Boosted tipranavir versus darunavir in treatment-experienced patients: observational data from the randomized POTENT trial.

Background: The POTENT trial compared the safety and efficacy of tipranavir/ritonavir (TPV/r) to darunavir/ritonavir (DRV/r), each with an optimized background regimen (OBR) in triple-class experienced HIV-1-infected patients with resistance to more than one protease inhibitor (PI).

Methodology/principal Findings: POTENT was a prospective, open-label study of triple-class (PI, non-nucleoside reverse transcriptase inhibitors [NNRTI], nucleoside reverse transcriptase inhibitors [NRTI]), treatment-experienced, HIV-positive patients. Subjects were randomized to either TPV/r (500/200 mg twice daily) or DRV/r (600/100 mg twice daily) on a genotype-guided, investigator-selected OBR.

Susceptibility of HIV-1 to tipranavir and other antiretroviral agents in treatment-experienced patients: The UTILIZE Study.

Objectives: The primary objective was to assess HIV-1 susceptibility to the protease inhibitor (PI) tipranavir and other antiretroviral (ARV) agents among treatment-experienced patients (TEP). Secondarily, clinicians' use of resistance testing was examined.

Methods: UTILIZE was an observational study conducted at 40 sites in the United States.

Pharmacokinetic interactions between buprenorphine/naloxone and tipranavir/ritonavir in HIV-negative subjects chronically receiving buprenorphine/naloxone.

HIV-infected patients with opioid dependence often require opioid replacement therapy. Pharmacokinetic interactions between HIV therapy and opioid dependence treatment medications can occur. HIV-seronegative subjects stabilized on at least 3 weeks of buprenorphine/naloxone (BUP/NLX) therapy sequentially underwent baseline and steady-state pharmacokinetic evaluation of open-label, twice daily tipranavir 500 mg co-administered with ritonavir 200 mg (TPV/r).

Pharmacokinetic assessment of nevirapine and metabolites in human immunodeficiency virus type 1-infected patients with hepatic fibrosis.

Nevirapine is a nonnucleoside reverse transcriptase inhibitor used as part of combination therapy for human immunodeficiency virus (HIV) infection. Nevirapine may be prescribed for patients with hepatic fibrosis and cirrhosis. Significant autoinduction of cytochrome P450 3A4 and 2B6 following multiple dosing prompted an assessment of the metabolic profiles in patients with liver disease receiving chronic nevirapine therapy.

Effect of ritonavir-boosted tipranavir or darunavir on the steady-state pharmacokinetics of elvitegravir.

Objective: Elvitegravir (EVG) is in phase 3 development in combination with ritonavir (RTV)-boosted protease inhibitors in treatment-experienced, HIV-infected patients. Two studies evaluated pharmacokinetic (PK) interactions among EVG and RTV-boosted tipranavir (TPV/r) or darunavir (DRV/r).

Methods: Healthy volunteers received EVG/r alone (study 1: 200/100 mg once daily; study 2: 125/100 mg once daily), TPV/r (500/200 mg twice daily) or DRV/r (600/100 mg twice daily) alone, and EVG (200 or 125 mg as applicable) added to TPV/r (500/200 mg twice daily) or DRV/r (600/100 mg twice daily) in a randomized crossover design, with assessment of steady-state PK for EVG, TPV, DRV, and RTV.

Ritonavir-boosted protease inhibitors: impact of ritonavir on toxicities in treatment-experienced patients.

The purpose of this review is to discuss the basis for ritonavir boosting of protease inhibitors as well as the complications and benefits associated with ritonavir boosting when designing an antiretroviral regimen for treatment-experienced patients. Such patients have fewer viable options because of cross-resistance arising from previous regimen failures. Ritonavir administered at a low dose to boost another protease inhibitor may be a useful strategy for achieving virological efficacy while minimizing the toxicities associated with full-dose ritonavir.

Interaction between fosamprenavir, with and without ritonavir, and nevirapine in human immunodeficiency virus-infected subjects.

