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BACKGROUND: In a randomized, placebo-controlled, clinical trial, bamlanivimab, a SARS-CoV-2-neutralizing monoclonal antibody, given in combination with remdesivir, did not improve outcomes among hospitalized patients with COVID-19 based on an early futility assessment.OBJECTIVE: To evaluate the a priori hypothesis that bamlanivimab has greater benefit in patients without detectable levels of endogenous neutralizing antibody (nAb) at study entry than in those with antibodies, especially if viral levels are high.DESIGN: Randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT04501978).SETTING: Multicenter trial.PATIENTS: Hospitalized patients with COVID-19 without end-organ failure.INTERVENTION: Bamlanivimab (7000 mg) or placebo.MEASUREMENTS: Antibody, antigen, and viral RNA levels were centrally measured on stored specimens collected at baseline. Patients were followed for 90 days for sustained recovery (defined as discharge to home and remaining home for 14 consecutive days) and a composite safety outcome (death, serious adverse events, organ failure, or serious infections).RESULTS: Among 314 participants (163 receiving bamlanivimab and 151 placebo), the median time to sustained recovery was 19 days and did not differ between the bamlanivimab and placebo groups (subhazard ratio [sHR], 0.99 [95% CI, 0.79 to 1.22]; sHR > 1 favors bamlanivimab). At entry, 50% evidenced production of anti-spike nAbs; 50% had SARS-CoV-2 nucleocapsid plasma antigen levels of at least 1000 ng/L. Among those without and with nAbs at study entry, the sHRs were 1.24 (CI, 0.90 to 1.70) and 0.74 (CI, 0.54 to 1.00), respectively (nominal P for interaction = 0.018). The sHR (bamlanivimab vs. placebo) was also more than 1 for those with plasma antigen or nasal viral RNA levels above median level at entry and was greatest for those without antibodies and with elevated levels of antigen (sHR, 1.48 [CI, 0.99 to 2.23]) or viral RNA (sHR, 1.89 [CI, 1.23 to 2.91]). Hazard ratios for the composite safety outcome (LIMITATION: Subgroup analysis of a trial prematurely stopped because of futility; small sample size; multiple subgroups analyzed.CONCLUSION: Efficacy and safety of bamlanivimab may differ depending on whether an endogenous nAb response has been mounted. The limited sample size of the study does not allow firm conclusions based on these findings, and further independent trials are required that assess other types of passive immune therapies in the same patient setting.PRIMARY FUNDING SOURCE: U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.

Tracheostomy is an established tool for the management of the critically ill. The dominant indication is to facilitate weaning from invasive respiratory support, and it is no surprise that the COVID-19 pandemic has seen a rapid increase in the use of tracheostomy in the critically ill, rising from around 12% to around 20% of all ventilated admissions. The pandemic has thrown a spotlight onto existing and unanswered questions around tracheostomy candidacy, timing, technique and optimal post-procedural care. However, the very nature of tracheostomy insertion and subsequent management risks of aerosolization of potentially infectious particles, bringing new questions particularly focused on providing timely, high-quality care while protecting healthcare workers. A new paradigm has emerged where strategies are needed to balance the needs of the workforce as well as the needs of the patient and their families. This state-of-the-art review of tracheostomy care during the pandemic examines the emerging literature built on best practices, informed by global collaboration and quality improvements. As we learn more about COVID-19 disease and reflect on adaptations to practice, critical care staff can continue to provide the high quality, safe and efficient care—for their patients and for their staff.

Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 patients (n = 123), non-COVID-19 ICU sepsis patients (n = 25) and healthy controls (n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia is associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22–2.77] adjusted for age and sex). RNAemia is comparable in performance to the best protein predictors. Mannose binding lectin 2 and pentraxin-3 (PTX3), two activators of the complement pathway of the innate immune system, are positively associated with mortality. Machine learning identified ‘Age, RNAemia’ and ‘Age, PTX3’ as the best binary signatures associated with 28-day ICU mortality. In longitudinal comparisons, COVID-19 ICU patients have a distinct proteomic trajectory associated with mortality, with recovery of many liver-derived proteins indicating survival. Finally, proteins of the complement system and galectin-3-binding protein (LGALS3BP) are identified as interaction partners of SARS-CoV-2 spike glycoprotein. LGALS3BP overexpression inhibits spike-pseudoparticle uptake and spike-induced cell-cell fusion in vitro., Here the authors use RT-qPCR and mass spectrometry to analyze longitudinal blood samples from intensive care unit (ICU) COVID-19 patients and controls. They find that viral RNA and pentraxin-3 predict 28-day ICU mortality and that galectin-3-binding protein is an interaction partner of SARS-CoV-2 spike glycoprotein with antiviral properties.

BACKGROUND: One strategy being pursued to clear latently infected cells that persist in people living with HIV (PLWH) on antiretroviral therapy (ART) is to activate latent HIV infection with a latency reversing agent (LRA). Surrogate markers that accurately measure virus production following an LRA are needed.METHODS: We quantified cell-associated unspliced (US), multiply spliced (MS) and supernatant (SN) HIV RNA by qPCR from total and resting CD4+ T cells isolated from seven PLWH on ART before and after treatment ex vivo with different LRAs, including histone deacetylase inhibitors (HDACi). MS and plasma HIV RNA were also quantified from PLWH on ART (n-11) who received the HDACi panobinostat.FINDINGS: In total and resting CD4+ T cells from PLWH on ART, detection of US RNA was common while detection of MS RNA was infrequent. Primers used to detect MS RNA, in contrast to US RNA, bound sites of the viral genome that are commonly mutated or deleted in PLWH on ART. Following ex vivo stimulation with LRAs, we identified a strong correlation between the fold change increase in SN and MS RNA, but not the fold change increase in SN and US RNA. In PLWH on ART who received panobinostat, MS RNA was significantly higher in samples with detectable compared to non0detectable plasma HIV RNA.INTERPRETATION: Following administration of an LRA, quantification of MS RNA is more likely to reflect an increase in virion production and is therefore a better indicator of meaningful latency reversal.FUNDING: NHMRC, NIH DARE collaboratory.

International audience; BACKGROUND: An efavirenz-based regimen (with a 600-mg dose of efavirenz, known as EFV600) was the World Health Organization preferred first-line treatment for human immunodeficiency virus type 1 (HIV-1) infection until June 2018. Given concerns about side effects, dolutegravir-based and low-dose efavirenz-based combinations have been considered as first-line treatments for HIV-1 in resource-limited settings.METHODS: We conducted an open-label, multicenter, randomized, phase 3 noninferiority trial in Cameroon. Adults with HIV-1 infection who had not received antiretroviral therapy and had an HIV-1 RNA level (viral load) of at least 1000 copies per milliliter were randomly assigned to receive either dolutegravir or the reference treatment of low-dose efavirenz (a 400-mg dose, known as EFV400), combined with tenofovir and lamivudine. The primary end point was the proportion of participants with a viral load of less than 50 copies per milliliter at week 48, on the basis of the Food and Drug Administration snapshot algorithm. The difference between treatment groups was calculated, and noninferiority was tested with a margin of 10 percentage points.RESULTS: A total of 613 participants received at least one dose of the assigned regimen. At week 48, a viral load of less than 50 copies per milliliter was observed in 231 of 310 participants (74.5%) in the dolutegravir group and in 209 of 303 participants (69.0%) in the EFV400 group, with a difference of 5.5 percentage points (95% confidence interval [CI], -1.6 to 12.7; P1000 copies per milliliter) was observed in 3 participants in the dolutegravir group (with none acquiring drug-resistance mutations) and in 16 participants in the EFV400 group. More weight gain was observed in the dolutegravir group than in the EFV400 group (median weight gain, 5.0 kg vs. 3.0 kg; incidence of obesity, 12.3% vs. 5.4%).CONCLUSIONS: In HIV-1-infected adults in Cameroon, a dolutegravir-based regimen was noninferior to an EFV400-based reference regimen with regard to viral suppression at week 48. Among participants who had a viral load of at least 100,000 copies per milliliter when antiretroviral therapy was initiated, fewer participants than expected had viral suppression. (Funded by Unitaid and the French National Agency for AIDS Research; NAMSAL ANRS 12313 ClinicalTrials.gov number, NCT02777229.).

