Antiviral Therapy

Data is limited on the use of 8 weeks of therapy with ledipasvir/sofosbuvir (LDV/SOF) for special populations such as HCV–HIV-coinfected patients. The primary objective of this analysis was to compare sustained virological response at 12 weeks after end of therapy (SVR12) rates among HCV-monoinfected and HCV–HIV-coinfected patients in a real-world clinical setting. Additionally, we compared SVR12 rates among patients receiving 8 versus 12 weeks of therapy.

This was a single-centre, retrospective study of HCV-infected patients prescribed LDV/SOF at ambulatory clinics associated with the University of Maryland Medical Center (UMMC) from May 2015 to May 2016. Data were obtained from UMMC electronic medical records and outpatient pharmacy claims database. Comparisons between groups were made using χ² or Fisher's exact test for categorical variables and Student's t-test or Wilcoxon rank-sum for continuous variables. All analyses were per-protocol; patients missing SVR12 data (25.2%) could not be evaluated for our stated objectives.

A total of 274 patients were included. Median age was 58 years; 62.8% were male; 82.5% were Black. SVR12 data was available for 65 HCV–HIV-coinfected patients, of which 62 (95.4%) achieved SVR12. There was no difference in SVR12 rate between HCV–HIV-coinfected patients and HCV-monoinfected patients (86/90; 95.6%; P=0.959). Additionally, there was no difference in SVR12 attainment between HIV–HCV-coinfected patients who received 8 versus 12 weeks of therapy (P=0.101).

8 weeks of LDV/SOF was effective for treatment-naive, non-cirrhotic, HCV genotype-1 patients in this real-world setting, regardless of HIV status. Increased uptake of the 8-week regimen can decrease costs for patients and payers without compromising outcomes.

Active illicit drug use can present a barrier to the medical management of HIV infection by complicating adherence to antiretroviral therapy (ART). Plasma HIV-1 RNA viral load (VL) rebound, defined as a period of detectable HIV VL following ART and VL suppression, can lead to the generation of viral resistance and potential treatment failure. We sought to investigate the contribution of substance use patterns on rates of VL rebound.

We used data from the ACCESS study, a long-running community-recruited prospective cohort of HIV-positive people who use illicit drugs in Vancouver, Canada, a setting of universal no-cost HIV treatment. We analysed time to VL rebound (that is, two consecutive observations ≥1,000 copies/ml) after ART initiation and sustained viral suppression (that is, two consecutive observations <50 copies/ml) using extended Cox regression models with a recurrent events framework.

Between May 1996 and November 2013, 564 ART-exposed participants achieved at least one instance of VL suppression and contributed 1,893.8 person-years of observation. Over follow-up, 198 (35.1%) participants experienced ≥ one instance of VL rebound. In adjusted analyses, VL rebound was associated with younger age (adjusted hazard ratio [AHR] =0.97, 95% CI: 0.95, 0.98), heroin injection (≥ daily versus < daily, AHR =1.52, 95% CI: 1.01, 2.30), crack use (≥ daily versus < daily, AHR = 1.73, 95% CI: 1.08, 1.92) and heavy alcohol use (≥ four versus < four drinks/day, AHR =1.97, 95% CI: 1.17, 3.31).

The present study suggests that in addition to heavy alcohol use, high-intensity illicit drug use, particularly ≥ daily heroin injection and ≥ daily crack smoking are risk factors for VL rebound. In addition to the impact of high-intensity drug use on health-care engagement and ART adherence, some evidence exists on the direct impact of psychoactive substances on ART metabolism and the natural progression of HIV disease. At-risk individuals should be provided additional supports to preserve virological control and maintain the benefits of ART.

In previous research, we have demonstrated that sodium tanshinone IIA sulfonate (STS) has anti-porcine reproductive and respiratory syndrome virus (PRRSV) activity, but whether autophagy is involved in this process is still unknown. In this study, the autophagy effect of STS against PRRSV infection was investigated in vitro.

Quantitative real-time PCR (qRT-PCR) and western blot was used to evaluate the inhibition ability of STS on the mRNA expression levels on cell autophagy genes, that is Beclin1, ATG5 and ATG7. Simultaneously, the effect of STS on N protein/gene expression was assessed by indirect immuno-fluorescence assay (IFA), qRT-PCR and western blot.

