PI-containing Regimen Research Articles

Remission from Kaposi's sarcoma on HAART is associated with suppression of HIV replication and is independent of protease inhibitor therapy

Highly active antiretroviral therapy (HAART) reduces the incidence and improves the prognosis of Kaposi's sarcoma (KS). This study was designed to identify factors associated with KS clinical responses in HIV-infected patients during HAART. We reviewed the files of 138 HIV-1-infected patients with KS. Epidemiologic and HIV-related clinical and biological parameters were recorded at KS diagnosis (baseline) and every 6 months thereafter. In a subset of 73 antiretroviral-naive patients, we compared the clinical outcome of KS according to the use or nonuse of protease inhibitors (PI). After 6 months of follow-up, KS remission was more frequent in patients who were naive of HAART and who were at ACTG stage S0 at baseline (P=0.03 and 0.02). Undetectable HIV viral load was strongly associated with KS remission (P⩽0.004 at all time points), while CD4 cell count was not. Among the 73 antiretroviral-naive patients at baseline, and who were studied for 24 months, KS outcome did not differ between patients who were prescribed PI-containing and PI-sparing regimens. Intercurrent multicentric Castleman's disease was associated with poor outcome after 60 months of follow-up (P⩽0.0001). Fourteen deaths occurred after a median follow-up of 37.5 months, eight of which were KS related. Suppression of HIV replication appears to be crucial to control KS. Non-PI-based regimens were equivalent to PI-based regimens as regards the clinical and virological outcome of antiretroviral-naive HIV-infected patients with KS.

Serum concentrations of protease inhibitors as predictors of HIV-related clinical events in patients on antiretroviral therapy

Serum concentrations of protease inhibitors (PIs) show large interindividual variations. It is not clear what clinical impact these differences in drug concentrations might have. In this study we explored the association between serum concentration of protease inhibitors and HIV-related disease. 130 patients on PI-containing regimen underwent PI concentration measurement in serum. The results were divided into 3 categories: high level, therapeutic level, and low level. HIV-related events (CDC category B and C) and death were prospectively recorded after the drug monitoring. The results were statistically analysed employing Cox regression. Median follow-up was 709 d, and 22 patients reached an endpoint. For the trough concentrations the hazard ratio (HR) for patients with therapeutic level vs low level was 0.63 (95% CI 0.20-1.95) and high level vs low level was 0.56 (95% CI 0.14-2.26). For the maximum concentrations the HR for therapeutic level vs low level was 1.32 (95% CI 0.48-3.62) and high level vs low level was 0.47 (95% CI 0.06-3.90). In conclusion, in this small pilot study we could not show any association between the serum concentrations of PIs and subsequent clinical HIV-related events. Larger studies are needed to explore this subject further.

In VivoEffects of Highly Active Antiretroviral Therapies Containing the Protease Inhibitor Nelfinavir on Mitochondrially Driven Apoptosis

BackgroundIn vitro studies have reported controversial effects of protease inhibitors (PIs) on mitochondrially driven apoptosis. Additionally, since PIs in the clinical setting are almost always given in combination with nucleoside analogues, which may have negative effects on mitochondrial DNA (mtDNA), the impact of PI-containing highly active antiretroviral therapy (HAART) on apoptosis and mtDNA content is unclear.Patients and methodsA cross-sectional study was performed including 20 HIV-negative (HIV-) patients, 16 HIV-positive, antiretroviral-naive (HIV+) patients and 17 HIV-positive patients receiving the PI nelfinavir (NFV) plus zidovudine and lamivudine (AZT+3TC) or didanosine and stavudine (ddI+d4T) - collectively known as HIV+PI - as first-line antiretroviral treatment for at least 12 months. Peripheral blood mononuclear cells (PBMCs) were isolated. BCL2 expression (anti-apoptotic) and the levels of the cleaved, active form of caspase-9 (pro-apoptotic) were determined by western blot. An index of mitochondrially driven apoptotic activation was estimated calculating the ratio caspase-9:BCL2. Mitochondrial DNA content was measured by real-time PCR.ResultsBCL2 expression was lower in HIV+ than in HIV-patients ( P<0.01), whereas levels of caspase-9 were higher ( P=0.001). The caspase-9:BCL2 ratio was significantly increased in HIV+ compared with HIV- individuals ( P<0.001). Mitochondrial DNA content was also decreased in HIV+ compared with HIV- patients ( P<0.001). The HIV+PI group exhibited a trend to normalization for BCL2 expression and caspase-9 compared with the HIV+ group, whereas the caspase-9:BCL2 ratio significantly improved (decreased, P<0.05 compared with HIV+ group). The mtDNA content in the HIV+PI group was similar to that of the HIV+ group, although the results of mtDNA content differed depending on whether NFV was combined with AZT+3TC (preserved) or with ddI+d4T (depleted). Conversely, no differences were found in apoptotic markers between the two subgroups of HIV+PI.ConclusionsNFV-based PI-containing HAART regimens may exert some beneficial effects counteracting the increased mitochondrially driven apoptosis present in HIV-infected people.