Summary Background Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults. Methods We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of −10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively. Findings Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −2·6%, 95% CI −6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −0·7%, 95% CI −4·3 to 2·9), showing non-inferiority at a −10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference −1·7%, 95% CI −4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication. Interpretation The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection. Funding ViiV Healthcare.

Fever is the leading cause of paediatric outpatient consultations in Sub-Saharan Africa. Although most are suspected to be of viral origin, a putative causative pathogen is not identified in over a quarter of these febrile episodes. Using a de novo assembly sequencing approach, we report the detection (15.4%) of dicistroviruses (DicV) RNA in sera collected from 692 febrile Tanzanian children. In contrast, DicV RNA was only detected in 1/77 (1.3%) plasma samples from febrile Tanzanian adults, suggesting that children could represent the primary susceptible population. Estimated viral load by specific quantitative real-time RT–PCR assay ranged from < 1.32E3 to 1.44E7 viral RNA copies/mL serum. Three DicV full-length genomes were obtained, and a phylogenetic analyse on the capsid region showed the presence of two clusters representing tentative novel genus. Although DicV-positive cases were detected throughout the year, a significantly higher positivity rate was observed during the rainy season. This study reveals that novel DicV RNA is frequently detected in the blood of Tanzanian children, paving the way for further investigations to determine if DicV possibly represent a new agent in humans.

Objectives: To evaluate and compare the performance of six HIV-RNA-based quality of care indicators for predicting short-term and long-term outcomes. Design: Multinational cohort study. Methods: We included EuroSIDA patients on antiretroviral therapy (ART) with at least three viral load measurements after baseline (the latest of 01/01/2001 or entry into EuroSIDA). Using multivariate Poisson regression, we modelled the association between short-term (resistance, triple-class failure) and long-term (all-cause mortality, any AIDS/non-AIDS clinical event) outcomes and the indicators: viraemia copy years; consecutive months with viral load ≥50 copies/ml; percentage of time on ART spent fully suppressed (%FS); stable on ART; 48 weeks snapshot; and current viral load. Indicators were compared using area under the ROC curve (AUC) and different measures of model fit. Results: Adjusted incidence rate ratios for all outcomes tended to increase with increasing viraemia copy years, number of consecutive months with viral load ≥50 copies/ml, current viral load and with lower %FS, but the gradient of increased risk was weak across strata. None of the indicators reliably identified those at risk of long-term outcomes (AUC 0.54-0.58), but performed consistently better with short-term outcomes [triple class failure (AUC 0.67-0.76) and resistance (AUC 0.64-0.79)]. Goodness of fit varied with the outcome evaluated, but differences between indicators were small. Conclusion: Differences between quality of care indicators were small and no indicator performed consistently better than current viral load. Given the simplicity in assessing and interpreting this indicator, we propose to use current viral load when HIV-RNA-based indicators are used to evaluate the efficacy of ART programs.

Background Viral hepatitis is an important public health issue in sub-Saharan Africa. Due to rising mortality from cirrhosis and hepatocellular carcinoma and limited implementation of screening and treatment programmes, it has been characterised as a neglected tropical disease. Synthesis of the existing evidence on the epidemiology of viral hepatitis B, C and D in Malawi is required to inform policy and identify research gaps. Methods We searched Pubmed, EMBASE and Scopus for studies reporting the epidemiology of viral hepatitis B, C and D in Malawi from 1990 to 2018. Articles reporting prevalence estimates were included provided they described details of participant selection, inclusion criteria and laboratory methods (detection of HBsAg, anti-HCV or anti-HDV antibody, HCV antigen or HCV RNA or HDV RNA). We assessed study quality using a prevalence assessment tool. Where appropriate, a pooled prevalence was calculated using a DerSimonian Laird random effects model. Results Searches identified 199 studies, 95 full text articles were reviewed and 19 articles were included. Hepatitis B surface antigen (HBsAg) seroprevalence was assessed in 14 general population cohorts. The pooled prevalence among adults was 8.1% (95% CI 6.1, 10.3). In 3 studies where HBsAg was stratified by HIV status, no effect of HIV on HBsAg prevalence was observed (OR 1.2 (95% CI: 0.8, 1.6, p = 0.80)). In a single study of HIV/HBV infected individuals, anti-hepatitis D antibody (anti-HDV) prevalence was low (1.5%). HCV antibody prevalence (anti-HCV) ranged from 0.7 to 18.0% among 12 cohorts in general populations. Among three studies which used PCR to confirm current infection, the pooled rate of HCV RNA confirmation among anti-HCV positive individuals was only 7.3% (95% CI: 0.0, 24.3). Conclusions Hepatitis B is highly prevalent in Malawi. There is a paucity of epidemiological data from rural areas where 85% of the population reside, and the Northern region. Priority research needs include large-scale representative community studies of HBV, HDV and HCV seroprevalence, assessment of children following introduction of the HBV vaccine in 2002, prevalence estimates of viral hepatitis among individuals with cirrhosis and HCC and data on HCV prevalence using PCR confirmation, to support a viral hepatitis strategy for Malawi. Electronic supplementary material The online version of this article (10.1186/s12879-018-3428-7) contains supplementary material, which is available to authorized users.

Objectives: The aim of the study was to evaluate differences in immunovirological response to combination antiretroviral therapy (cART) in migrant and native men and women within a European collaboration of HIV cohorts Collaboration of Observational HIV Epidemiological Research in Europ (COHERE) in EuroCoord, 2004-2013. Methods: Migrants were defined as those with geographical origin (GO) different from the reporting country and were grouped as originating from Western Europe and Western Countries (WEWC), Eastern Europe (EE), North Africa and the Middle East (NAME), sub-Saharan Africa (SSA), Latin America (LA), Caribbean (CRB) and Asia/Oceania (ASIA/OCE). Native (NAT) individuals were defined as those originating from the reporting country. CD4 cell counts were modelled using piecewise linear mixed-effects models with two slopes, whereas models to estimate subdistribution hazard ratios (sHRs) were used for time to virological response (VR) (i.e. time from cART initiation to the first of two successive HIV RNA measurements < 400 HIV-1 RNA copies/ml). Results: Of 32 817 individuals, 25 799 (78.6%) were men. The percentage of migrants was higher in women (48.9%) than in men (21.2%) and migrants from SSA accounted for the largest migrant group (29.9% in men and 63.3% in women). Migrant men and women from SSA started at lower CD4 cell counts than NAT individuals, which remained lower over time. VR was ≥ 85% at 12 months for all groups except CRB women (77.7%). Compared with NAT men and women, lower VR was experienced by NAME [sHR 0.91; 95% confidence interval (CI) 0.86-0.97] and SSA (sHR 0.88; 95% CI 0.82-0.95) men and CRB (sHR 0.77; 85% CI 0.67-0.89) women, respectively. Conclusions: Immunovirological response to cART in Western Europe varies by GO and sex of patients. ART benefits are not equal for all, underlining the point that efforts need to prioritize those most in need.

