We have upgraded our Computational Analysis of Novel Drug Opportunities (CANDO) platform for shotgun drug repurposing by including ligand-based, data fusion, and decision tree pipelines. The goal of shotgun drug repurposing is to screen and rank every existing human use drug or compound for every disease/indication. The first version of CANDO implemented a structure-based pipeline that modeled interactions between compounds and proteins on a large scale, generating compound-proteome interaction signatures used to infer the similarity of drug behavior; the new pipelines accomplish this by incorporating molecular fingerprints and the Tanimoto coefficient. We obtain improved benchmarking performance with the new pipelines across all three evaluation metrics used: average indication accuracy, pairwise accuracy, and coverage. The best performing pipeline achieves an average indication accuracy of 19.0% at the top10 cutoff, compared to 11.7% for v1, and 2.2% for a random control. Our results demonstrate that the CANDO drug recovery accuracy is substantially improved by integrating multiple pipelines, thereby enhancing our ability to generate putative therapeutic repurposing candidates, and increasing drug discovery efficiency.

The pharmacoenhancement of plasma concentrations of protease inhibitors by coadministration of so-called boosters has been an integral part of antiretroviral therapy for human immunodeficiency virus (HIV) for 1.5 decades. Nearly all HIV protease inhibitors are combined with low-dose ritonavir or cobicistat, which are able to effectively inhibit the cytochrome-mediated metabolism of HIV protease inhibitors in the liver and thus enhance the plasma concentration and prolong the dosing interval of the antiretrovirally active combination partners. Therapies created in this way are clinically effective regimens, being convenient for patients and showing a high genetic barrier to viral resistance. In addition to ritonavir, which has been in use since 1996, cobicistat, a new pharmacoenhancer, has been approved and is widely used now. The outstanding property of cobicistat is its cytochrome P450 3A-selective inhibition of hepatic metabolism of antiretroviral drugs, in contrast with ritonavir, which not only inhibits but also induces a number of cytochrome P450 enzymes, UDP-glucuronosyltransferase, P-glycoprotein, and other cellular transporters. This article reviews the current literature, and compares the pharmacokinetics, pharmacodynamics, and safety of both pharmacoenhancers and discusses the clinical utility of cobicistat in up-to-date and future HIV therapy.

There are currently several suitable and different antiretroviral regimens to start highly active antiretroviral therapy (HAART), and many clinicians and patients prefer once-daily therapy. The efficacy and potency of efavirenz (EFV) has been established in many clinical trials and cohort studies; its pharmacokinetics, allowing for a convenient once-daily administration, make EFV one of the first agents to be included in once-daily regimens in naive patients. The two nucleoside reverse transcriptase inhibitors (NRTIs) accompanying the third drug have become the central skeleton, or the 'backbone' of the therapeutic scheme. Among the different NRTI pairs, a didanosine-lamivudine (3TC) or emtricitabine backbone for combination antiretroviral therapy may be a good option compared with any current NRTI-combinations due to its security, tolerance and once-daily dose. In this article, we review the advantages and drawbacks of didanosine-XTC-EFV as the initial regimen of HAART in HIV-infected patients.

With effective treatment of HIV-1, hepatitis C virus (HCV) has become increasingly recognized as a major cause of morbidity and mortality in this population. Rapid progression of liver disease and cirrhosis has been documented in HIV/HCV co-infected individuals, particularly with lower CD4-counts (< 200/μL). Therefore, HCV treatment has become a priority for many clinicians, despite the presence of many. An important issue among HIV/HCV co-infected patients is the selection of antiretroviral therapy (ART) during treatment with pegylated interferon, ribavirin (RBV), plus new HCV protease inhibitors. Extensive drug-drug interactions (DDI) and overlapping drug-associated adverse events can impact the outcome of HCV therapy. In this review, we focus on the important data and studies regarding optimizing antiretroviral regimens before starting HCV treatment in HIV/HCV co-infected patients to increase the chance of sustained virologic response (SVR).

Hepatitis C virus-Human immunodeficiency virus (HCV-HIV) coinfections are identified in up to 30% of patients infected with HIV and in 8% of patients infected with HCV. Now that progression of HIV and deaths due to AIDS can be prevented by highly active antiretroviral therapy (HAART), it is clear that HCV coinfection is associated with accelerated progression to cirrhosis and increased liver-related morbidity and mortality. Antiviral therapy with pegylated interferon and ribavirin for HCV in HCV-HIV coinfected patients is less successful than in patients with HCV monoinfection, and HAART can cause drug-induced liver injury. Multiple barriers limit the number of HCV-HIV coinfected patients who receive antiviral therapy for HCV, and the role of orthotopic liver transplantation (OLT) in HIV monoinfected and HCV-HIV coinfected patients remains controversial. Clinical trials of HCV-specific protease or polymerase inhibitors combined with pegylated interferon and ribavirin are needed urgently in coinfected patients, both before and after OLT.