Fosamprenavir (FPV) with and without ritonavir (RTV) was added to the antiretroviral regimens of human immunodeficiency virus-infected subjects receiving nevirapine (NVP) to evaluate this drug interaction. Significant reductions in plasma amprenavir exposure (25 to 35%) were observed following coadministration of 1,400 mg of FPV twice a day (BID) and 200 mg of NVP BID. A regimen of 700 mg of FPV BID plus 100 mg of RTV BID may be coadministered with NVP without dose adjustment.

Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experienced HIV-1-infected patients in the T-20 versus optimized background regimen only 1 and 2 clinical trials.

Background: The T-20 Versus Optimized Background Regimen Only (TORO) 1 and TORO 2 clinical trials are open-label, controlled, parallel-group, phase 3 studies comparing enfuvirtide plus an optimized background (OB) of antiretrovirals (n = 661) with OB alone (n = 334) in treatment-experienced HIV-1-infected patients.

Methods: The primary objective at week 48 was to investigate durability of efficacy, as measured by the percentage of patients maintaining their week 24 response or improving. Efficacy analyses used the intent-to-treat population.

Strategies for initiating combination antiretroviral therapy.

Numerous potent antiretroviral regimens have proven successful as initial therapy in treatment-naive HIV-infected patients. As the development of new agents makes possible new treatment regimens, providers are faced with increasingly complex questions of when to initiate treatment and which regimen to select for individual patients. Clinical trial data provide a foundation for choosing an initial regimen and play a key role in the formation of treatment guidelines issued by the United States Public Health Service and other organizations.

Atazanavir: A novel once-daily protease inhibitor.

Atazanavir (formerly BMS-232632), an azapeptide protease inhibitor (PI), is a new human immunodeficiency virus (HIV) treatment that has recently received marketing approval from the FDA. It has a pharmacokinetic profile that supports once-daily dosing and has demonstrated a unique resistance profile and superior virologic potency compared with other antiretrovirals in vitro. In subjects with HIV, atazanavir (400 mg once daily) produced rapid and sustained improvements in viral load and CD4 counts in both antiretroviral-naive as well as previously treated patients when used in combination with dual nucleoside reverse transcriptase inhibitor (NRTI) treatment.

Atazanavir--a once-daily HIV protease inhibitor that does not cause dyslipidemia in newly treated patients: results from two randomized clinical trials.

Protease inhibitor (PI) treatment can result in dyslipidemia in a significant proportion of patients. Atazanavir (ATV) is a once-daily PI that has not been associated with clinically relevant increases in total cholesterol (TC), fasting low-density lipoprotein cholesterol (LDL-C), or fasting triglyceride (TG) concentrations. The objectives of this paper were to evaluate lipid profiles in untreated patients, and investigate the frequency and severity of dyslipidemia in the same individuals after treatment with ATV or nelfinavir (NFV) for 48 weeks.

Pharmacokinetic properties of nucleoside/nucleotide reverse transcriptase inhibitors.

Options for antiretroviral therapy in patients infected with HIV continue to expand as new drugs are integrated into treatment regimens. Nonetheless, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) remain the backbone of highly active antiretroviral therapy (HAART). With the approval of emtricitabine in 2003, there are now 8 Food and Drug Administration (FDA)-approved NRTIs/NtRTIs.

An assessment of herbal therapy use, adherence and utilization of pharmacy services in HIV clinics.

Objective: To assess herbal therapy use, adherence to antiretroviral therapy (ART) and pharmacy service utilization in two HIV clinics using a prospective questionnaire-based assessment.

Results: Seventy-six patients completed the questionnaire. Twenty-six patients (34%) reported using at least one herbal therapy; 14 (54%) reported this to their provider.

Pharmacokinetics and safety of GW433908 and ritonavir, with and without efavirenz, in healthy volunteers.

Objective: To evaluate the safety and pharmacokinetic interaction between GW433908, ritonavir (RTV), and efavirenz (EFV).

Methods: In period 1, subjects received either a once daily (QD) regimen of GW433908 1395 mg + RTV 200 mg (Study 1) or a twice daily (bid) regimen of GW433908 700 mg + RTV 100 mg (Study 2) for 14 days. In period 2, subjects received EFV 600 mg QD with either the same GW433908 + RTV regimen as in period 1 (arm 1) or with a GW433908 + RTV regimen that included an additional 100 mg of RTV (arm 2) for 14 days.

