Antiviral Therapy

Seasonal interpandemic influenza causes >200,000 annual hospitalizations in the United States. Optimal antiviral treatment in hospitalized patients is not established.

During three interpandemic influenza seasons, 137 patients hospitalized with suspected acute influenza were randomized to 5-day treatment with intravenous peramivir 400 mg or 200 mg once daily or oral oseltamivir 75 mg twice daily. Time to clinical stability and quantitative changes in viral titres from nasopharyngeal specimens were primary and key secondary end points, respectively.

Infection was confirmed in 122 patients with influenza A (H1N1), influenza A (H3N2) or influenza B. Median times (95% CI) to clinical stability were 37.0 h (22.0, 48.7) with peramivir 400 mg, 23.7 h (16.0, 38.9) with peramivir 200 mg and 28.1 h (22.0, 37.0) with oseltamivir (P=0.306). Patients (n=97) who were clinically unstable at enrolment had median times (95% CI) to clinical stability of 24.3 h (21.2, 47.5) with peramivir 400 mg, 31.0 h (17.2, 47.7) with peramivir 200 mg and 35.5 h (23.3, 37.9) with oseltamivir (P=0.541). Titres of influenza A viruses in nasopharyngeal specimens decreased similarly across treatments, but more rapid decreases in titres of influenza B occurred with peramivir treatment. There were no deaths among patients with confirmed influenza and the incidence of adverse events was low and generally similar among treatment groups.

Treatment of acute seasonal influenza in hospitalized adults with either peramivir or oseltamivir resulted in generally similar clinical outcomes. Treatment with peramivir was generally safe and well tolerated and could be of benefit in this population.

Little is known about patient preferences for selection of chronic hepatitis B (CHB) treatment. This issue is important as it affects the therapeutic choices available for patients and, in the long term, the health of CHB patients.

The study was a questionnaire-led survey directed at patients attending a CHB follow-up clinic. Patients were asked questions regarding their knowledge on CHB treatment, preferred route and frequency of administration, duration of treatment, cost, adverse events, viral resistance, efficacy and whether treatment options were discussed with doctors. Patients were also asked to rank their priorities when selecting treatment for CHB. In addition, a summary of the profile of current agents was shown to patients who were then asked to select their preferred therapy. Finally, patients were asked questions regarding their willingness to pay for CHB treatment and expectations of treatment. Questionnaires were self-administered and statistical analysis was performed using SPSS (version 10.0).

Lamivudine was the best-known drug among patients. Only 30% of patients were treatment-naive. Most patients preferred oral therapy with once-daily dosing and a fixed duration of treatment. Drug efficacy was considered the most important factor in drug selection. When shown the profile of the different drugs available for the treatment of CHB, entecavir was the preferred choice of therapy. The majority of patients were willing to spend no more than S$10 (USD 8) daily for therapy with expectation of cure for their disease. Overall, 92% of patients would follow doctor's recommendations.

Patients’ preferences are important in evaluating drug selection for CHB.

The roadmap concept suggests the use of on-treatment HBV DNA to guide treatment strategy of chronic hepatitis B patients treated by telbivudine. Our aim was to validate the roadmap approach of entecavir switch therapy in patients with incomplete response to telbivudine.

Consecutive chronic hepatitis B patients on telbivudine monotherapy were studied. Incomplete virological response was defined as detectable HBV DNA after 6–12 months of treatment. Maintained virological response was defined as undetectable HBV DNA until the last follow-up.

Among the 79 patients on telbivudine, 39 (49%) had undetectable HBV DNA after 6–12 months of telbivudine treatment and 40 (51%) had incomplete virological response. In total, 33 incomplete responders switched to entecavir at 11 months (6–23), and 26 (79%) achieved maintained virological response after 25 months (4–46). Low HBV DNA level before switch therapy was the independent factor associated with maintained virological response to entecavir (P=0.01). A total of 24 of 25 (96%) patients with HBV DNA<2,000 IU/ml, versus 2 of 8 (25%) patients with HBV DNA≥2,000 IU/ml, had maintained virological response after switching to entecavir. Although rtM204I and/or rtL180M was detected in 3 of 7 patients with incomplete virological response to entecavir, none of the patients with HBV DNA<2,000 IU/ml during telbivudine treatment harboured these amino acid substitutions.