[Abstract] Objectives. To evaluate plasma mitochondrial DNA (mtDNA) levels among HIV-infected patients and its potential role as a biomarker of residual viral replication. Methods. HIV-infected patients on follow-up at a reference hospital in north-west Spain were selected. DNA was isolated from plasma samples and mtDNA levels were assessed using a quantitative real-time PCR assay. HIV-RNA levels and CD4+ cell counts were evaluated in the same blood samples used for plasma mtDNA quantification. Epidemiological and clinical variables were included for the analysis. Results. A total of 235 HIV-infected patients were included. Mean plasma mtDNA levels were 217 ± 656 copies/μL for naive (31.9%) and 364 ± 939 copies/μL for HIV-infected patients receiving ART and with suppressed viraemia (P = 0.043). Among the latter, mean plasma mtDNA levels were 149 ± 440 copies/μL for those with low-level viraemia (LLV; HIV-RNA 20–200 copies/mL), 265 ± 723 copies/μL for those with detected-not-quantified (DNQ) viraemia (HIV-RNA

This randomized study evaluated the efficacy and tolerability of continued treatment with protease inhibitor plus nucleoside-analogue combination regimens (n = 79) or a change to the simplified regimen of abacavir-lamivudine-zidovudine (n = 84) in patients with suppressed human immunodeficiency virus type 1 (HIV-1) RNA for ⩾6 months who did not have the reverse transcriptase 215 mutation. After a median follow-up of 84 weeks, virologic failure was 6% in the continuation and 15% in the simplified group (P = .081). Previous zidovudine monotherapy or dual therapy and archived reverse transcriptase resistance mutations in HIV-1 DNA at baseline were significant predictors of failure. Study treatment was discontinued because of adverse events in 20% of the continuation and 7% of the simplified group (P = .021). Simplification to abacavir-lamivudine-zidovudine significantly decreased nonfasting cholesterol and triglyceride levels; however, this switch strategy carries a risk of virologic failure when treatment history or resistance testing suggest the presence of archived resistance mutations to the simplified regimen.

OBJECTIVES: Direct-acting antiviral agents (DAAs) have provided an ultimate treatment duration of 12 weeks for most hepatitis C virus (HCV)-infected patients. The opportunity to reduce treatment duration to 6 or 8 weeks is being evaluated. Here, the HCV viral dynamics at short times during HCV therapies and its implications for monitoring and optimizing treatment duration have been assessed. PATIENTS AND METHODS: HCV chronic infected patients who began HCV therapy (March 2014 to June 2015) at a reference hospital of the Northwest of Spain were selected. HCV-RNA was quantified at different short time points during HCV therapy using Abbott RealTime HCV assay. Epidemiological, clinical, and virological data were recorded. RESULTS: Eleven HCV-infected patients were included; 90.9% had cirrhosis (>12.5 kPa) and 72.7% were treatment-experienced. HCV genotype 1b was the most prevalent (72.7%). All of the combinations were pegylated interferon-free and all included ribavirin. The median HCV-RNA (log IU/ml) at baseline was 5.8 (5.4-6.1); the decline between baseline and day 3, weeks 4, 8, and 12 was 3.2, 4.8, 5.1, and 5.6, respectively. Fewer than 50% of patients achieved undetectable viral load at weeks 4 and 8; however, all patients achieved a sustained virologic response at 12 weeks. CONCLUSION: Rapid and high HCV-RNA decline was observed among HCV-infected patients under DAA-based regimens, especially for those without cirrhosis. Despite low rates of patients with undetectable HCV-RNA at weeks 4 and 8, all achieved a sustained virologic response at 12 weeks. These findings suggest that the time points to monitor HCV-RNA during DAA therapies and the treatment duration need to be optimized.

The public health implications of hepatitis E virus (HEV) in Europe have changed due to increasing numbers of hepatitis E cases and recent reports of chronic, persistent HEV infections associated with progression to cirrhosis in immunosuppressed patients. The main infectious risk for such immunosuppressed patients is exposure to undercooked infected pork products and blood transfusion. We summarised the epidemiology of HEV infections among blood donors and also outlined any strategies to prevent transfusion-transmitted HEV, in 11 European countries. In response to the threat posed by HEV and related public and political concerns, most of the observed countries determined seroprevalence of HEV in donors and presence of HEV RNA in blood donations. France, Germany, Spain and the United Kingdom (UK) reported cases of transfusion-transmitted HEV. Ireland and the UK have already implemented HEV RNA screening of blood donations; the Netherlands will start in 2017. Germany and France perform screening for HEV RNA in several blood establishments or plasma donations intended for use in high-risk patients respectively and, with Switzerland, are considering implementing selective or universal screening nationwide. In Greece, Portugal, Italy and Spain, the blood authorities are evaluating the situation. Denmark decided not to implement the HEV screening of blood donations.

The clinical experience with the protease inhibitor darunavir/ritonavir (DRV/r) was retrospectively evaluated in a cohort of 173 HIV+ patients who initiated antiretroviral treatment including DRV/r (period 2007-2015). The 43.2% had a CD4 nadir ≤100 cells/mm3 , 64.1% were treatment-experienced, and 36.5% had failed to >3 lines of antiretroviral therapy. Nonetheless, the rate of virological suppression (HIV-RNA

BACKGROUND: Two drugs under consideration for inclusion in antiretroviral therapy (ART) regimens for human immunodeficiency virus (HIV) infection are dolutegravir (DTG) and tenofovir alafenamide fumarate (TAF). There are limited data on their use in low- and middle-income countries. METHODS: We conducted a 96-week, phase 3, investigator-led, open-label, randomized trial in South Africa, in which we compared a triple-therapy combination of emtricitabine (FTC) and DTG plus either of two tenofovir prodrugs - TAF (TAF-based group) or tenofovir disoproxil fumarate (TDF) (TDF-based group) - against the local standard-of-care regimen of TDF-FTC-efavirenz (standard-care group). Inclusion criteria included an age of 12 years or older, no receipt of ART in the previous 6 months, a creatinine clearance of more than 60 ml per minute (>80 ml per minute in patients younger than 19 years of age), and an HIV type 1 (HIV-1) RNA level of 500 copies or more per milliliter. The primary end point was the percentage of patients with a 48-week HIV-1 RNA level of less than 50 copies per milliliter (as determined with the Snapshot algorithm from the Food and Drug Administration; noninferiority margin, -10 percentage points). We report the primary (48-week) efficacy and safety data. RESULTS: A total of 1053 patients underwent randomization from February 2017 through May 2018. More than 99% of the patients were black, and 59% were female. The mean age was 32 years, and the mean CD4 count was 337 cells per cubic millimeter. At week 48, the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter was 84% in the TAF-based group, 85% in the TDF-based group, and 79% in the standard-care group, findings that indicate that the DTG-containing regimens were noninferior to the standard-care regimen. The number of patients who discontinued the trial regimen was higher in the standard-care group than in the other two groups. In the per-protocol population, the standard-care regimen had equivalent potency to the other two regimens. The TAF-based regimen had less effect on bone density and renal function than the other regimens. Weight increase (both lean and fat mass) was greatest in the TAF-based group and among female patients (mean increase, 6.4 kg in the TAF-based group, 3.2 kg in the TDF-based group, and 1.7 kg in the standard-care group). No resistance to integrase inhibitors was identified in patients receiving the DTG-containing regimens. CONCLUSIONS: Treatment with DTG combined with either of two tenofovir prodrugs (TAF and TDF) showed noninferior efficacy to treatment with the standard-care regimen. There was significantly more weight gain with the DTG-containing regimens, especially in combination with TAF, than with the standard-care regimen. (ADVANCE ClinicalTrials.gov number, NCT03122262.).

BACKGROUND: Hepatitis C virus (HCV) infection is a major cause of morbidity in HIV infected individuals. Coinfection with HIV is associated with diminished HCV-specific immune responses and higher HCV RNA levels. AIMS: To investigate whether long-term combination antiretroviral therapy (cART) restores HCV-specific T cell responses and improves the control of HCV replication. METHODS: T cell responses were evaluated longitudinally in 80 HIV/HCV coinfected individuals by ex vivo interferon-gamma-ELISpot responses to HCV core peptides, that predominantly stimulate CD4(+) T cells. HCV RNA levels were assessed by real-time PCR in 114 individuals. RESULTS: The proportion of individuals with detectable T cell responses to HCV core peptides was 19% before starting cART, 24% in the first year on cART and increased significantly to 45% and 49% after 33 and 70 months on cART (p=0.001). HCV-specific immune responses increased in individuals with chronic (+31%) and spontaneously cleared HCV infection (+30%). Median HCV RNA levels before starting cART were 6.5 log(10) IU/ml. During long-term cART, median HCV-RNA levels slightly decreased compared to pre-cART levels (-0.3 log10 IU/ml, p=0.02). CONCLUSIONS: Successful cART is associated with increasing cellular immune responses to HCV core peptides and with a slight long-term decrease in HCV RNA levels. These findings are in line with the favourable clinical effects of cART on the natural history of hepatitis C and with the current recommendation to start cART earlier in HCV/HIV coinfected individuals.

