommended in order to target steady-state tenofovir exposures consistent with those observed in subjects with normal renal function receiving tenofovir disoproxil fumarate 300 mg once daily. For subjects receiving thrice-weekly 4-hour maintenance haemodialysis sessions, tenofovir disoproxil fumarate 300 mg administered every 7 days after a haemodialysis session is recommended. HIV-infected patients with significant end-organ dysfunction should be monitored in accordance with clinical practice, including close management of their viral suppression and clinical chemistries.

Adenine↗
PubMed2006

Assessment of drug-drug interactions between tenofovir disoproxil fumarate and the nonnucleoside reverse transcriptase inhibitors nevirapine and efavirenz in HIV-infected patients.

BACKGROUND: Tenofovir disoproxil fumarate (DF) has been studied in combination with efavirenz in healthy volunteers and no interaction was found. No data are available on the possible interaction of tenofovir DF with nevirapine and efavirenz in HIV-infected patients. In this study the combination of nevirapine 200 mg twice daily with tenofovir DF 300 mg once daily and nevirapine 400 mg once daily with tenofovir DF 300 mg once daily were compared with nevirapine twice daily or once daily without tenofovir DF in HIV-infected patients. Furthermore, the combination of efavirenz 600 mg and tenofovir DF 300 mg once daily was compared with use of efavirenz 600 mg once daily only. METHODS: Data were retrospectively collected from routine therapeutic drug monitoring plasma samples. Nevirapine, efavirenz, and tenofovir plasma levels and tenofovir concentration ratios were analyzed. The concentration ratio represents the measured plasma concentration compared with the time-adjusted average concentration, as measured in a reference population. Six different groups were studied: 200 mg nevirapine twice daily, 400 mg nevirapine once daily, 600 mg efavirenz once daily, all without tenofovir DF (groups 1, 2, and 3, respectively), and the same groups with the drugs combined with tenofovir 300 mg once daily (groups 4, 5, and 6, respectively). RESULTS: Plasma samples were evaluable for 272, 18, 126, 32, 94, and 118 patients in the groups 1-6, respectively. No differences were found in plasma levels for tenofovir, nevirapine, and efavirenz for either of the combinations studied. Addition of tenofovir DF to efavirenz or nevirapine in HIV-infected patients does not influence the plasma levels of nevirapine or efavirenz. Furthermore, nevirapine and efavirenz have no effect on tenofovir plasma levels or tenofovir concentration ratios. CONCLUSION: Efavirenz or nevirapine can be coadministered with tenofovir DF in HIV-infected patients without dose modifications.

Adenine↗
PubMed2006

Tenofovir disoproxil fumarate-emtricitabine coformulation for once-daily dual NRTI backbone.

Truvada is the coformulation of tenofovir disoproxil fumarate (TDF; 300 mg) and emtricitabine (FTC; 200 mg) in a single tablet, providing the nucleotide backbone for once-daily dosing, as a component of highly active antiretroviral therapy (HAART). TDF (the bioavailable prodrug of tenofovir) is hydrolyzed to tenofovir intracellularly and phosphorylated to the active metabolite, tenofovir diphosphate. Tenofovir is a nucleotide analog of deoxyadenosine monophosphate, with activity against HIV-1, -2 and hepatitis B virus. FTC, the fluorinated derivative of lamivudine, is an analog of deoxycitidine, active against HIV-1, -2 and hepatitis B virus. Their long half-lives in plasma and in peripheral blood mononuclear cells allow once-daily dosing. Both are eliminated renally. Resistance mutation K65R is selected for by tenofovir and confers a two- to fourfold reduced susceptibility to this drug. The incidence of K65R is low (3%) and has not been observed in clinical trials with the concomitant use of tenofovir and FTC. FTC selects for M184V mutation less frequently than lamivudine. Tenofovir drug interactions include increased exposure to didanosine and inferior immune recovery that preclude their concomitant use. Boosted protease inhibitors increase exposure to tenofovir without dose adjustment required. FTC has no significant drug interactions. They are not metabolized by cytochrome P450, which confers little potential for interactions with drugs metabolized by these enzymes. As tenofovir and FTC are renally eliminated, drugs eliminated by tubular secretion must be avoided. Both antiretrovirals, as individual agents and in coadministration have evidenced antiviral potency in clinical trials. Pivotal study 934 evidenced superior efficacy of the combination TDF/FTC/efavirenz (EFV) versus zidovudine/FTC/EFV. The toxicity profile of tenofovir and FTC has been extensively studied. Lipid profile is more favorable with tenofovir than thymidine analog. Tenofovir requires surveillance of glomerular filtration rate and dosing interval adjustment when creatinine clearance is less than 50 ml/min and avoidance less than 30 ml/min. Fat loss is less likely with tenofovir than with thymidine analog. Clinical trials have assessed the performance of the coformulation of TDF and FTC.

