Experience with tenofovir disoproxil fumarate for antiretroviral therapy

BACKGROUND AND RATIONALE/OBJECTIVE: Tenofovir disoproxil fumarate was approved in the US in 2001 and a few months later by the European Medicines Evaluation Agency for use in the EU, initially for treatment-experienced HIV patients with early virological failure. The following year the HIV indication was expanded to include antiretroviral treatment na?ve adults over 18 years of age. RESULTS AND CONCLUSIONS: Ongoing clinical trials of tenofovir disoproxil fumarate's safety and efficacy have confirmed its position as a long-term, safe, effective and convenient backbone component in combination antiretroviral therapy for HIV-infected patients. With its favourable resistance profile, it is also an option for treatment-experienced patients. This article describes the efficacy and safety of tenofovir disoproxil fumarate from ongoing and recent clinical trials, and key aspects of its broad, clinical experience since its introduction.     

Raltegravir (MK-0518): an integrase inhibitor for the treatment of HIV-1

In the developed world, access to highly active antiretroviral therapy (HAART) has led to significant reductions in the morbidity and mortality attributed to HIV/AIDS. However, the continual emergence of HIV-1 strains resistant to currently available classes of antiretrovirals highlights the need to develop agents with novel mechanisms of action. Successful completion of the HIV-1 viral life cycle depends in part on the integration of complementary DNA mediated by the enzyme HIV-1 integrase, one of three essential enzymes encoded in the viral genome. The integrase inhibitors have demonstrated the ability to act specifically at the strand transfer step during integration, making HIV-1 integrase a valid and attractive chemotherapeutic target for the treatment of HIV/AIDS. In clinical trials, raltegravir has been shown to be a potent drug with a pharmacokinetic profile that supports a twice-daily dosing schedule. In addition, it has demonstrated a favorable side-effect profile in treatment-naive and -experienced patients and a subset of heavy treatment-experienced patients have been able a achieve virologic suppression with raltegravir as part of combination therapy despite limited treatment options. In October 2007, raltegravir was approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV-1 as part of combination antiretroviral therapy in treatment-experienced patients-providing an additional option for the management of the HIV-1 infected individual.     

Enfuvirtide: a review of its use in the management of HIV infection

Enfuvirtide (Fuzeon), a fusion inhibitor, is indicated in combination with other antiretroviral agents in the treatment of HIV infection in treatment-experienced adults and children aged >6 years.The addition of subcutaneous enfuvirtide to an optimised antiretroviral background regimen improved the virological and immunological response in treatment-experienced HIV-infected patients in the two large, well designed TORO (T-20 vs Optimised Regimen Only) trials. Although injection-site reactions occurred almost universally in enfuvirtide recipients, they were rarely treatment-limiting. Enfuvirtide was otherwise generally well tolerated. The challenge for clinicians is in determining the appropriate timing for enfuvirtide initiation, which requires consideration of the likelihood of a better virological response with the construction of an active background regimen versus the potential for a low rate of adherence to therapy in patients in the early stages of treatment and/or disease development. Enfuvirtide is a novel antiretroviral that is effective in HIV-infected patients whose treatment options are limited by multi-class antiretroviral resistance.     

Vicriviroc: a CCR5 antagonist for treatment-experienced patients with HIV-1 infection

Background: Despite the availability of 31 antiretroviral agents or fixed-dose combinations in the United States and European Union, there is a continuing need for antiretroviral agents with high genetic barriers to resistance, simple dosing schedules, and favorable tolerability and safety profiles. Vicriviroc is a small-molecule chemokine receptor antagonist that inhibits the binding of R5-tropic HIV-1 to host cells at the CCR5 co-receptor, thus preventing viral entry. Objective: To present an evidence-based assessment of the clinical efficacy, pharmacokinetics, and safety profile of vicriviroc. Method: We discuss available peer-reviewed publications as well as preliminary data presented at relevant scientific meetings. Results/conclusions: Vicriviroc has a favorable pharmacokinetic profile with a half-life that enables once-daily dosing. Minimal drug interactions have been demonstrated with other available antiretrovirals. Early clinical trials have established the safety of vicriviroc in both treatment-naive and treatment-experienced R5-tropic HIV-1 infected individuals. A Phase II study in treatment-experienced patients demonstrated early efficacy of 30 mg vicriviroc in a regimen containing a ritonavir-boosted protease inhibitor (PI/r). Phase III studies using the 30-mg PI/r dosing paradigm in R5-tropic treatment-experienced patients have completed 48 weeks, but data are not yet available. These results will further elucidate the role of vicriviroc in the treatment of HIV-1 infected individuals.     

