enfuvirtide and tipranavir

Antiretroviral rescue therapy has been revolutionized by the development of new drugs in the last few years: enfuvirtide (a fusion inhibitor), tipranavir/ritonavir (a high genetic barrier protease inhibitor), darunavir/ritonavir (a high genetic barrier protease inhibitor), etravirine (a non-nucleoside reverse transcriptase inhibitor active against nevirapine- and efavirenz- resistant HIV), maraviroc (a CCR5 coreceptor inhibitor) and raltegravir (an integrase inhibitor). The use of these drugs in rescue regimens has allowed the goal of antiretroviral rescue therapy to be the same as that in treatment naive-patients: to achieve a viral load lower than 50 copies of RNA of HIV/ml. Raltegravir is the first integrase inhibitor available for clinical use in Spain. This drug is primarily metabolized through UGT1A1-mediated glucuronidation and consequently has a low potential for interactions with drugs metabolized by the cytochrome P450 pathway. Raltegravir has been demonstrated to have high efficacy in two large clinical trials of rescue therapy, especially when combined with darunavir/ritonavir and enfuvirtide. Preliminary data suggest that raltegravir could also be an effective drug in treatment-naive patients and as substitution therapy in patients with toxicity due to boosted protease inhibitor therapy. The drug's unusual mechanism of action has reopened the possibility of a positive effect on latent HIV reservoirs.

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials as Topic; Cyclohexanes; Darunavir; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Enfuvirtide; Forecasting; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; Humans; Maraviroc; Nitriles; Peptide Fragments; Pyridazines; Pyridines; Pyrimidines; Pyrones; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Sulfonamides; Triazoles

Once patients have a triple class virological failure, their treatment options are limited and there is an increased risk of death. In order to construct active treatment regimens, new potent antiretroviral agents are available for these patients. The virological target in patients with treatment failure is now plasma HIV RNA level below 50 copies/ml when 2 or more potent drugs are identified. If at least two active drugs cannot be identified, the current regimen should be maintained until new drugs become available, assuming that there is an immunological and clinical stability, in order to avoid the use of a single-active drug that usually leads to rapid development of resistance, further limiting the future treatment options. In this article, the current state of knowledge about these new agents available and the guidelines of main societies are reviewed.

Topics: Anti-HIV Agents; Anti-Retroviral Agents; Darunavir; Drug Resistance, Viral; Drug Therapy, Combination; Enfuvirtide; HIV; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; Humans; Organic Chemicals; Peptide Fragments; Practice Guidelines as Topic; Pyridines; Pyrones; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; RNA, Viral; Sulfonamides

The human immunodeficiency virus (HIV) was discovered in 1982, but treatment strategies were not introduced until 5 years later. Early regimens consisted of one or two drugs and often led to treatment failure. Since the advent in 1995 of highly active antiretroviral therapy (HAART), which consists of at least three agents, a dramatic improvement has been seen in the number of patients attaining undetectable viral loads, improved CD4 counts, and improved survival. However, early HAART often consisted of drugs with complex dosing schedules, strict food requirements, treatment-limiting adverse effects, and the need to take 16-20 pills/day. These treatment barriers often led to patient nonadherence, with subsequent treatment failure and development of resistant strains. The CD4 count and viral load are the most important surrogate markers used to determine if treatment is indicated. Current guidelines suggest starting treatment in patients who are symptomatic with an acquired immunodeficiency syndrome-defining illness regardless of CD4 count or viral load, as well as in asymptomatic patients with a CD4 count of 350 cells/mm(3) or below. In patients with CD4 counts above 350 cells/mm(3) and viral loads above 100,000 copies/ml, some clinicians prefer to defer treatment, whereas others will consider starting therapy; treatment is deferred in patients with CD4 counts above 350 cells/mm(3) and viral load s below 100,000 copies/ml. If therapy is started, the selection of appropriate agents is based on comorbidities (liver disease, depression, cardiovascular disease), pregnancy status, adherence potential (dosage regimen, pill burden, dosing frequency), food restrictions (dosing with regard to meals), adverse drug effects, and potential drug-drug interactions. Within the last 8 years, newer antiretroviral agents have focused on ways to improve adherence, such as convenient dosing (fewer pills), pharmacokinetic and formulation changes to reduce dosing frequency or pill burden, and coformulated dosage forms that contain two or three drugs in one convenient pill. Other improvements include increased potency of newer agents, agents sensitive to a highly resistant virus, improved adverse-effect profile (e.g., less gastrointestinal effects, improved lipid profiles), as well as protease inhibitor boosting with ritonavir, which takes advantage of the potent cytochrome P450 inhibitory action of ritonavir. This review focuses on the concepts of antiretroviral therapy, barrier

