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. HIV-infected patients with hepatic fibrosis who were receiving a stable antiretroviral regimen containing nevirapine for > or = 6 weeks had liver biopsy specimens assessed by Ishak histologic scoring and were grouped by severity (group 1, Ishak scores of 1 and 2; group 2, Ishak scores of 3 and 4; group 3, Ishak scores of 5 and 6). Steady-state trough nevirapine levels were determined for all patients, and additional measurements were obtained at 1, 2, and 4 h following nevirapine dosing for a subset of patients. The pharmacokinetics of nevirapine and its five metabolites were characterized, and a comparison of the results for the different Ishak groups was performed. Among 51 patients with hepatic fibrosis, the majority of whom were coinfected with hepatitis C virus or hepatitis B virus, differences between the maximum and the minimum observed plasma concentrations demonstrated a statistically significant flattening of the systemic exposure curves with progression from Ishak group 1 to Ishak group 2 or 3, suggesting a decrease in systemic clearance with the progression of liver disease. However, there were no significant differences in the trough and the maximum nevirapine concentrations between the Ishak groups. The metabolite profiles were also comparable across the Ishak groups. In HIV-infected patients who were chronically treated with nevirapine and who had various degrees of hepatic fibrosis, including cirrhosis, trough plasma nevirapine concentrations were not significantly increased, and thus, no dose adjustment is warranted.

Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America.

BACKGROUND: The T-20 vs. Optimized Regimen Only Study 1 (TORO 1) was a randomized, open-label, phase 3 study of enfuvirtide (T-20), a human immunodeficiency virus type 1 (HIV-1) fusion inhibitor. METHODS: Patients from 48 sites in the United States, Canada, Mexico, and Brazil with at least six months of previous treatment with agents in three classes of antiretroviral drugs, resistance to drugs in these classes, or both, and with at least 5000 copies of HIV-1 RNA per milliliter of plasma were randomly assigned in a 2:1 ratio to receive enfuvirtide plus an optimized background regimen of three to five antiretroviral drugs or such a regimen alone (control group). The primary efficacy end point was the change in the plasma HIV-1 RNA level from base line to week 24. RESULTS: A total of 501 patients underwent randomization, and 491 received at least one dose of study drug and had at least one measurement of plasma HIV-1 RNA after treatment began. The two groups were balanced in terms of the median base-line HIV-1 RNA level (5.2 log10 copies per milliliter in both groups), median CD4+ cell count (75.5 cells per cubic millimeter in the enfuvirtide group, and 87.0 cells per cubic millimeter in the control group), demographic characteristics, and previous antiretroviral therapy. At 24 weeks, the least-squares mean change from base line in the viral load (intention-to-treat, last observation carried forward) was a decrease of 1.696 log10 copies per milliliter in the enfuvirtide group, and a decrease of 0.764 log10 copies per milliliter in the control group (P<0.001). The mean increases in CD4+ cell count were 76 cells per cubic millimeter and 32 cells per cubic millimeter, respectively (P<0.001). Reactions at the site of the injections were reported by 98 percent of patients receiving enfuvirtide. There were more cases of pneumonia in the enfuvirtide group than in the control group. CONCLUSIONS: The addition of enfuvirtide to an optimized antiretroviral regimen provided significant antiretroviral and immunologic benefit through 24 weeks in patients who had previously received multiple antiretroviral drugs and had multidrug-resistant HIV-1 infection.

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. There may be an increased risk of adverse events associated with increased plasma concentration of the concurrent protease inhibitor. Still, the incidence of these adverse events is generally low, and clinical trials have suggested that they rarely result in discontinuation or alteration of the regimen. In highly treatment-experienced patients in particular, the potential benefits associated with ritonavir boosting usually outweigh the risks.

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. This paper reviews the results of recent clinical trials focusing on initial therapy and addresses important considerations when beginning antiretroviral therapy (ART) in treatment-naive individuals.

