Antiviral Therapy

As a result of increased understanding of the HCV life cycle, a new generation of drugs known as direct-acting antivirals (DAAs) was developed and is constantly being improved. At baseline, HCV variants resistant to DAA therapy may pre-exist, increasing the likelihood of treatment failure. The aim of this study was to investigate the presence of resistance-associated variants (RAVs) in treatment-naive patients infected with HCV subtypes 1a and 1b.

Next-generation sequencing was used to assess the frequencies of NS3-4A, NS5A and NS5B RAVs in 100 HCV monoinfected DAA-naive patients (HCV-1a: n=51; HCV-1b: n=49).

Complete HCV sequence information was obtained for most samples. RAVs were detected in the NS3-4A (T54S, V55A, Q80K and R155K), NS5A (Q30H/R, H58P and Y93C/H/N) and NS5B (A421V) regions in 10%, 22% and 8%, respectively, of patients infected with HCV subtype-1a. Among the patients infected with HCV subtype-1b, mutations in the NS3-4A (F43I, T54S, Q80H, D168E and M175L), NS5A (L28M, R30Q, L31M, Q54H, A92T and Y93H) and NS5B (L159F, C316N, A421V and S556G) regions were observed in 12%, 53% and 31% of patients, respectively.

High-throughput DNA sequencing allows an easier and more complete analysis of DAA RAVs, including mutations that represent only a minor variant of the whole viral population. RAVs to the three different classes of DAAs were found in our population. The characterization of their profile in the circulating virus is relevant to determine the better treatment option for infected individuals or to guide the implementation of treatment policies.

Disparities in combined antiretroviral therapy (cART) outcomes have been consistently reported among people living with HIV (PLWHIV). The present study aims at investigating the mechanisms underlying those disparities among PLWHIV in France.

We used data from the Vespa2 survey, a large national cross-sectional survey, representative of HIV-infected people followed at hospitals in 2011. Among participants diagnosed ≥1996, HIV treatment-naive at the time of cART initiation and on cART for at least 12 months, the frequency of sustained virological suppression (SVS; undetectable viral load [<50 copies/ml] for at least 6 months) at the time of the survey, was assessed and its social determinants were measured through logistic regression, accounting for clinical and biological determinants of response to cART.

Among 1,246 participants, 77.7% had achieved SVS. SVS was less frequent among those unemployed (0.6 [range 0.3-1.0]) and those with the lowest level of education (0.4 [range 0.2-0.9]). The late presenters, diagnosed at a CD4⁺ T-cell count <200/mm³ (0.5 [range 0.3-0.9]) and the late starters, diagnosed at a CD4⁺ T-cell count >200 but initiating cART at CD4⁺ T-cell count <200 (0.3 [range 0.1-0.8]) were less likely than the ideal starters (≥350 CD4⁺ T-cells/mm³ at cART initiation) to achieve SVS, as were those who reported suboptimal adherence versus those reporting optimal adherence (0.4 [range 0.2-0.7]). In bivariate analyses, material deprivation, discrimination and a weak social network were also associated with a poorer treatment response.

Structural social factors remain strong determinants of treatment response and should be addressed in a broad approach of care, but wider political issues should also be investigated.

In this Phase IIIb study, we evaluated the efficacy and safety of the oral nucleotide analogue inhibitor sofosbuvir plus ribavirin, with special attention given to viral resistance, in Russian patients with HCV geno-type-1 or -3.

Treatment-naive patients with and without compensated cirrhosis were randomized (1:1) to receive 16 or 24 weeks of once-daily sofosbuvir 400 mg plus twice-daily oral ribavirin 1,000 or 1,200 mg/day. The primary efficacy end point was the proportion of patients with sustained viral response 12 weeks after the end of treatment (SVR12). Viral resistance testing was performed by deep sequencing on all baseline samples and for patients who experienced virological failure.

SVR12 rates for patients with genotype-1 HCV were 50% and 76% for those in the 16-week and 24-week groups, respectively, and for patients with geno-type-3 HCV, SVR12 rates were 87% and 90% for patients in the 16-week and 24-weeks groups, respectively. Geno-type-1 patients with the L159F resistance-associated variant who received 16 weeks of treatment had lower SVR12 rates than those without, but in patients who received 24 weeks of treatment, response rates were similar in those with and without L159F (80% versus 74%). Sofosbuvir plus ribavirin was well tolerated with no deaths, adverse event-related study drug discontinuations, or grade 3 or 4 adverse events, and few grade 3 or 4 laboratory abnormalities.

Sofosbuvir plus ribavirin for 16 or 24 weeks was associated with a high SVR rate in patients with HCV genotype-3. Among HCV genotype-1b patients, the presence of the L159F variant at baseline was associated with a lower SVR rate in those treated for 16 weeks but not in those treated for 24 weeks. Sofosbuvir plus ribavirin was safe and well tolerated regardless of treatment duration. Clinicaltrials.gov number NCT01896193.