Topics: Adenine; Animals; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Carbamates; Clinical Trials as Topic; Deoxycytidine; Dideoxynucleosides; Drug Administration Schedule; Drug Combinations; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Drugs, Investigational; Emtricitabine; Enfuvirtide; Furans; HIV Envelope Protein gp41; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Oligopeptides; Organophosphates; Organophosphonates; Patient Compliance; Peptide Fragments; Pyridines; Pyrones; Reverse Transcriptase Inhibitors; Sulfonamides; Tenofovir

Treatment-experienced patients with HIV may harbor virus that has accumulated several mutations conferring decreased susceptibility to one or more antiretroviral drugs. For clinicians treating these patients, identifying a tolerable antiretroviral regimen with a reasonable chance of a durable virologic effect represents a major challenge. The first priority is to identify and correct the mechanisms responsible for previous treatment failure. Resistance testing and drug level monitoring may be useful in this setting. The patient's history of antiretroviral drug tolerability, comorbidities, and concomitant medications should be considered. Patients embarking on multiple-drug regimens will require close monitoring for adherence, toxicities, and drug-drug interactions. The guiding principle when constructing a rescue or salvage regimen is to achieve a cumulative activity score greater than 2, recognizing that some agents will have only partial activity. Some new drugs are available that may be helpful if used carefully with an active background regimen.

Topics: Adenine; Anti-HIV Agents; Anti-Retroviral Agents; Atazanavir Sulfate; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Oligopeptides; Organophosphonates; Peptide Fragments; Pyridines; Pyrones; Randomized Controlled Trials as Topic; Sulfonamides; Tenofovir; Treatment Failure; Viral Load

The data on the use of tipranavir and enfuvirtide in pregnancy are very limited. We performed a pharmacokinetic profile in a pregnant woman with multidrug-resistant HIV-1 infection at 37 weeks gestation. Tipranavir levels were in the therapeutic range and the cord blood concentration at delivery was relatively high when compared with other protease inhibitors. No enfuvirtide was detected in the fetal compartment. Tipranavir and enfuvirtide were successfully used in pregnancy, but possible toxicities must be kept in mind.

Topics: Adult; Anti-HIV Agents; Enfuvirtide; Female; Fetal Blood; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments; Plasma; Pregnancy; Pregnancy Complications, Infectious; Pyridines; Pyrones; Sulfonamides

We compared tipranavir and darunavir concentrations measured at steady state in 20 human immunodeficiency virus (HIV)-infected patients enrolled in the EASIER-ANRS 138 clinical trial who switched from enfuvirtide to raltegravir while maintaining the same background regimen. The geometric mean ratios of the observed predose concentration (C(trough)), maximum concentration of drug observed in plasma (C(max)), and area under the plasma concentration-time curve (AUC) before (day 0) and after (week 24) the switch were 0.49, 0.76, and 0.67 and 0.82, 0.68, and 0.64 for tipranavir and darunavir, respectively. The virologic consequences of these drug interactions have yet to be determined.

Topics: Anti-HIV Agents; Darunavir; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; Humans; Male; Middle Aged; Peptide Fragments; Pyridines; Pyrones; Ritonavir; Sulfonamides

The effect of enfuvirtide (ENF) in 11 HIV-1 heavily antiretroviral-experienced children and adolescents enrolled in the HIV-1 Paediatric Spanish cohort was further investigated. Patients who received ENF with novel drugs (etravirine, darunavir, and/or tipranavir) reached and maintained undetectable plasma HIV-1 RNA levels and showed immunological recovery within the first 3 months of therapy that was maintained during the follow-up. Viremia was not fully suppressed in patients who did not combine ENF with novel drugs but interestingly, immunological benefit was observed in half of these patients. Therefore, ENF showed a greater and more stable efficacy when administrated with novel drugs.