A randomized controlled trial investigating the efficacy and safety of switching from a protease inhibitor to nevirapine in patients with undetectable viral load

To assess the antiviral efficacy and safety of switching from a protease inhibitor (PI) to nevirapine in patients with long-term HIV-1 RNA suppression on PI-containing regimens, and to assess its influence in the adherence to treatment. In an open-label multicentre study, 160 HIV-infected patients with undetectable viral load for at least 6 months on a PI-containing regimen were randomized to either continue with their PI regimen (n=79) or replace PI with nevirapine (n=81). Clinical assessment included plasma HIV-1 RNA, blood chemistry, haematology, lymphocyte counts and adverse events reports. Adherence to treatment and lipodystrophy syndrome were assessed by patient self-reporting. Treatment efficacy was equivalent in the two arms, for patients with viral loads either above or below 100 000 HIV-1 RNA copies/mL. The increase in CD4 cell count was significant in both arms (P<0.00001) but the average CD4 cell count at 48 weeks was slightly higher in the nevirapine arm (596 vs. 569; P=0.1588). The number of patients with severe hypertriglyceridaemia (>400 mg/dL) after 48 weeks of treatment decreased in the nevirapine arm (from 11 to six), but increased in the PI arm (from four to 11) and led to treatment discontinuation in two patients. Lipodystrophy changes increased in 15% of patients in the PI arm but decreased in 4% of patients in the nevirapine arm. Finally, although adherence was similar in the two arms, patients reported that it required significantly less effort to stay on treatment in the nevirapine arm. Conclusions The results indicate that switching from PI to nevirapine is as effective as continuing with PI for maintaining viral control, even in patients with baseline viral load above 100,000 copies/mL. In addition, reductions in hypertriglyceridaemia and lipodystrophy and in the effort required to stay on treatment were observed.

The dissociation between virological and immunological responses to HAART

While HAART allows for the reconstitution of immune functions in most treated HIV patients, discrepant responses including failure to achieve a significant increase in circulating CD4+ T cells despite undetectable plasma viral loads (pVL), or a good immunological response while not reaching undetectable viremia, may occur. Thus, to evaluate the incidence of and risk factors for discrepant responses to HAART, we conducted a retrospective study of all 446 patients treated with HAART between 1 January 1998 and 31 August 2004 in our HIV unit. CD4+ T cell counts and pVL values at baseline and end of study were parameters of the type of response. Within a mean follow-up period of 33 months, discrepant immunological and virological responses occurred in even 50% patients. Of these, 174 (39%) did not have a rise in CD4+ T cells to above 400 per μl despite a good virological response (type 1 dissociation), while 49 (11.0%) had a rise in the CD4+ T cell count to at least 200 per μl but their pVL was not undetectable (type 2 dissociation). The risk factors for immunological failure despite an undetectable pVL were baseline CD4+ T cells below 100 per μl (OR 1.44, 95%CI 1.02–2.03) and HAART composed of three NRTIs (OR 1.92, 95%CI 1.35–2.73), while usage of two NRTIs in combination with PI(s) (OR 0.36, 95%CI 0.26–0.49), as well as simultaneous usage of all three drug classes (OR 0.37, 95%CI 0.26–0.53) were shown to be protective. The usage of PI-containing HAART regimens was protective against type 2 dissociation (OR = 0.40, 95%CI 0.19–0.83). Importantly, there were no differences in the survival of HAART-treated patients irrespective of the type of response.

