Antiviral Therapy

Haematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients are at high risk for severe influenza and its complications, and may not be adequately protected by vaccination.

Liver, kidney, or liver–kidney transplant or allogeneic HSCT recipients aged ≥1 year were randomized to oseltamivir (75 mg once daily for those ≥13 years or weight-based dosing for children 1–12 years) or placebo for 12 weeks during periods of local influenza circulation. Patients were assessed for influenza infection via daily diary, every-other-week culture and PCR, and baseline and end-of-treatment serology.

A total of 477 subjects were enrolled (239 oseltamivir and 238 placebo); most were adults (96%) and SOT recipients (81%). In the intent-to-treat population, the frequency of laboratory-confirmed clinical influenza (culture positive and/or >4-fold increase in haemagglutinin antibody inhibition [primary end point]) was similar in the oseltamivir and placebo groups (2.1% [5/237] and 2.9% [7/238]). Incidence of laboratory-confirmed influenza was significantly reduced in the oseltamivir group versus placebo when determined by reverse transcriptase-PCR (1.7% [4/237] versus 8.4% [20/238]; 95% CI 2.8, 11.1) or viral culture (<1% [1/237] versus 3.8% [9/238]; 95% CI 0.7, 6.6), giving protective efficacies of 79.9 and 88.8%, respectively. Serious adverse events (oseltamivir 8% and placebo 10%) and adverse events (oseltamivir 55% and placebo 58%) were reported in both arms with a similar frequency. One illness due to oseltamivir-resistant A/H1N1 virus was detected in each group.

Oseltamivir prophylaxis is generally well-tolerated and may reduce culture- or PCR-confirmed influenza incidence in transplant recipients.

There is an increasing need for new diagnostic tools to monitor antiretroviral drug-related toxicities. Magnetic resonance (MR) imaging and MR spectroscopy are non-invasive diagnostic methods used in the detection and quantification of liver fat. The aim of this study was to compare sensitivity and specificity of different MR techniques in the quantitative assessment of liver steatosis, using liver biopsy as the reference standard, in patients with and without HIV infection.

Sequentially evaluated patients with suspected steatosis who were referred for liver biopsy at our tertiary care site were eligible. MR liver fat content (LFC) was estimated by T2-weighted and fat-suppressed T2-weighted spin-echo, dual-phase T1-weighted gradient-echo, multiecho gradient-echo and ¹H spectroscopy. Association between LFC and histological steatosis percentage was calculated by using univariate linear regressions and Pearson's coefficient. Respective receiver operating characteristic (ROC) curves were used to compare specificity and sensitivity of MR methods in diagnosis (cutoff 5%) and in quantitative evaluation (cutoff 33%) of steatosis.

A total of 28 patients were identified: 12 refused or had contraindications for liver biopsy and 16 had biopsies plus MR. LFC and histological steatosis percentage were strongly associated (fat-suppressed r=0.86 [P<0.001], dual-phase r=0.88 [P<0.001], multiecho r=0.95 [P<0,001] and spectroscopy r=0.84 [P=0.01]). MR techniques had high sensitivity and specificity in diagnosis and quantitative assessment of steatosis (areas under ROC curves ranging from 0.88 to 0.98).

This pilot study confirms that MR may be a sensitive non-invasive alternative to biopsy for the quantitative assessment of liver fat and a potential end point to monitor antiretroviral-drug-related toxicities.

There is no standard management of chronic hepatitis B (CHB) patients with suboptimal response to nucleoside/nucleotide analogues (NAs). This study aimed to evaluate two different NA combination therapies in patients with suboptimal response to adefovir (ADV).

In this study, 72 CHB patients with suboptimal response to ADV were assessed, with 37 patients receiving lamivudine plus ADV (group A) and 35 patients receiving telbivudine plus ADV (group B).