Topics: Adolescent; Child; Darunavir; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infectious Disease Transmission, Vertical; Nitriles; Peptide Fragments; Pyridazines; Pyridines; Pyrimidines; Pyrones; Sulfonamides; Time Factors; Treatment Outcome; Young Adult

For intensively pretreated pediatric patients with human immunodeficiency virus type 1 (HIV-1) infection, the treatment options available are limited. We report the case of a highly treatment-experienced 12-year-old boy with multidrug-resistant HIV-1, who was successfully treated with highly active antiretroviral therapy (HAART) including ritonavir-boosted tipranavir oral solution, a novel non-peptic protease inhibitor, and enfuvirtide.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Peptide Fragments; Pyridines; Pyrones; Remission Induction; Ritonavir; Sulfonamides; Treatment Outcome

The Veterans Health Administration (VHA) develops guidelines for VHA providers that delineate specific criteria for use of certain complex, costly medications indicated for specialized populations. These criteria are disseminated to all VHA facilities.. To (a) assess the concordance with VHA guidelines for use of 4 antiretrovirals (atazanavir, darunavir, enfuvirtide, and tipranavir), and (b) to describe prescribing of these agents before and after implementation of the guideline criteria.. In this retrospective cohort study, we evaluated all veterans in VHA care who received their first outpatient prescription for a target antiretroviral between its FDA approval date and December 31, 2007, using outpatient prescription records obtained from the VHA Human Immunodeficiency Virus (HIV) Clinical Case Registry (CCR:HIV), an observational registry database created through extraction of specific clinical data from the VHA's electronic medical record. Adherence to the VHA guideline criteria was assessed using CCR:HIV data overall and during 3 time periods: (a) pre-criteria: from FDA approval date to criteria implementation date (range 38 days to 192 days), (b) early-criteria: the first 6 months after criteria implementation, and (c) late-criteria: from 180 days after criteria implementation until December 31, 2007 (range 184 days to 1,525 days).. VHA providers prescribed target antiretroviral medications in accordance with the VHA guidelines for use more than 70% of the time. Comparing the pre-criteria with the post-criteria period (i.e., early-criteria and late-criteria combined), no significant differences in the percentages of veterans satisfying all VHA criteria were observed for any drug except atazanavir (P = 0.010). For atazanavir in the post-criteria period compared with the pre-criteria period, significantly more antiretroviral-naive veterans met criteria for cardiovascular disease or risk (72.8% post-criteria vs. 45.5% pre-criteria, P = 0.045), and significantly more antiretroviral-experienced veterans met criteria for resistance to other protease inhibitors requiring the need for ritonavir-boosted atazanavir (61.7% vs. 50.5%, respectively, P < 0.001); however, fewer antiretroviral-experienced veterans met criteria for having documented intolerance to other protease inhibitors (78.9% vs. 89.9%, respectively, P < 0.001). Fewer darunavir-treated patients in the post-criteria period than in the pre-criteria period met the criteria for treatment experience including failure of at least 1 prior protease inhibitor regimen (87.8% vs. 96.0%, respectively, P = 0.002). Adherence to all darunavir criteria significantly waned over time (early-criteria 78.8% vs. late-criteria 62.5%, P < 0.001). Overall, adherence to atazanavir criteria increased over time (66.3% early-criteria vs. 72.9% late-criteria, P < 0.001).. After implementation of antiretroviral specific guideline criteria, the proportion of veterans prescribed a target antiretroviral medication in accordance with VHA guideline criteria varied by agent and improved only for atazanavir. Although adherence to criteria for atazanavir, enfuvirtide, and tipranavir persisted or improved during the post-criteria period, darunavir adherence to criteria waned over time, perhaps indicating that later prescribing patterns reflected changing practice patterns and the need for updated criteria. Revisiting and updating criteria may be especially important for HIV due to the speed with which new information becomes available.

