Antiviral Therapy

To analyse the effect of drug resistance mutations (DRM) on CD4⁺ T-cell (CD4) trends in HIV-positive people maintained on virologically failing anti-retroviral therapy (ART).

Individuals from two large cohorts experiencing virological failure (VF) while maintained on ART with ≥1 CD4 count and ≥1 resistance test were included. CD4 slopes were estimated using linear mixed models. Principal component analysis (PCA) was used to assess the effect of clusters of mutations, defined using extracted component based scores from the PCA, on CD4 decline.

5,357 individuals contributing 7,661 VF episodes were included: any DRM were detected in 88.8% of episodes. After adjustment, CD4 counts declined less steeply during episodes where DRM were detected compared to episodes with no DRM (difference =28 cells/mm³/year, 95% CI =18, 39; P<0.001). Among individuals with at least one DRM, we found evidence that any nucleoside/ nucleotide reverse transcriptase inhibitor (NRTI) resistance, the reverse transcriptase (RT) mutations M184V, D67N and T215Y as well as the protease mutations V82A and I54V were associated with reduced CD4 declines. The detection of any non-nucleoside reverse transcriptase inhibitor resistance, the RT mutations V179D and L74V were associated with steeper CD4 declines. The presence of some mutation patterns similar to the clusters identified by the PCA also affected the CD4 decline.

Detection of resistance and of certain DRM during VF of ART has a small but significant favourable effect on CD4 decline.

Potent antiretroviral treatment has resulted in near normal life expectancy for people living with HIV. Consequently, there is an increased focus on comorbidities, frailty and quality of life.

We assessed and compared the prevalence of frailty, associated factors and relationship with quality of life in older Australian men living with HIV in a cross-sectional study using three frailty measurements. The Frailty Phenotype, Frailty Index and Edmonton Frail Scale were applied to 93 HIV-infected men aged over 50 years, on antiretroviral therapy. Multivariable ordinal logistic regression was used to analyse the associations of frailty with covariates and quality of life.

The prevalence of frailty was 10.8% (n=10) using the Frailty Phenotype; 22.6% (n=21) using the Frailty Index and 15.1% (n=14) using the Edmonton Frail Scale. Frailty Phenotype-defined pre-frailty/frailty was associated with pre-1996 ART initiation (OR, 3.56; CI, 1.23, 10.36; P=0.020) and depression (OR, 3.74; CI, 1.24, 11.27; P=0.019). Osteoporosis, serious non-AIDS events and AIDS were associated with Frailty Index-defined frailty (OR, 4.84, CI, 1.27, 18.43, P=0.021; OR, 4.27, CI, 1.25, 14.58, P=0.020; OR, 4.62, CI, 1.30, 16.45, P=0.018, respectively) and Edmonton Frail Scale-defined frailty (OR, 7.51; CI, 1.55, 36.42; P=0.012; OR, 7.71; CI, 1.62, 36.75; P=0.010; OR, 8.53; CI, 1.70, 42.73; P=0.009, respectively), independent of age and current CD4⁺ T-cell count. Frailty, defined by any of the instruments, was significantly associated with poorer quality of life (P<0.001).

Identifying frailty is an increasingly important contemporary consideration of HIV care related to ageing and quality of life.

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. The aim of the present study was to evaluate the sustained virological response (SVR) impact on LSM and clinical parameters of DAA-therapy on a real-life population of HCV patients with F3/F4 fibrosis.

A total of 749 HCV genotype 1–4 patients with F3/F4 hepatitis undergoing antiviral therapy were consecutively enrolled in four centres of hepatology in Italy. Clinical, biochemical and imaging data were collected at the baseline (T0), at the end of treatment (EoT) and after 12 weeks (SVR12).

Out of 749 patients, 69.7% were F4 and 30.3% were 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= not significant). Moreover, in F4 no significant differences were found in Child and MELD between T0, EoT and SVR12 (P= not significant). At the univariate analysis of clinical and liver parameters, baseline high glucose (P<0.005), type 2 diabetes (P<0.001), low alanine aminotransferase (ALT; P<0.001), low platelets (P<0.005), and the presence of esophageal varices (EV; P<0.001) were found to be associated with a lack of a significant EoT LSM improvement. At multiple regression, ALT (P<0.05), diabetes (P<0.005) and EV (P<0.05) were inversely associated with significant LSM reduction.

Virological response to DAA is associated with fibrosis regression and recovery of liver functionality and this can be detected as early as EoT. HCV eradication is associated with a rapid and significant clinical improvement that lasts over time and seems to be negatively influenced by diabetes and EV.

Few data are available about efficacy and durability of simplification from multi-tablet antiretroviral regimens to co-formulated efavirenz (EFV)/emtricitabine (FTC)/tenofovir (TDF) versus rilpivirine (RPV)/FTC/TDF in virologically suppressed HIV-1-infected patients.