Adenine↗
PubMed2002

Tenofovir disoproxil fumarate: a nucleotide reverse transcriptase inhibitor for the treatment of HIV infection.

BACKGROUND: Tenofovir disoproxil fumarate (DF) is the first nucleotide reverse transcriptase inhibitor approved for use in combination with other antiretroviral agents in the treatment of HIV-1 infection in the United States. Unlike the nucleoside reverse transcriptase inhibitors, which must undergo 3 intracellular phosphorylation steps for activation. nucleotide analogues such as tenofovir require only 2 such steps. This reduction in the phosphorylation requirement has the potential to produce more rapid and complete conversion of the drug to its pharmacologically active metabolite. OBJECTIVE: This article describes the pharmacologic properties and potential clinical usefulness of tenofovir DF. METHODS: Relevant information was identified through searches of MEDLINE (1996-April 2002), Iowa Drug Information Service (1996-April 2002), and International Pharmaceutical Abstracts (1970-April 2002), as well as from meeting abstracts of major HIV/AIDS conferences (1996-2002), using the search terms tenofovir tenofovir disoproxil fumarate, PMPA, bis(POC)PMPA, GS-4331-05, acyclic nucleoside phosphonate, and nucleotide reverse transcriptase inhibitor. Additional information was obtained from material submitted to the US Food and Drug Administration by the manufacturer of tenofovir DF in support of its New Drug Application. RESULTS: In vitro, tenofovir DF has exhibited anti-HIV activity in various HIV-infected cell lines and has produced a synergistic or additive effect against HIV when combined with other antiretroviral agents. In adult humans, tenofovir has a volume of distribution of 0.813 L/kg, is minimally bound to plasma protein (7.2%), has a plasma elimination half-life of 12.0 to 14.4 hours, and is mainly excreted unchanged in urine (70%-80%). Dose adjustment based on sex or body weight does not appear to be necessary, although dose reduction may be necessary in the elderly; there are currently no data on tenofovir DF in renal or hepatic insufficiency. The results of clinical trials suggest the efficacy of tenofovir DF in reducing plasma levels of HIV-1 RNA when used as an add-on to a stable antiretroviral regimen. The most commonly (>3%) reported adverse events in clinical trials have included nausea, diarrhea, asthenia, headache, vomiting, flatulence, abdominal pain, and anorexia. The most commonly (>2%) reported laboratory abnormalities (grade III or IV) included increases in creatine kinase, triglycerides, amylase, aspartate aminotransferase, and alanine aminotransferase, as well as hyperglycemia and glucosuria. Serious adverse events leading to discontinuation of tenofovir DF were infrequent (5%), occurring with an incidence similar to that with placebo (8%). The recommended dosage of tenofovir DF in adults is 300 mg/d PO; pharmacokinetic and efficacy studies in children are ongoing. CONCLUSION: Although additional studies are needed, tenofovir DF appears to be a promising agent for the treatment of HIV infection.

Adenine↗
PubMed2006

Intracellular metabolism and in vitro activity of tenofovir against hepatitis B virus.