Drug-Class-Wide Resistance to Antiretrovirals in HIV-Infected Patients Failing Therapy: Prevalence, Risk Factors and Virological Outcome

Drug-class-wide resistance (DCWR) to antiretrovirals substantially reduces treatment options. A database of 602 patients failing highly active antiretroviral therapy (HAART) undergoing genotypic resistance test (GRT) was analysed. DCWR was defined according to the International AIDS Society consensus. A multiple logistic regression model was built to define factors significantly associated with DCWR and to assess virological response to salvage regimens. NRTI DCWR was observed in 28.5% of 592 NRTI-exposed patients, NNRTI DCWR in 57.7% of 284 NNRTI exposed patients, PI DCWR in 19.9% of 412 PI exposed patients, and three-class resistance in 21.4% of 112 three-class-exposed patients. The prevalence of NRTI and PI DCWR increased significantly by year of exposure to the same class from 8.9% (< 1 year) to 35.3% (> 4 years) and from 1.2% (< 1 year) to 34.8% (> 4 years), respectively (P < 0.001, for trend). The risk of developing NRTI and PI DCWR increased by 25% (95% confidence interval [CI]: 1.6%-51.3%) and by 53% (20.5%-94.3%) for each year of treatment, and by 17% (95% CI: 5.6%-29.3%) and by 32% (17.7%-50.3%) for each previous failing NRTI- and PI-containing regimen, respectively. NRTI DCWR due to at least four nucleoside analogues mutations (NAMs) increased by year of NRTI exposure from 8.9% (< 1 year) to 32.6% (> 4 years; P < 0.001, for trend). After adjustment for confounding factors, the probability of achieving plasma viral load < 500 copies/ml was significantly reduced in patients with NRTI (OR: 0.750; 95% CI: 0.574-0.979), NNRTI (OR: 0.746; 95% CI: 0.572-0.975), PI (OR: 0.655; 95% CI: 0.456-0.941), three-class (OR: 0.220; 95% CI: 0.082-0.593) resistance. The probability of developing NRTI and PI DCWR increased with length of class exposure and with the number of previously failing regimens. By contrast, high levels of NNRTI DCWR were observed within 1 year in NNRTI-failing patients, with a steady prevalence over time. The increase in prevalence with time of NRTI DCWR was due to the accumulation of NAMs. DCWR to NRTIs, NNRTIs, PIs or all the three together was associated with an increased probability of virological failure to subsequent HAART regimens.

Cardiovascular disease in HIV-positive patients

Cardiovascular disease in HIV-positive patients

Monitoring processed, mature Human Immunodeficiency Virus type 1 particles immediately following treatment with a protease inhibitor-containing treatment regimen

Protease inhibitors (PIs) block HIV-1 maturation into an infectious virus particle by inhibiting the protease processing of gag and gag-pol precursor proteins. We have used a simple anti-HIV-1 p24 Western blot to monitor the processing of p55gag precursor into the mature p24 capsid immediately following the first dosage of a PI-containing treatment regimen. Evidence of PI activity was observed in plasma virus as early as 72 hours post treatment-initiation and was predictive of plasma viral RNA decrease at 4 weeks.

Neuropsychological Functioning and Viral Load in Stable Antiretroviral Therapy-Experienced HIV-Infected Children

Neuropsychological functioning and its correlation with viral load were investigated for previously treated HIV-infected children who underwent a change in treatment regimen. Thirteen age-appropriate measures of cognitive, neurologic, and behavioral functioning were administered to 489 HIV-infected children who were aged 4 months to 17 years and had been treated previously for at least 16 weeks with antiretroviral therapy. These clinically and immunologically stable children were randomized onto 1 of 7 drug treatment combinations, 6 of which included a protease inhibitor (PI), and evaluated prospectively for 48 weeks with respect to changes in neuropsychological performance and viral load. Neuropsychological functioning was significantly poorer at baseline for the HIV-infected children as compared with established norms for their age. Children with higher viral load had poorer cognitive, both-hands fine-motor, and neurologic signs at baseline, but single-hand fine-motor and behavioral functioning were not correlated with viral load. After 48 weeks of treatment with PI-containing combination therapy, there was significant improvement in only the vocabulary score. Neuropsychological changes did not differ among the 6 PI-containing combination regimens. At week 48, even children with a viral load response below the level of detection (RNA < or =400 copies/mL) still showed poorer neuropsychological functioning compared with established norms. Poor neuropsychological functioning was seen for HIV-infected children and was worse for children with higher viral loads. Only 1 measure of neuropsychological functioning showed improvement after treatment with PI-containing combination therapy, and the extent of that improvement was relatively minor. Treatment strategies for children with HIV disease need to be reevaluated so that they consider restoration of neuropsychological functioning in addition to lowering the viral load.

