Gemogenovatucel-T (Vigil): bi-shRNA plasmid-based targeted immunotherapy.

We describe in this review the historical evidence leading up to the concept and design of Vigil and subsequent clinical applications including safety and efficacy in a randomized, controlled Phase IIB trial. Vigil (gemogenovatucel-T) is a unique triple function targeted immunotherapy that demonstrates preclinical and clinical systemic anticancer activity. Construction of Vigil involves harvest of autologous malignant tissue for neoantigen targeting (ideally containing clonal neoantigens) followed by a two-day process involving transfection with a plasmid to provide a permissive 'training environment' for the patient's immune system. Transfected plasmid components contain an expressive human GMCSF DNA segment to enhance anticancer immune functional response and a second component expressing bi-shRNAfurin which reduces TGFß isomers (TGFß1 and TGFß2) thereby reducing cancer inhibition of the targeted immune response. Results generated to date justify advancement to confirmatory clinical trials supporting product regulatory approval.

Vigil is an anticancer treatment that employs three methods of enhancing the body's immune system to identify and kill cancer cells. The construction of Vigil involves cancer cells from the same person being treated (personalized therapy) in combination with added anticancer genetic signals to enhance the number and function anti-anticancer immune cells and to guide the immune cells to the cancer and not to normal organs of the body. In this manner, an army of immune cells are created that can move to attacking the cancer using blood vessels to get to the cancer anywhere it tries to grow in the body. One study (Phase I) performed with this product to determine safety and dose range demonstrated an optimal dose and schedule. Another study (Phase IIA) showed initial clinical benefit. A third more complex study (Phase IIB) in patients treated with Vigil compared with standard of care without Vigil demonstrated the ability to prolong the patients life and time without their cancer getting worse without any significant side effects associated with the treatment in a unique subset of ovarian cancer patients, those with the ability to repair their DNA. Based on the composite of these results, Vigil is an attractive targeted immunotherapy justified for late-stage clinical testing.

Clonal Neoantigen: Emerging "Mechanism-based" Biomarker of Immunotherapy Response.

Clonal mutations represent the initiating molecular defects related to cellular transition of a normal phenotype to a malignant phenotype. Molecular genomic assessment utilizing next generation and whole exome sequencing is now being increasingly applied to biomarker determination to refine the use of targeted immune therapies. Case examples followed by retrospective study assessment have convincingly demonstrated clonal neoantigens provide a relevant predictor of response to checkpoint inhibition. A meta-analysis, by Litchfield et al., of over 1000 cancer patients from 12 landmark trials demonstrated no clinical benefit to checkpoint inhibitor (CPI) therapy in correlation to high subclonal tumor mutational burden (TMB), whereas high clonal TMB was found to be significantly correlated with better overall survival (p = 0.000000029). We discuss the mechanism of clonal vs. subclonal neoantigen targeting relationship to homologous recombination proficient (HRP) profile, evidence of preclinical and clinical benefit related to clonal neoantigens, and review a novel developing therapy called Vigil®, designed to expand the clonal neoantigen targeting effector cell populations. Vigil® is an autologous cellular immunotherapy which is designed to carry the full set of personal clonal neoantigens. Phase 2b results demonstrate a durable recurrence-free survival (RFS) and overall survival (OS) advantage for Vigil® in a subset ovarian cancer population with an HRP cancer profile.

ENTPD1/CD39 as a predictive marker of treatment response to gemogenovatucel-T as maintenance therapy in newly diagnosed ovarian cancer.