Topics: Anti-Retroviral Agents; Atazanavir Sulfate; Darunavir; Enfuvirtide; Guideline Adherence; Guidelines as Topic; Health Plan Implementation; HIV Envelope Protein gp41; HIV Infections; Humans; Oligopeptides; Peptide Fragments; Practice Patterns, Physicians'; Pyridines; Pyrones; Retrospective Studies; Sulfonamides; Time Factors; United States; United States Department of Veterans Affairs

In recent years, novel antiretroviral drugs have become available for multi-experienced HIV-infected patients with limited options. We enrolled seven advanced HIV-patients, failing multiple previous HAART regimens, in virological failure on their current HAART regimen and showing recent clinical and immunological progression. All patients were prescribed a double-boosted tipranavir plus enfuvirtide based regimen, in addition to zidovudine, tenofovir and lamivudine for salvage therapy. To assess susceptibility to tipranavir, the tipranavir genotypic resistance score was calculated and two years later this was re-evaluated on an updated tipranavir genotypic score algorithm. At baseline, CD4 were 139/mcL (more or less 145), HIV-1 RNA was 822,700 cp/mL. All patients achieved HIV-1 RNA levels less than 400 cp/mL between 12 weeks and 24 weeks of observation; two reached less than 50 cp/mL during this period. At 48 weeks three patients had reached less than 50 cp/mL; three other patients had HIV RNA less than 200 cp/mL. At 72 and 96 weeks HIV viraemia was less than 50 cp/mL in six patients; CD4 T-cell counts 285/mcL (more o less 198). No AIDS-defining events were recorded. Adverse events did not need to stop or change HAART. Strong 3 NRTI backbone could help efficacy and durability, and frequent evaluations in complex patients can help to manage toxicity.

Topics: Adult; Algorithms; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease Progression; Enfuvirtide; Female; Follow-Up Studies; Genotype; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Mutation; Peptide Fragments; Phenotype; Pyridines; Pyrones; Salvage Therapy; Sulfonamides; Time Factors; Treatment Outcome

The new non-peptidic protease inhibitor tipranavir is used boosted with ritonavir in a 500/200 mg bid scheme. Multiple drug interactions are described for both drugs because of their different action in CYP450 3A4 and p-glycoprotein. In this retrospective analysis of 22 patients during therapy with tipranavir/ritonavir (TPV) 500 mg/200 mg bid, we found significantly decreased TPV-trough levels in combination with tenofovir (15.32+/-5.22 microg/ml) in comparison to TPV trough levels without tenofovir (20.21+/-14.87 microg/ml). Therapeutic drug monitoring of TPV is recommended.

Topics: Adenine; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Drug Interactions; Drug Monitoring; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Organophosphonates; Peptide Fragments; Pyridines; Pyrones; Retrospective Studies; Ritonavir; Sulfonamides; Tenofovir

In RESIST, enfuvirtide co-administered with ritonavir-boosted tipranavir was associated with higher plasma tipranavir concentrations, which seldom rose above those associated with an increased risk of grade 3/4 transaminase elevations. Transaminase elevation rates (6.5%) and clinical hepatic event rates (5.9 events/100 person exposure years) were lower in the tipranavir/ritonavir with enfuvirtide group than in the tipranavir/ritonavir without enfuvirtide group. Observed increases in plasma tipranavir concentrations thus had no apparent effect on the risk of hepatotoxicity.

Topics: Alanine Transaminase; Anti-HIV Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Liver Diseases; Lopinavir; Peptide Fragments; Pyridines; Pyrimidinones; Pyrones; Randomized Controlled Trials as Topic; Ritonavir; Saquinavir; Sulfonamides; Treatment Outcome; Viral Load

