Tenofovir

(te noe' fo veer)

PCaution when used during lactation / LCI : Caution - pregnancy; Contraindication - lactation (breast feeding)

Molecule Info

| See TERMINOLOGY & ABBREVIATIONS |
WARNING

LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including Tenofovir, in combination with other antiretrovirals.
Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including Tenofovir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including Tenofovir. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

Content(s) & Description

Tenofovir disoproxil fumarate.

Each tablet contains tenofovir disoproxil fumarate 300 mg, equivalent to tenofovir disoproxil 245 mg. It also contains the following inactive ingredients: Croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose and pregelatinized starch. The tablets are coated with a white-colored film.
The chemical name of tenofovir disoproxil fumarate is 9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P·C4H4< span>O
4 and a molecular weight of 635.52.
Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in distilled water at 25°C. It has an octanol/phosphate buffer (pH 6.5) partition coefficient (log p) of 1.25 at 25°C.

Indication(s) In combination with other antiretroviral agents for the treatment of HIV-1 infection. This is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in controlled studies of Tenofovir in treatment-naive adults and in treatment-experienced adults.
Additional important information regarding the use of Tenofovir for the treatment of HIV-1 infection: There are no study results demonstrating the effect of Tenofovir on clinical progression of HIV-1.
The use of Tenofovir should be considered for treating adult patients with HIV-1 strains that are expected to be susceptible to tenofovir as assessed by laboratory testing or treatment history (see Clinical Studies under Actions).
Dosage & Administration The dose of Tenofovir is 300 mg once daily taken orally, without regard to food. 
Dose Adjustment for Renal Impairment: Significantly increased drug exposures occurred when Tenofovir was administered to patients with moderate to severe renal impairment. The dosing interval of Tenofovir should be adjusted in patients with baseline creatinine clearance <50 mL/min using the recommendations in Table 9. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated, therefore, clinical response to treatment and renal function should be closely monitored in these patients. 
The pharmacokinetics of tenofovir have not been evaluated in nonhemodialysis patients with CrCl <10 mL/min; therefore, no dosing recommendation is available for these patients.
Overdose Limited clinical experience at doses higher than the therapeutic dose of Tenofovir 300 mg is available.
In Study 901, tenofovir disoproxil fumarate 600 mg was administered to 8 patients orally for 28 days. No severe adverse reactions were reported. The effects of higher doses are not known.
If overdose occurs, the patient must be monitored for evidence of toxicity and standard supportive treatment applied as necessary.
Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300-mg dose of Tenofovir, a 4-hr hemodialysis session removed approximately 10% of the administered tenofovir dose.
Contraindications Patients with previously demonstrated hypersensitivity to tenofovir or to any of the components of Tenofovir.
Warnings & Precautions

Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals. Majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Tenofovir should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Renal Impairment: Tenofovir is principally eliminated by the kidney. Dosing interval adjustment is recommended in all patients with CrCl <50 mL/min. No safety data are available in patients with renal dysfunction who received Tenofovir using these dosing guidelines.
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported in association with the use of Tenofovir (see Adverse Reactions). The majority of these cases occurred in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents, however, some cases occurred in patients without identified risk factors. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent. Patients at risk for, or with a history of, renal dysfunction and patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.

Patients with HIV and Hepatitis B Virus Co-Infection: It is recommended that all patients with HIV be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy. Tenofovir is not indicated for the treatment of chronic HBV infection and the safety and efficacy of Tenofovir have not been established in patients co-infected with HBV and HIV. Exacerbations of HBV have been reported in patients after the discontinuation of Tenofovir. Patients co-infected with HIV and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping Tenofovir treatment.

Bone Effects: In study 903 through 48 weeks, decreases from baseline in bone mineral density (BMD) were seen at the lumbar spine and hip in both arms of the study. At 48 weeks, percent decreases in BMD from baseline (mean±SD) were greater in patients receiving Tenofovir + lamivudine + efavirenz (spine, -3.3%; hip, -3.2%±3.6) compared with patients receiving stavudine + lamivudine + efavirenz (spine, -2%±3.5; hip, 1.8%±3.3). The proportion of patients who met a protocol-defined value of BMD loss (5% decrease in spine or 7% decrease in hip) was higher in the Tenofovir group than the stavudine group. In addition, there were significant increases in levels of 4 biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide and urinary N-telopeptide) in the Tenofovir group relative to the stavudine group, suggesting increased bone turnover. Serum parathyroid hormone levels were also higher in the Tenofovir group. Except for bone-specific alkaline fracture reported in the Tenofovir group compared with 4 in the stavudine group; no pathologic fractures were identified over 48 weeks of study treatment. The clinical significance of the changes in BMD and biochemical markers is unknown and follow-up is continuing to assess long-term impact.

Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Animal Toxicology: Tenofovir and tenofovir disoproxil fumarate administered in toxicology studies to rats, dogs and monkeys at exposures (based on AUCs) ≥6-fold those observed in humans caused bone toxicity. In monkeys, the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.
Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2-20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

Carcinogenicity, Mutagenicity & Impairment of Fertility: Long-term carcinogenicity studies of tenofovir disoproxil fumarate in rats and mice are in progress.
Tenofovir disoproxil fumarate was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In anin vivo mouse micronucleus assay, tenofovir disoproxil fumarate was negative when administered to male mice.
There were no effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate was administered to male and female rats at a dose equivalent to 19 times the human dose based on body surface area (BSA) comparisons. There was, however, an alteration of the estrous cycle in female rats.
Use in pregnancy: Pregnancy Category B: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on BSA comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Tenofovir should be used during pregnancy only if clearly needed.
Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to Tenofovir, an Antiretroviral Pregnancy Registry has been established.
Use in lactation: The Centers for Disease Control and Prevention recommend that HIV-infected mothers do not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that tenofovir is secreted in milk. It is not known whether tenofovir is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Tenofovir.
Use in children: Safety and effectiveness in pediatric patients have not been established.
Use in the elderly: Clinical studies of Tenofovir did not include sufficient numbers of subjects ≥65 years to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.

Adverse Drug Reaction(s) Clinical Trials: More than 12,000 patients have been treated with Tenofovir alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in phase I-III clinical trials and expanded access studies. A total of 1287 patients have received Tenofovir 300 mg once daily in phase I-III clinical trials; over 11,000 patients have received Tenofovir in expanded access studies.
Treatment-Experienced Patients: Treatment-Emergent Adverse Events: The most common adverse events that occurred in patients receiving Tenofovir with other antiretroviral agents in clinical trials were mild to moderate gastrointestinal events eg, nausea, diarrhea, vomiting and flatulence. Less than 1% of patients discontinued participation in the clinical studies due to gastrointestinal adverse events (Study 907). 
Laboratory Abnormalities: Laboratory abnormalities observed in this study occurred with similar frequency in the Tenofovir- and placebo-treated groups. 

Treatment-Naive Patients: Treatment-Emergent Adverse Events: The adverse reactions seen in a double-blind comparative controlled study in which 600 treatment-naive patients received Tenofovir (N=299) or stavudine (N=301) in combination with lamivudine and efavirenz for 48 weeks (Study 903) were generally consistent, with the addition of dizziness, with those seen in treatment-experienced patients. Mild adverse events (grade 1) were common with a similar incidence in both arms and included dizziness, diarrhea and nausea. 