The results indicated that STS inhibits autophagy induced by PRRSV. In addition, STS effectively suppresses PRRSV's N protein replication and N gene expression in Marc-145 cells infected with PRRSV in a time-dependent manner.

Our results suggest that STS exhibits anti-PRRSV activity in vitro by suppressing autophagy-related genes, which may provide a theoretical basis for further pharmacological agent development regarding PRRSV infection.

Optimal treatment for patients with HCV genotype-3 infection and liver cirrhosis remains a medical priority. Daclatasvir+sofosbuvir and ribavirin is a recommended option for such patients, but clinical trial data are lacking for treatment >16 weeks.

This was a single-arm, Phase III study of daclatasvir+sofosbuvir+ribavirin for 24 weeks in patients with compensated cirrhosis and HCV genotype-3 infection. The primary end point was sustained virological response at post-treatment week 12 (SVR12); the primary objective was to demonstrate statistical superiority to historical SVR12 data for 12 weeks’ daclatasvir+sofosbuvir without ribavirin in genotype-3-infected patients with cirrhosis (95% CI lower bound >79.0%).

A total of 78 patients were treated (54 treatment-naive, 24 treatment-experienced including 8 with prior sofosbuvir exposure). SVR12 was achieved by 87% (68/78; 95% CI 77.7, 93.7%) of patients in the primary analysis of central laboratory data. One additional patient achieved SVR12 by local testing resulting in an overall SVR12 rate of 88% (95% CI 79.2, 94.6%) and the lower bound of the 95% CI above the historical threshold. SVR12 rates were 93% (50/54) for treatment-naive and 79% (19/24) for treatment-experienced patients. Of the nine non-SVR12 patients, four were lost to follow-up, two relapsed (both sofosbuvir-experienced), two had end-of-treatment virological failure and one discontinued early. There were no unexpected safety signals; only one patient discontinued for an adverse event.

Daclatasvir+sofosbuvir+ribavirin for 24 weeks was well tolerated and efficacious in HCV genotype-3-infected patients with compensated cirrhosis, with SVR12 outcomes comparable to previously reported outcomes in patients treated with this regimen for 12–16 weeks.

The male genital tract (MGT) is a viral sanctuary and likely HIV reservoir; understanding MGT pharmacokinetics (PK) of antiretrovirals (ARVs) used for curative strategies is critical to eradication and cure. Tenofovir alafenamide (TAF) is a tenofovir (TFV) formulation designed to maximize efficacy/minimize toxicity with unknown MGT PK.

HIV-positive and HIV-negative men receiving TFV-based regimens provided six paired blood plasma (BP) and semen samples. Extracellular (TFV, TAF, emtricitabine [FTC]) drug concentrations in BP and seminal plasma (SP), and intracellular metabolite (IM) and endogenous nucleotide (EN) concentrations were measured in peripheral blood mononuclear cells (PBMCs) and seminal mononuclear cells (SMCs). Exposure ratios for SP:BP, SMC:PBMC and IM:EN were calculated from PK parameters generated by noncompartmental analysis. HIV viral load was measured in BP and SP.

Sixteen HIV-positive (n=8, TDF/FTC; n=8, TAF/FTC) and eight HIV-negative (TDF/FTC) men provided samples. Median TFV SP:BP ratios differed between TDF and TAF (1.5 versus 7.4), due to lower TFV BP concentrations with TAF coupled with TFV SP concentrations similar to TDF. FTC SP:BP ratios were approximately 3. SMC concentrations of IMs and ENs were a fraction of PBMC concentrations (1–22%), though IM:EN ratios exceed a suggested protective threshold.

TAF SP PK was unexpected. IM SMC concentrations were low relative to PBMC, as were EN concentrations, suggesting differences in cell phenotype and lineage in the MGT; these differences in phenotype and pharmacology may have an impact on selecting and dosing ARVs used in cure strategies.

Frailty and falls occur commonly and prematurely in HIV-infected populations. Whether frailty in middle-age predicts future falls among HIV-infected women is unknown.