Ledipasvir/sofosbuvir ± ribavirin administered for 12 weeks to patients with genotype-1 HCV infection and compensated cirrhosis is effective and well-tolerated. The Phase II TRILOGY-1 and TRILOGY-2 studies investigated whether ledipasvir/sofosbuvir plus the non-nucleotide NS5B inhibitor GS-9669 or the NS3/4A protease inhibitor vedroprevir could reduce treatment duration and/or eliminate the need for ribavirin in genotype-1 HCV-infected patients with compensated cirrhosis.

In TRILOGY-1, 100 cirrhotic patients were randomized (1:1:1) to 8 weeks of ledipasvir/sofosbuvir plus ribavirin, ledipasvir/sofosbuvir plus GS-9669 250 mg or ledipasvir/sofosbuvir plus GS-9669 500 mg. In TRIL-OGY-2, 46 previously treated cirrhotic patients were randomized (1:1) to 8 weeks of ledipasvir/sofosbuvir plus vedroprevir ± ribavirin. The primary end points were the proportion of patients with sustained virological response 12 weeks after treatment discontinuation (SVR12) and safety.

In both studies, most patients were male (each 65%) and white (92–96%), infected with HCV genotype-1a (62–70%) and had IL28B non-CC genotypes (82–87%). In total, 37–39% of patients were Hispanic or Latino. SVR12 rates were similar across treatment arms in TRIL-OGY-1 (82–91%) and TRILOGY-2 (88–95%); no patient had on-treatment virological failure. Two serious adverse events (acute myocardial infarction and cardiomyopathy) were reported in two patients participating in TRILOGY-1, both of whom had pre-existing cardiac conditions. Laboratory abnormalities were infrequent.

All ledipasvir/sofosbuvir-based regimens were well-tolerated. To shorten therapy and eliminate ribavirin, use of a more potent third agent or a third agent with a different mechanism of action may be required.

Nucleoside drug transporter polymorphisms play a significant role in patient responses to drugs. The aim was to investigate the effect of multi-drug resistance protein 4, multi-drug resistance protein 5 and human concentrative nucleoside transporter 1 gene polymorphisms on the response to entecavir treatment in chronic hepatitis B patients.

A total of 324 chronic HBV treatment-naive Chinese Han patients treated with entecavir 0.5 mg daily for 1 year were enrolled. Patients were divided into a response group and non-response group according to the decline of HBV DNA levels. A multiplex SNaPshot single-base extension method was designed for genotyping.

The rs3751333GG genotype of multi-drug resistance protein 4 was significantly different between the response group and non-response group at 6 and 12 months (P=0.005 and P=0.019, respectively). Multivariate analysis showed that the rs37751333GG genotype was significantly associated with responses at 6 and 12 months (odds ratio 2.630, 95% CI 1.391, 4.974, P=0.003; odds ratio 2.968, 95% CI 1.416, 6.221, P=0.004).

The multi-drug resistance protein 4 variant was significantly associated with HBV DNA level suppression in chronic hepatitis B patients treated with entecavir, and therefore, patients with the rs3751333GG genotype might respond better to entecavir in the Chinese Han population.

To determine the frequency and risk factors for falls among middle-aged HIV+ and HIV- women in the Women's Interagency HIV Study (WIHS).

We quantified self-report of any and multiple (≥2) falls in the prior 6 months among 1,412 HIV+ and 650 HIV- women with mean age 48 years. Logistic regression was used to evaluate associations of demographics, behavioural factors, comorbid conditions and medications with odds of any fall (versus none) and multiple falls (versus ≤1 fall).

At least one fall was reported in 263 HIV+ (19%) versus 119 HIV- (18%) women, and ≥2 falls reported in 133 HIV+ (9%) versus 65 HIV- (10%) women. HIV infection was not associated with falls in multivariate analyses. Factors independently associated with any fall included age (adjusted odds ratio [aOR] 1.71, 95% CI 1.17, 2.49 age 50-59 versus <39 years; aOR 2.26, 95% CI 1.38, 3.71 age ≥60 versus <39), current marijuana use (aOR 2.19, 95% CI 1.53, 3.13) depressive symptoms (aOR 1.57, 95% CI 1.21, 2.05 for Center for Epidemiology Studies Depression score ≥16), subjective cognitive complaints (aOR 2.19, 95% CI 1.56, 3.08), neuropathy (aOR 1.59, 95% CI 1.19, 2.13), obesity (aOR 1.39, 95% CI 1.08, 1.80), number of central nervous system active agents (aOR 2.98, 95% CI 1.90, 4.68 for ≥3 agents versus 0) and WIHS site. Factors associated with ≥2 falls included age, marijuana use, number of central nervous system active agents, subjective cognitive complaints, depressive symptoms, neuropathy and study site.

Falls were associated with factors affecting cognition, but not HIV status in this large cohort of women. Longitudinal studies are needed to determine the incidence and consequences of falls by HIV status as women age.

The three drug direct-acting antiviral regimen (3D regimen) of ombitasvir, paritaprevir/ritonavir and dasabuvir, with and without ribavirin, was evaluated in one Phase II trial and six Phase III trials in over 2,300 HCV genotype-1-infected patients. Patients continued taking their protocol-permitted co-medications while receiving the 3D ± ribavirin regimen. The effects of the co-medications on exposures of the 3D regimen and ribavirin were examined.