Tenofovir is an acyclic nucleotide analog with activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). Tenofovir disoproxil fumarate (tenofovir DF), a bis-alkoxyester prodrug of tenofovir, is approved for the treatment of HIV and is currently being developed to treat chronic hepatitis B. In this report, we further characterize the in vitro activity of tenofovir against HBV as well as its metabolism in hepatic cells. We show that tenofovir is efficiently phosphorylated to tenofovir diphosphate (TFV-DP) in both HepG2 cells and primary human hepatocytes. TFV-DP has a long intracellular half-life (95 h) and is a potent and competitive inhibitor of HBV polymerase (Ki = 0.18 microM). Tenofovir has a 50% effective concentration of 1.1 microM against HBV in cell-based assays, and potency is improved > 50-fold by the addition of bis-isoproxil progroups. Tenofovir has previously demonstrated full activity against lamivudine-resistant HBV in vitro and clinically. Here we show that the major adefovir resistance mutation, rtN236T, confers three- to fourfold-reduced susceptibility to tenofovir in cell culture; the clinical significance of this susceptibility shift has not yet been determined. The rtA194T HBV polymerase mutation recently identified in tenofovir DF-treated HIV/HBV-coinfected patients did not confer in vitro resistance to tenofovir as a single mutation or in a lamivudine-resistant viral background. Overall, the antiviral and metabolic profile of tenofovir supports its development for the treatment of chronic hepatitis B.

Adenine↗
PubMed2003

Tenofovir disoproxil fumarate.

OBJECTIVE: To review the pharmacology, virology, pharmacokinetics, efficacy, safety, resistance profile, and clinical use of tenofovir disoproxil fumarate. DATA SOURCES: A MEDLINE search was performed (1966-August 2002) using the following terms: tenofovir, tenofovir disoproxil fumarate, PMPA (9-(R)-[2-(phosphonomethoxy)propyl]adenine), and Viread. Abstracts from HIV-related meetings were reviewed. DATA EXTRACTION AND STUDY SELECTION: Publications and meeting abstracts regarding tenofovir were reviewed. The most recent and pertinent items were included. DATA SYNTHESIS: Tenofovir disoproxil fumarate is a nucleotide prodrug that is diphosphorylated to its active moiety, tenofovir diphosphate. In this form, tenofovir acts as a reverse transcriptase inhibitor to inhibit HIV-1 replication. In clinical trials, tenofovir was effective at suppressing HIV-1 RNA and boosting CD4+ cell counts. Tenofovir has a long intracellular half-life, which permits once-daily dosing. Since tenofovir does not interact with the cytochrome P450 pathway, it exhibits minimal drug interactions, with the exception of didanosine. Compared with other reverse transcriptase inhibitors, tenofovir may have advantages in terms of toxicity and medication adherence profiles. Ongoing studies are also analyzing tenofovir's activity against hepatitis B virus. CONCLUSIONS: Tenofovir has been shown to be active against HIV-1 in combination with other antiretrovirals. The drug's benefit as a single-agent intensifier of highly active antiretroviral therapy in treatment-experienced patients has been established, and preliminary data for treatment-naïve patients are encouraging.

Adenine↗
PubMed2003

Tenofovir: a nucleotide analog for the management of human immunodeficiency virus infection.