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. Amprenavir (APV) pharmacokinetic sampling and safety assessments were performed on the last day of each period. RESULTS: Plasma APV exposure was not significantly altered when EFV was coadministered with GW433908 700 mg twice daily (BID) + RTV 100 mg BID. Plasma APV exposure was decreased when EFV was coadministered with GW433908 1395 mg QD + RTV 200 mg QD. However, administration of EFV with GW433908 1395 mg QD + RTV 300 mg QD (i.e., adding an extra 100 mg of RTV) was able to negate this interaction. Adverse events were consistent with prior data for each of the separate agents. CONCLUSION: When EFV is coadministered with the GW433908 700 mg + RTV 100 mg BID regimen, no dosage adjustment is recommended. However, when EFV is coadministered with the GW433908 1400 mg + RTV 200 mg QD regimen, an increase to RTV 300 mg QD is needed to maintain plasma APV exposure.

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. RESULTS: Circulating TREC levels correlated inversely with age, with HIV RNA levels, with activation markers on circulating T cells and with naive CD4 but not CD8 cell frequencies. With initiation of antiretroviral therapy, TREC and naive T cell frequencies increased in peripheral blood during the first 2 weeks of treatment and these changes correlated negatively with TREC frequencies in lymph node aspirates, particularly among CD8 T cells. CONCLUSIONS: These findings suggest that recent thymic emigrants are sequestered in lymphoid tissue during uncontrolled HIV replication and are selectively released into circulation rapidly after initiation of antiretroviral therapies.

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.

Atazanavir: a novel HIV-1 protease inhibitor.

The introduction of HIV-1 protease inhibitors in 1995 ushered in the era of highly active antiretroviral therapy. For the first time, inhibition of two key enzymes responsible for HIV replication, reverse transcriptase and protease, was possible. The combination of two nucleoside reverse transcriptase inhibitors with a single protease inhibitor proved highly effective at reducing viral burden. In resource-rich countries where such combination therapy is readily available, dramatic reductions in HIV-related morbidity and mortality have been seen. However, long-term use of highly active antiretroviral therapy has led to several issues, including development of drug resistance and metabolic complications. Atazanavir (formerly BMS-232632), a novel azapeptide protease inhibitor, is a potent protease inhibitor that is not associated with significant dyslipidaemia as seen with other protease inhibitors. In this review, the current standard approach to the treatment of HIV in the US will be discussed as background to understand the potential utility of this new antiretroviral agent.

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.

Case report. Hepatitis B virus and HIV coinfection.

Coinfection with HIV and hepatitis B virus (HBV) is more common than that with HIV and hepatitis C virus (HCV), although more attention has been given to HCV coinfection as a result of its higher frequency of chronic disease. Natural history studies with HIV-HCV coinfection have also shown more rapid progression of liver disease, and end-stage liver disease due to hepatitis C is now a leading cause of death in HIV-infected patients. Like HCV infection, HBV infection can also be associated with significant morbidity and mortality in patients with HIV infection. Fortunately, treatment options of hepatitis B are expanding and may have a clinical impact on slowing disease progression. A case study of a patient with severe HBV-HIV coinfection is presented to illustrate what is known about this increasingly problematic disease state.

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. This article provides a review of the literature on drug interactions among addiction therapies, recreational drugs, and HAART.

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. Early favorable response is also an indicator of adequate pharmacokinetic profile and potent antiviral activity of the drug regimen. It also can indicate that the predominant HIV strain infecting the patient is sensitive to the treatment regimen. These factors of adherence, drug levels, potency, and susceptibility favor a long-term durable response. Evaluation of early treatment responses may create the opportunity to promptly change the HAART regimen in the event of an anticipated long-term failure, delaying or preventing the evolution of drug resistance, and improving the effectiveness of treatment overall.