Baseline characteristics between two groups were similar. At month 12, rates of biochemical response (BR) and virological response (VR) were similar between groups A and B (17/19 versus 18/20 for BR, [P=0.269] and 30/37 versus 31/35 for VR [P=0.377]), and cumulative rates of serological response were greater in group B than in group A (10/26 versus 2/28 in hepatitis B e antigen [HBeAg] loss [P=0.006] and 7/26 versus 1/28 in HBeAg/ hepatitis B e antibody seroconversion [P=0.022]). After 12-month treatment, 8.1% (3/37) of patients in group A and 5.7% (2/35) of patients in group B had VR; among patients in group A, two had rtM204V/I and rtL180M and one had rtN236T, whereas the two patients in group B had rtM204I+rtL180M.

Both combination therapies led to a significant decrease in HBV DNA. HBeAg serological outcomes were higher with telbivudine plus ADV combination therapy.

Norovirus (NoV) is the leading cause of epidemic gastroenteritis worldwide. The lack of a cell culture has significantly hampered the development of effective therapies against human NoV. Clinically approved nucleoside and non-nucleoside analogues have been used successfully against RNA viruses.

In this study, we evaluated the efficacy of four nucleoside analogues (2′-C-MeC, 2′-F-2′-C-MeC, β-D-N(4)-hydroxycytidine [NHC] and lamivudine) on Norwalk virus (NV) RNA levels and protein expression in NV replicon-harbouring cells (HG23 cells), and their efficacy in blocking murine norovirus (MNV) replication in RAW 264.7 cells.

2′-C-MeC and 2′-F-2′-C-MeC reduced MNV RNA levels and infectivity in RAW 264.7 cells in a concentration- and time-dependent manner. The median effective concentrations (EC₅₀) of 2′-C-MeC and 2′-F-2′-C-MeC were 6.9 μM and 12.7 μM, respectively. 2′-C-MeC, 2′-F-2′-C-MeC and NHC reduced NV RNA levels and protein expression in HG23 cells. For the NV replicon, the EC₅₀ of 2′-C-MeC (1.3 μM) was comparable to the antiviral activity of NHC (1.5 μM) and twofold more potent than 2′-F-2′-C-MeC (3.2 μM). The combination of 2′-C-MeC/ ribavirin resulted in modest synergistic activity, whereas NHC/ribavirin was antagonistic for NV replication in HG23 cells.

The antiviral activity of 2′-C-MeC against strains of two different NoV genogroups and the low EC₅₀ suggest that this nucleoside analogue may be effective against the more prevalent GII NoVs. In the absence of a vaccine, antiviral agents could be an effective intervention to control the spread of human NoV in populations at a high risk for NoV disease.

The selection of antiretroviral (ARV) drugs for treatment of HIV-1 infection is based on several factors including potency, toxicity, resistance and ease of administration. Emtricitabine (FTC) or lamivudine (3TC), components of recommended initial ARV regimens, are structurally related and share the same resistance mutation (M184V/I). However they differ with respect to potency and incidence of M184V/I.

Resistance-associated mutation (RAM) prevalence data were obtained from genotype test results performed in a large reference laboratory from 2003–2010; subsets of data were defined by mutation pattern to resemble those following failure of non-nucleoside reverse transcriptase inhibitor (NNRTI)-based combination therapy. Mutational trend data were compared to contemporaneous ARV prescription information.

In the unfiltered data set (n=107,231), the prevalence in 2010 decreased compared to 2003 for all nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) RAMs, such as M184V/I (44.0% to 17.9%), T215Y (22.7% to 4.1%), and K65R (4.3% to 2.1%). Among samples resembling those typical of first-line NNRTI-based failures, prevalence of K103N increased slightly, but prevalence of M184V/I decreased (49.8% to 36.8%), as did other NRTI RAMs. These decreases were coincident with a shift in ARV prescriptions away from zidovudine and 3TC towards tenofovir and FTC, and an increase in use of fixed-dose combinations.

RAM prevalence decreased substantially since 2003 among samples submitted for resistance testing in the US. The causes of this decrease are multifactorial, but our results suggest a possible role of increased use of potent ARVs that are available as fixed-dose combinations or as single-tablet regimens.

