Antiviral Therapy

The aim of this study was to assess the effect of antiretroviral therapy (ART) versus HIV on mitochondria in fat. Subcutaneous fat was collected from 45 HIV-infected patients on ART with lipoatrophy, 11 HIV-infected ART-naive patients and nine healthy controls. Three mitochondrial transcripts: NADH dehydrogenase subunit 1 (ND1), cytochrome B (CYTB) and NADH dehydrogenase subunit 6 (ND6) genes were quantitated using TaqMan probes and normalized to nuclear-encoded ribosomal L13. ND1/L13 and CYTB/L13 were lower in HIV-positive patients on ART with lipoatrophy versus ART-naive patients (3.4 versus 7.2 [P=0.017] and 2.5 versus 4.6 [P=0.006], respectively). No difference was found between ART-naive patients and controls (P>0.70). ND6/L13 was similar between all groups. Dual-energy X-ray absorptiometry-measured limb fat and mitochondrial DNA in fat were also lower in HIV-positive patients on ART with lipoatrophy versus HIV-infected, ART-naive patients (4,382 versus 7,662 g [P=0.02] and ...

The development of new antiviral therapies in the treatment of hepatitis C virus (HCV) is reviewed, including a discussion of the potential advances that this treatment will bring. Data from new molecules in Phase I and II clinical trials, specifically polymerase and protease inhibitors, will be discussed. The potential for resistance has been reported when these have been used as monotherapy. However, their use in combination with pegylated interferon, particularly in the presence of ribavirin, has resulted in significant improvements in antiviral activity. Preliminary studies have confirmed that the new molecules are well tolerated and further clinical studies are underway to evaluate their efficacy. Nevertheless, because of its critical role at all stages of therapy, pegylated interferon is likely to remain the cornerstone of HCV therapy.

Objectives To examine the in vivo effects of highly active antiretroviral therapy (HAART) regimens on adipose tissue mitochondrial DNA (mtDNA) depletion, mitochondrial organellar proliferation, and markers of adipocyte differentiation and phenotype. Design and methods DNA and mRNA quantification using real-time PCR methods was performed on adipose tissue samples from 31 HIV-infected individuals, of whom 11 were treatment-naive and 20 were receiving HAART. mtDNA depletion was measured as mtDNA copies/cell, and mitochondrial proliferation by quantification of mitochondrial protein mass. Regulation of mitochondrial biogenesis was assessed by NRF-1 and mtTFA mRNA. PPAR γ, UCP2 and UCP1 mRNA expression was used to assess adipocyte differentiation and phenotype. Results Stavudine-based HAART recipients (n=10) displayed significant mtDNA depletion (12.8% of control, P<0.001), mildly increased mitochondrial protein mass (2.6-fold of control, P=0.032) and decreased expression of PPARγ (53...

Adenovirus infections are a frequent and serious complication following allogeneic haematopoietic stem cell transplantation (HSCT). The antiviral drugs cidofovir and ribavirin have been used as first-line therapy for disseminated infections with variable results. In the present study, in vitro susceptibility to these two drugs was evaluated on HEp-2 cells in adenovirus reference strains representing serotypes of each of the six species and in clinical isolates. Susceptibility to cidofovir was comparable between species with inhibition of replication of all tested serotypes in a narrow dose range (IC50= 17–81 μM). However, susceptibility to ribavirin was highly dependent on the species. Serotypes from species A, B, D, E and F were all resistant to ribavirin (IC50=396 to >500 μM). Only replication of serotypes from species C was inhibited by ribavirin (IC50=48–108 μM). This species-dependent susceptibility of adenovirus to ribavirin was confirmed in clinical isolates. When tested o...

Background Haematological adverse events related to pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy could affect the patients’ quality of life; however, the risk factors for severe haematological toxicity associated with this therapy in patients coinfected with hepatitis C virus (HCV) and HIV are unclear. The objective of this study was to identify predictors of severe haematological toxicity among HIV-HCV-coinfected patients treated with PEG-IFN plus RBV. Methods This retrospective multicentric study included 237 HIV-HCV-coinfected patients on PEG-IFN plus RBV. Predictors of severe anaemia, neutropenia, thrombocytopenia and overall haematological toxicity were analyzed. Results Eighty (34%) individuals showed an episode of severe haematological toxicity. Severe anaemia, neutropenia and thrombocytopenia occurred in 32 (13%), 42 (18%) and 26 (11%) patients, respectively. In the multivariate analysis, zidovudine use (adjusted odds ratio [AOR] 3.3; 95% confidence interval [C...