HIV-1 genotype resistance pattern and evolution in patients failing nelfinavir-containing regimens

Clinical and in vitro studies have suggested that nelfinavir (NFV)-containing regimens may not preclude the use of other protease inhibitors (PIs) in treatment sequencing. We have studied the prevalence of 30N mutation in a human immunodeficiency virus-1 (HIV-1)-infected cohort and the virological response to a PI-containing regimen in patients who had previously failed NFV. A total of 335 patients were included in the study; 32 of them were antiretroviral-naive and 303 were antiretroviral-experienced (251 were PI-experienced). Mutations 30N and/or 90M were not detected in sequences obtained either from the antiretroviral naive or non-PI-experienced patients. The 30N mutation was detected in 21/251 (8.3%) of PI-experienced patients and 90M in 103/251 (41%). Moreover, we have observed that the 88D and 77I mutations were present in more than 75% of patients harbouring the 30N HIV-1 variant and the 71T mutation was present in almost 50% of them. Finally, mutations 30N+90M were never detected together in the same HIV-1 strain. The 30N and 90M mutations were not observed together. The presence of mutations at positions 36, 46, 71, 77, and/or 88 in a 30N background, increases the risk of the cross-resistance to other PIs. The use of NFV as a first-line PI, as an application of drug sequencing strategies, may help preserve future PI options.

Genotypic resistance analyses in nucleoside-pretreated patients failing an indinavir containing regimen: results from a randomized comparative trial: (Novavir ANRS 073)

Different studies have shown that most patients failing a first-line treatment containing a protease-inhibitor (PI) had low PI plasma levels and no PI-related resistance mutations. NOVAVIR was a randomized trial comparing stavudine/lamivudine/indinavir (d4T/3TC/IDV) and zidovudine/lamivudine/indinavir (AZT/3TC/IDV) in patients pretreated with AZT, didanosine (ddI) and/or zalcitabine (ddC) but naive for PIs. To study the mechanisms of virological failure in NOVAVIR trial through analyses of genotypic resistance profiles of reverse transcriptase (RT) and protease (PR), and plasma IDV concentrations at time to failure. Plasma HIV-RNA PR and RT sequences were determined in 27 failing patients (d4T/3TC/IDV n=11; AZT/3TC/IDV n=16) at baseline and at time to failure. IDV plasma measurements were performed in both samples. At baseline, 20 out of the 27 patients had at least two thymidine analogs associated mutations. At time to failure, mutation M184V in the RT gene was present in 22 out of the 27 failing patients. Thirteen out of the 27 (48%) patients had acquisition of PI mutations compared to baseline sequence. Of the 26 patients with adherence data, 13 (50%) subjects were classified as having difficulty in adherence. The proportion of patients with low adherence was higher in the subgroup of patients failing without acquisition of new PI mutations. In patients experienced with NRTIs, failure to PI-containing regimen may occur in spite of appropriate adherence to therapy and is associated with emergence of PI mutations in half of the cases. These results suggest that, although PIs have a high genetic barrier, sub-optimal activity of associated drugs may favor the selection of PI resistance mutations.

Human immunodeficiency virus type 1 protease inhibitors block toll-like receptor 2 (TLR2)- and TLR4-Induced NF-kappaB activation.

Coinfections with opportunistic and pathogenic bacteria induce human immunodeficiency virus (HIV) replication through microbial antigen activation of NF-kappaB. Here, we assessed whether HIV type 1 protease inhibitors (PI) block microbial antigen activation of NF-kappaB. Human microvessel endothelial cells were transiently transfected with either endothelial cell-leukocyte adhesion molecule NF-kappaB luciferase or interleukin 6 (IL-6) promoter luciferase constructs by using FuGENE 6, and they were treated with PI (nelfinavir, ritonavir, or saquinavir) prior to stimulation with the Toll-like receptor 4 (TLR4) and TLR2 ligands, with lipopolysaccharide (LPS), soluble Mycobacterium tuberculosis factor, or Staphylococcus epidermidis phenol-soluble modulin, respectively, or with tumor necrosis factor alpha (TNF-alpha). Luciferase activity was measured by using a Promega luciferase kit. TNF-alpha release from the supernatant was measured by enzyme-linked immunosorbent assay. Cell death was assessed by lactate dehydrogenase assay. We observed that PI pretreatment blocked the TLR2- and TLR4- as well as the TNF-alpha-mediated NF-kappaB activation, in a dose-dependent manner. PI pretreatment also blocked the LPS-induced IL-6 promoter transactivation and TNF-alpha secretion. These data suggest that PI block HIV replication not only by inhibiting the HIV protease but also by blocking the TLR- and TNF-alpha-mediated NF-kappaB activation and proinflammatory cytokine production. These findings may help explain the immunomodulatory effects of PI, and they suggest an advantage for PI-containing drug regimens in the treatment of HIV-infected patients who are coinfected with opportunistic and pathogenic bacteria.