The occurrence of viral control after interruption of an antiretroviral treatment (ART) initiated during primary HIV-1 infection (PHI) is rare and the frequency and predictive factors of such a control are unknown.

Within the French ANRS PRIMO Cohort, 164 patients interrupted ART initiated during PHI. We compared patients whose viral load (VL) remained undetectable (<50 copies/ml) or low (50–500 copies/ml) 1 year after ART interruption to those who evidenced a rapid viral rebound.

After ART interruption, VL remained undetectable for a median time of 4.5 years in 14 patients (‘post-ART controllers') and low in another 14 patients for a median time of 1.5 years. Post-ART controllers also maintained higher CD4⁺ T-cell counts compared to other patients. Female gender, a high CD4⁺ T-cell count and low VL during PHI, and a high CD4⁺ T-cell count and low HIV DNA levels at interruption, were associated with post-ART HIV control. Treatment characteristics did not differ between controllers and non-controllers. Post-ART controllers had lower specific CD8⁺ T-cell frequencies and CD8⁺ T-cell activation on ART and after ART interruption than non-controllers.

Few patients maintain very low VL after interruption of treatment initiated during PHI. Early patient characteristics were the main factors of viral control, although early initiation of ART and the effect of ART on reservoir might contribute to control.

The aim of this study was to investigate the effect on fasting lipid parameters of switching to tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) from abacavir (ABC) plus lamivudine (3TC; both fixed-dose combinations), while maintaining ritonavir-boosted lopinavir (LPV/r).

This was an open-label randomized two-arm 12-week controlled study in virologically suppressed HIV-infected patients with elevated cholesterol (≥5.2 mmol/l). Patients stable on ABC/3TC plus LPV/r either continued treatment or switched to TDF/FTC plus LPV/r for 12 weeks. Standard efficacy and safety end points (including fasting lipids) were assessed.

In total, 85 subjects were treated (n=42 ABC/FTC and n=43 TDF/3TC). A statistically significant decrease in total cholesterol was observed in the TDF/FTC group: from median (IQR) 6.22 mmol/l (5.91–6.77) at baseline to 5.75 mmol/l (5.04–6.18) at week 12 (median [IQR] change from baseline -0.73 mmol/l [-1.20— 0.18]; P<0.001). No notable change was observed for the ABC/3TC group. The difference between groups at week 12 was -0.82 mmol/l (P<0.001). For TDF/FTC (but not for ABC/3TC), statistically significant reductions (P<0.05) from baseline were observed in total, low-density lipoprotein, high-density lipoprotein (HDL)-and non-HDL cholesterol (at weeks 4 and 12). Statistically significant decreases were observed in median estimated creatinine clearance (Cockcroft–Gault) from baseline to week 12 for patients who switched to TDF/FTC (-5.47 ml/ min) versus the ABC/3TC group (-2.15 ml/min; P=0.016 between groups). Virological suppression was maintained in both groups. No new safety issues were identified.

Switching to TDF/FTC from ABC/3TC was associated with rapid improvements in fasting lipid parameters and continued virological control in patients receiving LPV/r as the third component of antiretroviral therapy. The effect of these changes on clinical end points remains unclear and would need to be evaluated in a longer-term study.

In HIV-infected patients, elevated plasma concentrations of the endogenous nitric oxide synthase inhibitor and cardiovascular risk factor asymmetric dimethylarginine (ADMA) are documented, and levels correlate with markers of immune activation, such as neopterin.

In this study, the effect of antiretroviral therapy (ART) on arginine, ADMA and symmetric dimethylarginine (SDMA) levels was investigated and related to changes of immune activation markers and lipids. Concentrations of ADMA, SDMA, arginine, C-reactive protein (CRP) and neopterin were determined in 112 HIV-infected patients after 12 months of successful ART, as refected by undetectable HIV RNA levels, and compared to baseline levels. ADMA, SDMA, arginine and urine neopterin levels were determined by HPLC, and plasma neopterin concentrations by ELISA. Disease activity before and after treatment was monitored by determination of HIV RNA levels and CD4⁺ T-cell counts. Lipids and CRP were determined by routine laboratory assays.