Background: Broadened use of predictive molecular and phenotypic profiling amongst oncologists has facilitated optimal integration of targeted- and immuno-therapeutics into clinical care. However, the use of predictive immunomarkers in ovarian cancer (OC) has not consistently translated into clinical benefit. Vigil (gemogenovatucel-T) is a novel plasmid engineered autologous tumor cell immunotherapy designed to knock down the tumor suppressor cytokines, TGFß1 and TGFß2, augment local immune function via increased GMCSF expression and enhance presentation of clonal neoantigen epitopes. Methods: All patients enrolled in the VITAL trial (NCT02346747) of maintenance Vigil vs. placebo as front-line therapy with homologous recombination proficient (HRP) stage IIIB-IV newly diagnosed ovarian cancer underwent NanoString gene expression analysis. Tissue was obtained from surgically resected ovarian tumor tissue following surgical debulking. A statistical algorithm was used to analyze the NanoString gene expression data. Results: Using the NanoString Statistical Algorithm (NSA), we identify high expression of ENTPD1/CD39 (which functions as the rate-limiting step in the production of the immune suppressor adenosine from ATP to ADP) as a presumptive predictor of response to Vigil versus placebo regardless of HRP status on the basis of relapse free survival (median not achieved vs 8.1 months, p = 0.00007) and overall survival (median not achieved vs 41.4 months, p = 0.013) extension. Conclusion: NSA should be considered for application to investigational targeted therapies in order to identify populations most likely to benefit from treatment, in preparation for efficacy conclusive trials.

Treatment options are limited in patients with advanced stage ovarian cancer. Treatments that stimulate the immune system to target the cancer are sometimes effective, however determining which patients will have benefit has been difficult. It is therefore important to develop new markers to predict which patients will respond to therapy. In this study, we looked at the levels of a large number of genes in tumors from patients treated with Vigil (gemogenovatucel-T), a treatment that modifies patient's own tumor cells to activate the immune system. We demonstrate that high expression of a gene named ENTPD1/CD39 predicts a positive response to Vigil therapy. This finding could help clinicians to determine which patients might benefit from Vigil treatment and therefore might guide decisions on who should receive this treatment.

A 96-week comparison of lopinavir-ritonavir combination therapy followed by lopinavir-ritonavir monotherapy versus efavirenz combination therapy.

Antiretroviral-naive HIV-1-infected volunteers received zidovudine/lamivudine plus either lopinavir/ritonavir (n=104) or efavirenz (n=51). Lopinavir/ritonavir-treated subjects demonstrating 3 consecutive monthly HIV-1 RNA levels <50 copies/mL started lopinavir/ritonavir monotherapy. In previous-failure=failure analysis, 48% (lopinavir/ritonavir) and 61% (efavirenz) maintained HIV-1 RNA at <50 copies/mL through week 96, (P= .17; 95% confidence interval [CI] for the difference, -29% to 4%); in noncompletion=failure analysis, 60% (lopinavir/ritonavir) and 63% (efavirenz) maintained HIV-1 RNA at <50 copies/mL at week 96 (P= .73; 95% CI for the difference, -19% to 13%). Significant sparing of peripheral lipoatrophy was noted in the lopinavir/ritonavir simplification strategy. This study has provided important information for future studies using treatment simplified to lopinavir/ritonavir monotherapy.

Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy.

Residual viremia can be detected in most HIV-1-infected patients on antiretroviral therapy despite suppression of plasma RNA to <50 copies per ml, but the source and duration of this viremia is currently unknown. Therefore, we analyzed longitudinal plasma samples from 40 patients enrolled in the Abbott M97-720 trial at baseline (pretherapy) and weeks 60 to 384 by using an HIV-1 RNA assay with single-copy sensitivity. All patients were on therapy (lopinavir/ritonavir, stavudine, and lamivudine) with plasma HIV RNA <50 copies per ml by week 96 of the study and thereafter. Single-copy assay results revealed that 77% of the patient samples had detectable low-level viremia (>/=1 copy per ml), and all patients had at least one sample with detectable viremia. A nonlinear mixed effects model revealed a biphasic decline in plasma RNA levels occurring over weeks 60 to 384: an initial phase of decay with a half-life of 39 weeks and a subsequent phase with no perceptible decay. The level of pretherapy viremia extrapolated for each phase of decay was significantly correlated with total baseline viremia for each patient (R(2) = 0.27, P = 0.001 and R(2) = 0.19, P < 0.005, respectively), supporting a biological link between the extent of overall baseline viral infection and the infection of long-lived reservoirs. These data suggest that low-level persistent viremia appears to arise from at least two cell compartments, one in which viral production decays over time and a second in which viral production remains stable for at least 7 years.