Effectiveness of antiretroviral therapy after protease inhibitor failure: an analytic overview.

To examine effectiveness of subsequent antiretroviral therapy (ART), studies published during the period of 1 January 1997 through 31 May 2003 involving patients who had failed a protease inhibitor (PI)-containing regimen and were switched to another regimen were reviewed. Twelve studies describing 1197 patients were analyzed. A total of 38% of patients had human immunodeficiency virus (HIV) RNA levels of <500 copies/mL at 24 weeks. After adjustment for baseline HIV RNA level, the rate of virologic suppression ranged from 16% for patients switching drugs within previously failed classes to 54% for nonnucleoside reverse-transcriptase inhibitor (NNRTI)-naive patients switched to boosted PI- and NNRTI-containing regimens. ART regimens in patients who failed a PI-containing regimen provided virologic suppression only in a few patients. The best response was seen in NNRTI-naive patients receiving NNRTI- and boosted PI-containing regimens. New approaches are needed to achieve better suppression in pretreated HIV-infected patients.

Crunching the Numbers on "Switch" Studies

Long-term PI use is associated with substantial adverse effects, including fat redistribution, lipid abnormalities, insulin resistance, and perhaps cardiovascular disease. In addition, some PI-containing regimens can be complicated -- with dietary restrictions and a large pill burden -- making adherence difficult for many patients. In numerous small studies, researchers have evaluated whether switching from a PI-containing to a simplified, PI-sparing regimen can reduce toxicity and complexity while maintaining virologic control. Most of these studies varied in their clinical endpoints and had small sample sizes, making it difficult to reach conclusions about the effects of switching to PI-sparing regimens. Bucher and colleagues conducted a meta-analysis of select switch studies published or presented between 1996 and 2001. The …

Hospitalized HIV-infected patients in the HAART era: a view from the inner city.

To evaluate hospitalizations of HIV-infected patients in the highly active antiretroviral therapy (HAART) era, we analyzed 2736 admissions of 1562 HIV-infected patients to Cook County Hospital from September 20, 1999 to July 10, 2002. Patients were predominantly African American (81%), male (72%), and active substance abusers (74%). Only 48% of patients with a prior HIV diagnosis were taking HAART and 37% of them had a viral load less than 1000 copies per milliliter. Patients on protease inhibitor (PI)-sparing regimens more frequently achieved a viral load less than 1000 copies per milliliter than those on a PI-containing regimens (41% vs. 34% p = 0.036). For patients with CD4 cell counts less than 200 cells per milliliter, those not taking HAART were more likely African American (83% vs. 76%, p < 0.031), homeless (13% vs. 5%, p < 0.001), active substance abusers (79% vs. 65%, p < 0.001), female (28% vs. 22%, p = 0.001), new to the hospital system (19% vs. 6%, p < 0.001), or not recently seen in the outpatient clinic (42% vs. 17%, p < 0.001). In our population, active substance abuse was prevalent and only a minority of patients was taking HAART. Women were receiving HAART less often, independent of race and substance abuse. Aggressive programs are needed in high-risk populations to address substance abuse issues and to improve patient use of HAART.

