Antiviral Therapy

In Ethiopia, HBV and HIV are co-circulating. Since patients are not routinely tested for HBV, the use of antiretroviral drugs could contribute to unintended HBV drug resistance and surface gene variability during HIV coinfection.

A total of 161 hepatitis B surface antigen (HBsAg)-positive sera from 58 HIV-coinfected and 103 drug-naive HBV-monoinfected individuals were characterized for HBV drug resistance and immune escape HBsAg variants. HBV polymerase/surface gene fragment of 716 bp was analysed by direct sequencing.

In 34 out of 161 study subjects (21.1%) HBV drug resistance mutations (DRMs) were detected with a frequency of 3.1% rtL80F/I, 0.6% rtA181V, 1.2% rtT184S, 6.2% rtV173L, 10.6% rtL180M, 10.6% rtM204V/I and 8.1% rtI233V. The prevalence of the major DRMs in HBV–HIV-coinfected individuals was significantly higher than monoinfected individuals (41.4% versus 10.7%). Lamivudine selected DRMs, that is, rtL180M (29.3%) and rtM204V/I (29.3%) and rtV173L (15.5%) were more prevalent in HBV–HIV-coinfected individuals but absent in HBV-monoinfected individuals. Despite the finding that rtL180M and rtM204V/I were higher among ART-experienced individuals, the overall prevalence of DRMs (48.0% versus 36.4%) showed no significance difference among antiretroviral therapy (ART) status. The study also revealed higher frequency and heterogeneity of putative and known immune escape HBsAg mutations both in the major hydrophilic region (MHR; 68.3%) and outside the MHR (82.5%) of the surface gene. In particular, the ‘a’ determinant surface gene mutations (sT125S, sA128V, sQ129H/R, sT131I, sC137S, sT143M, sD144D/E, sG145R, sT148P) and the majority of clustered/multiple as well as drug selected immune escape HBsAg mutations were more prevalent in HBV–HIV-coinfected individuals.

HIV therapy without HBV co-management in Ethiopia fosters emergence and circulation of HBV variants of public health importance. It is highly recommended to include HBV testing and co-management as part of routine HIV care programmes for a better ART selection.

The role of oxidized lipoproteins (high-density [HDLox] and low-density [LDLox]) and total lipoprotein particle (Lp) number and size in HIV-related cardiovascular disease (CVD) is unclear. The goal of this study was to evaluate changes of these biomarkers and their associations with rate of carotid intima media thickness progression over 3 years (ΔCIMT) in chronic HIV infection.

Prospective study of 234 HIV-infected anti-retroviral treatment-naive participants without CVD who were randomized to receive tenofovir-emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir or raltegravir (RAL) and achieved plasma HIV-1 RNA <50 copies/ml by week 24 and thereafter. Biomarker changes over 24, 48 or 96 weeks from baseline and pairwise treatment group comparisons were examined. Associations of these bio-markers with δCIMT were analysed with mixed effects linear regression.

HDLp number increased with both protease inhibitors (PIs) over 48 weeks, while LDLp number declined with RAL; Lp size did not change. Over 96 weeks, normalized HDLox declined with both PIs; LDLox increased in all groups. Few treatment group differences were observed across all biomarkers. Associations between ΔCIMT and oxidized lipoproteins at all time points were not apparent (P≥0.10). There was some evidence of slower ΔCIMT for higher HDLp number (P=0.06) and for lower LDLp number (P=0.08) measured at baseline.

Unexpectedly, LDLox increased modestly in all treatment groups after ART initiation. Associations of plasma HDLox and LDLox with ΔCIMT were not apparent. While plasma levels of abnormal lipoproteins have been shown to be associated with CVD outcomes, clear associations with sub-clinical atherosclerosis progression were not apparent in our study.

Chest imaging is performed for a variety of reasons in HIV-infected adults. There are limited data on the prevalence of incidental findings, progression of these findings over time and the relationship with inflammation in antiretroviral therapy (ART)-treated HIV-infected adults.

This study utilized data from a randomized clinical trial of rosuvastatin in HIV-infected adults on ART. Incidental findings were reported from chest computed tomography (CT) scans obtained for coronary artery calcium score at entry, week 48 and 96. Markers of immune activation and inflammation were measured concurrently. Poisson regression and generalized estimating equations were used.

A total of 147 participants were enrolled. Median age was 46 years, 78% were male, 68% African American and 63% current smokers. At baseline, 57% of participants had at least one incidental lung finding (ILF) and four additional participants had at least one ILF by week 96. At baseline, older age, current smoking, lower nadir CD4⁺ T-cell count and low-density lipoprotein and higher lipoprotein-associated phospholipase A2 (Lp-PLA2) were independently associated with having a greater number of ILFs. In the longitudinal analyses, older age, lower nadir CD4⁺ T-cell count and higher baseline soluble tumour necrosis factor α-receptor I (sTNF-RI) were independently associated with having a greater number of ILFs over 96 weeks.

