In this preliminary study, a combination of a protease inhibitor, a nonnucleoside polymerase inhibitor, and ribavirin was effective for the treatment of HCV genotype 1 infection.
Hepatitis C virus ...(HCV) infection is a leading cause of cirrhosis, liver cancer, and liver transplantation. Peginterferon-free regimens of direct-acting antiviral agents have the potential to improve both the safety and efficacy of HCV therapy, as compared with the current standard treatment of peginterferon and ribavirin with telaprevir or boceprevir.
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Interferon is associated with substantial toxicity, and many patients with HCV infection are not eligible for interferon therapy owing to coexisting medical or psychiatric conditions or adverse events related to interferon, or they decline such therapy.
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There is also a large population of HCV-infected patients in whom interferon . . .
In this phase 2 study, peginterferon-free regimens were effective in patients with hepatitis C virus genotype 1 infection.
Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis, ...liver cancer, and end-stage liver disease.
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The current standard of care for chronic HCV genotype 1 infection is pegylated interferon (peginterferon) and ribavirin, with a protease inhibitor (boceprevir or telaprevir).
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Although the addition of a protease inhibitor has been associated with a significant increase in response rates, only approximately one third of patients who had not had a response to prior therapy with peginterferon and ribavirin had a sustained virologic response when re-treated with the addition of a protease inhibitor.
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Furthermore, these therapies are associated with adverse . . .
Decreased bone mineral density (BMD) has been described in HIV-infected patients initiating antiretroviral therapy (ART), but the contributions of ART and immunologic and/or virologic factors remain ...unclear.
We compared total BMD changes over 96 weeks in 106 ART-naive HIV-infected subjects who were randomized to receive efavirenz (EFV) + zidovudine/lamivudine (n = 32) or lopinavir/ritonavir (LPV/r) + zidovudine/lamivudine induction (n = 74) for 24-48 weeks followed by LPV/r monotherapy. We also sought to identify factors associated with BMD loss, including markers of systemic inflammation soluble tumor necrosis factor-alpha receptors (sTNFR I and II).
After 96 weeks, the mean percent change from baseline in total BMD was -2.5% (LPV/r) and -2.3% (EFV) (P < 0.01 for within-group changes in either arm; P = 0.86 for between-group differences). No alteration in the rate of BMD change was observed upon simplification to LPV/r monotherapy. Although soluble tumor necrosis factor-alpha receptor II concentrations at baseline and 24 weeks were at least marginally associated with subsequent changes in BMD (P = 0.06 and P = 0.028, respectively), these associations were no longer significant after adjustment for CD4 T cell count. Subjects with lower baseline CD4 T cell count, non-black race, and higher baseline glucose demonstrated a higher risk for >5% decrease in BMD.
Similar decreases in BMD over 96 weeks occurred in ART-naive subjects receiving either EFV-based regimen or LPV/r-based regimen, which was not altered by simplification to LPV/r monotherapy and was unrelated to markers of tumor necrosis factor-alpha activity.
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 (R² = 0.27, P = 0.001 and R² = 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.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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. Trial registration. ClinicalTrials.gov identifier: NCT00075231.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Background & Aims Paritaprevir, ombitasvir, and dasabuvir are direct-acting antivirals for treatment of chronic hepatitis C virus (HCV) infection. The aim of this study was to characterize the ...effects of mild, moderate, and severe hepatic impairment on the pharmacokinetics of these drugs. Methods HCV-negative subjects with normal hepatic function (n = 7) or mild (Child-Pugh A, n = 6), moderate (Child-Pugh B, n = 6), or severe (Child-Pugh C, n = 5) hepatic impairment received a single-dose of the combination of paritaprevir plus ritonavir (paritaprevir/r, 200/100 mg), ombitasvir (25 mg), and dasabuvir (400 mg). Plasma samples were collected through 144 hours after administration for pharmacokinetic assessments. Results Paritaprevir, ombitasvir, dasabuvir, and ritonavir exposures (maximal plasma concentration, Cmax , and area under the concentration-time curve, AUC) were minimally affected in subjects with mild or moderate hepatic impairment. Differences in exposures between healthy controls and subjects with mild or moderate hepatic impairment were less than 35%, except for 62% higher paritaprevir AUC in subjects with moderate hepatic impairment. Paritaprevir and dasabuvir AUC were significantly higher in subjects with severe hepatic impairment (950% and 325%, respectively). However, ombitasvir AUC was 54% lower and ritonavir AUC was comparable. Adverse events included eye stye, insomnia, and pain from an infiltrated intravenous line. Conclusions The changes observed in paritaprevir, ritonavir, ombitasvir, and dasabuvir exposures in subjects with mild or moderate hepatic impairment do not necessitate dose adjustment. Subjects with severe hepatic impairment had substantially higher paritaprevir and dasabuvir exposures.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
To compare the safety and antiviral activity of once (QD) or twice (BID) daily lopinavir/ritonavir (LPV/r) in combination with investigator-selected nucleoside/nucleotide reverse transcriptase ...inhibitors (NRTIs) in treatment-experienced subjects.
Subjects failing treatment with HIV-1 RNA > 1000 copies per milliliter received LPV/r tablets 800/200 mg QD (n = 300) or 400/100 mg BID (n = 299) with investigator-chosen nucleoside/nucleotide reverse transcriptase inhibitors. Efficacy was determined by the intent-to-treat time to loss of virologic response (ITT-TLOVR) algorithm. Safety, tolerability, adherence, impact of baseline protease mutations on virologic response, and emergence of resistance on therapy were assessed.
Demographics were comparable across groups. By intent-to-treat time to loss of virologic response, 166 QD subjects (55.3%) and 155 BID subjects (51.8%) were responders at week 48 (P = 0.413), with similar mean increases in CD4 T-cell count. QD subjects demonstrated better adherence than BID subjects. The occurrence of treatment-related moderate/severe adverse events was comparable for all events except nausea, which was reported more frequently among BID-treated subjects. Emergence of new protease resistance mutations on treatment was similarly infrequent in both groups.
LPV/r dosed QD resulted in increased treatment adherence and was as efficacious as BID LPV/r while providing similar safety, tolerability, and limited resistance evolution.
In this trial in previously untreated patients with HCV genotype 1 infection and no cirrhosis, high rates of sustained response were achieved with three new direct-acting antiviral agents and ...ribavirin. Serious adverse events and treatment discontinuation were infrequent.
Approximately 184 million people worldwide have chronic hepatitis C virus (HCV) infection, and more than 350,000 people die of HCV-related liver disease each year.
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Until recently, the standard of care for chronic HCV genotype 1 infection was a first-generation protease inhibitor, telaprevir or boceprevir, with peginterferon and ribavirin; this therapy resulted in rates of sustained virologic response of 67 to 75% among previously untreated patients.
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The new standard of care is peginterferon and ribavirin combined with either the nucleotide nonstructural (NS) 5B polymerase inhibitor sofosbuvir or the protease inhibitor simeprevir.
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Peginterferon-based treatment is associated with clinically significant systemic . . .
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