Impact of Various Antiretroviral Drugs and Their Plasma Concentrations on Plasma Lipids in Heavily Pretreated HIV-Infected Patients

Objective: To evaluate the frequency and the magnitude of lipid abnormalities (LA) in respect to the nature of the antiretroviral drug and its plasma concentrations. Patients/Method: Trough concentrations (Ctrough) of protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) were assessed at Weeks 4, 8, 24, 28, and 32. Fasting triglycerides (TG) and total cholesterol (CH) were sampled at Weeks 0, 12, 20, and 32. We analyzed the probability of occurrence of grade 3-4 CH (> 7.8 mmol/L) and TG (> 8.4 mmol/L) during a 24-week period according to the drug taken using a Kaplan-Meier analysis and log rank test. Relation between Week 8 PI or NNRTI Ctrough and Week 12 lipid levels was assessed using the Kendall correlation measure. Results: The PharmAdapt study included 252 patients (mean age 41 years, 83% males); the patients received a PI (73%), an NNRTI (50%), and/or a ritonavir (RTV) booster-containing (46%) regimen. Compared to any other regimen, use of lopinavir (LPV)/RTV or efavirenz (EFV) was associated with a higher risk of grade 3-4 CH. Use of LPV/RTV and RTV booster was associated with a higher risk of grade 3-4 TG. Use of any PI-containing regimen was associated with a higher risk for grade 3-4 CH and TG compared to non PI-based regimens. Kendall correlation coefficients for PI or NNRTI Ctrough and blood lipid levels were close to zero for all drugs and CH or TG, showing the absence of relation between drug concentrations and lipid levels. Conclusion: Severity of lipid abnormalities is related to the nature of the antiretroviral drug. There is no short-term relation between PI or NNRTI trough concentrations and blood lipid levels in heavily pretreated patients.

Tipranavir: a protease inhibitor from a new class with distinct antiviral activity.

Tipranavir (TPV) is the first of a new class of non-peptidic protease inhibitors (NPPIs). It is a sulphonamide-containing dihydropyrone, which is highly selective for the HIV protease enzyme and demonstrates potent in vitro activity against wild-type HIV-1 and HIV-2. The IC90 for TPV was 0.1 microM against clinical HIV isolates. Since CYP3A is the major cytochrome P450 isoform for the phase I metabolism of TPV, its exposure is markedly enhanced in the presence of ritonavir (RTV). In one clinical study, using the new self emulsifying drug delivery system (SEDDS) formulation of TPV, plasma concentrations in excess of 20 microM were maintained for 12 hours, allowing for twice-a-day dosing following administration of TPV 300 mg/RTV(r) 200 mg twice a day. The 20 microM target represents 10-fold the IC90 for multiple protease inhibitor (PI)-resistant strains. Both in vitro data and pharmacokinetic results indicate that TPV will be active in vivo against PI-resistant viruses, when given twice a day in combination with low dose RTV. Of 105 HIV viral isolates taken from patients who had been heavily pretreated with PI-based regimens: 90% were fully susceptible to TPV; 8% exhibited intermediate resistance; and 2% were more than 10-fold resistant. In patients who had failed at least two PI-based regimens, only 12.2% of the HIV isolates exhibited four to 10-fold reduced susceptibility to TPV after one year of treatment with a regimen containing the NPPI (Study BI1182.2). A reduction of approximately 1.5 log10 copies/mL in the plasma viral load (pVL) was observed in treatment-naive patients after 15 days of monotherapy with TPV (300 or 1200 mg twice a day) co-administered with RTV (200 mg twice a day) (TPV/r) in a dose-ranging study (Study BI1182.3). The safety and efficacy of TPV (500 or 1250 mg) plus ritonavir (100 mg twice a day) plus two new nucleoside reverse transcriptase inhibitors (NRTIs) was studied in patients failing their first PI-containing regimen (Study BI1182.4). Similar decreases in pVLs (1.44-1.79 log10 copies/mL) were observed after 16 weeks of treatment with either dose of TPV/r. Two doses of TPV/r plus efavirenz (EFV) and a new NRTI have been studied in non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive patients who had failed two or more PI-containing regimens (BI1182.2). Between 50% and 78.9% of patients maintained a pVL < 50 copies/mL for 48 weeks. Clinical studies have shown that TPV/r-associated adverse events are generally gastrointestinal-associated, transient and mild. A phase II study will define the optimal dose of TPV/r for highly treatment-experienced patients. The safety and efficacy of this dose of TPV/r will be evaluated in two phase III studies that will enroll more than 1300 patients worldwide. Tipranavir's robust activity against PI-resistant strains results from its molecular flexibility, which allows it to fit into the active pocket of the protease enzyme in viruses that have become resistant to other PIs.