Pharmacodynamics and clinical use of anti-HIV drugs.

Antiretroviral drug exposure has been linked to both antiviral efficacy and the development of toxicity and further research in this area is ongoing and necessary. Use of these data may have important implications for TDM of HAART regimens in clinical practice. TDM, in conjunction with an assessment of the patient's viral resistance in the form of an IQ, needs to be examined and validated in large clinical trials.

Mechanisms of lipid elevations associated with the treatment of patients with HIV infection.

Objective: Dyslipidemia and other metabolic abnormalities, which are associated with the use of highly active antiretroviral therapy (HAART) for the treatment of HIV infection, are of concern to patients and healthcare providers. The objective of this review is to present the current understanding of the dyslipidemia associated with the protease inhibitor (PI)-component of HAART: its possible origin, potential consequences, and management techniques.

Data Sources, Study Selection: Peer-reviewed, published literature was identified via MEDLINE.

Drug interactions associated with HAART: focus on treatments for addiction and recreational drugs.

The advent of HAART has improved survival in patients infected with HIV; however, treatment is complicated by potential drug interactions. The risk of drug interactions is compounded by the use of additional therapies for comorbid conditions, such as substance abuse, and by the use of recreational drugs. HIV health care providers should be aware of the potential interaction of recreational drugs and addiction treatments with HAART because of the potential for significant adverse effects for their HIV-infected patients.

In vitro-in vivo model for evaluating the antiviral activity of amprenavir in combination with ritonavir administered at 600 and 100 milligrams, respectively, every 12 hours.

The study objective was to evaluate the pharmacodynamics of amprenavir in an in vitro system, develop an exposure target for maximal viral suppression, and determine the likelihood of target attainment based on the pharmacokinetics of amprenavir and ritonavir in human immunodeficiency virus (HIV)-infected patients. Population pharmacokinetic data were obtained from 13 HIV-infected patients receiving amprenavir and ritonavir in doses of 600 and 100 mg, respectively, every 12 h. A 2,500-subject Monte Carlo simulation was performed.

Early factors in successful anti-HIV treatment.

Rapid suppression of plasma HIV RNA and sustained increase in CD4 cell count following highly active antiretroviral therapy (HAART) regimens can be prognostic indicators of long-term virologic treatment success. Routine measurement of plasma HIV RNA levels (viral load or VL) at four and eight or 12 weeks is recommended after initiating treatment because favorable changes are predictive of durable success at six months and longer. Early favorable response of VL, as soon as six days after HAART initiation, can signify that the patient is initially adherent to treatment, which is necessary in the long term for a successful regimen.

Simplified regimens for treating HIV infection and AIDS.

Purpose: To review the variables that greatly affect adherence to the complex treatment regimens used in HIV disease and to examine available options that could improve patient outcomes.

Data Sources: Comprehensive review of current medical and scientific literature, drug-prescribing literature, and randomized clinical trials of drug treatments.

Conclusions: Effective treatment of HIV infection is dependent on consistent adherence to prescribed antiretroviral medications.

T cells containing T cell receptor excision circles are inversely related to HIV replication and are selectively and rapidly released into circulation with antiretroviral treatment.

Objective: To examine baseline predictors of T-cell receptor rearrangement excision circle (TREC) levels and their changes during treatment with combined antiretroviral therapy.

Methods: Peripheral blood and lymph node lymphocytes were examined for the presence of TREC by real-time polymerase chain reaction and circulating lymphocyte phenotypes were examined by flow cytometry. Correlates for CD4 and CD8 cell TREC levels at baseline were identified among CD4 and CD8 immunophenotypes, viral load and patient demographics; the significance of TREC changes after initiation of antiretroviral therapy was assessed.

Guillain-Barré syndrome associated with immune reconstitution.

We report a case of acute Guillain-Barré syndrome (GBS) associated with a prompt and vigorous immune reconstitution and decrease in the virus load noted during treatment with a potent regimen of highly active antiretroviral therapy. We hypothesize that GBS may have been due to an aberrant immune response or an adverse drug reaction in association with preexisting peripheral neurologic disease.