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.

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). Twelve subjects were enrolled and 10 completed the study. Prior to starting TPV/r, the geometric mean BUP AUC(0-24h) and C(max) were 43.9 ng h/mL and 5.61 ng/mL, respectively. After achieving steady-state with TPV/r (> or = 7 days), these values were similar at 43.7 ng h/mL and 4.84 ng/mL, respectively. Similar analyses for norBUP, the primary metabolite of BUP, demonstrated a reduction in geometric mean for AUC(0-24h) [68.7-14.7 ng h/mL; ratio=0.21 (90% CI 0.19-0.25)] and C(max) [4.75-0.94 ng/mL; ratio=0.20 (90% CI 0.17-0.23)]. The last measurable NLX concentration (C(last)) in the concentration-time profile, never measured in previous BUP/NLX interaction studies with antiretroviral medications, was decreased by 20%. Despite these pharmacokinetic effects on BUP metabolites and NLX, no clinical opioid withdrawal symptoms were noted. TPV steady-state AUC(0-12h) and C(max) decreased 19% and 25%, respectively, and C(min) was relatively unchanged when compared to historical control subjects receiving TPV/r alone. No dosage modification of BUP/NLX is required when co-administered with TPV/r. Though mechanistically unclear, it is likely that decreased plasma RTV levels while on BUP/NLX contributed substantially to the decrease in TPV levels. BUP/NLX and TPV/r should therefore be used cautiously to avoid decreased efficacy of TPV in patients taking these agents concomitantly.

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.

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. Safety was assessed by clinical monitoring. Studies were powered to conclude lack of an interaction if the 90% confidence interval for the geometric mean ratios of the AUCtau and Cmax for EVG, TPV, and DRV were within predefined no-effect boundaries. Trough concentrations were also assessed. RESULTS: No subjects discontinued for adverse events during treatment with EVG/r alone. On coadministration, AUCtau and Cmax of EVG and TPV and EVG and DRV were within prespecified no-effect boundaries versus treatment alone; trough concentrations were also not substantially altered. CONCLUSIONS: The PK of EVG and TPV or DRV were not altered after coadministration of EVG with TPV/r or DRV/r. EVG PK was similar with varied RTV doses of 100 mg once daily, 100 mg twice daily, or 200 mg twice daily. EVG can be added to TPV/r or DRV/r regimens without dose adjustment.

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.

Efficacy and safety of three doses of tipranavir boosted with ritonavir in treatment-experienced HIV type-1 infected patients.

The efficacy, safety, and pharmacokinetics of three doses of tipranavir/ritonavir (TPV/r) in highly treatment-experienced human immunodeficiency virus (HIV)-1-infected patients with protease inhibitor (PI)-resistant isolates were evaluated. A 24-week multicenter, double-blind, randomized, dose-finding trial was conducted. All patients were three-drug class experienced and had taken at least two PI-based regimens. All had at least one primary PI mutation and had plasma HIV-RNA > 1000 copies/ml. Patients remained on their background non-PI antiretroviral medications for the first 14 days. After this 14-day period of functional TPV/r monotherapy, the background antiretroviral medications were optimized based on treatment history and the screening genotype. A total of 216 patients were randomized. All groups [TPV/r 500 mg/100 mg (n = 73), 500 mg/200 mg (n = 72), and 750 mg/200 mg (n = 71) twice daily] achieved an approximate 1 log10 reduction in the median HIV-RNA at week 2. A significant reduction was sustained through 24 weeks in the TPV/r 500 mg/200 mg and 750 mg/200 mg groups. The 500 mg/200 mg dose achieved optimal median TPV trough concentrations and lower interpatient variability. The most frequently reported adverse events (AEs) were diarrhea, nausea, vomiting, fatigue, and headache. The TPV/r 750 mg/200 mg group had the highest rate of grade 3 or 4 laboratory abnormalities and study discontinuations due to AEs. All doses of TPV/r tested in this study were associated with HIV-1 viral load reductions through 24 weeks. The 500 mg/200 mg dose achieved the best efficacy, safety, and pharmacokinetic profile in this highly treatment-experienced population and was selected for the pivotal phase 3 studies.

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.

Pharmacokinetics, pharmacodynamics and safety of once-daily versus twice-daily dosing with enfuvirtide in HIV-infected subjects.