Laboratory Abnormalities: With the exception of triglyceride elevations that were more common in the stavudine group (8%) compared with Tenofovir (2%), laboratory abnormalities observed in this study occurred with similar frequency in the Tenofovir and stavudine treatment arms. 
Post-Marketing Experience: In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of Tenofovir. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting or potential causal connection to Tenofovir.
Immune System Disorders: Allergic reaction.
Metabolism and Nutrition Disorders: Hypophosphatemia, lactic acidosis.
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea.
Gastrointestinal Disorders: Abdominal pain, pancreatitis.
Renal and Urinary Disorders: Renal insufficiency, renal failure, acute renal failure, Fanconi syndrome, proximal tubulopathy, proteinuria, increased creatinine, acute tubular necrosis.
Drug Interactions When administered with Tenofovir, Cmax and AUC of didanosine administered as either the buffered or enteric-coated formulation increased significantly (see Table 4). The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse events, including pancreatitis and neuropathy. In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg when it is co-administered with Tenofovir. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. When co-administered, Tenofovir and didanosine EC may be taken under fasted conditions or with a light meal (<400 kCal, 20% fat). Co-administration of didanosine-buffered tablet formulation with Tenofovir should be under fasted conditions. Co-administration of Tenofovir and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse events. Didanosine should be discontinued in patients who develop didanosine-associated adverse events. Since tenofovir is primarily eliminated by the kidneys, co-administration of Tenofovir with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to, adefovir dipivoxil, cidofovir, acyclovir, valacyclovir, ganciclovir and valganciclovir.
Pregnancy Category (FDA) Category B: Either animal-reproduction studies have not demonstrated a foetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the 1sttrimester (and there is no evidence of a risk in later trimesters).
Storage Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F).
Pharmacology
Tenofovir disoproxil fumarate (a prodrug of tenofovir) is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. In vivo tenofovir disoproxil fumarate is converted to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase.
Microbiology: Mechanism of Action: Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases alpha, beta and mitochondrial DNA polymerase gamma.
Antiviral Activity In Vitro: The in vitro antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The IC50 (50% inhibitory concentration) values for tenofovir were in the range of 0.04-8.5 microM. In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors [NRTIs] (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors [NNRTIs] (delavirdine, efavirenz, nevirapine) and protease inhibitors [PIs] (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Most of these drug combinations have not been studied in humans. Tenofovir displayed antiviral activity in vitro against HIV-1 clades A, B, C, D, E, F, G and O (IC50 values ranged from 0.5-2.2 microM).
Drug Resistance: HIV-1 isolates with reduced susceptibility to tenofovir have been selected in vitro. These viruses expressed a K65R mutation in reverse transcriptase and showed a 3- to 4-fold reduction in susceptibility to tenofovir.
Tenofovir-resistant isolates of HIV-1 have also been recovered from some patients treated with tenofovir in combination with certain antiretroviral agents. In treatment-naive patients treated with Tenofovir + lamivudine + efavirenz, viral isolates from 7/29 (24%) patients with virologic failure showed reduced susceptibility to tenofovir. In treatment-experienced patients, 14/304 (4.6%) of the Tenofovir-treated patients with virologic failure showed reduced susceptibility to tenofovir.
Genotypic analysis of the resistant isolates showed a mutation in the HIV-1 reverse transcriptase gene resulting in the K65R amino acid substitution.
Cross-Resistance: Cross-resistance among certain reverse transcriptase inhibitors has been recognized. The K65R mutation selected by tenofovir is also selected in some HIV-1-infected subjects treated with abacavir, didanosine or zalcitabine. HIV isolates with this mutation also show reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors the K65R mutation. HIV-1 isolates from patients (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated reverse transcriptase mutations (M41L, D67N, K70R, L210W, T215Y/F or K219Q/E/N), showed a 3.1-fold decrease in the susceptibility to tenofovir. Multinucleoside-resistant HIV-1 with a T69S double insertion mutation in the reverse transcriptase showed reduced susceptibility to tenofovir.
Pharmacokinetics: The pharmacokinetics of tenofovir disoproxil fumarate have been evaluated in healthy volunteers and HIV-1-infected individuals. Tenofovir pharmacokinetics are similar between these populations.
Absorption: Tenofovir is a water-soluble diester prodrug of the tenofovir. The oral bioavailability of tenofovir from Tenofovir in fasted patients is approximately 25%. Following oral administration of a single dose of Tenofovir 300 mg to HIV-1-infected patients in the fasted state, maximum serum concentrations (Cmax) are achieved in 1±0.4 hr. Cmax and AUC values are 296±90 ng/mL and 2287±685 ng·hr/mL, respectively.
The pharmacokinetics of tenofovir are dose-proportional over a Tenofovir dose range of 75-600 mg and are not affected by repeated dosing.
Effects of Food on Oral Absorption: Administration of Tenofovir following a high-fat meal (approximately 700-1000 kCal containing 40-50% fat) increases the bioavailability, with an increase in tenofovir AUC0-∞ of approximately 40% and an increase in Cmax of approximately 14%. However, administration of Tenofovir with a light meal did not have a significant effect on the pharmacokinetics of tenofovir when compared to fasted administration of tenofovir. Food delays the time to tenofovir Cmax by approximately 1 hr. Cmax and AUC of tenofovir are 326±119 ng/mL and 3324±1370 ng·hr/mL following multiple doses of Tenofovir 300 mg once daily in the fed state, when meal content was not controlled.
Distribution: In vitro binding of tenofovir to human plasma or serum proteins is <0.7% and 7.2%, respectively over the tenofovir concentration range of 0.01-25 mcg/mL. The volume of distribution at steady state is 1.3±0.6 L/kg and 1.2±0.4 L/kg, following IV administration of tenofovir 1 mg/kg and 3 mg/kg.
Metabolism and Elimination: In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP450 enzymes.
Following IV administration of tenofovir, approximately 70-80% of the dose is recovered in the urine as unchanged tenofovir within 72 hrs of dosing. Following single dose, oral administration of Tenofovir, the terminal elimination t1/2 of tenofovir is approximately 17 hrs. After multiple oral doses of Tenofovir 300 mg once daily (under fed conditions), 32±10% of the administered dose is recovered in urine over 24 hrs.
Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.
Special Populations: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations.
Tenofovir pharmacokinetics are similar in male and female patients.
Pharmacokinetic studies have not been performed in children (<18 years) or in the elderly (>65 years). The pharmacokinetics of tenofovir following a 300-mg single dose of Tenofovir have been studied in non-HIV-infected patients with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired patients. No change in Tenofovir dosing is required in patients with hepatic impairment. The pharmacokinetics of tenofovir is altered in patients with renal impairment (see Renal Impairment under Warnings). In patients with CrCl <50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax and AUC0-∞ of tenofovir were increased (see Table 1). It is recommended that the dosing interval for Tenofovir be modified in patients with CrCl <50 mL/min or in patients with ESRD who require dialysis (see Dosage & Administration).