Escalating drug resistance in treatment-experienced HIV-1-infected patients has made management increasingly difficult. In clinical trials, tipranavir (TPV) has produced potent and durable responses in such patients, although experience in clinical cohorts is limited. A retrospective clinical case review was undertaken of triple-class experienced HIV-1-infected patients receiving optimized boosted TPV-containing regimens and T20 with up to 108 weeks follow-up. Antiretroviral therapy (ART) resistance profiles were characterized using International Aids Society (IAS)-USA scoring and 'TPV resistance score' (TPV-RS) at baseline and failure. Five of 12 patients had undetectable virus (<50 copies/mL) after median 84 weeks (range 60-108), and 1/12 < had 700 copies/mL after 40 weeks. Six of 12 patients failed after 36 (range 12-48) weeks and were more likely to have > or = 3 TPV-RS mutations than non-failures (P = 0.06). Presence of a major IAS-USA mutation at baseline was strongly associated with absence of a 1 log viral load drop at 24 weeks (P = 0.02). TPV-containing regimens showed impressive efficacy and tolerability in this heavily experienced cohort.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Enfuvirtide; Genotype; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Middle Aged; Peptide Fragments; Pyridines; Pyrones; Retrospective Studies; Salvage Therapy; Sulfonamides; Treatment Outcome

Topics: Adult; Antiretroviral Therapy, Highly Active; Drug Resistance, Multiple, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Infectious Disease Transmission, Vertical; Peptide Fragments; Pregnancy; Pregnancy Complications, Infectious; Pyridines; Pyrones; Sulfonamides

Treatment options for HIV-1 infected individuals who have received extensive previous antiretroviral therapy are limited. We compared efficacy and safety of the novel non-peptidic protease inhibitor tipranavir co-administered with ritonavir plus an optimised background regimen with that of an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI-ritonavir) in such patients.. We did a combined analysis of 48-week data from two ongoing, randomised, open-label, multinational, phase III, RESIST studies. HIV-1-infected adults with 3 months or longer previous triple antiretroviral class experience, two or more previous protease inhibitor regimens, HIV-1 RNA 1000 copies per mL or greater, and genotypically demonstrated primary resistance to protease inhibitor, were eligible. Primary endpoints were proportion of treatment responders (with reduction in viral load of 1 log(10) copies per mL or greater below baseline without treatment change) at 48 weeks and time to treatment failure through 48 weeks (intention-to-treat analysis). The RESIST studies are registered with ClinicalTrials.gov, numbers NCT00054717 (RESIST-1) and NCT00144170 (RESIST-2).. 3324 patients were screened; 746 received tipranavir-ritonavir and 737 CPI-ritonavir. 486 (65.1%) patients on tipranavir-ritonavir and 192 (26.1%) on CPI-ritonavir remained on assigned treatment until week 48. At week 48, more patients achieved and maintained treatment response in the tipranavir-ritonavir group than in the CPI-ritonavir group (251 [33.6%] vs 113 [15.3%]; p<0.0001). Median time to treatment failure was significantly longer in the tipranavir-ritonavir group than in the CPI-ritonavir group (113 days vs 0 days; p<0.0001). Gastrointestinal system disorders and raised transaminase, cholesterol, and triglycerides were more frequent in the tipranavir-ritonavir group than in the CPI-ritonavir group.. Compared with CPI-ritonavir, tipranavir-ritonavir with an optimised background regimen provides better virological and immunological responses over 48 weeks in patients who have received extensive previous antiretroviral treatment.

Topics: Adult; Drug Resistance, Viral; Drug Therapy, Combination; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Logistic Models; Male; Multicenter Studies as Topic; Peptide Fragments; Pyridines; Pyrones; Randomized Controlled Trials as Topic; Ritonavir; Sulfonamides; Time Factors; Treatment Failure; Viral Load

Fifty-five patients placed on tipranavir/ritonavir 500/200 mg twice a day (27 with enfuvirtide and 28 without) underwent tipranavir and ritonavir plasma concentration measurements by high-pressure liquid chromatography. Markedly higher tipranavir and ritonavir trough concentrations were observed in enfuvirtide recipients. The modelling of sparse plasma samples using a first order absorption and elimination monocompartmental model without time lag predicted higher tipranavir elimination half-life and volume of distribution in enfuvirtide takers. This unexpected drug-drug interaction warrants further investigation.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cohort Studies; Drug Interactions; Enfuvirtide; Female; Half-Life; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Peptide Fragments; Pyridines; Pyrones; Ritonavir; Sulfonamides