OBJECTIVE: To investigate predictors of continued HIV RNA viral load suppression in individuals switched to abacavir (ABC), lamivudine (3TC) and zidovudine (ZDV) after successful previous treatment with a protease inhibitor or non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy. DESIGN AND METHODS: An observational cohort study, which included individuals in the Swiss HIV Cohort Study switching to ABC/3TC/ZDV following successful suppression of viral load. The primary endpoint was time to treatment failure defined as the first of the following events: two consecutiveviral load measurements > 400 copies/ml under ABC/3TC/ZDV, one viral load measurement > 400 copies/ml and subsequent discontinuation of ABC/3TC/ZDV within 3 months, AIDS or death. RESULTS: We included 495 individuals; 47 experienced treatment failure in 1459 person-years of follow-up [rate = 3.22 events/100 person-years; 95% confidence interval (95% CI), 2.30-4.14]. Of all failures, 62% occurred in the first year after switching to ABC/3TC/ZDV. In a Cox regression analysis, treatment failure was independently associated with earlier exposure to nucleoside reverse transcriptase inhibitor (NRTI) mono or dual therapy [hazard ratio (HR), 8.02; 95% CI, 4.19-15.35) and low CD4 cell count at the time of the switch (HR, 0.66; 95% CI, 0.51-0.87 by +100 cells/microl up to 500 cells/microl). In patients without earlier exposure to mono or dual therapy, AIDS prior to switch to simplified maintenance therapy was an additional risk factor. CONCLUSIONS: The failure rate was low in patients with suppressed viral load and switch to ABC/3TC/ZDV treatment. Patients with earlier exposure to mono or dual NRTI therapy, low CD4 cell count at time of switch, or AIDS are at increased risk of treatment failure, limiting the use of ABC/3TC/ZDV in these patient groups.

BACKGROUND: Virus-specific cellular immune responses mediated by CD4 and CD8 T lymphocytes are thought to be central to the effective control of HIV-1 replication in vivo. However, quantitative correlations between HIV-specific T lymphocyte frequencies and plasma virus load (pVL) have proved difficult to establish in infected human individuals. This most likely reflects the complex interactions between the virus and these immune effector cells in the absence of treatment. OBJECTIVE: To assess frequencies of HIV-specific T lymphocytes after prolonged suppression of viral replication, i.e., under conditions where the effects of virus on the immune response are standardized and minimized, thereby fixing an important variable in a dynamic multivariate system. METHODS: HIV-specific CD4 and CD8 T lymphocyte frequencies were measured in 122 individuals after prolonged periods of successful combination antiretroviral therapy (ART) administered during chronic HIV-1 infection. RESULTS: The residual frequency of both CD4 and CD8 T lymphocytes specific for HIV-1 was inversely related to the pretreatment pVL. This relationship appeared to be non-linear, indicating the presence of a threshold pretreatment pVL level above which HIV-specific CD4 and CD8 T lymphocyte responses could not be maintained when antigenic drive was suppressed. Substantial populations of functional HIV-specific CD4 and CD8 T lymphocytes were generally detectable after prolonged ART only in those individuals with a pretreatment plasma HIV-1 RNA < 100,000 copies/ml. CONCLUSION: These findings identify a quantitative immune associate of host-virus interactions in established HIV-1 infection.

There is a continuing search for better ways to use existing drugs against human immunodeficiency virus (HIV). One idea is to use short therapy interruptions to “autovaccinate” HIV-infected patients. A group of 13 chronically HIV-infected patients enrolled in a trial of such so-called structured treatment interruptions (STIs) were intensively studied with respect to their viral load (VL) and HIV-specific CD8+T-cell (cytotoxic T-lymphocyte [CTL]) responses. We found that 10 of the 13 patients had plateau VLs after STIs that were lower than their pretreatment VLs. While viral rebound rates became lower over STIs, there were no changes in clearance rates. Although numbers of CTLs did increase over the same time that viral rebounds decreased, there was no correlation between CTL count and either viral rebound rates or clearance rates. Finally, we asked whether absolute numbers of or changes in numbers of CTLs predict plateau VLs after STIs. No measure of CTLs was able to predict plateau VLs. Thus, there was no signature in these data of an important contribution to virological control from HIV-specific CD8+T lymphocytes.

In the Netherlands, immigrant people living with HIV (PLWH) have poorer psychological and treatment outcomes than Dutch PLWH. This cross-sectional field study examined risk factors for non-adherence to combination Antiretroviral Therapy (cART) among immigrant PLWH. First and second generation immigrant PLWH attending outpatient clinics at two HIV-treatment centers in Rotterdam were selected for this study. Socio-demographic and clinical characteristics for all eligible participants were collected from an existing database. Trained interviewers subsequently completed questionnaires together with consenting participants (n = 352) to gather additional data on socio-demographic characteristics, psychosocial variables, and self-reported adherence to cART. Univariable and multivariable logistic regression analyses were conducted among 301 participants who had used cART ≥6 months prior to inclusion. Independent risk factors for self-reported non-adherence were (I) not having attended formal education or only primary school (OR = 3.25; 95% CI: 1.28-8.26, versus University), (II) experiencing low levels of social support (OR = 2.56; 95% CI: 1.37-4.82), and (III) reporting low treatment adherence self-efficacy (OR = 2.99; 95% CI: 1.59-5.64). Additionally, HIV-RNA >50 copies/ml and internalized HIV-related stigma were marginally associated (P

OBJECTIVES: Stavudine is widely used in Thailand and is associated with mitochondrial toxicity. Here, we evaluated the effect of switching from stavudine/didanosine to tenofovir/lamivudine on measures of metabolic and mitochondrial toxicity in Thai patients. METHODS: Thirty-five Thai patients with full HIV RNA suppression were switched from stavudine/didanosine to tenofovir/lamivudine while receiving saquinavir/ritonavir 1600/100 mg once daily. Patients were assessed at the time of switch and 24 and 48 weeks after for lipids, liver enzymes, lactate, mitochondrial DNA content and limb/total fat mass by dual energy X-ray absorptiometry (DEXA) scanning. RESULTS: Forty-eight weeks after the switch, there were significant reductions in lipids and lactate, but no change in liver enzymes. There was reversal of lipoatrophy, as shown by rises in limb fat mass (+0.38 kg, P = 0.006) and total fat mass (+0.69 kg, P = 0.02) on DEXA scan. Patients perceived weight improvement, but did not report reversal of lipoatrophy of individual body parts. The mitochondrial DNA/nuclear DNA ratio rose (+1.06, P < 0.0001). CONCLUSIONS: After the nucleoside reverse transcriptase inhibitor switch, reversal of mitochondrial toxicity was consistent with switch studies of mainly Caucasian patients, although the peripheral mononuclear cell mitochondrial DNA rise exceeded previous reports.