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300-mg dose of Tenofovir, a 4-hr hemodialysis session removed approximately 10% of the administered tenofovir dose.
Drug Interactions: At concentrations substantially higher (approximately 300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the following human CYP450 isoforms: CYP3A4, CYP2D6, CYP2C9 or CYP2E1. However, a small (6%) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450-mediated interactions involving tenofovir with other medicinal products is low (see Pharmacokinetics).
Tenofovir is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. Co-administration of Tenofovir with drugs that are eliminated by active tubular secretion may increase serum concentrations of either tenofovir or the co-administered drug, due to competition for this elimination pathway. Drugs that decrease renal function may also increase serum concentrations of tenofovir.
Tenofovir has been evaluated in healthy volunteers in combination with abacavir, didanosine, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, methadone and oral contraceptives. Tables 2 and 3 summarize pharmacokinetic effects of co-administered drug on tenofovir pharmacokinetics and effects of Tenofovir on the pharmacokinetics of co-administered drug.
When administered with multiple doses of Tenofovir, the Cmax and AUC of didanosine 400 mg increased significantly. The mechanism of this interaction is unknown. When didanosine 250 mg enteric-coated capsules were administered with Tenofovir, systemic exposures to didanosine were similar to those seen with the 400-mg enteric-coated capsules alone under fasted conditions.

Following multiple dosing to HIV-negative subjects receiving chronic methadone maintenance therapy or oral contraceptives, steady-state tenofovir pharmacokinetics were similar to those observed in previous studies, indicating lack of clinically significant drug interactions between these agents and Tenofovir.

Description of Clinical Studies: Treatment-Experienced Patients: Study 907: Tenofovir + Standard Background Therapy (SBT) Compared to Placebo + SBT:Study 907 was a 24-week, double-blind, placebo-controlled multicenter study of Tenofovir added to a stable background regimen of antiretroviral agents in 550 treatment-experienced patients. After 24 weeks of blinded study treatment, all patients continuing on study were offered open-label Tenofovir for an additional 24 weeks. Patients had a mean baseline CD4 cell count of 427 cells/mm3(range 23-1385), median baseline plasma HIV-1 RNA of 2340 (range 50-75,000) copies/mL, and mean duration of prior HIV-1 treatment was 5.4 years. Mean age of the patients was 42 years, 85% were male and 69% were Caucasian, 17% Black and 12% Hispanic.

At 24 weeks of therapy, there was a higher proportion of patients in the Tenofovir arm compared to the placebo arm with HIV-1 RNA <50 copies/mL (19% and 1%, respectively). Mean change in absolute CD4 counts by week 24 was +11 cells/mm3 for the Tenofovir group and -5 cells/mm3 for the placebo group. Mean change in absolute CD4 counts by week 48 was +4 cells/mm3 for the Tenofovir group. Through week 24, one patient in the Tenofovir group and no patients in the placebo arm experienced a new CDC class C event.
Treatment-Naive Patients: Study 903: Tenofovir + Lamivudine + Efavirenz Compared to Stavudine + Lamivudine + Efavirenz: Data through 48 weeks are reported for Study 903, a double-blind, active-controlled multicenter study comparing Tenofovir (300 mg once daily) administered in combination with lamivudine and efavirenz versus stavudine, lamivudine and efavirenz in 600 antiretroviral-naive patients. Patients had a mean age of 36 years (range 18-64), 74% were male, 64% were Caucasian and 20% were Black. The mean baseline CD4 cell count was 279 cells/mm3 (range 3-956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL (range 417-5,130,000). Patients were stratified by baseline HIV-1 RNA and CD4 count. Forty-three percent of patients had baseline viral loads >100,000 copies/mL and 39% had CD4 cell counts <200 cells/mL.