Hepatitis C virus (HCV) infects over 170 million people worldwide and is the leading cause of chronic liver diseases, including cirrhosis, liver failure, and liver cancer. Available antiviral therapies cause severe side effects and are effective only for a subset of patients, though treatment outcomes have recently been improved by the combination therapy now including boceprevir and telaprevir, which inhibit the viral NS3/4A protease. Despite extensive efforts to develop more potent next-generation protease inhibitors, however, the long-term ...

Objective Immune reconstitution in highly active anti-retroviral therapy (HAART)-treated individuals is incomplete and immunomodulatory compounds are needed to improve the outcome of HIV therapy. In a Phase I/II clinical trial performed on HIV-positive patients we analysed the safety and immunomodulating effects of tucaresol, a novel compound that has previously been described to enhance cell-mediated immune responses. Patients and methods Sixteen weeks pulse dose escalation protocol. Four groups of HIV-positive patients were enrolled: group A (n=6): HAART, CD4+ 300–500 cells/μl, HIV RNA <80 copies/ml; group B (n=6): HAART-naive, CD4+ <500 cells/μl, HIV RNA >10 000 copies/ml; group C (n=3): HAART-naive, CD4+ >500 cells/μl, HIV RNA <10 000 copies/ml; and group D (n=6): HAART, CD4+ <200 cells/μl, HIV RNA <80 copies/ml. Tucaresol was added to HAART in group A and D patients; group B patients started tucaresol with HAART, group C patients received tucaresol alone. C...

It has been suggested that the addition of ribavirin (RBV) as a part of the treatment for chronic hepatitis C virus (HCV) in HIV co-infected patients on didanosine (ddI) or stavudine (d4T) might increase the nucleoside-induced impairment of mitochondrial function. Comparative study to investigate the impact on mitochondrial function of adding RBV to a long-term treatment with ddI, d4T or both in HCV/HIV non-cirrhotic, asymptomatic patients. We included 26 patients: 16 continued with their current antiretroviral therapy (control group) and 10 patients received a concomitant 24-week course of RBV plus pegylated interferon (PEG-IFN) alpha-2b therapy (HCV-treated group). We assessed peripheral blood mononuclear cells mitochondrial DNA (mtDNA) content and mitochondrial respiratory chain (MRC) function at baseline and at 24 weeks of follow-up. In the HCV-treated group we performed additional determinations at 12 weeks during anti-HCV therapy and 24 weeks after finishing anti-HCV therapy. ...

Direct Antiviral Agents (DAA) demonstrated high efficacy among HCV-infected patients in registered trials. Nevertheless, the impact of these therapies on liver stiffness measurement(LSM) and liver functionality in "real-life" is not well-known. Aim of the present study was to evaluate the SVR impact on LSM and clinical parameters of DAA-therapy on a real-life population of HCV patients with F3/F4 fibrosis. 749 HCV genotype 1-4 patients with F3/F4 hepatitis undergoing antiviral therapy, were consecutively enrolled in four centers of Hepatology of Italy. Clinical, biochemical and imaging data were collected at the baseline(T0), at the End of Therapy(EoT) and after 12 weeks(SVR12). Out of 749 patients, 69.7% was F4 and 30.3% was F3. SVR12 was reached in 97,5%. LSM significantly decreased from T0 to EoT(p<0.001) whereas it did not from EoT to SVR12(p:ns). Moreover, in F4 no significant differences were found in Child and MELD between T0, EoT and SVR12(p=ns). At the univaria...

To examine the in vivo effects of highly active antiretroviral therapy (HAART) regimens on adipose tissue mitochondrial DNA (mtDNA) depletion, mitochondrial organellar proliferation, and markers of adipocyte differentiation and phenotype. DNA and mRNA quantification using real-time PCR methods was performed on adipose tissue samples from 31 HIV-infected individuals, of whom 11 were treatment-naive and 20 were receiving HAART. mtDNA depletion was measured as mtDNA copies/cell, and mitochondrial proliferation by quantification of mitochondrial protein mass. Regulation of mitochondrial biogenesis was assessed by NRF-1 and mtTFA mRNA. PPARgamma, UCP2 and UCP1 mRNA expression was used to assess adipocyte differentiation and phenotype. Stavudine-based HAART recipients (n=10) displayed significant mtDNA depletion (12.8% of control, P<0.001), mildly increased mitochondrial protein mass (2.6-fold of control, P=0.032) and decreased expression of PPARgamma (53.9% of control, P=0.021), UCP2 ...