Under treatment with ART, concentrations of ADMA, SDMA and arginine dropped in parallel with decreasing HIV RNA levels and neopterin concentrations, while cholesterol, triglyceride levels and CD4⁺ T-cell counts increased. CRP levels did not change. After ART, a significant inverse association between ADMA and plasma cholesterol was observed.

Successful ART, defined by HIV RNA levels below the limit of detection, leads to decreasing levels of methylated arginines and immune activation markers. Thus, it is unlikely that disturbances of dimethylarginine metabolism account for the increased risk of cardiovascular events of HIV-infected patients under ART.

Hepatitis delta virus (HDV) infection therapy is unclear. This systematic analysis aimed to clarify the evidence on the efficacy of interferon (IFN)-α-based therapy in HDV.

We performed a systematic search on electronic databases including MEDLINE (1970 to January 2011), Web of Science, The Cochrane Library and ClinicalTrials.gov. Randomized clinical trials (RCTs) comparing IFN-α-based therapy with either another drug, placebo or no intervention were included. We excluded paediatric studies. We calculated relative risks (RRs) for comparison of treatment options on the primary outcome measure, which was defined as undetectable levels of HDV RNA and normal alanine aminotransferase at end of treatment (EOT; 1 year).

Nine RCTs were included. Seven trials evaluated the treatment with IFN-α (n=132). The remaining two trials evaluated treatment with pegylated (PEG)-IFN-α (n=45). We found that 1-year treatment with high-dose IFN-α achieved better primary outcome rates than with PEG-IFN-α (RR=4.14, 95% CI 1.00, 17.14). Data for 1-year treatment with low-dose IFN-α compared with PEG-IFN-α were similar (RR=2.83, 95% CI 0.65, 12.40), as were low-dose IFN-α versus high-dose IFN-α (RR=0.68, 95% CI 0.31, 1.50). High-dose IFN-α and PEG-IFN-α reached similar HDV RNA suppression 24 weeks after EOT (RR=1.00, 95% CI 0.51, 1.97). None of the 55 patients assigned to no intervention obtained undetectable levels of HDV RNA and only one patient achieved normalization of alanine aminotransferase level.

Based on available RCTs, 1-year high-dose IFN-α monotherapy appears to be more effective than PEG-IFN-α for treatment of HDV patients, with efficacy rates of approximately 30%. There is a lack of head-to-head comparisons. Combination therapies and longer treatment duration need to be investigated.

Estimates of treatment failure, change and interruption are lacking for individuals treated in early HIV infection.

Using CASCADE data, we compared the effect of treatment in early infection (within 12 months of seroconversion) with that seen in chronic infection on risk of virological failure, change and interruption. Failure was defined as two subsequent measures of HIV RNA>1,000 copies/ml following suppression (<500 copies/ml), or >500 copies/ml 6 months following initiation. Treatment change and interruption were defined as modification or interruption lasting >1 week. In multivariable competing risks proportional subdistribution hazards models, we adjusted for combination antiretroviral therapy (cART) class, sex, risk group, age, CD4⁺ T-cell count, HIV RNA and calendar period at treatment initiation.

Of 1,627 individuals initiating cART early (median 1.8 months from seroconversion), 159, 395 and 692 failed, changed and interrupted therapy, respectively. For 2,710 individuals initiating cART in chronic infection (median 35.9 months from seroconversion), the corresponding values were 266, 569 and 597. Adjusted hazard ratios (HRs; 95% CIs) for treatment failure and change were similar between the two treatment groups (0.93 [0.72, 1.20] and 1.06 [0.91, 1.24], respectively). There was an increasing trend in rates of interruption over calendar time for those treated early, and a decreasing trend for those starting treatment in chronic infection. Consequently, compared with chronic infection, treatment interruption was similar for early starters in the early cART period, but the relative hazard increased over calendar time (1.54 [1.33, 1.79] in 2000).