Background Temporary increases in plasma HIV RNA ('blips') are common in HIV patients on combination antiretroviral therapy (cART). Blips above 500 copies/mL have been associated with subsequent viral rebound. It is not clear if this relationship still holds when measurements are made using newer more sensitive assays. Methods We selected antiretroviral-naive patients that then recorded one or more episodes of viral suppression on cART with HIV RNA measurements made using more sensitive assays (lower limit of detection below 50 copies/ml). We estimated the association in these episodes between blip magnitude and the time to viral rebound. Results Four thousand ninety-four patients recorded a first episode of viral suppression on cART using more sensitive assays; 1672 patients recorded at least one subsequent suppression episode. Most suppression episodes (87 %) were recorded with TaqMan version 1 or 2 assays. Of the 2035 blips recorded, 84 %, 12 % and 4 % were of low (50–199 copies/mL), medium (200–499 copies/mL) and high (500–999 copies/mL) magnitude respectively. The risk of viral rebound increased as blip magnitude increased with hazard ratios of 1.20 (95 % CI 0.89-1.61), 1.42 (95 % CI 0.96-2.19) and 1.93 (95 % CI 1.24-3.01) for low, medium and high magnitude blips respectively; an increase of hazard ratio 1.09 (95 % CI 1.03 to 1.15) per 100 copies/mL of HIV RNA. Conclusions With the more sensitive assays now commonly used for monitoring patients, blips above 200 copies/mL are increasingly likely to lead to viral rebound and should prompt a discussion about adherence. Electronic supplementary material The online version of this article (doi:10.1186/s12879-015-1120-8) contains supplementary material, which is available to authorized users.

Background: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. Methods: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA

BACKGROUND & AIMS The efficacy and tolerability of faldaprevir, a potent hepatitis C virus (HCV) NS3/4A protease inhibitor, plus peginterferon and ribavirin was assessed in a double-blind, placebo-controlled phase 3 study of treatment-naïve patients with HCV genotype-1 infection. METHODS Patients were randomly assigned (1:2:2) to peginterferon/ribavirin plus: placebo (arm 1, n=132) for 24 weeks; faldaprevir (120 mg, once daily) for 12 or 24 weeks (arm 2, n=259); or faldaprevir (240 mg, once daily) for 12 weeks (arm 3, n=261). In arms 2 and 3, patients with early treatment success (HCV RNA

UnlabelledPharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7–7.7 relative to baseline) within the first hours following each romidepsin administration. Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4–5.0; p = 0.03). Plasma HIV-1 RNA increased from Trial registrationclinicaltrials.gov NTC02092116.

Background The efficacy of first-generation protease inhibitor based triple-therapy against hepatitis C virus (HCV) infection is limited in HIV/HCV-coinfected patients with advanced liver fibrosis and non-response to previous peginterferon-ribavirin. These patients have a low chance of achieving a sustained virologic response (SVR) using first generation triple-therapy, with a success rate of only 20%. We investigated the efficacy and safety of lead-in therapy with intravenous silibinin followed by triple-therapy in this difficult-to-treat patient group. Methodology Inclusion criteria were HIV/HCV coinfection with advanced liver fibrosis and documented previous treatment failure on peginterferon-ribavirin. The intervention was a lead-in therapy with intravenous silibinin 20 mg/kg/day for 14 days, followed by triple-therapy (peginterferon-ribavirin and telaprevir) for 12 weeks, and peginterferon-ribavirin alone for 36 weeks. Outcome measurements were HCV-RNA after silibinin lead-in and during triple-therapy, SVR data at week 12, and safety and tolerability of silibinin. Results We examined sixteen HIV/HCV-coinfected patients with previous peginterferon-ribavirin failure, of whom 14 had a fibrosis grade METAVIR ≥F3. All were on successful antiretroviral therapy. Median (IQR) HCV-RNA decline after silibinin therapy was 2.65 (2.1–2.8) log10 copies/mL. Fifteen of sixteen patients (94%) had undetectable HCV RNA at weeks 4 and 12, eleven patients (69%) showed end-of-treatment response (i.e., undetectable HCV-RNA at week 48), and ten patients (63%) reached SVR at week 12 (SVR 12). Six of the sixteen patients (37%) did not reach SVR 12: One patient had rapid virologic response (RVR) (i.e., undetectable HCV-RNA at week 4) but stopped treatment at week 8 due to major depression. Five patients had RVR, but experienced viral breakthroughs at week 21, 22, 25, or 32, or a relapse at week 52. The HIV RNA remained below the limit of detection in all patients during the complete treatment period. No serious adverse events and no significant drug-drug interactions were associated with silibinin. Conclusion A lead-in with silibinin before triple-therapy was safe and highly effective in difficult-to-treat HIV/HCV coinfected patients, with a pronounced HCV-RNA decline during the lead-in phase, which translates into 63% SVR. An add-on of intravenous silibinin to standard of care HCV treatment is worth further exploration in selected difficult-to-treat patients. Trial Registration ClinicalTrials.gov NCT01816490

Potent antiretroviral therapy has dramatically improved the prognosis of patients infected with HIV-1. Primary and secondary prophylaxis against Pneumocystis carinii, Mycobacterium avium, cytomegalovirus, and other pathogens can be discontinued safely once CD4 cell counts have increased beyond pathogen-specific thresholds. Approximately one-third of individuals receiving antiretroviral therapy will not reach CD4 cell counts above 500 cells per muL after 5 years despite continuous suppression of plasma HIV-1 RNA. Whether this failure represents a risk factor for the long-term incidence of opportunistic diseases--eg, tuberculosis or malignancies--remains uncertain. We describe the time course of CD4 cell concentrations in patients whose plasma HIV-1 RNA is durably suppressed by antiretroviral therapy, in patients with incomplete suppression of plasma HIV-1 RNA, and during treatment interruptions. In addition, immune reconstitution disease, an inflammatory syndrome associated with immunological recovery occurring days to weeks after the start of antiretroviral therapy, is briefly described.

ObjectiveTo assess the efficacy and safety of first-line treatment with once-daily saquinavir/ritonavir with two nucleoside reverse transcriptase inhibitors (NRTIs), as induction therapy before enrollment in a randomized trial of structured treatment interruption strategies.DesignTwo-hundred antiretroviral-naive patients with CD4+cell counts between 200–350 at screening were enrolled in this open-label 24week study.MethodsPatients were followed up every 8 weeks for CD4+cells, HIV RNA, and clinical and laboratory toxicities. Results: Two-hundred patients were enrolled with median baseline CD4+cell count of 267 cells/μl and HIV RNA 50 118 (4.7 log10) copies/ml. After 24 weeks of treatment, 191 of 200 (96%) patients had below 400 copies/ml HIV RNA, with 177/200 (89%) below 50 copies/ml (intent to treat, missing equals failure method), with a median rise in CD4+cell count of 122 cells/μl. There was no significant correlation between the minimum concentration of saquinavir and HIV RNA reductions at week 8 ( P=0.957) or absolute HIV RNA at week 24 ( P=0.77).ConclusionFirst-line highly active antiretroviral therapy (HAART) with once-daily saquinavir/ritonavir plus two NRTIs showed strong antiviral efficacy over 24 weeks, and should be evaluated in larger prospective randomized clinical trials.

BACKGROUND: The CD4 T cell count recovery in human immunodeficiency virus type 1 (HIV-1)-infected individuals receiving potent antiretroviral therapy (ART) shows high variability. We studied the determinants and the clinical relevance of incomplete CD4 T cell restoration. METHODS: Longitudinal CD4 T cell count was analyzed in 293 participants of the Swiss HIV Cohort Study who had had a plasma HIV-1 RNA load or =5 years. CD4 T cell recovery was stratified by CD4 T cell count 5 years after initiation of ART (> or =500 cells/microL was defined as a complete response, and .05). Older age (adjusted odds ratio [aOR], 1.71 per 10-year increase; 95% confidence interval [CI], 1.21-2.43), lower baseline CD4 T cell count (aOR, 0.37 per 100-cell increase; 95% CI, 0.28-0.49), and longer duration of HIV infection (aOR, 2.39 per 10-year increase; 95% CI, 1.19-4.81) were significantly associated with a CD4 T cell count