Access to highly active antiretroviral therapy (HAART) for persons infected with HIV in sub-Saharan Africa has greatly improved over the past few years. However, data on long-term clinical outcomes of Africans receiving HAART, patterns of HIV resistance to antiretroviral drugs and implications of HIV type-1 (HIV-1) subtype diversity in Africa for resistance, are limited. In resource-limited settings, concerns have been raised that deficiencies in health systems could create the conditions for accelerated development of resistance. Coordinated surveillance systems are being established to assess the emergence of resistance and the factors associated with resistance development, and to create the possibility for adjusting treatment guidelines as necessary. The purpose of this report is to review the literature on HIV-1 resistance to antiretroviral drugs in sub-Saharan Africa, in relation to the drug regimens used in Africa, HIV-1 subtype diversity and overall prevalence of resistance....

To investigate metabolic changes associated with second-line antiretroviral therapy (ART) following virological failure of first-line ART. SECOND-LINE was an open-label randomized controlled trial. Participants were randomized 1:1 to receive ritonavir-boosted lopinavir (LPV/r) with 2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTI-group) or raltegravir (RAL-group) Two hundred and ten participants had a dual energy X-ray absorptiometry (DXA)-scan at baseline, week 48 and 96. We categorized participants according to second-line ART backbone: 1. thymidine analogue (ta-NRTI)+lamivudine/emtricitabine (3[F]TC) [ta-NRTI group]; 2. tenofovir (TDF)+3[F]TC [TDF group]; 3. TDF+ta-NRTI+/-3[F]TC [TDF+ta-NRTI group]; 4. RAL. Changes in fasted total cholesterol, LDL-cholesterol, HDL-c, TC/HDL-cholesterol ratio, triglycerides and glucose from baseline to week 96 were examined. We explored the association between metabolic and DXA-assessed soft-tissue changes. Linear regression met...

This study compared time to virologic suppression and rebound between Indigenous and non-Indigenous individuals living with HIV in Canada initiating combination antiretroviral therapy (cART). Data were from the Canadian Observational Cohort collaboration; 8 studies of treatment-naïve persons with HIV initiating cART after 1/1/2000. Fine and Gray models were used to estimate the effect of ethnicity on 1) time to virologic suppression (two consecutive viral loads (VLs) <50 copies/mL at least three months apart) after adjusting for the competing risk of death and 2) time until virologic rebound (two consecutive VLs >200 copies/mL at least three months apart) following suppression. Among 7,080 participants were 497 Indigenous persons of whom 413 (83%) were from British Columbia. The cumulative incidence of suppression one year after cART initiation was 54% for Indigenous persons, 77% for Caucasian and 80% for African, Caribbean, or Black (ACB) persons. The cumulative incidence of ...

This study aimed to evaluate HIV type-1 (HIV-1) drug resistance pretreatment and in those failing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) in South Africa. This was an observational cohort. Genotypic resistance testing was performed on treatment-naive individuals and those failing first-line ART (confirmed HIV-1 RNA>1,000 copies/ml) from public sector clinics in Cape Town (2002-2007). Resistance profiles and mutations relative to timing of known virological failure were examined. In total, 230 patients (120 treatment-naive and 110 with virological failure) were included: 98% had clade C virus. Among treatment-naive patients, prevalence of primary resistance was 2.5% (95% confidence interval 0.0-5.3). Three patients had one significant reverse transcriptase mutation: K65R, Y181C and G190A. Among treatment-experienced patients, 95 (86%) individuals had therapy-limiting NNRTI mutations, including K103N (55%), V106M (31%) an...

Aim To evaluate the benefits of haematopoietic growth factors (HGFs) during the treatment of chronic hepatitis C virus (HCV) infection with severe haematotoxicity. Methods This was a 1-year retrospective study of HCV-positive patients receiving pegylated interferon and ribavirin. Patients received different HGFs, depending on certain criteria: they received erythropoietin (EPO) when their haemoglobin (Hb) levels were less than 10 g/dl and granulocyte colony-stimulating factor (G-CSF) when their neutrophil count was less than 750 cells/mm3. Haematological data, adherence and virological response were analysed and compared according to HGF use. Results In total, 132 patients were studied and 31 (23.5%) required HGF. Under multivariate analysis, baseline Hb levels of less than 13g/dl or a drop in Hb levels of over 2% per week predicted severe anaemia, and a base-line neutrophil count under 2900/mm3 predicted severe neutropaenia. HGF administration restored Hb values and the neutrophil ...