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. Two multinational, randomized, active-controlled, blinded trials compared the safety and efficacy of ATV and NFV in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) in antiretroviral (ARV)-naive patients. Serum lipid concentrations were analyzed in patients who had available measurements both at baseline and at week 48. Patients who had missing data at either time point were not included. Lipid levels remained within baseline ranges at week 48 with ATV treatment, whereas clinically relevant elevations in TC, fasting LDL-C, and fasting TG concentrations occurred with NFV treatment. Mean changes from pre-treatment baseline in fasting LDL-C ranged from -6 percent to +6 percent in the ATV-treatment groups, and from +27 percent to +31 percent in the NFV-treatment groups. After 48 weeks, there was a substantive increase in the proportion of NFV-treated patients who would be recommended for lipid-lowering treatment by National Cholesterol Education Program (NCEP) guidelines, whereas a lesser proportion of ATV-treated patients would be recommended for lipid-lowering treatment. Atazanavir does not lead to dyslipidemia in ARV-naive patients, and may limit the need for lipid-lowering strategies to reduce the risk of cardiovascular disease.

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. A large pill burden, multiple daily doses, and adverse events are some of the complexities that negatively impact patient adherence. For example, lipodystrophy and hyperlipidemia are two serious side effects associated with some agents. Once-daily antiretroviral agents offer many advantages over historical treatment options but are associated with possible drawbacks. IMPLICATIONS FOR PRACTICE: Currently, four single agents are available for once-daily administration, and a few others are under investigation. In addition, combination therapy with either dual or boosted protease inhibitor regimens is becoming a popular way of overcoming the poor pharmacokinetic characteristics of individual protease inhibitors.

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. Other sources included abstracts from recent HIV-related conferences that presented data pertinent to the topic. Studies were selected based on their impact on our understanding of HIV infection and its treatment. DATA EXTRACTION, SYNTHESIS: Relevant portions of the publications considered were compiled and conclusions were drawn based on the clinical experience of the author. CONCLUSION: Dyslipidemia associated with current PIs should be a serious consideration when initiating long-term treatment of HIV infection. Current management techniques that include lipid-lowering agents may be improved and streamlined by incorporating a lipid-friendly PI into HAART.

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. CD4+ counts and HIV viral loads were assayed at key timepoints. The primary endpoint was time to virologic failure (viral load ≥500copies/mL). POTENT was prematurely terminated due to slow enrollment. Thirty-nine patients were treated with either TPV/r (n = 19) or DRV/r (n = 20); 82% were male, 77% White, with mean age of 43.6 years. Mean baseline HIV RNA was 3.9 log(10) copies/mL. Median prior antiretrovirals was 11, with no prior raltegravir or maraviroc exposure. Raltegravir was the most common novel class agent in the OBRs (n = 14 TPV/r; n = 12 DRV/r). In both groups, patients achieved mean viral load decreases ≥2 log(10) copies/mL by week 8, and by week 12 mean CD4+ counts rose by 40-50 cells/mm3. Total observation time was 32 weeks. Drug-related adverse events were reported in 21% (TPV/r) and 25% (DRV/r) of patients. CONCLUSIONS/SIGNIFICANCE: TPV/r- and DRV/r-based regimens showed similar short-term safety and efficacy. These data support the use of next-generation PIs such as tipranavir or darunavir with novel class antiretroviral agents (integrase inhibitors, CCR5 antagonists, or fusion inhibitors).

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. Patients currently failing a PI-based regimen were randomized to receive either a genotype (GT) or combined phenotype-genotype test (PGT) and a treatment decision was made at the second study visit. RESULTS: 246 patients enrolled, 236 had resistance test results, and 139 (59%) had evidence of HIV-1 resistance to >or=1 PI. Among these 139 patients, more than 50% had viruses that remained sensitive to tipranavir and darunavir, whereas susceptibility to other PIs was markedly lower (<22%). Increasing prior PI exposure was associated with reduced susceptibility to most ARV agents. After obtaining resistance test results, 83% of patients changed therapy. Newly available or investigational ARVs were used frequently. The reason investigators most often cited for changing therapy was the patient resistance test results (82%) and the most common reason for not changing therapy was the inability to construct an active regimen. The majority of patients who exhibited PI resistance received two or more active agents in the new regimen. CONCLUSIONS: Overall, 59% of TEPs failing a PI-based regimen had HIV-1 with PI resistance. The majority of these patients' viruses remained sensitive to either tipranavir or darunavir. Investigators used results from resistance assays to construct a new regimen, frequently with newer agents. In PI-experienced patients, tipranavir and darunavir remain the most likely available active PIs.