Tenofovir disoproxil fumarate, an acyclic nucleotide analog of adenosine monophosphate, is the most recent addition to the antiretroviral arsenal. After conversion to tenofovir by diester hydrolysis, subsequent phosphorylation by cellular enzymes to form the active tenofovir diphosphate is necessary for antiretroviral activity. Preliminary data suggest that tenofovir is as safe and efficacious as stavudine when given in combination with lamivudine and efavirenz for the treatment of antiretroviral-naïve patients. In antiretroviral-experienced patients, the addition of tenofovir to stable background antiretroviral therapy resulted in approximately a 0.6 log10 copies/ml reduction in viral load relative to placebo. Extended follow-up suggests that such virologic gains may be durable. In vitro, recombinant human immunodeficiency virus (HIV) expressing the K65R mutation showed a 3-4-fold increase in the 50% inhibitory concentrations of tenofovir when compared with wild type. In vivo, this mutation thus far appears to occur infrequently and is associated with variable virologic responses. Response rates to tenofovir vary with the number and pattern of thymidine analog mutations present before starting treatment with this agent. Tenofovir appears to be a well-tolerated agent in patients who are heavily pretreated and who have advanced disease. The main adverse effects appear to be gastrointestinal in nature and include nausea, vomiting, and diarrhea. In animals, osteomalacia and nephrotoxicity have occurred with tenofovir at exposures much higher than those observed in humans. Although no patient had to discontinue therapy as a result of elevated creatinine levels or hypophosphatemia through 58 weeks of treatment, the toxicities associated with long-term tenofovir therapy in humans are unknown. Concomitant administration of tenofovir and didanosine increases the area under the concentration-time curve of the latter by 44-60%; monitoring for signs and symptoms of didanosine toxicity is recommended. The approved dosage of tenofovir is 300 mg (one tablet) once/day with meals. Given the ease of administration and relative safety from the perspectives of adverse effects and drug interactions, tenofovir has the potential to assume a large role in the treatment of patients with HIV infection.

Adenine↗
PubMed2001

Hydroxyurea does not enhance the anti-HIV activity of low-dose tenofovir disoproxil fumarate.

Tenofovir disoproxil fumarate (DF) is an adenosine analogue with significant activity against HIV-1. Hydroxyurea decreases the intracellular concentrations of deoxyadenosine triphosphate, the active metabolite of adenosine. We therefore tested the hypothesis that hydroxyurea could enhance the anti-HIV activity of low-dose tenofovir in vivo. Eight patients received tenofovir DF, 75 mg, plus hydroxyurea, 500 mg bid, for 28 days. Changes in plasma HIV RNA levels were compared with a previously studied cohort of patients treated with tenofovir DF, 75 mg once daily ( n = 8), or tenofovir placebo ( n = 12). The median change in HIV RNA levels after 28 days of continuous treatment was -0.01 log(10) copies/ml for tenofovir placebo, -0.33 log(10) copies/ml for tenofovir 75 mg once daily, and -0.22 log(10) copies RNA/ml for tenofovir plus hydroxyurea. The difference between placebo and tenofovir-treated groups was significant ( p <.05); however, the difference between the tenofovir and tenofovir plus hydroxyurea groups was not significant ( p =.90). We conclude that hydroxyurea does not significantly enhance the antiviral activity of low-dose tenofovir.

Adenine↗
PubMed2003

Extended treatment with tenofovir disoproxil fumarate in treatment-experienced HIV-1-infected patients: genotypic, phenotypic, and rebound analyses.