Roadmap approach using entecavir switch at month 6–12 among incomplete responders to telbivudine is recommended if the HBV DNA is <2,000 IU/ml at the time of switching.

In Africa, success of antiretroviral treatment (ART) seems to lag behind in children compared with adults, and high therapeutic failure rates have been reported. We aimed to identify prevalence and determinants of virological failure in HIV-infected children treated under programmatic conditions.

All patients <18 years on ART presenting to the HIV clinic at the Bamenda Regional Hospital, a secondary referral hospital in rural Cameroon, from September 2010 to August 2011, were enrolled in this cross-sectional study. Clinical data, self-reported adherence, CD4⁺ T-cell counts and viral load were recorded. Therapeutic drug monitoring was performed on stored plasma samples. Determinants of virological failure were identified using descriptive statistics and logistic regression.

A total of 230 children with a mean age of 8.9 years (sd 3.7) were included. At the time of analysis, the mean duration of HAART was 3.5 years (sd 1.7) and 12% had a CD4⁺ T-cell count <200 cells/μl. In total, 53% of children experienced virological failure (>200 copies/ml). Among children on nevirapine (NVP), plasma levels were subtherapeutic in 14.2% and supratherapeutic in 42.2%. Determinants of virological failure included male sex, lower CD4⁺ T-cell counts, subtherapeutic drug levels, longer time on ART and a deceased mother. Poor adherence was associated with subtherapeutic NVP plasma levels and advanced disease stages (WHO stage 3/4).

This study demonstrates high virological failure rates and a high variability of NVP plasma levels among HIV-infected children in a routine ART programme in rural Cameroon. Strategies to improve adherence to ART in HIV-infected children are urgently needed.

Entecavir is a potent nucleoside analogue for treating chronic hepatitis B (CHB). Quantitative hepatitis B surface antigen (qHBsAg) levels are predictive of response to interferon-α in CHB treatment; however, the clinical utility of qHBsAg in nucleoside/ nucleotide analogue-based CHB therapy is not fully characterized. This study assessed changes in qHBsAg in patients treated with entecavir in the Phase III study ETV-022.

This retrospective post hoc analysis included nucleoside/nucleotide-naive, hepatitis B e antigen (HBeAg)-positive patients receiving entecavir (0.5 mg daily) in ETV-022 who had samples available for qHBsAg analysis through week 48. qHBsAg, HBV DNA and alanine aminotransferase levels were assessed for the overall patient cohort, for cohorts with or without HBeAg loss or HBsAg loss by week 48, and by HBV genotype.

Overall, 95 patients from ETV-022 had available samples for qHBsAg analysis through week 48. In all cohorts, 48 weeks of entecavir therapy resulted in effective HBV DNA suppression. In the overall cohort, qHB-sAg declined by -0.92 log₁₀ IU/ml through week 48. The decline in qHBsAg was more pronounced in patients with subsequent HBeAg loss or HBsAg loss, and in patients infected with HBV genotype D or A. On-treatment qHBsAg changes did not correlate with changes in HBV DNA; no on-treatment or baseline factor was found to be predictive of HBeAg loss or HBsAg loss.

Through 48 weeks of entecavir therapy, qHBsAg declined predominantly in those patients who achieved seroclearance of HBeAg or HBsAg. However, unlike with interferon-α-based therapy, early qHBsAg decline was not predictive of serological response at year 1 of entecavir treatment.