We retrospectively analysed HIV-infected patients with HIV RNA <50 copies/ml switching to co-formulated EFV/FTC/TDF or RPV/FTC/TDF at five Italian centres. Patients were followed from time of switch until regimen discontinuation or a maximum of 3-years follow-up. Time to treatment discontinuation (TD) and virological failure (VF; defined as two consecutive HIV RNA >50 copies/ml or a single determination >1,000 copies/ml) and their predictors were investigated.

1,560 patients were reviewed of which 1,097 (70%) switched to EFV/FTC/TDF and 463 (30%) to RPV/FTC/TDF. During follow-up, VF and TD occurred in 44 (4%) and 242 (22%) patients in EFV/FTC/TDF and in 29 (6%) and 50 (11%) patients in RPV/FTC/TDF, respectively. The 3-year estimated probability of remaining free from VF was 96.2% with EFV/FTC/TDF versus 92.7% with RPV/FTC/TDF (P=0.003). At multivariate analysis, regimen type (EFV/FTC/TDF versus RPV/FTC/TDF aHR 0.24; P=0.004) and time of virological suppression (aHR 0.85; P=0.048) were the only independent predictors of VF. The estimated 3-year probability of remaining free from TD was 77.4% with EFV/FTC/TDF versus 88.4% with RPV/FTC/TDF (P=0.001). Predictors of TD were female sex, switching from PI-based regimens, older age, shorter time of virological suppression and regimen type (EFV/FTC/TDF versus RPV/FTC/TDF aHR 2.48; P<0.001). RPV/FTC/TDF showed a safer lipid profile and a greater increase in creatinine.

Both regimens showed good safety and efficacy in this real-life setting, although switch to RPV/ FTC/TDF seemed better tolerated while EFV/FTC/TDF was associated with a lower probability of VF.

According to current recommendations diagnosis and management of HCV infection need detection and quantification of nucleic acids. In the era of direct-acting antivirals (DAA) it is essential to develop an inexpensive and simple method replacing polymerase chain reaction. Since there is no available data on HCV core antigen (HCVcAg) versus HCV RNA kinetics in the early phase of treatment with DAA, we carried out this study to evaluate the possible application of HCVcAg quantitative measurement for management of HCV infection.

33 patients with HCV infection were enrolled and treated with either ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PRV/r±DSV±RBV) or ledipasvir/ sofosbuvir (LDV/SOF). Samples for quantitative HCV RNA and HCVcAg measurement were collected at the baseline, after 1, 7, 28 days and at the end of treatment, and then after 12 and 24 weeks of post-treatment follow-up.

There was positive correlation between HCVcAg and HCV RNA levels at the baseline and after 1 day of treatment. Mean HCVcAg concentration declined faster than HCV RNA levels during the treatment phase. At week 4 HCV RNA was undetectable in 24, whereas HCVcAg in 28 patients. At the end of treatment and after 12 weeks of follow-up all patients were undetectable for both HCV RNA and HCVcAg.

HCVcAg concentration and its early on-treatment testing can predict virological response. Simple testing procedures and significantly lower cost compared to HCV RNA testing support possible replacement of the viral load measurement in management of the majority of HCV-infected patients.

Laninamivir octanoate is a recently developed inhaled neuraminidase inhibitor for treating influenza virus infection. We performed meta-analyses to clarify the efficacy of laninamivir octanoate on influenza treatment and prevention.

MEDLINE and CENTRAL were searched to identify eligible studies. The log median time to event ratios (logMRs) and log odds ratios (logORs) were combined with meta-analysis.

Nine studies in treatment settings and three studies in prophylaxis settings were eligible for this meta-analysis. There was no significant difference between laninamivir octanoate and oseltamivir (8 studies, logMR 0.04, 95% CI [-0.05, 0.14]; P=0.36) or zanamivir (4 studies, logMR -0.01, 95% CI [-0.12, 0.11]; P=0.93) in alleviating fever. However, laninamivir octanoate was associated with significantly longer fever duration in treating H3N2 influenza as compared to oseltamivir (4 studies, logMR 0.29, 95% CI [0.00, 0.59]; P=0.047). Laninamivir octanoate was associated with significantly longer duration of fever as compared to peramivir (4 studies, logMR 0.46, 95% CI [0.14, 0.77]; P=0.004). Laninamivir octanoate significantly reduced the incidence of clinical influenza in post-exposure settings (3 studies, logOR -1.17, 95% CI [-1.72, -0.62]; P<0.001).

Overall, the efficacy of laninamivir octanoate in treating influenza was comparable to that of oseltamivir or zanamivir, but it should be noted that laninamivir octanoate was associated with significantly longer fever duration in treating influenza H3N2 as compared to oseltamivir and oseltamivir-resistant mutations in seasonal influenza H1N1 might have affected the results. Peramivir may be superior to laninamivir in treating influenza. Laninamivir octanoate is effective in preventing influenza in post-exposure settings as compared to placebo.