Over half of participants had at least one incidental finding on chest CT. Beyond traditional factors of older age and smoking, lower nadir CD4⁺ T-cell count and higher markers of inflammation were associated with having a greater number of ILFs in HIV-infected adults on ART.

The scaling-up of access to antiretroviral therapy, particularly in low- to middle-income countries, was facilitated by the introduction and widespread use of generic antiretroviral medicines and fixed-dose combinations. Generic medicines are approved by regulatory authorities based on the demonstration of bioequivalence with the innovator or reference product, as well as meeting quality standards. In clinical practice, however, it is not unusual for generics to be interchanged between each other. This study investigated the differences in bioavail-ability between WHO-prequalified first-line antiretroviral generics by means of adjusted indirect comparisons to ensure interchangeability between these generics.

Data on 34 products containing emtricitabine, tenofovir disoproxil fumarate, lamivudine and efavirenz in single formulations or fixed-dose combinations were included in the analysis. The 90% CI for the adjusted indirect comparisons was calculated using the homoscedastic method that uses the conventional t-test, and assumes homogeneity of variances between the studies and small sample sizes. The combined standard deviation of both bioequivalence studies was calculated from the variability of each individual study.

The adjusted indirect comparisons between generics showed that the differences, expressed as 90% CIs, are less than 30%. Confidence in the interchange-ability of two generic products was reduced if the mean difference between the test and reference in the original studies is more than 10%.

From a bioequivalence perspective, the generic antiretroviral medicines prequalified by WHO are interchangeable with the reference, as well as between each other without safety or efficacy concerns.

We aimed to measure the effect of raltegravir (RAL) on insulin sensitivity and surrogates of cardiovascular risk in healthy HIV-seronegative volunteers compared to that of lopinavir/r (LPV/r), a positive control.

An open-label, two phase crossover study in HIV-negative male subjects randomized 1:1 to receive either 2 weeks of LPV/r followed by a 2-week washout period and 2 weeks of RAL, or RAL initially followed by LPV/r. A hyperinsulinaemic euglycaemic clamp was performed prior to and following each 2-week dosing phase. Fasting samples for lipids, adiponectin, leptin, vascular inflammatory biomarkers and CD36 were also taken.

A total of 16 subjects completed the study. At the baseline visit the mean insulin-stimulated glucose disposal per unit insulin (M/I) was 7.97 and 8.30 for LPV/r and RAL, respectively. The mean (sem) percentage change from baseline was -16.10% (3.84) after 2 weeks of LPV/r and -0.43% (4.83) after 2 weeks of RAL. Absolute M/I was 25% lower for LPV/r than for RAL (P=0.001). Triglycerides and total cholesterol rose significantly with LPV/r (+0.5 mmol/l, P=0.002 and +0.4 mmol/l, P<0.0001), but were unchanged with RAL. Proathrogenic lipid subfractions of low-density lipoprotein (LDL) cholesterol increased with LPV/r and were unaffected with RAL. LDL peak and mean particle diameter and LDL I significantly decreased with LPV/r (P<0.05), and trend of increased LDL III was detected. High-sensitivity C-reactive protein declined with RAL (-0.2 mg/l, P=0.043) but was elevated after LPV/r (+0.25 mg/l, P=0.03).

RAL was not associated with measurable change in glycaemic, metabolic or inflammatory effects.

HIV infection is accompanied by various systemic host responses, including activation of coagulation and the vascular endothelium. We sought to determine the impact of opportunistic coinfections in a central African setting.

This prospective study included 98 HIV-infected individuals in Gabon initiating combination antiretroviral therapy (cART) and followed them up for 6 months. Patients were stratified according to the presence of active tuberculosis (TB; n=19), mucocutaneous opportunistic infection (n=9) or no opportunistic infection (n=70). HIV-uninfected subjects were included as controls (n=32). Plasma concentrations of 14 markers of coagulation, endothelial activation, extracellular matrix formation and tissue damage were measured with a multiplex assay at baseline and months 3 and 6 after cART initiation.

HIV-infected patients showed elevated plasma levels of all biomarkers measured with exception of protein C, which was reduced. Concurrent TB was only associated with elevated concentrations of D-dimer, metal-lopeptidase inhibitor 1 and Tenascin-C. Mucocutaneous coinfection did not alter HIV-associated responses. Most markers measured declined but remained elevated despite response to cART.

HIV infection is associated with systemic pro-coagulant, vascular and damage responses. In an ambulatory setting, concurrent opportunistic infections have little if any influence on these responses and normalization is incomplete after response to cART. This suggests that these responses are mainly driven by HIV-associated immune activation and less so by opportunistic infections.