OBJECTIVE: To investigate the pharmacokinetics, safety/tolerability and antiviral activity of enfuvirtide administered once-daily (QD) versus twice-daily (BID). DESIGN: An open-label, randomized, multiple dose, two-period crossover study comparing 180 mg enfuvirtide, two injections QD versus 90 mg enfuvirtide, two injections, BID. METHODS: Steady-state intensive pharmacokinetic samples were obtained on days 7 and 14. RESULTS: Thirty-seven subjects received at least one dose of enfuvirtide. Thirty-three subjects completed both dosing periods. The regimens were bioequivalent based on the ratio of geometric mean area under the curve (AUC)0-tau [112 +/- 6.2 microg x h/ml QD; 115 +/- 6.4 microg x h/ml 2 x BID; QD/BID 0.98; 90% confidence interval (CI) 0.89,1.07]. The maximum observed plasma concentration within a dosing interval (Cmax) was 49% higher for QD (9.5 +/- 2.7 microg/ml) versus BID (6.3 +/- 1.7 microg/ml) and the pre-dose plasma concentration (Ctrough) was 57% lower for QD (1.6 +/- 1.1 microg/ml) versus BID (3.8 +/- 1.3 microg/ml). The LSM decrease in viral load from baseline to day 7 was 1.0 +/- 0.14 log10 (n = 18) for QD and 1.4 +/- 0.2 log10 (n = 17) for BID (LSM difference 0.385; P = 0.07). Linear regression analysis suggested that decline in viral load up to day 7 was associated with Ctrough but not Cmax or AUC. There were no significant differences in adverse events between the two dosing regimens. CONCLUSIONS: Administration of enfuvirtide 180 mg QD results in bioequivalence compared with 90 mg BID based on AUC with a similar short-term safety profile, but a trend towards a weaker antiretroviral effect. Larger and longer-term studies are needed to determine if 180 mg once daily is an effective dosing alternative for enfuvirtide.

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. RESULTS: A total of 73.7% of patients randomized to the enfuvirtide group remained on treatment through week 48 versus 21.3% originally randomized to the control group. At week 48, a higher proportion of week 24 responders maintained their response or were new responders in the enfuvirtide group than in the control group in each responder category: HIV-1 RNA level > or =1.0 log(10) change from baseline, <400 copies/mL and <50 copies/mL (37.4%, 30.4%, and 18.3% in the enfuvirtide group vs. 17.1%, 12.0%, and 7.8% in the control group, respectively; P < 0.0001 for all comparisons). CD4 cell count increases from baseline were twice as great in the enfuvirtide group as in the control group. CONCLUSION: These data demonstrate durable efficacy of enfuvirtide plus OB over 48 weeks.

Safety of enfuvirtide in combination with an optimized background of antiretrovirals in treatment-experienced HIV-1-infected adults over 48 weeks.

BACKGROUND: Antiretroviral tolerability is a critical factor contributing to treatment outcome. The T-20 Versus Optimized Background Regimen Only (TORO) studies assessed the safety and efficacy of enfuvirtide in treatment-experienced HIV-1-infected patients. METHODS: A total of 997 patients were randomized at a 2:1 ratio to an optimized background antiretroviral regimen plus enfuvirtide (n = 663) or an optimized background regimen alone (control group; n = 334). Control patients could switch to enfuvirtide on virologic failure. RESULTS: In total, 26.5% of patients randomized to enfuvirtide and 36.6% to the control group discontinued study treatment before week 48; the percentage of patients withdrawn for safety reasons (including adverse events [AEs], deaths, and laboratory abnormalities) was 14.0% in the enfuvirtide group and 11.6% in the control group. Injection site reactions (ISRs) occurred in 98% of enfuvirtide patients and led to treatment discontinuation in 4.4%. Treatment-related (defined as possibly, probably, or remotely) AE rates per 100 patient-years were lower with enfuvirtide (96.2) than in the control group (149.9); diarrhea, nausea, and fatigue, the most frequently reported AEs, were significantly less frequent with enfuvirtide than in the control group. Pneumonia was significantly more frequent in patients treated with enfuvirtide (6.7 vs. 0.6 events per 100 patient-years), although the incidence was within expected ranges for this population. Lymphadenopathy was also higher in enfuvirtide-treated patients (7.1 vs. 1.2 events per 100 patient-years) for control patients. CONCLUSION: The addition of enfuvirtide to an optimized background regimen does not exacerbate AEs commonly associated with antiretrovirals. ISRs limited treatment in <5% of patients.