Population pharmacokinetic model-predicted steady-state area under the curve (AUC_24,ss) values were evaluated in the presence/absence of the co-medications. Interactions resulting in a greater than 50% reduction or 100% increase in an AUC_24,ss value were examined as covariates for an effect on apparent clearance (CL/F).

More than 1,200 co-medications belonging to 15 drug classes and/or 19 enzyme and transporter inhibitor and/or inducer categories were used concomitantly with the 3D regimen in the trials. Approximately 1,500 patients (65%) in Phase III trials received two or more co-medications from multiple drug classes or categories. No co-medication class/category decreased or increased ombitasvir, dasabuvir, ritonavir or ribavirin AUC_24ss by more than half or twofold, respectively. Opioids, antipsychotics, anti-epileptics, antidiabetics and non-ethinyl estradiol-containing hormone replacement therapies appeared to have an effect (AUC_24ss ratio ≤0.5 or ≥2.0) on paritaprevir exposures. However, when these classes were included in the paritaprevir population pharmacokinetic model, only opioids and antidiabetics had a statistically significant effect on CL/F, but with no clinically meaningful increase in exposures (≤55%).

No dose adjustment is necessary for the 3D + ribavirin regimen when used with the co-medications included in this analysis as there were no clinically meaningful effects on exposures of the DAAs.

First-line antiretroviral therapy (1st ART) is an important step in a patient's management and often considered a long-term therapy at treatment initiation.

To describe the duration of 1st ART and the factors associated with treatment modification in a recent real-life setting, antiretroviral-naive patients who began their 1st ART in six French hospitals in 2009– 2012 were included in a cohort. Clinical, immunological, virological and therapeutic data, as well as the reasons for therapeutic changes, if any, were retrospectively collected.

A total of 206 patients started 1st ART, mainly a protease inhibitor-based triple therapy (73%), with a tenofovir-including backbone (87%). Of these, 89 (43%) had their 1st ART modified after a median of 16.5 months (IQR 8.0–32.8). Having a CD4⁺ T-cell count <200 cells/mm³, being pregnant, or 1st ART including zidovudine + lamivudine or lopinavir/r were significantly associated with a higher risk for treatment modification in multivariate analysis. In 47 patients (53%), 1st ART was modified for safety reasons, with no significant association with a given anti-retroviral drug or class. No significant difference in virological, immunological and clinical outcomes was observed between the patients who had their 1st ART modified and those who did not.

The proportion of modifications of the 1st ART during the first 2 years remains high. These modifications are frequently because of safety issues and the willingness to simplify treatment, and less often driven by virological failure, thus emphasizing that 1st ART is not – or is no longer – a lifelong treatment.

The Social Health Clinic at the National Center for HIV/AIDS, Dermatology & STDs (SHC-NCHADS) in Phnom Penh is a major provider of antiretroviral therapy (ART) in Cambodia. However, patient access to viral load monitoring is uncommon. We conducted a cross-sectional evaluation of HIV viral load in SHC-NCHADS patients on ART to determine the proportion experiencing virological failure and to identify factors associated with virological failure in this population.

Patients who had been using their current first-or second-line ART regimen for ≥6 months were eligible. Virological failure was defined as a viral load >1,000 copies/ml, death, lost-to-follow-up or the absence of viral load testing despite presenting for care. Factors associated with virological failure were evaluated using logistic regression.

Overall, 463 patients (53.1% male, median age 42.1 years) were included in the investigation. At the time of current regimen initiation, median CD4⁺ T-cell count was 101 cells/mm³ and 89.0% of patients had experienced a WHO stage III/IV event. At the time of testing/ last clinic visit, 28 (6.0%) patients met our definition of virological failure. Median viral load among those failing was 9,633 copies/ml. Shorter time on current ART regimen, low CD4⁺ T-cell count at the time of viral load testing/last clinic visit and a record of suboptimal adherence were the strongest predictors of virological failure.

This work demonstrates the high rate of viral suppression being achieved by the treatment programme at SHC-NCHADS and the need for future work to phase-in routine viral load monitoring in Cambodia.

Obtaining direct-acting antiviral (DAA) medications for treatment of HCV is labour-intensive for providers. The purpose of this study was to assess the amount of unbillable time and to estimate the financial burden of obtaining DAAs for HCV.

Patients prescribed DAA therapy from 30 September 2014 to 19 March 2015 at an academic hepatology practice were enrolled prospectively. Providers recorded the amount of time required to obtain HCV therapy for each patient.

A total of 79 patients consented, 27 of whom were excluded due to incomplete data or deferment of therapy. In our patient population 56% of patients had private insurance, 27% Medicare and 15% Medicaid. The median time spent per patient was 92.5 min (IQR 80.00–108.80). The median cost spent per patient was $78.85 (IQR 66.75–94.30).

Development of a streamlined process to reduce the time and cost for physicians to obtain DAAs is needed. Removing this barrier will encourage physicians to adopt HCV treatment to address the large number of patients in need.