Seven-year efficacy of a lopinavir/ritonavir-based regimen in antiretroviral-naïve HIV-1-infected patients.

OBJECTIVE: Evaluate efficacy and tolerability of lopinavir/ritonavir (LPV/r) plus stavudine and lamivudine long term in antiretroviral-naïve patients. DESIGN: Open-label follow-up of prospective, randomized, multicenter trial. METHOD: Antiretroviral-naïve HIV-infected subjects (N = 00) received of 3 doses of LPV/r plus stavudine and lamivudine for 48 weeks then received LPV/r soft-gel capsules 400/00 mg plus stavudine and lamivudine. After 6 years, subjects replaced stavudine with tenofovir. RESULTS: At 7 years, by intent-to-treat analysis, 61 % had plasma HIV-RNA <400 copies/mL and 59% had < 50 copies/mL. Thirty-nine subjects discontinued treatment due to adverse events (n = 6), personal/other reasons (0), loss to follow-up (9), and noncompliance (4). Among 28 subjects qualifying for drug resistance testing, no protease inhibitor or stavudine resistance was observed and 4 showed lamivudine resistance. Most common drug-related moderate or severe adverse events were diarrhea (28%), nausea (6%), and abdominal pain (11 %). Subjects who received stavudine (median 6.6 years) and switched to tenofovir demonstrated significant improvements in total cholesterol (p = .009), triglycerides (p = .023), apolipoprotein C-III (p < .001 ), adiponectin (p = .008), fasting insulin (p = .04), and leptin (p = .03). CONCLUSION: LPV/r-based therapy demonstrated sustained efficacy with no protease inhibitor or stavudine resistance through 7 years in antiretroviral-naïve patients. Switching from stavudine to tenofovir resulted in significant improvements in multiple metabolic parameters.

High-dose lopinavir/ritonavir in highly treatment-experienced HIV-1 patients: efficacy, safety, and predictors of response.

OBJECTIVE: To investigate the efficacy and safety of high-dose lopinavir/ritonavir (LPV/r) therapy in multiple protease inhibitor, non-nucleoside reverse transcriptase inhibitor (NNRTI)-experienced subjects. METHOD: Thirty-six HIV-1-infected subjects were randomized to LPV/r 400/300 mg or 667/167 mg bid in a 48-week, open-label study. Subjects also received investigator-selected nucleoside reverse transcriptase inhibitors (NRTIs). Primary outcomes were the proportion of subjects with HIV-1 RNA levels <50 copies/mL at week 24 and time until loss of virologic response through week 48. RESULTS: Six of 17 (35%) and 10 of 19 (53%) subjects in the 400/300 and 667/167 groups, respectively, completed 48 weeks of treatment. Median durations of follow-up in discontinued subjects and all subjects were 15 weeks and 32 weeks, respectively. Forty-four percent of subjects achieved HIV-1 RNA <50 copies/mL at least once; 18% (400/300 mg) and 21% (667/167 mg) of subjects achieved HIV-1 RNA <50 copies/mL at week 24 (intent-to-treat analysis). Corresponding results at week 48 were 18% (400/300 mg) and 26% (667/167 mg). No statistically significant differences in adverse event incidence occurred between treatment groups, except for a higher vomiting rate in the 400/300 mg dose group. Predictors of response included baseline LPV inhibitory quotient and number of active NRTIs. CONCLUSION: Higher doses of LPV/r may provide substantial antiviral activity in multiple class-experienced subjects.

ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia.

Current antiretroviral therapy is effective in suppressing but not eliminating HIV-1 infection. Understanding the source of viral persistence is essential for developing strategies to eradicate HIV-1 infection. We therefore investigated the level of plasma HIV-1 RNA in patients with viremia suppressed to less than 50-75 copies/ml on standard protease inhibitor- or non-nucleoside reverse transcriptase inhibitor-containing antiretroviral therapy using a new, real-time PCR-based assay for HIV-1 RNA with a limit of detection of one copy of HIV-1 RNA. Single copy assay results revealed that >80% of patients on initial antiretroviral therapy for 60 wk had persistent viremia of one copy/ml or more with an overall median of 3.1 copies/ml. The level of viremia correlated with pretherapy plasma HIV-1 RNA but not with the specific treatment regimen. Longitudinal studies revealed no significant decline in the level of viremia between 60 and 110 wk of suppressive antiretroviral therapy. These data suggest that the persistent viremia on current antiretroviral therapy is derived, at least in part, from long-lived cells that are infected prior to initiation of therapy.