Achievement of plasma HIV-1 RNA concentrations of <400 copies/mL at week 48 was similar between the 2 treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (< or >100,000 copies/mL) and CD4 cell count (< or ≥200 cells/mm3).
Through 48 weeks of therapy, 76% and 79% of patients in the Tenofovir and stavudine arms, respectively, achieved HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4 cell count was 169 cells/mm3 for the Tenofovir arm and 167 cells/mm3 for the stavudine arm. Through 48 weeks, 8 patients in the Tenofovir group and 6 patients in the stavudine group experienced a new CDC class C event.
Genotypic Analyses of Tenofovir in Patients with Previous Antiretroviral Therapy:The virologic response to Tenofovir therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment-experienced patients participating in 2 controlled trials.
The use of resistance testing and the clinical interpretation of genotypic mutations is a complex and evolving field. Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change pending additional data.
In 2 clinical studies, 94% of the participants evaluated had baseline HIV-1 isolates expressing at least 1 NRTI mutation. These included resistance mutations associated with zidovudine (M41L, D67N, K70R, L210W, T215Y/F or K219Q/E/N), the lamivudine/abacavir-associated mutation (M184V) and others. In addition, the majority of participants evaluated had mutations associated with either PI or NNRTI use. Virologic responses for patients in the genotype substudy were similar to the overall study results.
Several exploratory analyses were conducted to evaluate the effect of specific mutations and mutational patterns on virologic outcome. Descriptions of numerical differences in HIV-1 RNA response are shown in Table 7. Because of the large number of potential comparisons, statistical testing was not conducted.
Varying degrees of cross-resistance of Tenofovir to preexisting zidovudine-associated mutations were observed and appeared to depend on the number of specific mutations. Tenofovir-treated patients whose HIV-1 expressed ≥3 zidovudine-associated mutations that included either the M41L or L210W reverse transcriptase mutation showed reduced responses to Tenofovir therapy; however, these responses were still improved compared with placebo. The presence of the D67N, K70R, T215Y/F or K219Q/E/N mutation did not appear to affect responses to Tenofovir therapy. 

In the protocol-defined analyses, virologic response to Tenofovir was not reduced in patients with HIV-1 that expressed the lamivudine/abacavir-associated M184V mutation. In the absence of zidovudine-associated mutations, patients with the M184V mutation receiving Tenofovir showed a -0.84 log10 copies/mL decrease in their HIV-1 RNA relative to placebo. In the presence of zidovudine-associated mutations, the M184V mutation did not affect the mean HIV-1 RNA responses to Tenofovir treatment. HIV-1 RNA responses among these patients were durable through week 48.
There were limited data on patients expressing some primary NRTI mutations and multidrug-resistant mutations at baseline. However, patients expressing the K65R mutation appeared to have reduced virologic responses to Tenofovir.
The presence of at least one HIV-1 PI or NNRTI mutation at baseline did not appear to affect the virologic response to Tenofovir. Cross-resistance between Tenofovir and HIV-1 PIs is unlikely because of the different enzyme targets involved.
Phenotypic Analyses of Tenofovir in Patients with Previous Antiretroviral Therapy:The virologic response to Tenofovir therapy has been evaluated with respect to baseline phenotype (N=100) in treatment-experienced patients participating in 2 controlled trials. Phenotypic analysis of baseline HIV-1 from patients in these studies demonstrated a correlation between baseline susceptibility to Tenofovir and response to Tenofovir therapy. 
ATC Classification J05AF07 - tenofovir disoproxil; Belongs to the class of nucleoside and nucleotide reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.

Brand/Product Info


Total Products : 4    
Brand Name Manufacturer/Marketer Composition Dosage Form Pack Size & Price
FOVIRAL ACI Ltd. Tenofovir disoproxil fumarate INN 300mg Film Coated Tablet 8's: 680.00 MRP
PROXIVIR Square Pharmaceuticals Ltd. Tenofovir Disoproxil Fumarate 300mg Tablet 2x6
T-FOVIR Drug International Ltd Tenofovir disoproxil fumarate INN 300mg Film Coated Tablet 7's: 595.00 MRP
Xynovir Incepta Pharmaceuticals Limited Tenofovir Disoproxil Fumarate INN 300mg Tablet 12's:MRP 1020 Tk

| See FDA approved Brand Manufacturer's Prescribing Information | 

Back to top