The KLEAN Study of Fosamprenavir-Ritonavir Versus Lopinavir-Ritonavir, Each in Combination with Abacavir-Lamivudine, for Initial Treatment of HIV Infection over 48 Weeks: A Randomised Non-Inferiority Trial

Department of Medicine, Division of Infectious Diseases, University of North Carolina, Chapel Hill, NC 27599, USA.
The Lancet (Impact Factor: 45.22). 09/2006; 368(9534):476-82. DOI: 10.1016/S0140-6736(06)69155-1
Source: PubMed


Lopinavir-ritonavir is a preferred protease inhibitor co-formulation for initial HIV-1 treatment. Fosamprenavir-ritonavir has shown similar efficacy and safety to lopinavir-ritonavir when each is combined with two nucleoside reverse transcriptase inhibitors. We compared the two treatments directly in antiretroviral-naive patients.
This open-label, non-inferiority study included 878 antiretroviral-naive, HIV-1-infected patients randomised to receive either fosamprenavir-ritonavir 700 mg/100 mg twice daily or lopinavir-ritonavir 400 mg/100 mg twice daily, each with the co-formulation of abacavir-lamivudine 600 mg/300 mg once daily. Primary endpoints were proportion of patients achieving HIV-1 RNA less than 400 copies per mL at week 48 and treatment discontinuations because of an adverse event. The intent-to-treat analysis included all patients exposed to at least one dose of randomised study medication. This study is registered with, number NCT00085943.
At week 48, non-inferiority of fosamprenavir-ritonavir to lopinavir-ritonavir (95% CI around the treatment difference -4.84 to 7.05) was shown, with 315 of 434 (73%) patients in the fosamprenavir-ritonavir group and 317 of 444 (71%) in the lopinavir-ritonavir group achieving HIV-1 RNA less than 400 copies per mL. Treatment discontinuations due to an adverse event were few and occurred with similar frequency in the two treatment groups (fosamprenavir-ritonavir 53, 12%; lopinavir-ritonavir 43, 10%). Diarrhoea, nausea, and abacavir hypersensitivity were the most frequent drug-related grade 2-4 adverse events. Treatment-emergent drug resistance was rare; no patient had virus that developed reduced susceptibility to fosamprenavir-ritonavir or lopinavir-ritonavir.
Fosamprenavir-ritonavir twice daily in treatment-naive patients provides similar antiviral efficacy, safety, tolerability, and emergence of resistance as lopinavir-ritonavir, each in combination with abacavir-lamivudine.