Lack of effect of gastric acid-reducing agents on the pharmacokinetics of lopinavir/ritonavir in HIV-infected patients.

Recent studies have shown that coadministration of certain protease inhibitors (PIs) with gastric acid-reducing agents results in decreased plasma concentrations of the PI. To assess the effect of acid-reducing agents on lopinavir/ritonavir, data from two clinical trials (n = 38 and 190) were pooled. Both trials randomized antiretroviral-naïve, HIV-infected patients to receive lopinavir/ritonavir 400/100 mg twice-daily or 800/200 mg once-daily in combination with stavudine and lamivudine, or tenofovir and emtricitabine. Concurrent administration of gastric acid-reducing agents including antacids of various brand names, proton pump inhibitors (omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole), and H(2)-receptor antagonists (ranitidine, famotidine, cimetidine, and nizatidine) was reported in both trials. Lopinavir and ritonavir pharmacokinetic parameters were evaluated. Thirty subjects were considered users of acid-reducing agents at the times of pharmacokinetic evaluation. HIV-infected patients who received gastric acid-reducing agents during administration of lopinavir/ritonavir-based treatment regimens did not appear to have a reduction in lopinavir or ritonavir exposures.

The tablet formulation of lopinavir/ritonavir provides similar bioavailability to the soft-gelatin capsule formulation with less pharmacokinetic variability and diminished food effect.

Lopinavir, an HIV protease inhibitor, is coformulated with ritonavir to enhance the bioavailability and pharmacokinetics of lopinavir. The original solid oral formulation of lopinavir/ritonavir, a soft-gelatin capsule (SGC), requires refrigerated storage, is taken as 6 capsules daily at the recommended adult dose, and is administered with food to maximize the bioavailability of lopinavir. Melt extrusion technology was used to produce a tablet formulation reducing the number of dosage units administered per day and simplifying storage requirements. Three studies assessed the bioavailability of tablet doses of lopinavir/ritonavir at 800/200 mg or 400/100 mg under different meal conditions compared with equal doses of the SGC after a moderate-fat meal. The tablet was bioequivalent to the SGC after a moderate-fat meal with respect to lopinavir and ritonavir areas under the concentration-time curve. Compared with the SGC formulation, the tablet formulation resulted in more consistent lopinavir and ritonavir exposures within and across studies and across meal conditions. The diminished food effect and decreased variability of the tablet are likely to result in more consistent lopinavir and ritonavir exposures, minimizing the likelihood of extreme high or low values compared with the SGC.

Cost effectiveness of lopinavir/ritonavir compared with atazanavir in antiretroviral-naive patients: modelling the combined effects of HIV and heart disease.