We evaluated associations of frailty with single and recurrent falls 10 years later among 729 HIV-infected and 326 uninfected women in the Women's Interagency HIV Study (WIHS) with frailty measured in 2005 and self-reported falls in 2014–2016. Frailty was defined as ≥3 of 5 Fried Frailty Index components: slow gait, reduced grip strength, exhaustion, unintentional weight loss and low physical activity. Stepwise logistic regression models determined odds of single (versus 0) or recurrent falls (≥2 versus 0) during the 2-year period; separate models evaluated frailty components.

HIV-infected women were older (median 42 versus 39 years; P<0.0001) and more often frail (14% versus 9%; P=0.04) than uninfected women. Over 2 years, 40% of HIV-infected versus 39% of uninfected women reported a fall (single fall in 15% HIV+ versus 18% HIV-women; recurrent falls in 25% HIV+ versus 20% HIV-women [overall P=0.20]). In multivariate models, frailty independently predicted recurrent falls (adjusted odds ratio [aOR] 1.84, 95% CI: 1.13, 2.97; P=0.01), but not a single fall. Among frailty components, unintentional weight loss independently predicted single fall (aOR 2.31, 95% CI: 1.28, 4.17; P=0.005); unintentional weight loss (aOR 2.26, 95% CI: 1.32, 3.86; P=0.003) and exhaustion (aOR 1.66, 95% CI: 1.10, 2.50; P=0.02) independently predicted recurrent falls.

Early frailty measurement among middle-aged women with or at-risk for HIV may be a useful tool to assess future fall risk.

Two-drug regimens are increasingly used in clinical practice as switch strategies. We compared the efficacy and safety of two dolutegravir (DTG)-based dual therapies: DTG plus lamivudine (3TC group) versus DTG plus rilpivirine (RPV group).

In a multicentre cohort of virologically suppressed (HIV RNA <50 copies/ml) HIV+ patients switching to DTG+3TC or DTG+RPV we analysed the incidence of virological failures (VF) and treatment discontinuations (TD), as well as their predictors.

We analysed 416 patients, 229 in the 3TC group and 187 in the RPV group. The 3TC group, during 344.4 person-years of follow-up (PYFU), had 10 VF without the emergence of resistance mutations, while 30 patients discontinued the regimen. In the RPV group, during 371.0 PYFU, there were 5 VF (1 developed non-nucleoside reverse transcriptase inhibitor mutations Y181C and E138Q) and 13 TD. The estimated probability of remaining free from VF at 48 weeks showed no significant difference between groups (log-rank 0.172). We found a higher risk of VF in patients with peak viral load >500,000 copies/ml in both treatment groups (log-rank P=0.004 in each group). The estimated probability of remaining in the study regimen at week 48 was 89.0% with DTG+3TC and 96.1% with DTG+RPV (log-rank 0.015). After adjusting for potential confounders, treatment group was not associated with TD. A significant decrease in total cholesterol was observed at week 48 in both groups while renal function remained unchanged.

DTG+RPV and DTG+3TC were compared in populations with different characteristics in clinical practice: both regimens showed good effectiveness and improved lipid profile.

The pilot Phase IIb VIKING study suggested that dolutegravir (DTG), an HIV integrase inhibitor (INI), is efficacious in INI-resistant patients at the 50 mg twice-daily dose. However, DTG response was most reduced in subjects carrying resistance-associated mutations at position G140 and Q148. These mutations can cause a 10–20-fold reduced susceptibility to DTG as well as a 96% lower odds of achieving HIV-1 RNA <50 copies/ml at week 24 if compared with those with no mutations at these positions.

Five multi-experienced patients harbouring the mutation complex G140-Q148, resistant to at least three drug classes, and previously exposed to DTG 50 mg twice daily, were treated with an increased dose of DTG (100 mg twice daily) in association with an optimized background regimen (OBR) based on their individual viral genotyping assays. The blood concentration of DTG was measured in order to determine whether a solubility issue is related with this high dosage.

Four out of five patients attained an HIV-1 RNA <50 copies/ml at week 48 and no relevant adverse events were detected. The measured DTG blood concentration was that expected for the administered dosage, ruling out any solubility concerns.

For the first time 100 mg twice daily of DTG was administered to five multi-experienced patients harbouring the mutation complex G140-Q148. Although a small number of patients were tested, the results show a potential for a high-dose regimen of DTG as a rescue therapy in patients harbouring integrase strand transfer inhibitor resistant viruses.