OBJECTIVE: To study the potential development of genotypic and phenotypic resistance to tenofovir disoproxil fumarate (tenofovir DF) when used as a part of a 96-week HIV-1 treatment regimen for antiretroviral treatment-experienced HIV-infected patients. DESIGN AND METHODS: Clinical trial GS-98-902 was a placebo-controlled, 48-week phase 2 study of three doses of tenofovir DF when added to stable antiretroviral therapy for 189 treatment-experienced HIV-infected patients (mean of 4.6 years of prior antiretroviral treatment; 94% had nucleoside reverse transcriptase [RT] inhibitor [NRTI]-associated mutations). There was a statistically significant reduction in the mean HIV-1 RNA level at week 24 (average change in HIV-1 RNA level of -0.58 log(10) through week 24) with 300 mg of tenofovir DF once daily that was durable through week 48 (average change in HIV-1 RNA level of -0.62 log(10) through week 48). At week 48, 135 patients enrolled in an open-label, 48-week extension phase with 300 mg of tenofovir DF once daily added to their antiretroviral therapy. Genotypic analysis of plasma HIV-1 was performed for all patients after 96 weeks of study or upon early termination. Phenotypic analyses were performed at week 96 for patients with increases in HIV-1 RNA levels of > or =0.5 log(10) from week 48 to week 96. RESULTS: Genotypic results were obtained for 96 of 135 patients. NRTI-associated mutations developed in 41 (30%) of 135 patients from week 48 to week 96. Those mutations were primarily thymidine analog-associated mutations (33/41 patients) and developed while patients were receiving either stavudine or zidovudine. Two patients (1.5%) developed the K65R RT mutation (selected by tenofovir in vitro) but maintained HIV-1 suppression (-0.39 log(10)). These 96-week results were analogous to the 48-week results, in which 33% (n = 63) and 2.1% (n = 4) of patients developed thymidine analog-associated mutations or the K65R mutation, respectively. Although most patients maintained HIV-1 RNA suppression, an analysis of patients with increases in HIV-1 RNA levels of > or =0.5 log(10) (n = 21) from week 48 to week 96 was performed. For eight of 21 patients, development of primary protease inhibitor-associated or non-NRTI-associated resistance mutations was likely responsible for the HIV-1 RNA rebound. The remaining patients developed either no mutation (n = 3) or a new NRTI-associated mutation (n = 10) and were analyzed phenotypically. No phenotypic changes for tenofovir were observed in these analyses. In addition, no new mutations potentially associated with tenofovir DF therapy were identified. Overall, patients had a similar reduction in HIV-1 RNA levels at week 96 and at week 48 compared with baseline (-0.55 and -0.60 log(10), respectively). CONCLUSIONS: Adding tenofovir DF (300 mg) to existing antiretroviral therapy for highly treatment-experienced patients with preexisting resistance mutations showed significant and durable reductions in HIV-1 RNA levels through week 96. Through 96 weeks of tenofovir DF therapy, 48 weeks of which included suboptimal doses of tenofovir DF, there was infrequent development of RT mutations associated with tenofovir DF therapy (K65R mutation, 3%), consistent with the durability of the observed HIV-1 RNA responses.

Adenine↗
PubMed2002

Phenotypic susceptibilities to tenofovir in a large panel of clinically derived human immunodeficiency virus type 1 isolates.

Tenofovir is a nucleotide analogue human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor, and its oral prodrug, tenofovir disoproxil fumarate, has recently been approved for the treatment of HIV-1 infection in the United States. The objective of this study was to characterize the in vitro susceptibility profiles of a large panel of clinically derived HIV-1 isolates for tenofovir. The distribution of tenofovir susceptibilities in over 1,000 antiretroviral-naive, HIV-1-infected individuals worldwide was determined using the Virco Antivirogram assay. In addition, phenotypic susceptibilities to tenofovir and other RT inhibitors were determined in a panel of nearly 5,000 recombinant HIV-1 clinical isolates from predominantly treatment-experienced patients analyzed as a part of routine drug resistance testing. Greater than 97.5% of isolates from treatment-naive patients had tenofovir susceptibilities <3-fold above those of the wild-type controls by the Antivirogram. The clinically derived panel of 5,000 samples exhibited a broad range of antiretroviral drug susceptibilities, including 69, 43, and 16% having >10-fold-decreased susceptibilities to at least one, two, and three antiretroviral drug classes, respectively. Greater than 88% of these 5,000 clinical isolates were within the threefold susceptibility range for tenofovir, and >99% exhibited <10-fold-reduced susceptibilities to tenofovir. Decreased susceptibility to tenofovir was not directly associated with resistance to other RT inhibitors; r(2) values of log-log linear regression plots of susceptibility to tenofovir versus susceptibility to other RT inhibitors were <0.4. The results suggest that the majority of treatment-naive and treatment-experienced individuals harbor HIV that remains within the normal range of tenofovir susceptibilities and may be susceptible to tenofovir disoproxil fumarate therapy.