BACKGROUND AND OBJECTIVE: The choice of initial highly active antiretroviral therapy (HAART) should take into account the need to balance efficacy, adverse event risk, resistance concerns for the treatment of HIV and treatment costs. Increased risk of coronary heart disease (CHD) may be of special concern in the selection of HAART therapy, because differences in potential CHD risk have been reported for different regimens. This study aimed to estimate the long-term combined effects of HIV disease and antiretroviral (ARV)-related risk for CHD on quality-adjusted survival and healthcare costs for ARV-naive patients. METHODS: A previously validated Markov model was updated and supplemented with the Framingham CHD risk equation. In the model, the average patient was male, aged 37 years and had a baseline 10-year CHD risk of 4.6%. Patients started with either lopinavir/ritonavir or unboosted atazanavir as the first protease inhibitor (PI). Clinical trial data were used to estimate the differences between these two therapies. The daily PI costs were $US18.52 for lopinavir/ritonavir and $US22.08 for atazanavir. Other costs were estimated from Medicaid billing databases and average wholesale drug price reports. All model costs were reported as the 2004 present value in US currency. The model's time horizon reflected a patient's lifetime, and the perspective of the analysis was that of the healthcare system and did not include indirect costs in the model cost estimates. Various CHD risk levels were tested in the sensitivity analysis. RESULTS: In the base case, the model predicted a median duration of initial PI regimen of 5.6 years for lopinavir/ritonavir and 3.8 years for atazanavir. Over 10 years, patients who started on atazanavir had 30 additional AIDS events per 100 patients. Only 0.7 additional CHD events per 100 patients occurred for those who started on lopinavir/ritonavir. The model estimated 10-year total healthcare cost savings of $US12,543 per patient in the lopinavir/ritonavir group. The lifetime incremental cost effectiveness of lopinavir/ritonavir versus atazanavir was $US6797 per quality-adjusted life-year gained. CONCLUSION: Lopinavir/ritonavir is a highly cost-effective regimen relative to atazanavir for the treatment of HIV. The effect of lopinavir/ritonavir on long-term CHD risk was minimal compared with the increased risk of AIDS/death projected for a less efficacious first PI regimen. The cost of lipid-lowering drugs and treatment of CHD for patients taking the lopinavir/ritonavir regimen was only 1.2% of the cost of AIDS care per person, which was too small to have a significant effect on the overall cost savings with lopinavir/ritonavir therapy. Thus, a decision to forgo potency and durability in an ARV regimen for an ARV-naive patient in favour of a less potent regimen with an improved lipid profile may prove to be costly over time, in terms of both budget impact and life expectancy.

A once-daily lopinavir/ritonavir-based regimen provides noninferior antiviral activity compared with a twice-daily regimen.

OBJECTIVE: To evaluate the safety and noninferiority and to explore the efficacy of administration of once-daily versus twice-daily lopinavir/ritonavir (LPV/r) in antiretroviral-naive HIV-1-infected subjects. DESIGN: Randomized, open-label, multicenter, comparative study. METHODS: One hundred ninety antiretroviral-naive subjects with plasma HIV-1 RNA level >1000 copies/mL and any CD4 cell count were randomized to lopinavir/ritonavir at a dose of 800/200 mg administered once daily (n = 115) or lopinavir/ritonavir at a dose of 400/100 mg administered twice daily (n = 75). Subjects also received tenofovir disoproxil fumarate (TDF) at a dose of 300 mg and emtricitabine (FTC) at a dose of 200 mg administered once daily. RESULTS: The median baseline plasma HIV-1 RNA level and CD4 count were 4.8 log10 copies/mL and 216 cells/mm, respectively. Before week 48, 20% (once daily) and 29% (twice daily) subjects discontinued. Virologic responses of the subjects through 48 weeks were comparable; 70% (once daily) and 64% (twice daily) achieved an HIV-1 RNA level <50 copies/mL by intent-to-treat, noncompleter = failure analysis. No subject demonstrated LPV or TDF resistance, but 3 subjects (2 in the once-daily group, 1 in the twice-daily group) demonstrated FTC resistance. Mean increases in CD4 count were similar. Diarrhea (16% in the once-daily group, 5% in the twice-daily group; P = 0.036) was the most common moderate or severe study drug-related adverse event. CONCLUSIONS: Through 48 weeks, a once-daily regimen of lopinavir/ritonavir + TDF + FTC appears to have similar virologic and immunologic responses in antiretroviral-naive subjects as the same regimen with lopinavir/ritonavir administered twice daily. Both regimens were relatively well tolerated, and no LPV or TDF resistance was observed.

Pharmacokinetics of lopinavir/ritonavir in HIV/hepatitis C virus-coinfected subjects with hepatic impairment.