OBJECTIVES: To explore the effect of granulocyte macrophage colony stimulating factor (GM-CSF) on viral load and CD4 cell count during interruption of highly active antiretroviral therapy (HAART). METHODS: Patients on effective HAART (CD4 cell count > 400 x 10(6)/l; viral load < 50 HIV RNA copies/ml) were randomized to one of two groups: 12 weeks' treatment interruption plus, during the first 4 weeks, 300 microg GM-CSF (Leucomax-Novartis) by subcutaneous injection three times weekly (GM-CSF group); 12 weeks' scheduled treatment interruption (STI-only group). Viral load, CD4 cell count, clinical events and side effects of treatment were monitored. RESULTS: Thirty-three patients, 15 in the GM-CSF group and 18 in the STI-only group, were evaluated according to the intention-to-treat principle. The two groups were well matched with regard to pre-HAART viral loads and CD4 cell counts. During STI, viraemia was approximately two to three times lower in the group receiving GM-CSF (max 4.97 versus 5.45 in STI-only group; P = 0.03). Fifteen out of 17 patients in the STI-only group showed a decrease in their CD4 cell count between weeks 0 and 4 (median decrease 231 x 10(6) cells/l; P < 0.001); there was no such tendency in the GM-CSF group (P = non-significant when comparing CD4 cell counts at weeks 0 and 4). The median CD4 cell AUC (area under the curve) from week 0 to week 12 was higher in the GM-CSF group (9166 cells.week) than in patients without GM-CSF (7257), P = 0.02. GM-CSF produced local reactions in 88% of patients, and generalized symptoms such as fever, back pain or headache in 82% of patients. Seventy-six percent of patients completed the planned course of 12 injections. CONCLUSIONS: The administration of GM-CSF blunted the viral rebound following interruption of HAART, and largely prevented a decrease of CD4 cell counts during a 12-weeks-treatment interruption. A better understanding of the underlying mechanism(s) may help to identify synergistic treatment targets and improved administration protocols to enhance control of chronic HIV infection.

Immortalization of B cells by Epstein-Barr virus (EBV) and their subsequent proliferation leads to B-cell non-Hodgkin's lymphoma in immunocompromised patients. The role of hepatitis C virus (HCV) in B-cell non-Hodgkin's lymphoma has recently been raised, and an interaction between HCV and EBV is supported by recent in vitro experiments. The aim of this study was to investigate in vivo interactions between HCV and EBV in patients with AIDS, i.e., patients exposed to the risk of EBV-related B-cell non-Hodgkin's lymphoma. A total of 135 patients were prospectively studied. Serological and molecular markers of HCV, EBV, and human immunodeficiency virus (HIV) infection were sought. All the patients harbored latent EBV infection, and 20% had detectable HCV RNA in serum. No significant relationship was found between HIV, HCV, and EBV viral load in peripheral blood mononuclear cells or plasma. There was no difference between anti-HCV-positive and -negative patients or between HCV RNA-positive and -negative patients with regard to the prevalence of EBV markers, especially EBV replication markers. The presence of EBV replication markers was not related to HCV RNA seropositivity or to HCV viral load. Five patients subsequently developed B-cell non-Hodgkin's lymphoma, none of whom had markers of EBV or HCV replication. These results argue against an in vivo interaction between HCV and EBV in patients with AIDS, and against a role of HCV infection in the occurrence of B-cell non-Hodgkin's lymphoma in these patients. J. Med. Virol. 67:510–515, 2002. © 2002 Wiley-Liss, Inc.

OBJECTIVES: Many patients have simplified their therapy by replacing protease inhibitors (PI) with efavirenz. In a large cohort study representative of clinical practice, we compared outcomes in patients who replaced PI with efavirenz (switchers), with patients who continued on PI (non-switchers). We investigated the likelihood of virological failure in switchers and non-switchers, and the tolerance of efavirenz-containing regimens in different transmission risk groups. DESIGN, SETTING, AND METHODS: Using the database of the Swiss HIV Cohort Study, we identified patients who switched from PI-containing to efavirenz-containing highly active antiretroviral therapy for reasons of tolerance, toxicity, or convenience. Switchers were matched to non-switchers on the basis of calendar time, CD4 cell count, and viral load. RESULTS: The probability of virological failure was less in patients who switched to efavirenz values after one year: 9.4% [95% confidence interval (CI) 5.5-15.9] versus 27.2% (95% CI 21.5-34.1), odds ratio (OR) for failure 0.34. The effect was more pronounced when injection drug users (IDU) were omitted from the analysis (OR 0.19, 95% CI 0.09-0.43); it was absent in IDU (OR 0.95, 95% CI 0.44-2.04). IDU stopped efavirenz more frequently during the first 2 months of treatment than non-IDU [22.6% (95% CI 11.5-41.6) versus 6.6% (95% CI 3.6-11.8) at 2 months]. No difference between IDU and non-IDU was evident when the frequency of stopping indinavir or nelfinavir was measured. CONCLUSION: Switchers had less virological failure and less chance of further treatment changes than non-switchers. However, efavirenz was less successful in IDU than in other transmission categories.

In vitro data have shown that the hepatitis C virus (HCV) core protein binds to protein members of the tumour necrosis factor receptor (TNFR) superfamily. Since this interaction could be relevant to HCV persistence and oncogenesis, this study assessed whether HCV may interfere with the apoptotic cascade in vivo. Apoptosis (by TUNEL) and Fas and TNFR1 expression (by immunohistochemistry) were scored in the liver of 60 chronic hepatitis C patients. Results were compared with the liver disease grading and staging scores and the HCV replication level in serum and liver. Apoptotic hepatocytes were stained in 29 cases. Fas was expressed in 35 cases and TNFR1 in 21, 15 patients (25%) being negative for both receptors. Overall, the numbers of TUNEL-, Fas- and TNFR-positive hepatocytes did not correlate with the extent of intrahepatic CD8+ T-lymphocyte infiltration, the grading and staging of liver disease, or the serum or liver HCV RNA levels. Furthermore, when patients expressing either Fas or TNFR1 were stratified according to serum HCV RNA levels, cases with detectable hepatocyte apoptosis had higher HCV viraemias. In conclusion, an HCV-mediated, in vivo blockade of hepatocyte apoptosis via the Fas- or TNFR1-dependent pathways seems unlikely.

Gene therapy is becoming one of the most promising modalities for the treatment of acquired immunodeficiency syndrome. The purpose of this study was to investigate the mobilization and collection of peripheral blood progenitor cells from human immunodeficiency virus (HIV)-infected individuals using granulocyte colony-stimulating factor (G-CSF). A total of 10 patients (9 male, 1 female; median age 36.5 years) with varying circulating CD4+ cell counts (13.9-1467/microL) were administered 10 microg/kg G-CSF daily for 6 days. Peripheral white blood cells (WBCs), CD34+ cell counts, lymphocyte subsets, and plasma viremia were monitored before each G-CSF injection. An average sixfold increase in WBCs was observed, which stabilized on day 4 or thereafter. The level of CD34+ cells was increased by 20-fold, and did not differ between days 5 and 6. Smaller increases in CD4+, CD8+, and CD4+CD8+ cells were observed. HIV viral load, as measured by RNA copy number in plasma, was not significantly altered by G-CSF administration. The leukapheresis product (LP), collected on day 7, contained an average of 6.25+/-4.52 (mean +/- standard deviation) x 10(10) WBCs and 3.08+/-2.98 x 10(6) CD34+ cells/kg. The levels of different CD34+ cell subsets were similar to those in the LPs of G-CSF-mobilized healthy individuals from an earlier study. Primitive hematopoietic cells (CD38- and CD38-HLA-DR+ cells) were detected in LPs (1.19+/-0.46% and 0.87+/-0.23%, respectively, of CD34+ cells). All parameters (WBC counts, lymphocyte populations, CD34+ cells, and HIV-1 RNA copies) measured 3 weeks after leukapheresis returned to baseline values. The administration of G-CSF was well tolerated by the HIV patients; side effects included bone pain, headache, flulike symptoms, and fatigue. There were no correlations between baseline CD4+ cell count and the WBCs, mononuclear cells, or CD34+ cells collected in the LP. Similarly, no correlation existed between baseline CD4+ and CD34+ cells, peak CD34+ cells, or days to achieve peak CD34+ cell counts after G-CSF mobilization. Our results showed that: (1) maximal mobilization can be achieved after 4 days of G-CSF administration; (2) therapeutic quantities of hematopoietic cells can be collected and used for gene therapy; and (3) G-CSF administration is well tolerated and does not cause a clinically significant increase in viremia.