Tipranavir: a review of its use in the management of HIV infection

Tipranavir (Aptivus) is a selective nonpeptidic HIV-1 protease inhibitor (PI) that is used in the treatment of treatment-experienced adults with HIV-1 infection. Tipranavir is administered orally twice daily and must be given in combination with low-dose ritonavir, which is used to boost its bioavailability.The durable efficacy of tipranavir, in combination with low-dose ritonavir (tipranavir/ritonavir 500 mg/200 mg twice daily), has been demonstrated in well designed trials in treatment-experienced adults infected with multidrug-resistant strains of HIV-1. In treatment-experienced adults with HIV-1 infection receiving an optimized background regimen, viral suppression was greater and immunological responses were better with regimens containing tipranavir/ritonavir than with comparator ritonavir-boosted PI-containing regimens. The efficacy benefit appeared to be more marked in patients receiving two fully active drugs in the regimen, with the combination of tipranavir/ritonavir and enfuvirtide (for the first time) appearing to be the most successful. Although tipranavir is generally well tolerated, clinical hepatitis and hepatic decompensation, and intracranial haemorrhage have been associated with the drug. Tipranavir also has a complex drug-interaction profile. Thus, tipranavir, administered with ritonavir, is an effective treatment option for use in the combination therapy of adults with HIV-1 infection who have been previously treated with other antiretroviral drugs.     

Maraviroc, a chemokine CCR5 receptor antagonist for the treatment of HIV infection and AIDS

Pfizer Inc is developing maraviroc, a CCR5 receptor antagonist for the treatment of HIV-1 infection and rheumatoid arthritis. In April 2007, the FDA advisory committee voted to approve maraviroc for HIV-1 infection. Phase II and III clinical trials, and post-approval studies are ongoing in both treatment-experienced and -naive HIV patients. Phase II trials have also been initiated in patients with rheumatoid arthritis.     

The effect of admission to a geriatric ward on medication use: 2002 versus 1985

PURPOSE: To investigate the changes in pharmacotherapy of patients during and after admission to a geriatric ward in 2002 and to investigate if this goes along with reduction of drugs. To describe the differences of the admitted patients and their medication in 2002 compared to 1985. METHODS: Included patients were admitted to the geriatric ward of a general hospital in the Netherlands during 2002 (n = 258, mean age 84.2 years). Medication at admission, during admission and at discharge were described after retrospective reviewing of medical charts. A comparable study was performed at the same ward in 1985. RESULTS: In 2002, most frequently used medication at admission was acetylsalicylic acid (30.2%). Pantoprazole was during admission used in 38.8% of patients and at discharge in 31.8%. Folic acid that was at admission used by 11.6% of patients was at discharge increased to 23.4%. At discharge, vitamin D was used in 21.5% of patients, whereas lisinopril was used in 17.8% of patients. Both in 1985 and 2002 vitamins were added and use of antibiotics was increased during admission. A mean addition of 1.0 drug in 1985 and of 0.7 drugs in 2002 was observed. CONCLUSIONS: Geriatric hospital admission resulted both in 1985 and 2002 in addition of medication. In both periods reductions in medication were nullified by addition of medication for reason of therapy optimisation. Compared to 1985 admitted patients receive more medication resulting from new insights into pharmacotherapy and more use of preventive medicine.     

Raltegravir, an HIV-1 integrase inhibitor for HIV infection

Merck & Co has developed and launched raltegravir, an HIV-1 integrase inhibitor for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. This drug is the lead from a series of integrase strand transfer inhibitors and, by April 2008, it had been launched in Canada, the US, the UK, France, Germany and Spain, and had been filed for approval in Japan.     

Treatment of HIV infection with the CCR5 antagonist maraviroc

Importance of the field: The emergence of resistance in treatment-experienced HIV patients often limits therapeutic success of the currently available antiretroviral drugs. New drug classes are thus required. Maraviroc is the first chemokine receptor 5 antagonist approved for use in treatment experienced HIV patients with a R5-tropic virus.

Areas covered in this review: For this review, data from pharmacokinetic, Phase II and III clinical trials were reviewed.

What the reader will gain: The objectives of this review were to discuss the pharmacokinetics and clinical efficacy and safety of maraviroc in treatment-experienced and -naive HIV patients with R5-tropic virus. Additionally, tropism testing was discussed.

Take home message: Maraviroc is effective in previously treated patients with R5-tropic virus only. Also, maraviroc will be an attractive option for HIV-1-infected treatment-naive patients with R5-tropic viruses only, once genotypic assays have been validated.     