The effect of hepatic impairment on lopinavir/ritonavir pharmacokinetics was investigated. Twenty-four HIV-1-infected subjects received lopinavir 400 mg/ritonavir 100 mg twice daily prior to and during the study: 6 each with mild or moderate hepatic impairment (and hepatitis C virus coinfected) and 12 with normal hepatic function. Mild and moderate hepatic impairment showed similar effects on lopinavir pharmacokinetics. When the 2 hepatic impairment groups were combined, lopinavir Cmax and AUC12 were increased 20% to 30% compared to the controls. Hepatic impairment increased unbound lopinavir AUC12 by 68% and Cmax by 56%. The effect of hepatic impairment on low-dose ritonavir pharmacokinetics was more pronounced in the moderate impairment group (181% and 221% increase in AUC12 and Cmax, respectively) than in the mild impairment group (39% and 61% increase in AUC12 and Cmax, respectively). While lopinavir/ritonavir dose reduction is not recommended in subjects with mild or moderate hepatic impairment, caution should be exercised in this population.

Substitution with lopinavir/ritonavir improves patient-reported outcomes including quality of life in patients who were intolerant to their antiretroviral therapy.

PURPOSE: Adverse effects are important determinants of quality of life (QOL) during highly active antiretroviral therapy (HAART). The PLATO study investigated the association between changes in patient-reported outcomes including QOL and substitution with lopinavir/ritonavir in patients experiencing side effects (SEs). METHOD: HIV-1-infected participants (N = 849) with undetectable viral load experiencing Grade-2 SEs of the protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) component of their HAART regimen were randomized to immediate (baseline) or deferred (week 4) substitution with lopinavir/ritonavir soft-gel capsules 400/100 mg bid. The primary endpoint was change in the total score from the AIDS Clinical Trials Group (ACTG) Symptoms Distress Module (ASDM), supplemented with two items for nephrolithiasis. Secondary endpoints included Medical Outcomes Study (MOS)-HIV scores and Center for Epidemiologic Studies-Depression (CES-D) scores. RESULTS: Immediate substitution resulted in improved ASDM total score at week 4 compared with deferred substitution (p <.001) and significant improvements in all MOS-HIV domains, while significant improvement was observed in CES-D scores at week 8. Primary SEs resolved at week 8 in 65% of participants in the immediate substitution group. Suppression of HIV-1 was maintained. Treatment was well-tolerated and associated with elevations in cholesterol and triglycerides. CONCLUSION: Substitution with LPV/r improved patient-reported outcomes including QOL in patients experiencing Grade-2 SEs, while maintaining viral suppression.

Liver injury and changes in hepatitis C Virus (HCV) RNA load associated with protease inhibitor-based antiretroviral therapy for treatment-naive HCV-HIV-coinfected patients: lopinavir-ritonavir versus nelfinavir.

BACKGROUND: Highly active antiretroviral therapy (HAART) initiation in patients coinfected with human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) has been associated with transaminase and HCV viral load flares. Previous studies have included highly variable antiretroviral regimens. We compared effects of 2 protease inhibitor-based regimens on alanine aminotransferase (ALT) levels and HCV loads in HCV-HIV-coinfected patients initiating HAART. METHODS: Seventy HIV-infected patients with positive baseline results of HCV enzyme-linked immunosorbant assay from a treatment trial comparing lopinavir-ritonavir with nelfinavir were evaluated during a 48-week period. HCV and HIV titers were analyzed at baseline, at weeks 24 and 48 of treatment, and during flares in the ALT level of >5 times the upper limit of normal. RESULTS: A total of 57 of 70 patients tested positive for HCV RNA at baseline. HCV titers for patients in lopinavir-ritonavir and nelfinavir groups, respectively, were as follows: baseline, 6.07 and 6.22 log IU/mL; week 24 of treatment, 6.68 and 6.48 log IU/mL; and week 48 of treatment, 6.32 and 6.44 log IU/mL. Of patients with a CD4+ cell count of <100 cells/mm3 at baseline, 5 of 11 in the nelfinavir group and 0 of 10 in the lopinavir-ritonavir group had an increase in the HCV load of >0.5 log IU/mL from baseline to week 48. The mean ALT level increased by 45 U/L at 24 weeks and 18 U/L at 48 weeks in the nelfinavir group but decreased by 18 U/L at 24 weeks and 7 U/L at 48 weeks in the lopinavir-ritonavir group. Eight patients in the nelfinavir group and 2 patients in the lopinavir-ritonavir group had grade 3 or 4 flares in the ALT level. CONCLUSIONS: HAART initiation is associated with increased HCV loads and ALT levels. A low baseline CD4+ cell count is associated with persistent increases in the HCV RNA load in nelfinavir-treated patients. These results warrant careful interpretation of abnormalities in the ALT load after HAART initiation in HCV-HIV-coinfected patients to prevent premature discontinuation of treatment.