International audience; This study aimed to identify factors associated with virological response (VR) to raltegravir (RAL)-containing regimens in 468 treatment-experienced but integrase inhibitor-naive HIV-1 patients receiving a RAL-containing regimen. VR was defined at Month 6 (M6) as HIV-1 RNA viral load (VL) 50 copies/mL at M6, integrase mutations selected were characterised. Median baseline VL was 4.2 log(10)copies/mL (IQR 3.3-4.9 log(10) copies/mL) and CD4 count was 219 cells/mm(3) (IQR 96-368 cells/mm(3)). At M6, 71% of patients were responders. In multivariate analysis, baseline VL and CD4 count and ≥ 2 new antiretrovirals among darunavir, etravirine, maraviroc and enfuvirtide were associated with VR to RAL. Neither HIV-1 subtype nor baseline integrase polymorphisms were associated with VR to RAL. Among 63 failing patients at M6, selection of ≥ 1 change in the integrase gene was observed in 49 (77.8%), and 27/63 (42.9%) were considered as RAL-associated resistance mutations. Factors independently associated with the occurrence of ≥ 1 RAL-associated resistance mutation were VL at failure >3 log(10) and having no new drugs associated with RAL. RAL showed great potency in treatment-experienced patients. The number of new drugs associated with RAL was an important factor associated with VR. HIV-1 subtype and baseline integrase polymorphisms do not influence the RAL VR.

International audience; BACKGROUND: Surveillance of HIV-1 drug resistance in treated patients with plasma viral load (VL) >50 copies/mL. METHODS: The protease and reverse transcriptase (RT) genes were systematically sequenced in samples from 756 patients with VL >50 copies/mL in 2009. The genotyping results were interpreted for each antiretroviral drug (ARV) by using the ANRS algorithm v21. Weighted analyses were used to derive representative estimates of percentages of patients. Prevalence rates were compared with those obtained in 2004 among patients with VL >1000 copies/mL. RESULTS: Sequences were obtained for 506 patients. Sequencing was successful in 45%, 80% and 96% of samples with VL of 51-500, 501-1000 and >1000 copies/mL, respectively. Resistance or possible resistance to at least one ARV was observed in 59% of samples. Overall, 0.9% of samples contained viruses resistant to all drugs belonging to at least three drug classes. All resistance prevalence rates were significantly lower in 2009 than in 2004. CONCLUSION: In France, where 86% of patients were receiving combination antiretroviral therapy in 2009, only 15.0% of patients had a VL >50 copies/mL, suggesting that only 8.9% of treated patients could potentially transmit resistant viruses. Only 0.08% of patients harboured viruses fully resistant to at least three antiretroviral drug classes. Further studies are needed to determine whether resistance continues to decline over time.

OBJECTIVE: To decrease viraemia levels in primary HIV infection by using a combination of zidovudine (ZDV) and L-697,661. DESIGN: Four primary HIV-infected patients were treated for 6 months with ZDV, 250 mg twice daily, in association with the non-nucleoside reverse transcriptase inhibitor L-697,661 500 mg three times daily. Viraemia, proviral DNA, CD4 and CD8 cell counts were measured serially during 18 months. RESULTS: Viraemia decreased to undetectable levels (< 200 RNA copies/ml) in two patients. A third patient had a marked decrease followed by a rebound during therapy; viraemia levels did not vary markedly in the fourth patient. A rebound in viraemia levels was observed within 15 days of discontinuation of therapy in the three responding patients. Proviral levels evolved in parallel with viraemia but were always detectable in all patients. In the three patients with an initial decrease of viraemia, CD4 cell counts were within the normal range 2 months after initiation of therapy and did not markedly decrease after discontinuation of therapy. In the two patients with partial or no response of viraemia, mutations associated with low level of resistance to L-697,661 appeared during treatment. CONCLUSION: A marked decrease of viraemia can be achieved in some primary HIV-infected patients with combined therapy. Six months of treatment does not prevent a rebound of viraemia, which was observed within 15 days of interruption of therapy.

Background Minor protease inhibitor (PI) mutations often exist as polymorphisms in HIV-1 sequences from treatment-naive patients. Previous studies showed that their presence impairs the antiretroviral treatment (ART) response. Evaluating these findings in a larger cohort is essential. Methods To study the impact of minor PI mutations on time to viral suppression and time to virological failure, we included patients from the Swiss HIV Cohort Study infected with HIV-1 subtype B who started first-line ART with a PI and two nucleoside reverse transcriptase inhibitors. Cox regression models were performed to compare the outcomes among patients with 0 and ≥1 minor PI mutation. Models were adjusted for baseline HIV-1 RNA, CD4 cell count, sex, transmission category, age, ethnicity, year of ART start, the presence of nucleoside reverse transcriptase inhibitor mutations, and stratified for the administered PIs. Results We included 1199 patients of whom 944 (78.7%) received a boosted PI. Minor PI mutations associated with the administered PI were common: 41.7%, 16.1%, 4.7% and 1.9% had 1, 2, 3 or ≥4 mutations, respectively. The time to viral suppression was similar between patients with 0 (reference) and ≥1 minor PI mutation (multivariable hazard ratio (HR): 1.1 [95% confidence interval (CI): 1.0–1.3], P = .196). The time to virological failure was also similar (multivariable HR:.9 [95% CI:.5–1.6], P = .765). In addition, the impact of each single minor PI mutation was analyzed separately: none was significantly associated with the treatment outcome. Conclusions The presence of minor PI mutations at baseline has no effect on the therapy outcome in HIV infected individuals.

We aimed to determine the antibody responses and effect on viral load of the AS03-adjuvanted pandemic H1N1 vaccine in HIV-infected patients.A total of 121 HIV-infected patients and 138 healthy subjects were enrolled in a prospective, open-label study. Healthy subjects received one dose and HIV-infected patients two doses of the AS03-adjuvanted split influenza A/09/H1N1 vaccine (Pandemrix®; GlaxoSmithKline, Brentford, United Kingdom.) at an interval of 3-4 weeks. The study was extended in 2010/2011 for 66 patients. Geometric mean titres (GMTs), seroprotection rates (post-vaccination titre ≥ 1:40) and HIV-1 RNA levels were measured before and 4 weeks after immunization.After two immunizations, the seroprotection rate (94.2 vs. 87%, respectively) and GMT (376 vs. 340, respectively) in HIV-infected patients were as high as in healthy subjects after one dose, regardless of CD4 cell count. Four weeks after immunization, HIV RNA was detected in plasma samples from 40 of 68 (58.0%) previously aviraemic patients [median 152 HIV-1 RNA copies/mL; interquartile range (IQR) 87-509 copies/mL]. Subsequent measures indicated that HIV RNA levels had again declined to20 copies/mL in most patients (27 of 34; 79.4%). Following (nonadjuvanted) influenza immunization in 2010/2011, HIV RNA levels only slightly increased (median final level 28 copies/mL) in three of 66 (4.5%) previously aviraemic patients, including two of 25 (8%) patients in whom an increase had been elicited by AS03-adjuvanted vaccine the year before.Most HIV-infected patients developed seroprotection after two doses of AS03-adjuvanted pandemic vaccine. A transient effect on HIV RNA levels was observed in previously aviraemic patients. A booster dose of the nonadjuvanted influenza vaccine containing the A/09/H1N1 strain the following year did not reproduce this finding, indicating a non-antigen-specific adjuvant effect.