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    • "fosamprenavir/ritonavir (FPV/r), indeed, induce greater increment in the lipid parameters than saquinavir/ ritonavir or atazanavir/ritonavir or darunavir/ritonavir (DRV/r) [Hill et al., 2009], with no differences between LPV/r and FPV/r on their impact on the lipid profile [Eron et al., 2006]. "
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    ABSTRACT: Metabolic abnormalities associated with cumulative exposure to antiretroviral therapy have been linked to an increased risk of myocardial infarction in HIV positive individuals. The aim of this study was to evaluate whether the switch from lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) to darunavir/ritonavir (DRV/r) is able to improve the lipid profile. A total of 13 Caucasian subjects (7 from LPV/r and 6 from FPV/r) were enrolled in the study and received DRV/r at the dose of 800/100 mg, without change in their NRTI backbone. Viro-immunological parameters, triglycerides (TGs), total cholesterol (TCh), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, fasting glucose, HOMA-IR, indexes of hepatic and renal functionality, microalbuminuria and cystatin C were measured at baseline (T0), 3 months (T3), 6 months (T6), and 12 months (T12). The switch to DRV/r reduced levels of TCh, LDL, and TGs at T3. Similar improvements were confirmed further at T6 and at T12. A 14% increase in CD4+ count cells (P < 0.05) was observed. Serum cystatin C values showed a statistically significant decrease. After 12 months of switching to DRV/r from LPV/r or FPV/r, patients infected with HIV with TGs above 200 mg/dl, showed a 49% decrease in TGs, along with a 16% reduction of LDL and 19% reduction of TCh. Switching to DRV/r also improved immunological parameters, such as CD4+ cells count and cystatin C plasmatic levels, which may translate into a reduction of the cardiovascular risk. In conclusion, a switch to DRV/r should be considered in those HIV positive patients undergoing antiretroviral therapy, who also present abnormal lipid profiles. J. Med. Virol. 85:755-759, 2013. © 2013 Wiley Periodicals, Inc.
    Journal of Medical Virology 05/2013; 85(5):755-759. DOI:10.1002/jmv.23543 · 2.35 Impact Factor
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    • "The effective treatment of HIV in persons with advanced cirrhosis may be challenging due to cirrhosis-induced alterations in the hepatic metabolism of antiretroviral drugs and the potential for increased risk of drug-induced liver injury. To prevent possible liver toxicity, drug doses may be reduced and certain otherwise preferred drugs may be avoided [23,24]. Reducing antiretroviral doses and hence plasma concentrations, however, may also lower the barrier to the emergence of drug-resistant HIV. "
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    ABSTRACT: Background Although there have been dramatic strides made recently in the treatment of chronic hepatitis C virus infection, interferon-α based therapy remains challenging for certain populations, including those with unfavorable IL28B genotypes, psychiatric co-morbidity, HIV co-infection, and decompensated liver disease. We have recently shown that ATIII, a serine protease inhibitor (serpin), has broad antiviral properties. Results We now show that ATIII is capable of inhibiting HCV in the OR6 replicon model at micromolar concentrations. At a mechanistic level using gene-expression arrays, we found that ATIII treatment down-regulated multiple host cell signal transduction factors involved in the pathogenesis of cirrhosis and hepatocellular carcinoma, including Jun, Myc and BMP2. Using a protein interactive network analysis we found that changes in gene-expression caused by ATIII were dependent on three nodes previously implicated in HCV disease progression or HCV replication: NFκB, P38 MAPK, and ERK1/2. Conclusions Our findings suggest that ATIII stimulates a novel innate antiviral host cell defense different from current treatment options.
    Virology Journal 10/2012; 9(1):226. DOI:10.1186/1743-422X-9-226 · 2.18 Impact Factor
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    • "Both NNRTI- and PI-based regimens result in suppression of HIV RNA levels and CD4+ T-cell increases in a large majority of patients [9-13]. The use of ritonavir-boosted PIs have led to improved virological suppression compared to non-ritonavir PI regimens, as detailed in clinical trials [[14,15], and [16]] and cohort studies [17], as well as improved clinical outcomes in observational cohort studies [18]. "
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    ABSTRACT: This study examines the cost and consequences of initiating an ARV regimen including Lopinavir/ritonavir (LPV/r) or Efavirenz (EFV), using data from a recent clinical trial in a previously published model of HIV-disease. We populated the Markov model of HIV-disease with data from ACTG 5142 study to estimate the economic outcomes of starting ARV therapy with a PI-containing regimen as compared to an NNRTI-containing regimen, given their virologic and immunologic efficacy and effects on cholesterol and lipoatrophy. CNS toxicities and GI tolerability were not included in the model because of their transient nature or low cost remedies, and therefore lack of economic impact. CD4+ T-cell counts and the HIV-1 RNA (viral load) values from the study were used to assign a specific health state (HS) to each patient for each quarter year. The resulting frequencies used as "raw" data directly into the model obviate the reliance on statistical tests, and allow the model to reflect actual patient behavior in the clinical trial. An HS just below the last observed HS was used to replace a missing value. The modeled estimates (undiscounted) for the LPV/r-based regimen resulted in 1.41 quality-adjusted life months (QALMs) gained over a lifetime compared to the EFV-based regimen. The LPV/r-based regimen incurred $7,458 (1.8%) greater cost over a lifetime due to differences in drug costs and survival. The incremental cost effectiveness ratio using the discounted cost and QALYs was $88,829/QALY. Most of the higher costs accrue before the 7th year of treatment and were offset by subsequent savings. The estimates are highly sensitive to the effect of lipoatrophy on Health-related Quality of Life (HRQOL), but not to the effect of cholesterol levels. The cost effectiveness of ARV regimens may be strongly affected by enduring AEs, such as lipoatrophy. It is important to consider specific AE effects from all drugs in a regimen when ARVs are compared. ( number, NCT00050895http://[]).
    Cost Effectiveness and Resource Allocation 05/2011; 9(1):5. DOI:10.1186/1478-7547-9-5 · 0.87 Impact Factor
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