The durability of first-line regimen is important to achieve long-term treatment success for the management of HIV infection. Our analysis describes the duration of sequential ART regimens and identifies the determinants leading to treatment change in HIV-positive patients initiating in Asia.

All HIV-positive adult patients initiating first-line ART in 2003–2013, from eight clinical sites among seven countries in Asia. Patient follow-up was to May 2014. Kaplan–Meier curves were used to estimate the time to second-line ART and third-line ART regimen. Factors associated with treatment durability were assessed using Cox proportional hazards model.

A total of 16,962 patients initiated first-line ART. Of these, 4,336 patients initiated second-line ART over 38,798 person-years (pys), a crude rate of 11.2 (95% CI 10.8, 11.5) per 100 pys. The probability of being on first-line ART increased from 83.7% (95% CI 82.1, 85.1%) in 2003–2005 to 87.9% (95% CI 87.1, 88.6%) in 2010–2013. Third-line ART was initiated by 1,135 patients over 8,078 pys, a crude rate of 14.0 (95% CI 13.3, 14.9) per 100 pys. The probability of continuing second-line ART significantly increased from 64.9% (95% CI 58.5, 70.6%) in 2003–2005 to 86.2% (95% CI 84.7, 87.6%) in 2010–2013.

Rates of discontinuation of first- and second-line regimens have decreased over the last decade in Asia. Subsequent regimens were of shorter duration compared to the first-line regimen initiated in the same year period. Lower CD4⁺ T-cell count and the use of suboptimal regimens were important factors associated with higher risk of treatment switch.

Although fracture rates are higher in HIV+ than HIV- women, whether HIV infection increases risk of falls is unclear. We determined the longitudinal occurrence and risk factors for falls in the Women's Interagency HIV Study (WIHS), and explored associations with cognitive complaints.

Recent (prior 6 months) self-reported falls were collected in 1,816 (1,250 HIV+; 566 HIV-) women over 24 months. Generalized estimating equation models using stepwise selection determined odds of any fall (versus none).

HIV+ women were older than HIV- women (median 49 versus 47 years; P=0.0004), more likely to report neuropathy (20% versus 16%; P=0.023), and had greater central nervous system (CNS) medication use. At least one fall was reported in 41% HIV+ versus 42% HIV- women, including ≥2 falls in 25% HIV+ and 24% HIV-(overall P=0.30). Cognitive complaints were associated with falls among HIV+ (odds ratio [OR] 2.38; 95% CI 1.83, 3.09) and HIV- women (OR 3.43; 95% CI 2.37, 4.97); in adjusted models, cognitive complaints remained significant only in HIV- women (adjusted [aOR] 2.26; 95% CI 1.46, 3.48). Factors associated with any fall in adjusted analyses included: depressive symptoms and neuropathy (both HIV+ and HIV-); age, marijuana use, multiple CNS medications, and HCV infection (HIV+ only); and cognitive complaints, quality of life, hypertension and obesity (HIV- only).

Middle-aged HIV+ and HIV- women had similar fall rates. Among HIV+ women, factors affecting cognition such as age, depressive symptoms, marijuana use and multiple CNS medications were important predictors of falls, however, cognitive complaints were not.

HIV is transmitted primarily through sexual intercourse, and the objective of this study was therefore to assess whether there is occult viral replication and resistance in genital secretions in patients on protease inhibitor (PI)-based second-line therapy.

HIV-infected adults taking ritonavir-boosted lopinavir with either two nucleoside reverse transcriptase inhibitors (NRTIs), raltegravir or as monotherapy for 96 weeks, were enrolled at seven clinical sites in Uganda. Viral load (VL) was measured in cervico-vaginal secretions or semen and in a corresponding plasma sample. Genotypic resistance was assessed in genital secretion samples and plasma samples. Results were compared between compartments and with the plasma resistance profile at first-line failure.

Of the 111 participants enrolled (91 female, 20 male), 16 (14%) and 30 (27%) had VL >1,000 and >40 copies/ml, respectively, in plasma; 3 (3%) and 23 (21%) had VL >1,000 copies/ml and >40 copies/ml, respectively, in genital secretions. There was 74% agreement between plasma and genital secretion VL classification above/below 40 copies/ml threshold (kappa-statistic =0.29; P=0.001). RT mutations (both NRTI and non-nucleoside reverse transcriptase inhibitor) were detected in genital secretions in four patients (similar profile to corresponding plasma sample at first-line failure) and PI mutations were detected in two (one polymorphism with no impact on resistance; one with high-level PI resistance).

High level (>1,000 copies/ml) viral replication and development of new RT or PI resistance in the genital compartment were rare. The risks of transmission arising from resistance evolution in the genital compartment are likely to be low on PI-based second-line therapy.