Antiviral activity and safety of 873140, a novel CCR5 antagonist, during short-term monotherapy in HIV-infected adults.

OBJECTIVE: 873140 is a spirodiketopiperazine CCR5 antagonist with prolonged receptor binding and potent antiviral activity in vitro. This study evaluated plasma HIV RNA, safety, and pharmacokinetics following short-term monotherapy in HIV-infected adults. DESIGN: Double-blind, randomized, placebo-controlled multi-center trial. METHODS: Treatment-naive or experienced HIV-infected subjects with R5-tropic virus, CD4 cell count nadir > 200 x 10 cells/l, viral load > 5000 copies/ml and not receiving antiretroviral therapy for the preceding 12 weeks were enrolled. Forty subjects were randomized to one of four cohorts (200 mg QD, 200 mg BID, 400 mg QD, 600 mg BID) with 10 subjects (eight active, two placebo) in each cohort, and received treatment for 10 days. Serial HIV RNA, pharmacokinetics, and safety evaluations were performed through day 24. RESULTS: Of the 40 subjects, 21 were treatment-experienced; 35 were male, 20 were non-white, and eight were coinfected with hepatitis C virus. Median baseline HIV RNA ranged from 4.26 log10 to 4.46 log10. 873140 was generally well tolerated with no drug-related discontinuations. The most common adverse events were grade 1 gastrointestinal complaints that generally resolved within 1-3 days on therapy. No clinically significant abnormalities were observed on electrocardiogram or in laboratory parameters. Mean log changes in HIV RNA at nadir, and the percentage of subjects with > 1 log10 decrease were -0.12 (0%) for placebo, -0.46 (17%) for 200 mg once daily, -1.23 (75%) for 200 mg twice daily, -1.03 (63%) for 400 mg once daily, and -1.66 (100%) for 600 mg twice daily. An Emax relationship was observed between the area under the 873140 plasma concentration-time curve and change in HIV RNA. CONCLUSIONS: 873140 demonstrated potent antiretroviral activity and was well tolerated. These results support further evaluation in Phase 2b/3 studies.

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.

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.

Developments in HIV treatments: strategies for success.

The current primary goal of therapy for HIV-1 infection is suppression of viral replication to below detectable levels (less than 50 copies/mL). The most important challenge facing current HIV-1 research is designing agents that prevent the emergence of or overcome drug-resistant HIV-1 variants. Shortcomings of antiretroviral therapy have sparked interest in immunologic enhancement through vaccines and immunomodulators, specifically antigen stimulation, induction of HIV-1 specific memory and cytotoxic T-cell responses, and activation of resting CD4+ cells within latent HIV-1 reservoirs. New classes of antiretroviral agents include entry inhibitors and nucleotide reverse transcriptase inhibitors. This article discusses the status of successful HIV treatment strategies, including new treatment practices, antiretroviral agents, and immune-enhancing agents.

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. Several of these agents are effective as once-daily therapy, including didanosine, lamivudine, extended-release stavudine (FDA approved, but not currently available), tenofovir DF, and emtricitabine. Recent results from pharmacokinetic and clinical trials indicate that another NRTI, abacavir, may also be effective as a once-daily therapy, and FDA approval of once-daily dosing is anticipated. NRTIs are inactive as administered, requiring anabolic phosphorylation within target cells to achieve their antiretroviral effects. All NRTIs are converted to nucleoside triphosphates, which serve as the active metabolites (the NtRTI, tenofovir DF, only requires conversion to the diphosphate form). Frequency of drug administration is closely related to the pharmacokinetic properties of a drug. The key parameter is the half-life; however, the plasma elimination half-life of the NRTIs/NtRTIs as administered is of little use in developing a dosing schedule. Rather, the intracellular half-life of the nucleoside triphosphate is the relevant parameter. This article reviews the pharmacokinetic properties, particularly those of the various phosphorylation steps, of the NRTIs/NtRTIs.

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.