Use of combination antiretroviral therapy (cART) and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) with or without rituximab for treatment of diffuse large B-cell lymphoma (DLBCL) in HIV substantially increases response rates but may also increase toxicity, possibly due to antiretroviral– antineoplastic drug interactions. The objective of this study was to evaluate the frequency of complete remission (CR) of DLBCL in patients treated with CHOP while receiving a protease inhibitor (PI) versus a non-PI-based cART.

A retrospective multicentre pilot study was conducted in HIV-infected patients on cART treated for DLBCL with CHOP between 2002–2010 in three academic hospitals.

A total of 34 patients were included with 65% and 35% of patients receiving a PI and non-PI-based cART, respectively. Baseline characteristics between groups were similar; overall 85% were male, median age was 43 years, 50% had an International Prognostic Index (IPI) of 2–3 and median CD4⁺ T-cell count was 225 cells/mm³. CR was achieved in 77% and 58% of patients in the PI and non-PI groups, respectively (P=0.21), with 65% and 63% of patients achieving 2-year overall survival (P=1.00). A multivariate analysis showed that lower IPI score alone was significantly associated with higher CR rates (P=0.05). Toxicity was similar between both groups.

Similar efficacy and toxicity of CHOP was observed in patients receiving a PI and non-PI-based cART.

Achievement of early viral suppression is important in patients with chronic HCV infection treated with telaprevir (TLV) or boceprevir (BOC) to avoid selection of drug resistance and attain cure. No head-to-head studies comparing TLV and BOC have been performed so far.

All consecutive individuals who initiated triple HCV therapy with TLV or BOC outside clinical trials at three European clinics were evaluated. Rapid virological response (RVR) was defined as unquantifiable HCV RNA (<25 IU/ml) at week 4 for TLV and at week 8 for BOC (4 weeks after lead-in).

A total of 106 patients were evaluated, 33 treated with BOC and 73 with TLV. Median age, gender, body mass index, baseline HCV RNA, HCV subtype 1a (45% versus 42%) and IL28B-CC alleles (29% versus 23%) did not differ significantly in BOC and TLV groups, respectively. HIV coinfection was more prevalent in patients on TLV than BOC (24% versus 44%). Conversely, more patients on BOC than TLV had previously failed pegylated interferon plus ribavirin (82% versus 64%). RVR was achieved by 82% of patients on TLV versus 59% on BOC (P=0.001). Multivariate logistic regression analysis confirmed that TLV use was the strongest predictor of RVR (OR 3.54 [95% CI 1.23, 10.24]; P=0.02), others being HCV subtype 1b versus 1a (OR 3.26 [95% CI 1.17, 9.09]; P=0.02) and low baseline HCV RNA (OR 0.41 [95% CI 0.16, 1.03]; P=0.06). Prior interferon exposure, HIV coinfection or absence of advanced liver fibrosis did not influence the likelihood of RVR.

Compared to BOC, triple therapy with TLV produces greater RVR rates. TLV might be a better option in more difficult-to-cure patients, such as those with high baseline HCV RNA and/or HCV 1a subtype. HIV coinfection does not influence early HCV RNA responses.

The recent availability of new direct-acting antivirals (DAAs) for HCV treatment, which significantly increase sustained virological response rates for genotype 1 HCV infection, has brought new optimism with respect to curative HCV treatment for HIV–HCV-coinfected patients. We describe the characteristics of coinfected patients who could be eligible for DAAs to determine potential challenges facing clinicians and patients hoping to take advantage of these new therapies.

We evaluated the sociodemographic and clinical characteristics of the genotype 1 HCV–HIV-infected participants in a Canadian prospective multicentre cohort study at their most recent visit to assess potential eligibility for combination HCV treatment with boceprevir or telaprevir.