Individuals initiating treatment in early HIV infection are more likely to interrupt treatment than those initiating later. However, rates of failure and treatment change were similar between the two groups.

Tenofovir disoproxil fumarate (TDF), an acyclic nucleotide analogue was shown to be effective in many HBV-infected patients with resistance to adefovir dipivoxil (ADV). This observation is intriguing because in vitro studies show that HBV mutations selected by ADV confer cross-resistance to TDF. To assess the clinical relevance of this cross-resistance, we studied the evolution of HBV polymerase gene variants in patients with genotypic resistance against ADV (rtN236T and/or rtA181V/T) during TDF treatment.

In 10 HBV-monoinfected patients (9 male, mean age 47 ±11 [range 27–67] years, 6 hepatitis B e antigen- positive) with virological breakthrough during ADV treatment associated with the mutations rtN236T and/or rtA181T/V, HBV polymerase gene variants were studied during up to 24 months of consecutive monotherapy with TDF by population sequencing, line probe assay and clonal analysis.

In all patients, switching to TDF resulted in a continuous reduction of HBV DNA from a median of 7.6 (4.6–9.4) log₁₀ copies/ml to 3.3 (2–5) log₁₀ copies/ml, remaining in 7 patients >400 copies/ml at 12 months. ADV-resistance mutations remained detectable throughout the whole observation period in most patients. Apart from an M204Q mutation in one sample, no new HBV polymerase gene mutations were found. In two patients with low level viraemia after 72 weeks of TDF, adding lamivudine led to a complete response within a few weeks.

ADV-resistant HBV variants may further become selected during TDF treatment, however they cause only a mild decrease in TDF susceptibility.

Pegylated interferon and ribavirin for 72 weeks improve sustained virological response (SVR) in HCV genotype 1 (HCV-1) slow viral responders. Whether interleukin 28B (IL28B) single nucleotide polymorphism (SNP) genotypes and on-treatment viral responses can identify non-rapid virological response (RVR) patients who benefit from 48 or 72 weeks of therapy remains unclear.

Treatment-naive HCV-1 patients who failed to achieve RVR were randomly assigned to receive 48 (n=168) or 72 (n=167) weeks of therapy. Baseline factors and on-treatment virological responses at weeks 8 and 12 were evaluated for SVR in 289 compliant patients who received ≥80% of drug dosages and treatment duration, and had end of follow-up viral response. The stratified SVR rates for independent factors were compared by treatment duration.

Treatment duration, IL28B rs8099917 genotypes, cirrhosis, week-8 viral response (undetectable HCV RNA at treatment week 8) and complete early virological response (cEVR) predicted SVR. In week-8 viral response patients, the SVR rates of 72-week and 48-week treatment were similar (75–88%), regardless of IL28B SNP genotypes or cirrhosis. In non-week-8 viral response patients who achieved cEVR, the SVR rate of 72-week treatment was higher than that of 48-week treatment for non-cirrhotic patients, regardless of IL28B SNP genotypes (91–100% versus 13–44%; P=0.001).

Although IL28B SNP genotypes predict SVR, they play a minor role when on-treatment viral responses are taken into consideration. On-treatment viral responses at weeks 8 and 12 are the key determinants to decide the optimal treatment duration in HCV-1 patients without RVR.

Vitamin D deficiency is common in HIV-infected individuals. In adults, traditional and HIV-related factors play a role in vitamin D status, and deficiency appears to impair immune restoration and exacerbate HIV complications, like cardiovascular disease (CVD). This study sought to determine factors contributing to vitamin D status in HIV-infected youth and investigate the relationship with CVD risk, inflammation and immune restoration.

HIV-infected subjects (1-25 years old) were enrolled prospectively along with healthy controls that were group-matched by age, sex and race. HIV data were collected for the HIV-infected group, while traditional risk factors, including vitamin D intake, sun exposure, skin pigmentation, physical activity level and body mass index (BMI) were collected for both groups. Fasting lipids, plasma 25-hydroxyvitamin D (25[OH]D), and inflammation markers were measured.