Drug-induced aminotransferase alterations during antiretroviral HIV post-exposure prophylaxis.

In 655 individuals receiving HIV postexposure prophylaxis (PEP), drug-induced aminotransferase alterations were frequent and severe in the nevirapine-including regimen, rare and mild-to-moderate in other combinations, and always reversible. Grade 3-4 incidence in protease inhibitor or nevirapine PEP was 0.5 and 25.0 per 100 person-months, respectively. Apart from nevirapine, continuing PEP appears to be safe even in the case of aminotransferase alterations. The usefulness of routine monitoring of liver function during PEP could be re-considered.

Impact of nevirapine on lipid metabolism.

Abnormal blood lipid profiles may be observed both in HIV-infected individuals who are untreated and in those receiving highly active antiretroviral therapy (HAART). Besides maintaining optimal control of HIV replication and the preservation of immunity, treatment regimens ideally should have minimal or no metabolic side-effects. Nevirapine (NVP)-based HAART has beneficial effects on the lipid profile, in both treatment-näive and treatment-experienced patients, unlike protease inhibitor (PI)-based HAART. In antiretroviral (ARV)-naive patients enrolled in the Fat Redistribution and Metabolic Substudy (FRAMS) of the Atlantic Study, the NVP-containing regimen increased total cholesterol, high density lipoprotein (HDL) cholesterol concentration and particle size and apolipoprotein A1 (apo A1) levels at 24 weeks. The changes in HDL cholesterol plasma levels were demonstrated to be sustained in a subset of 98 FRAMS patients at 96 weeks. Switching from a PI-containing regimen to a PI-sparing regimen containing NVP has likewise been shown to favorably alter lipid profiles in two open label studies. In one study, one or more lipid profile parameters (total cholesterol, low density lipoprotein [LDL] cholesterol, LDL particle size, very low density lipoprotein cholesterol [VLDL1] HDL cholesterol, HDL particle size) had reverted to normal after 24 weeks in significantly more NVP-treated patients than PI-treated patients (69% versus 23%, p < .05). The 12-month results from the Barcelona PI Switch Study indicated that NVP improved lipid profiles over 12 months after PI-treated patients were switched to NVP. In conclusion, first-line NVP treatment is associated with a favorable lipoprotein profile, i.e., an increase in HDL-cholesterol and apo A1 plasma levels The lipid profile observed in patients who are switched from a PI-based regimen to a NVP-based regimen improves in a very similar fashion. These favorable lipid profiles may be of clinical benefit in reducing the risk for coronary artery disease in HIV-1 infected patients who are receiving long-term antiretroviral therapy.

Effect of protease inhibitor-containing regimens on lymphocyte multidrug resistance transporter expression.

Increased expression of multidrug resistance transporters, such as P-glycoprotein (P-gp), has been suggested as a potential mechanism for decreased protease inhibitor (PI) availability at certain intracellular sites and tissue compartments. To investigate the effect of PIs on the surface lymphocyte expression of P-gp in vitro and in vivo. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy subjects (n = 15) and incubated (72 h) with 10 microM of each PI studied (saquinavir, ritonavir, nelfinavir, indinavir, amprenavir and lopinavir), or dimethyl sulphoxide (DMSO) control. PBMCs were also isolated from HIV-infected subjects (n = 50; viral load <50 copies/mL) on a PI- or a non-PI-containing combination antiretroviral regimen. P-gp expression was analysed by flow cytometry. No differences in surface P-gp expression on lymphocytes, CD4+ or CD8+ lymphocyte subsets were observed following incubation with 10 microM saquinavir, ritonavir, indinavir, amprenavir or lopinavir in vitro. Nelfinavir, however, increased P-gp expression. In vivo, no difference in P-gp expression on total lymphocytes was observed between patients receiving a PI-containing regimen [saquinavir n = 9, ritonavir n = 6, nelfinavir n = 7, indinavir n = 7 and lopinavir/ritonavir n = 13, and two nucleoside reverse transcriptase inhibitors (NRTIs)] and patients receiving a control regimen of three NRTIs alone (n = 8). This study suggests that, of the PIs, only nelfinavir increases P-gp expression in vitro, and in vivo the PI class of antiretrovirals do not increase P-gp expression on lymphocytes. It is clear that factors other than PI induction are important in the inter-individual variability in the lymphocyte expression of P-gp.