Relationship between adherence and the development of resistance in antiretroviral-naive, HIV-1-infected patients receiving lopinavir/ritonavir or nelfinavir.

BACKGROUND: Relationships between adherence to protease inhibitor (PI)-based therapy and resistance development have not been fully characterized. METHODS: We conducted a double-blind, randomized, controlled study of lopinavir/ritonavir versus nelfinavir, each administered with stavudine and lamivudine, in 653 antiretroviral-naive, human immunodeficiency virus (HIV)-1-infected patients. Relationships between adherence and probability of resistance development were evaluated by local linear regression or logistic regression. RESULTS: A higher risk of detectable HIV-1 RNA loads after week 24 was associated with lower adherence (odds ratio [OR], 1.08 per 1% decrease in adherence [95% confidence interval {CI}, 1.05-1.10]; P<.001) and nelfinavir use (OR, 2.4 vs. lopinavir/ritonavir [95% CI, 1.6-3.6]; P<.001). Among all nelfinavir-treated patients, a bell-shaped relationship between adherence and the risk of nelfinavir resistance was observed, with a maximum probability of 20% at 85%-90% adherence. No lopinavir resistance was observed. A bell-shaped relationship was also observed for the probability of lamivudine resistance, with a maximum probability of 50% at 75%-80% adherence to nelfinavir and of 15% at 80%-85% adherence to lopinavir/ritonavir. CONCLUSIONS: Bell-shaped relationships between adherence and resistance were observed. Irrespective of adherence level, the risk of detectable HIV-1 RNA loads or of PI or lamivudine resistance was significantly higher in nelfinavir-treated patients than in lopinavir/ritonavir-treated patients.

Selection of resistance in protease inhibitor-experienced, human immunodeficiency virus type 1-infected subjects failing lopinavir- and ritonavir-based therapy: mutation patterns and baseline correlates.

The selection of in vivo resistance to lopinavir was characterized by analyzing the longitudinal isolates from 54 protease inhibitor-experienced subjects who either experienced incomplete virologic response or viral rebound subsequent to initial response while on treatment with lopinavir-ritonavir in Phase II and III studies. The evolution of incremental resistance to lopinavir (emergence of new mutation[s] and/or at least a twofold increase in phenotypic resistance compared to baseline isolates) was highly dependent on the baseline phenotype and genotype. Among the subjects demonstrating evolution of lopinavir resistance, mutations at positions 82, 54, and 46 in human immunodeficiency virus protease emerged frequently, suggesting that these mutations are important for conferring high-level resistance. Less common mutations, such as L33F, I50V, and V32I together with I47V/A, were also selected; however, new mutations at positions 84, 90, and 71 were not observed. The emergence of incremental resistance contrasts greatly with the low incidence of resistance observed after initiating lopinavir-ritonavir therapy in antiretroviral-naive patients, suggesting that partial resistance accumulated during prior protease inhibitor therapy can compromise the genetic barrier to resistance to lopinavir-ritonavir. The emergence of incremental resistance was uncommon in subjects whose baseline isolates contained eight or more mutations associated with lopinavir resistance and/or displayed >60-fold-reduced susceptibility to lopinavir, providing insight into suitable upper genotypic and phenotypic breakpoints for lopinavir-ritonavir.

Cost-effectiveness of lopinavir/ritonavir versus nelfinavir as the first-line highly active antiretroviral therapy regimen for HIV infection.