Control of viral replication through combination antiretroviral therapy (cART) improves patient health outcomes. Yet many HIV-infected patients have comorbidities that pose social and clinical barriers to achieving viral suppression. Integration of subspecialty services into HIV primary care may overcome such barriers.

To evaluate effect of integrated HIV care (IHC) on suppression of HIV replication.

A retrospective cohort study of HIV patients from 5 Veterans Affairs healthcare facilities 2000 to 2006.

Patients with >3 months of follow-up, sufficient baseline HIV severity, on cART.

We measured and ranked Integrated Care at the facilities. These rankings were applied to patient visits to form an index of IHC utilization. We evaluated effect of IHC utilization on likelihood of achieving viral suppression while on cART, controlling for demographic and clinical factors using survival analysis.

: The 1018 HIV-infected patients eligible for analysis had substantial barriers to responding to cART: 93% had comorbidities with mean 3.2 comorbidities per patient (SD = 2.0); 52% achieved viral suppression in median 231 days (SD = 411.6). Patients visiting clinics that offered hepatitis, psychiatric, psychologic, and social services in addition to HIV primary care were 3.1 times more likely to achieve viral suppression than patients visiting clinics which offered only HIV primary care (hazard ratio = 3.1, P < 0.001).

Patients who visited IHC clinics were more likely to achieve viral suppression while on cART. Future research should investigate which elements of Integrated Care are most associated with viral control and what role provider experience plays in this association.

High levels of serum low-density lipoprotein cholesterol are associated with better response to pegylated interferon and ribavirin in hepatitis C virus monoinfected patients. There are no data concerning this topic in HIV/hepatitis C virus coinfected patients in whom lipid disorders are particularly common.

To assess the association between baseline lipid levels and sustained virologic response to pegylated interferon and ribavirin in coinfected patients.

A total of 260 HIV/hepatitis C virus coinfected patients under treatment with pegylated interferon and ribavirin and who had a baseline serum lipid profile were included in this retrospective study.

Thirty-eight (24%) patients with genotypes 1-4 and 64 (63%) with genotypes 2-3 achieved sustained virologic response. Forty-nine (44%) patients with serum low-density lipoprotein cholesterol levels 100 mg/dl or more showed sustained virologic response compared with 53 (36%) with lower values [adjusted odds ratio: 2.51; 95% confidence interval: 1.40-4.87; P = 0.003]. This association was independent of the remaining predictors of sustained virologic response which were genotypes 2-3, plasma hepatitis C virus RNA 600,000 IU/ml or less, exposure to at least 80% of the planned therapy and lack of concomitant antiretroviral therapy. The rate of sustained virologic response in patients with genotype 1 and low-density lipoprotein cholesterol at least 100 mg/ml was 31% compared with 17% in those with lower values (adjusted odds ratio: 2.19; 95% confidence interval: 1.04-4.66; P = 0.040). The corresponding figures in subjects with genotypes 2-3 were 73 and 58% [2.71 (0.99-7.46); P = 0.054]. No other lipid was associated with response.

Higher low-density lipoprotein cholesterol levels predict sustained virologic response to pegylated interferon and ribavirin in HIV/hepatitis C virus coinfected patients. This might be used to improve the rate of sustained virologic response in this setting.