A review of economic evaluations of darunavir boosted by low-dose ritonavir in treatment-experienced persons living with HIV infection

Darunavir boosted by low-dose ritonavir (DRV/r), at a daily dose of 600/100 mg twice a day (bid), has been shown to be superior to alternative highly active antiretroviral therapy (HAART) regimens for the management of treatment-experienced, HIV-infected adults in the phase IIb POWER trials and the phase III TITAN trial. Economic analyses of different types that have been performed for several countries to investigate the cost effectiveness and budgetary impact of DRV/r 600/100 mg bid for treatment-experienced people living with HIV (PLHIV) based on the clinical data gathered in the POWER and TITAN trials are reviewed for consistency and their value to different decision-makers is assessed. Cost-utility analyses for the USA and several European countries indicate that DRV/r-based HAART is cost effective compared with other standard of care protease inhibitor (PI)-based regimens in PLHIV with evidence of PI resistance. For all of these countries, the estimated cost-utility ratio is well below typical benchmark values and these ratios are robust, as demonstrated by one-way sensitivity and variability analyses and multi-way probabilistic sensitivity analyses. Studies using other metrics including the average 1-year drug cost per patient with a plasma HIV-RNA level less than 50 copies/mL at 48 weeks, the incremental drug cost per additional patient with a plasma HIV-RNA level less than 50 copies/mL at 48 weeks, the total (antiretroviral and non-antiretroviral) costs during the first year of treatment, and the total healthcare budget impact during the first 5 years of treatment provided further evidence of the positive economic outcomes with the use of DRV/r in treatment-experienced PLHIV. Different measures of economic outcomes are useful for different types of decision-makers and different types of decisions. In general, the results of these different types of analyses will be consistent with each other. For darunavir, the economic analyses reviewed in this paper demonstrate that the use of DRV/r 600/100 mg bid in the management of HIV-infected, treatment-experienced adults who have failed at least one of the other currently available PIs is cost effective and may be cost saving.     

Sitagliptin/metformin fixed-dose combination: in patients with type 2 diabetes mellitus

Sitagliptin/metformin is a single-tablet, fixed-dose combination of the dipeptidyl peptidase-4 inhibitor sitagliptin and the biguanide antihyperglycaemic metformin that achieves greater improvements in glycaemic control than either component alone in patients with type 2 diabetes mellitus. Recommended dosages of sitagliptin plus metformin, either as the fixed-dose tablet or a combination of the individual agents, significantly reduced glycosylated haemoglobin (HbA(1c)) levels in two well designed clinical trials in treatment-naive patients with type 2 diabetes. The improvements in glycaemic control seen with sitagliptin plus metformin therapy after 18 or 24 weeks were greater than those observed with the individual components alone and/or placebo, and sustained over treatment durations of up to 2 years. As add-on therapy in treatment-experienced patients with inadequate glycaemic control, the HbA(1c)-lowering efficacy of sitagliptin plus metformin was noninferior to that of glimepiride plus metformin in a 30-week, double-blind trial. Sitagliptin plus metformin and glipizide plus metformin lowered HbA(1c) levels by generally similar magnitudes, with the noninferiority of sitagliptin plus metformin to glipizide plus metformin being established in one 52-week study. As part of triple combination therapy, also in treatment-experienced patients with inadequate glycaemic control, sitagliptin added to ongoing glimepiride with or without metformin or ongoing insulin with or without metformin significantly improved glycaemic control over 24 weeks. Sitagliptin plus metformin, as the fixed-dose tablet or a combination of the individual agents, was generally well tolerated in patients with type 2 diabetes, and was associated with a low risk of hypoglycaemia.     

Treatment outcomes: first time versus treatment-experienced clients

A sample of treatment seeking clients was assessed at intake and 6, 12, 24 and 30 months later. Treatment-naive and treatment-experienced clients were compared in terms of baseline characteristics, 6-month outcomes, and predictors of these outcomes. Long-term outcomes of clients achieving an initially successful outcome were compared for the two groups. Results revealed significant short-term improvement for both groups, although treatment-experienced clients reported more serious drug use. The most consistent significant predictors of substance use outcomes were baseline severity of substance use and self-help participation. Outcome predictors unique to each group were also identified. Long-term outcomes for clients with an initial successful outcome tended to be better for treatment-experienced than treatment-naive clients. Both groups tended to have poorer outcomes as the follow-up duration increased. The results suggest that common and unique predictors of outcomes be considered in treating these two groups of clients. Additionally, treatment-naive clients may be at increased risk for poor outcomes even when initial success is achieved.