PURPOSE: Selecting the optimal treatment regimen for antiviral-naive patients may be difficult, given the concern about the antiviral activity, the development of drug resistance, and the increase in drug costs. This study evaluates the costs and effectiveness of using lopinavir/ritonavir (LPV/r) vs. nelfinavir (NFV), both coadministered with stavudine and lamivudine, as the first HAART regimen in treating HIV patients, based on the results from the published clinical trial M98-863. METHOD: A Markov model was developed using a combination of viral load (VL) and CD4 count as surrogate markers to define health states. VL and CD4 count data from the 48-week analysis of the clinical trial were used as measures of effect. The impact of resistance difference between NFV and LPV/r was also examined. RESULTS: Over the first 5 years, the model estimated that LPV/r could save $3,461 USD per patient in total HIV care costs compared with NFV. If the resistance advantage of LPV/r was taken into account, the cost savings by LPV/r increased to $5,546 USD. For longer term projection, without considering the resistance difference, the incremental cost-effectiveness ratio (CER) for LPV/r vs. NFV was $6,653 USD per quality-adjusted life-year (QALY). This CER compares favorably to therapies for HIV disease and for common drug treatments for other conditions and is well within accepted thresholds for health policy makers. CONCLUSION: When treatment options are being considered, this study suggests that use of LPV/r in the first antiretroviral regimen, as compared to NFV, is cost-effective based on improved efficacy and resistance.

Baseline HIV-1 RNA level and CD4 cell count predict time to loss of virologic response to nelfinavir, but not lopinavir/ritonavir, in antiretroviral therapy-naive patients.

Baseline CD4 cell counts and human immunodeficiency virus (HIV)-1 RNA levels have been shown to predict immunologic and virologic responses in HIV-infected patients receiving antiretroviral therapy. In our randomized, double-blind, comparative trial, 653 antiretroviral therapy-naive patients received lopinavir/ritonavir or nelfinavir, plus stavudine and lamivudine, for up to 96 weeks. The risk of loss of virologic response was significantly higher for nelfinavir-treated patients than for lopinavir/ritonavir-treated patients (Cox model hazard ratio, 2.2; 95% confidence interval, 1.7-3.0; P<.001). For nelfinavir-treated patients, but not for lopinavir/ritonavir-treated patients, higher baseline HIV-1 RNA levels and lower baseline CD4 cell counts were associated with a higher risk of loss of virologic response.

Long-term safety and durable antiretroviral activity of lopinavir/ritonavir in treatment-naive patients: 4 year follow-up study.

OBJECTIVE: Combination antiretroviral therapy with lopinavir/ritonavir (LPV/r) has been highly effective in clinical trials. Results of long-term therapy with LPV/r-based regimens have not been previously reported. This study describes the 4-year (204-week) safety and antiretroviral activity of LPV/r-based treatment in antiretroviral-naive individuals. DESIGN: Long-term, open-label follow-up of a phase II, prospective, randomized, multicenter trial. METHODS: A group of 100 antiretroviral-naive HIV-infected patients were randomized to one of three blinded doses of LPV/r [200/100 mg (n = 16), 400/100 mg (n = 51), or 400/200 mg (n = 33)] with stavudine 40 mg and lamivudine 150 mg every 12 hours. After 48 weeks, LPV/r was dosed open-label at 400/100 mg every 12 hours with stavudine and lamivudine. RESULTS: : Mean baseline plasma HIV-1 RNA and CD4 cell count were 4.9 log10 copies/ml and 338 x 10 cells/l, respectively. At week 204, 72 patients remained on study, 70 of whom had HIV-1 RNA < 50 copies/ml (70% by intent-to-treat analysis). Twenty-eight patients discontinued therapy prior to week 204 because of adverse events (n = 10), lost to follow-up (n = 9), or other reasons (n = 9). Of 15 patients who met protocol-defined criteria for virologic failure, seven remained on the study regimen and their HIV-1 RNA was re-suppressed to < 50 copies/ml at week 204. Genotypic analysis of rebound viral isolates was available from 10 patients, including all eight patients who discontinued the study prematurely. No isolate demonstrated primary or active site mutations in protease. The most common adverse events were gastrointestinal symptoms and lipid elevations. CONCLUSIONS: LPV/r-based therapy provides durable antiretroviral response and is generally well tolerated through 204 weeks of therapy.