Of the 1,020 coinfected participants enrolled in the cohort, 707 (85%) had evidence of chronic HCV infection (HCV-RNA-positive), of whom 497 (70%) were infected with genotype 1; 375 (75%) were naive to HCV treatment and 122 (25%) had previously received therapy and failed. Only 143 (38%) of HCV treatment-naive and 39 (32%) of treatment-experienced participants had no absolute contraindications for treatment. Alcohol abuse, active depression and decompensated liver disease were the most frequent reasons for treatment ineligibility. The majority would require alterations in antiretroviral regimens to avoid important drug–drug interactions.

Although the need for curative HCV therapy in HIV–HCV coinfection is great, the actual number of patients who could be eligible for DAAs at the present time may be quite low. There remains an urgent need to develop safe, simple and interferon-sparing treatments for coinfected individuals.

Telaprevir (TVR) is a protease inhibitor (PI) used in chronic hepatitis C treatment with pegylated interferon plus ribavirin. We analysed the prevalence and kinetic development of TVR resistance upon treatment.

A total of 24 cirrhotic patients (genotype 1a, n=8; genotype 1b, n=16) previously non-responders to standard therapy were treated with TVR-based therapy. The distribution of TVR-resistant variants was assessed at every HCV-RNA-positive time point by 454 ultra-deep pyrosequencing (UDPS) during a mean follow-up period of 9.4 months.

A median of 6,837 reads/specimen was studied. Based on control UDPS, we considered mutations as real when present >0.4%. TVR-resistant variants were found at baseline in 8/24 patients (33.3%). Four of the 24 patients (16.7%), all genotype 1a, did not achieve HCV RNA<100 IU/ml between week (W)2 and W12 and stopped treatment. No statistical significant difference was observed in the prevalence of resistant mutants between responders and non-responders (25% [5/20] and 75% [3/4], respectively). The proportion of genotype 1a patients with R155K/T/Q at baseline was higher in non-responders than in responders (50% versus 0%). During treatment failure, significant enrichment in V36A/M and R155K/T/Q was observed but their frequency reverted back to baseline after TVR discontinuation.

TVR-resistant variants are widely present at baseline. The presence of TVR-resistant mutants at baseline, even in high abundance (>20%), did not always preclude TVR treatment success. The detection of R155K/T/Q at baseline may predict failure in genotype 1a patients. At failure, which occurred in genotype 1a patients, a significant enrichment in V36A/M and R155K/T/Q was observed.

Greater adipose tissue is associated with increased circulating high-sensitivity C-reactive protein (hsCRP) levels in HIV-infected adults on antiretroviral therapy (ART), but the relationship between adiposity and other inflammation biomarkers is not well-characterized.

We measured total and regional adipose tissue deposits using dual energy X-ray absorptiometry (DXA) and serum levels of interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) receptor 1 and 2, macrophage inflammatory protein-1α (MIP-1α), macrophage chemotactic protein-1 (MCP-1), soluble CD14 and hsCRP in a cohort of adults on long-term ART. Regression models were adjusted for age, sex, CD4⁺ T-cell count, smoking status, protease-inhibitor-use and daily use of either non-steroidal anti-inflammatory drugs or aspirin.

The majority (77%) of the 85 study participants were male, median CD4⁺ T-cell count was 500 cells/ml (IQR 315-734) and median BMI was 25.1 kg/m² (IQR 22.7-28.1). DXA measurements of total fat mass were positively associated with serum hsCRP (β =1.82, P<0.01) and MIP-1α (β =1.36, P <0.01), but negatively associated with soluble CD14 (β =0.90, P<0.01). Results were similar for trunk fat, limb fat and serum leptin level. The positive relationship between DXA measurements and TNF-α receptor 1 approached significance (P≤0.07 for all). There was no consistent relationship between adiposity and serum IL-6, TNF-α receptor 2 or MCP-1 levels.

Total and regional adiposity was associated with serum hsCRP, but not other inflammatory cytokines shown to predict morbidity and mortality in treated HIV. Greater adiposity is associated with higher MIP-1α and lower soluble CD14 levels, possibly reflecting an important role for cells of the monocyte/macrophage lineage.