In total, 200 HIV-infected subjects and 50 controls were enrolled. HIV group had 53% male, 95% Black and a mean age of 17.2 ±4.6 years. There was no difference in 25(OH)D between groups; 77% of HIV+ and 74% of controls had 25(OH)D<20 ng/ml. Only Fitzpatrick skin type was independently associated with 25(OH)D. No HIV variables were associated with 25(OH)D, even when HIV sub-populations were examined. Inflammation, CVD risk factors and immune restoration were not independently associated with 25(OH)D.

Vitamin D deficiency is common among HIV-infected youth. However, HIV factors, CVD risk, inflammation and immune restoration do not appear to have the same relationship with vitamin D as has been shown in adults. Supplementation trials are needed to determine if increasing 25(OH)D concentrations could better elucidate these relationships.

Psychiatric disorders are relatively common among HIV-infected patients. However, there are few studies about their potential risk factors. This analysis aimed to measure the incidence of severe psychiatric events (PE) among patients receiving combination antiretroviral therapy (cART) of the French APROCO-COPILOTE (ANRS CO8) cohort, and to identify the medical and socio-behavioural correlates of their first episode of depression, suicide or suicide attempt (D/S/SA).

APROCO-COPILOTE is a cohort of patients started on a protease inhibitor regimen between 1997 and 1999, with prospective medical standardized records and self-administered questionnaires collecting socio-demographic and socio-behavioural data. This analysis included all 11-year follow-up visits for 1,095 patients having completed baseline self-administered questionnaires. A proportional hazard Cox model was used to identify the correlates of a first D/S/SA event.

The overall prevalence of severe PE remained low: 50 patients experienced 67 events (incidence rate [95% CI] =1.04 [0.82, 1.32] per 100 person-years). Depression (n=16), suicides (n=5) and suicide attempts (n=14) were the most frequently diagnosed PE (0.54 [0.39, 0.76] per 100 person-years) among 25 patients. Multivariate results showed that unemployment, unstable housing, detectable viral load and smoking more than 20 cigarettes/day were independently associated with D/S/SA.

Although the incidence of severe PE remained relatively low among the patients of APROCO-COPILOTE cohort, this study's results underline a clinically important problem in HIV-infected patients receiving cART. Furthermore, our findings not only emphasize the importance of comprehensive care, especially for socially vulnerable patients, but may also help future studies designed to assess the effectiveness of interventions in reducing the risk of PE during cART.

The effectiveness of neuraminidase inhibitors to reduce transmission when used as treatment in influenza-infected patients remains debated.

In a prespecified analysis of a blinded randomized controlled trial on the efficacy of oseltamivir– zanamivir combination therapy versus oseltamivir and zanamivir monotherapy conducted during the 2008– 2009 seasonal influenza epidemic, we compared the rate of secondary illness in household contacts of influenza-positive index patients between arms. Secondary illness was defined as occurrence in contacts of fever plus cough within 7 days from randomization of index patients. Analyses were conducted according to the delay between patients’ onset of symptoms and intervention.

A total of 543 household contacts of 267 index patients were included, of which 466 had follow-up assessment. A secondary illness was reported in 58 (12.5%) contacts with no significant difference between arms overall (P=0.07). When the analysis was limited to the 232 contacts of 136 index patients with first treatment intake within 24 h of onset of symptoms, a lower rate of secondary illness was reported in the combination therapy arm (2 of 56 [4%]) than in the oseltamivir arm (14 of 81 [17%]; P=0.014) and the zanamivir arm (14 of 95 [15%]; P=0.031). Multivariate analysis accounting for intra-household correlation confirmed these findings.

Our analysis suggests a greater effectiveness of the combination therapy to reduce transmissibility when given to the index patient within 24 h of onset of symptoms. As the finding was obtained from a subgroup analysis, it should be interpreted with caution.