Didanosine, which is a synthetic nucleoside analogue intracellularly phosphorylated to the active metabolite, inhibits the activity of HIV-1 reverse transcriptase by competing with the natural substrate. Currently, didanosine is mainly provided as an enteric-coated capsule. In vitro, the molecule is active against laboratory strains and clinical isolates of HIV-1 in resting and activated T cells and monocyte/macrophages. Didanosine may select for resistance mutations that may render the drug inactive against the virus; L74V and K65R remain as the main didanosine-related mutations. In vitro, phenotypic susceptibility to didanosine was decreased beyond a defined fold change clinical cut-off (1.7), and it is considered that genotypic resistance exists when five thymidine-associated mutations or four plus M184V are present. In vivo, clinical studies have shown that didanosine retains significant antiviral activity in patients who have up to five nucleoside analogue mutations at baseline. Didanosine is useful in patients with no previous therapy, as well as in experienced patients in whom one or more antiretroviral regimens has failed.Enteric-coated didanosine is taken once daily, its co-administration with food has been recently evaluated and a reduction of the efficacy of the antiretroviral treatment was not observed. Administered with lamivudine (or emtricitabine), it can be considered a good alternative for use in the nucleoside analogue backbone included in combination therapies for antiretroviral-naive patients. Didanosine could be used in initial treatments for patients intolerant of zidovudine, abacavir or tenofovir. It can be included in once-daily combination regimens, which are more convenient and patient friendly.Prospective, observational and open-label studies, as well as clinical trials (with durations between 24 and 96 weeks), have demonstrated the safety and efficacy of didanosine plus lamivudine (or emtricitabine) plus efavirenz (or nevirapine) in previously untreated HIV-1-infected patients. The administration of didanosine to treatment-experienced patients has been evaluated in two different contexts: patients in whom previous therapies have failed (rescue therapy) and those with controlled viraemia who are switched to a didanosine-containing regimen for simplification.Adverse events associated with the administration of didanosine have been well known since the initial clinical trials with the drug. Gastrointestinal intolerance, peripheral neuropathy and hyperamylasaemia/pancreatitis were the most frequently reported. In the highly active antiretroviral therapy (HAART) era, the rate of adverse events has decreased. The tolerability of didanosine has been clearly improved with the development of the enteric-coated capsule. Severe manifestations of mitochondrial toxicity, including lactic acidosis and abnormal fat distribution, are rare complications, and occur most frequently when didanosine is used in combination with stavudine.

Our objective was to evaluate the steady-state pharmacokinetics of ritonavir-boosted atazanavir when coadministered with tenofovir in HIV-1-infected adult patients.

Forty adult HIV-1-infected patients received either atazanavir/ritonavir 300/100 mg once daily and nucleoside reverse transcriptase inhibitors with (n = 20) or without (n = 20) tenofovir-disoproxil fumarate (tenofovir-DF) 300 mg once daily. Twenty-four-hour pharmacokinetics were assessed after at least 2 weeks of therapy according to a standardised therapeutic drug monitoring protocol.

Atazanavir/ritonavir plasma concentrations were measured by liquid chromatography tandem mass spectrometry, and the geometric means of minimum and maximum concentrations (C(min), C(max)), the area under the time-concentration curve (AUC), half-life (t(1/2)) and total clearance (CL(tot)) were subject to a matched pairs-analysis. Patients' pairs were matched for gender, ethnicity, weight and Center for Disease Control and Prevention (CDC) status.

The respective geometric means (90% CI) for atazanavir C(min), C(max) and AUC with tenfovir vs. without tenofovir were 405 (314-523) vs. 417 (304-572) ng/ml, 3,022 (2,493-3,664) vs. 2,817 (2,341-3,390) ng/ml and 34,822 (29,315-41,363) vs. 32,101 (26,206-39,321) ng x h/ml showing no significant differences between the groups. Atazanavir plasma concentrations measured at week 5 of therapy or later were lower than in the first 4 weeks (T-test for C(max), p = .080; AUC, p = .050 and CL(tot), p = .051).

The coadministration of tenofovir-DF did not impair the plasma concentrations of ritonavir-boosted atazanavir in a pharmacokinetic analysis of patient pairs matched for gender, ethnicity, weight and CDC status.

Drug toxicity is the leading cause of acute liver failure in the United States. Further understanding of hepatotoxicity is becoming increasingly important as more drugs come to market.

(i) To provide an update on recent advances in our understanding of hepatotoxicity of select commonly used drug classes. (ii) To assess the safety of these medications in patients with pre-existing liver disease and in the post-liver transplant setting. (iii) To review relevant advances in toxicogenomics which contribute to the current understanding of hepatotoxic drugs.

A Medline search was performed to identify relevant literature using search terms including 'drug toxicity, hepatotoxicity, statins, thiazolidinediones, antibiotics, antiretroviral drugs and toxicogenomics'.

Amoxicillin-clavulanic acid is one of the most frequently implicated causes of drug-induced liver injury worldwide. Statins rarely cause clinically significant liver injury, even in patients with underlying liver disease. Newer thiazolidinediones are not associated with the degree of liver toxicity observed with troglitazone. Careful monitoring for liver toxicity is warranted in patients who are taking antiretrovirals, especially patients who are co-infected with hepatitis B and C. Genetic polymorphisms among enzymes involved in drug metabolism and HLA types may account for some of the differences in individual susceptibility to drug hepatotoxicity.

Drug-induced hepatotoxicity will remain a problem that carries both clinical and regulatory significance as long as new drugs continue to enter the market. Future results from ongoing multicentre collaborative efforts may help contribute to our current understanding of hepatotoxicity associated with drugs.