Any strategy designed to decrease the macrophage content in adipose tissue (AT) is of great value as a way to decrease inflammation in this fat depot and also as a way to prevent or treat obesity and associated disorders. Maraviroc (MVC), a CCR5 antagonist approved for the treatment of HIV-infected patients, has beneficial effects on metabolism. The objective of this study was to investigate the effects of MVC on AT macrophage recruitment in a mouse model of obesity. The plausible underlying mechanisms of action were also investigated.

32 male C57BL/6 mice were randomly assigned to the following groups: control, MVC (300 mg/l MVC in drinking water), high-fat diet (HFD) or HFD+MVC. After 16 weeks of treatment, histopathological and molecular analyses were performed on epididymal fat.

Our results demonstrated that MVC reduced the presence of macrophages in epididymal fat despite the ingestion of an HFD. The inhibition of MCP-1 gene expression and JNK signalling pathway along with the upregulation of protective cytokines such as cardiotrophin-1 could contribute to these actions. MVC effects on AT macrophage recruitment were associated with a lower body weight gain and a partial improvement in insulin resistance despite an HFD.

We have demonstrated the ability of MVC to ameliorate the increased AT macrophage recruitment induced by an HFD in a mouse model of obesity. These actions could be of interest when designing antiretroviral treatments in HIV-patients.

The potential toxicity of long-term anti-retroviral therapy (ART) requires ongoing investigation of novel strategies for treatment of HIV-infected patients. Monotherapy with the integrase inhibitor (INSTI) dolutegravir (DTG) may offer a favourable safety profile. Additionally, DTG has a high barrier of resistance, crucial for successful maintenance of virological control. However, published data is sparse.

Retrospective, single-centre cohort study. We enrolled patients on suppressive ART who were switched to DTG monotherapy in routine clinical practice and fulfilled the following inclusion criteria: HIV RNA level <50 copies/ml for ≥6 months at time of switch (one blip <200 copies/ml with re-suppression accepted), no known INSTI resistance or prior INSTI failure, no replicative HBV infection and no history of AIDS.

We identified 31 patients with 24-weeks of follow-up data. Previous ART included a non-nucleoside reverse transcriptase inhibitor, a boosted protease inhibitor or an INSTI in 32%, 6% and 61% of patients, respectively. At week 24, HIV RNA remained <50 copies/ml in all but two patients (94%). One patient chose to discontinue DTG monotherapy and another developed confirmed virological failure (HIV RNA 538 copies/ml) with new INSTI mutations (Q148H/G140S). Immune status and renal and metabolic function showed no statistically significant changes, apart from a significant decrease in gamma-glutamyl transferase.

De-escalating to DTG monotherapy in selected patients might be a safe and feasible option. However, in one case evolution of INSTI resistance was observed. Further studies should assess particular risk factors for DTG mono-therapy failure. In the meanwhile, caution is warranted.

To describe direct medical costs of influenza in hospitalized elderly, with and without intensive care unit (ICU) admission, during the 2014–2015 season in Hong Kong.

A retrospective study was conducted in 110 inpatients aged ≥65 years with laboratory-confirmed influenza treated by antiviral therapy during season 2014–2015 in a tertiary hospital. Resource utilization of influenza-related diagnostic and laboratory tests, medications for influenza treatment, usage of general medical ward and ICU during the influenza-related length of hospital stay (IR-LOS) were collected.

There were 18 (16.4%) and 92 (83.4%) cases with and without ICU admission, respectively. The difference in influenza-related mortality rates between patients with (11.1%) and without ICU admission (2.2%) was not statistically significant (P=0.064). Patients with ICU admission reported longer IR-LOS (12.7 ±6.0 days versus 5.5 ±2.7 days; P<0.001) and higher direct costs (36,588 USD ±21,482 versus 5,773 USD ±2,017; P<0.001; 1 USD=7.8 HKD). Male gender (OR=14.50; 95% CI 1.68, 125.07) and respiratory complications (OR=9.61; 95% CI 1.90, 48.50) were positive predictors of ICU admission. Age ≥70 years (OR=0.09; 95% CI 0.02, 0.46) and antiviral therapy initiation within 7 days (OR=0.05; 95% CI 0.003, 0.79) were negative predictors of ICU admission. Influenza B was a positive predictor of high-cost hospitalization in non-ICU survivors (OR=7.33; 95% CI 1.24, 43.29). No predictor of mortality was identified.

Hospitalization cost in elderly for seasonal influenza was substantial in Hong Kong. The cost in patients with ICU admission was significantly higher than those without ICU care. Respiratory complications and male gender predicted ICU admission. Influenza B infection predicted high-cost hospitalization in non-ICU survivors.