Adenine↗
PubMed2002

Genotypic and phenotypic analyses of HIV-1 in antiretroviral-experienced patients treated with tenofovir DF.

OBJECTIVE: To evaluate the virologic responses and mutational profiles in antiretroviral-experienced patients adding tenofovir DF once-daily to their existing regimens. DESIGN: Resistance analyses were performed for patients in a phase II placebo-controlled clinical trial of tenofovir DF. METHODS: HIV-1 reverse transcriptase and protease genes from plasma samples were analyzed genotypically and phenotypically at baseline, week 24, and week 48. RESULTS: Of 184 patients, 173 (94%) had baseline HIV-1 expressing one or more nucleoside reverse transcriptase inhibitor-associated resistance mutation. Protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations were observed in 57% and 32% of patients, respectively. Compared to placebo, significant reductions in HIV-1 RNA were observed for tenofovir DF-treated patients who had thymidine analog- (TAM), lamivudine- (M184V), NNRTI- or protease inhibitor-associated mutations. Patients with phenotypic susceptibility to tenofovir within 4-fold of wild-type responded durably to tenofovir DF 300 mg therapy with a decline in plasma HIV-1 RNA of > or = 0.5 log10 copies/ml; few patients had a more than 4-fold reduced susceptibility to tenofovir at baseline. Four patients (2%) developed the K65R mutation (selected by tenofovir in vitro) and showed 3- to 4-fold reductions in tenofovir susceptibility but no evidence of rebound viremia. Thirty-four percent of patients developed additional TAMs, coincident with concurrent zidovudine or stavudine therapy, but also showed durable HIV-1 reductions. There was no evidence of novel resistance to tenofovir. CONCLUSIONS: Adding tenofovir DF 300 mg to an existing regimen in patients with ongoing viral replication and a wide range of genotypic resistance patterns resulted in significant and durable HIV-1 RNA reductions. In addition, there was a low incidence of genotypic or phenotypic resistance to tenofovir DF arising during 48 weeks of therapy.

Adenine↗
PubMed2005

Pharmacokinetic study of tenofovir disoproxil fumarate combined with rifampin in healthy volunteers.

Tenofovir disoproxil fumarate (tenofovir DF) was studied in combination with rifampin in 24 healthy subjects in a multiple-dose, open-label, single-group, two-period study. All subjects were given tenofovir DF at 300 mg once a day (QD) from days 1 to 10 (period 1). From days 11 to 20 the subjects received tenofovir DF at 300 mg combined with rifampin at 600 mg QD (period 2). The multiple-dose pharmacokinetics of tenofovir (day 10 and 20) and rifampin (day 20) were assessed. The drug-related adverse events (AEs) experienced during this study were mostly mild. Only one grade 3 AE possibly or probably related to the treatment (raised liver enzyme levels) occurred during period 2; the subject was withdrawn from the study. Pharmacokinetic data for 23 subjects were thus evaluable. Point estimates for the mean ratios of tenofovir with rifampin versus tenofovir alone for the area under the concentration-time curve from time zero to 24 h (AUC(0-24)), the maximum concentration of drug in plasma (C(max)), and the minimum concentration of drug in plasma (C(min)) were 0.88, 0.84, and 0.85, respectively. The 90% classical confidence intervals for AUC(0-24), C(max), and C(min) were 0.84 to 0.92, 0.78 to 0.90, and 0.80 to 0.91, respectively, thus suggesting pharmacokinetic equivalence. Similarly, coadministration of rifampin and tenofovir DF did not result in changes in the values of the tenofovir pharmacokinetic parameters. For rifampin, the values of the pharmacokinetic parameters found in this study were comparable to those found in the literature, indicating that tenofovir DF has no effect on the pharmacokinetics of rifampin. In conclusion, adaptation of either the rifampin or the tenofovir DF dose for the simultaneous treatment of tuberculosis and human immunodeficiency virus (HIV) infection in HIV-infected patients is probably not required.

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