Nucleoside reverse transcriptase inhibitors (NRTIs) are often administered in salvage therapy even if genotypic resistance tests (GRTs) indicate high-level resistance, but little is known about the benefit of these additional NRTIs.The effect of2 compared with 2 NRTIs on viral suppression (HIV-1 RNA50 copies/mL) at week 24 was studied in salvage patients receiving raltegravir. Intent-to-treat and per-protocol analyses were performed; last observation carried forward imputation was used to deal with missing information. Logistic regressions were weighted to create a pseudopopulation in which the probability of receiving2 and 2 NRTIs was unrelated to baseline factors predicting treatment response.One-hundred thirty patients were included, of whom 58.5% (n = 76) received2 NRTIs. NRTIs were often replaced by other drug classes. Patients with 2 NRTIs received less additional drug classes compared with patients with2 NRTIs [median (IQR): 1 (1-2) compared with 2 (1-2), P Wilcoxon0.001]. The activity of non-NRTI treatment components was lower in the 2 NRTIs group compared with the2 NRTIs group [median (IQR) genotypic sensitivity score: 2 (1.5-2.5) compared with 2.5 (2-3), P Wilcoxon0.001]. The administration of2 NRTIs was associated with a worse viral suppression rate at week 24. The odds ratios were 0.34 (95% confidence interval: 0.13 to 0.89, P = 0.027) and 0.19 (95% confidence interval: 0.05 to 0.79, P = 0.023) when performing the last observation carried forward and the per-protocol approach, respectively.Our findings showed that partially active or inactive NRTIs contribute to treatment response, and thus the use of 2 NRTIs in salvage regimens that include raltegravir seems warranted.

To investigate the independent association between the homeostasis model assessment of the insulin resistance (HOMA-IR) score and rapid virological response (RVR) and sustained virological response (SVR) in chronic hepatitis C (CHC).

Hepatitis D virus (HDV) infection involves a distinct subgroup of individuals simultaneously infected with the hepatitis B virus (HBV) and characterized by an often severe chronic liver disease. HDV is a defective RNA agent needing the presence of HBV for its life cycle. HDV is present worldwide, but the distribution pattern is not uniform. Different strains are classified into eight genotypes represented in specific regions and associated with peculiar disease outcome. Two major specific patterns of infection can occur, i.e. co-infection with HDV and HBV or HDV superinfection of a chronic HBV carrier. Co-infection often leads to eradication of both agents, whereas superinfection mostly evolves to HDV chronicity. HDV-associated chronic liver disease (chronic hepatitis D) is characterized by necro-inflammation and relentless deposition of fibrosis, which may, over decades, result in the development of cirrhosis. HDV has a single-stranded, circular RNA genome. The virion is composed of an envelope, provided by the helper HBV and surrounding the RNA genome and the HDV antigen (HDAg). Replication occurs in the hepatocyte nucleus using cellular polymerases and via a rolling circle process, during which the RNA genome is copied into a full-length, complementary RNA. HDV infection can be diagnosed by the presence of antibodies directed against HDAg (anti-HD) and HDV RNA in serum. Treatment involves the administration of pegylated interferon-α and is effective in only about 20% of patients. Liver transplantation is indicated in case of liver failure.

In Switzerland, intravenous drug use (IDU) accounts for 80% of newly acquired hepatitis C virus (HCV) infections. Early HCV treatment has the potential to interrupt the transmission chain and reduce morbidity/mortality due to decompensated liver cirrhosis and hepatocellular carcinoma. Nevertheless, patients in drug substitution programs are often insufficiently screened and treated.With the aim to improve HCV management in IDUs, we conducted a cross sectional chart review in three opioid substitution programs in St. Gallen (125 methadone and 71 heroin recipients). Results were compared with another heroin substitution program in Bern (202 patients) and SCCS/SHCS data.Among the methadone/heroin recipients in St. Gallen, diagnostic workup of HCV was better than expected: HCV/HIV-status was unknown in only 1% (2/196), HCV RNA was not performed in 9% (13/146) of anti-HCV-positives and the genotype missing in 15% (12/78) of HCV RNA-positives. In those without spontaneous clearance (two thirds), HCV treatment uptake was 23% (21/91) (HIV-: 29% (20/68), HIV+: 4% (1/23)), which was lower than in methadone/heroin recipients and particularly non-IDUs within the SCCS/SHCS, but higher than in the, mainly psychiatrically focussed, heroin substitution program in Bern (8%). Sustained virological response (SVR) rates were comparable in all settings (overall: 50%, genotype 1: 35-40%, genotype 3: two thirds). In St. Gallen, the median delay from the estimated date of infection (IDU start) to first diagnosis was 10 years and to treatment was another 7.5 years.Future efforts need to focus on earlier HCV diagnosis and improvement of treatment uptake among patients in drug substitution programs, particularly if patients are HIV-co-infected. New potent drugs might facilitate the decision to initiate treatment.

Background & Aims: Single nucleotide polymorphisms (SNPs) associated with IL28B influence the outcome of peginterferon-alpha/ribavirin therapy of chronic hepatitis C virus (HCV) infection. We analyzed the kinetics of HCV RNA during therapy as a function of IL28B SNPs. Methods: IL28B SNPs rs8099917, rs12979860, and rs12980275 were genotyped in 242 HCV treatment-naive Caucasian patients (67% genotype 1, 28% genotype 2 or 3) receiving peginterferon-alpha 2a (180 mu g weekly) and ribavirin (1000-1200 mg daily) with serial HCV-RNA quantifications. Associations between IL28B polymorphisms and early viral kinetics were assessed, accounting for relevant covariates. Results: In the multivariate analyses for genotype 1 patients, the T allele of rs12979860 (T(rs12979860)) was an independent risk factor for a less pronounced first phase HCV RNA decline (log(10) 0.89 IU/ml among T carriers vs. 2.06 among others, adjusted p

BACKGROUND/AIMS: Treatment of chronic HCV infection has become a priority in HIV+ patients, given the faster progression to end-stage liver disease. The primary endpoint of this study was to evaluate and compare antiviral efficacy of Peginterferon alpha 2a plus ribavirin in HIV-HCV co-infected and HCV mono-infected patients, and to examine whether 6 months of therapy would have the same efficacy in HIV patients with favourable genotypes 2 and 3 as in mono-infected patients, to minimise HCV-therapy-related toxicities. Secondary endpoints were to evaluate predictors of sustained virological response (SVR) and frequency of side-effects. METHODS: Patients with genotypes 1 and 4 were treated for 48 weeks with Pegasys 180 microg/week plus Copegus 1000-1200 mg/day according to body weight; patients with genotypes 2 and 3 for 24 weeks with Pegasys 180 microg/week plus Copegus 800 mg/day. RESULTS: 132 patients were enrolled in the study: 85 HCV mono-infected (38: genotypes 1 and 4; 47: genotypes 2 and 3), 47 HIV-HCV co-infected patients (23: genotypes 1 and 4; 24: genotypes 2 and 3). In an intention-to-treat analysis, SVR for genotypes 1 and 4 was observed in 58% of HCV mono-infected and in 13% of HIV-HCV co-infected patients (P = 0.001). For genotypes 2 and 3, SVR was observed in 70% of HCV mono-infected and in 67% of HIV-HCV co-infected patients (P = 0.973). Undetectable HCV-RNA at week 4 had a positive predictive value for SVR for mono-infected patients with genotypes 1 and 4 of 0.78 (95% CI: 0.54-0.93) and of 0.81 (95% CI: 0.64-0.92) for genotypes 2 and 3. For co-infected patients with genotypes 2 and 3, the positive predictive value of SVR of undetectable HCV-RNA at week 4 was 0.76 (95%CI, 0.50-0.93). Study not completed by 22 patients (36%): genotypes 1 and 4 and by 12 patients (17%): genotypes 2 and 3. CONCLUSION: Genotypes 2 or 3 predict the likelihood of SVR in HCV mono-infected and in HIV-HCV co-infected patients. A 6-month treatment with Peginterferon alpha 2a plus ribavirin has the same efficacy in HIV-HCV co-infected patients with genotypes 2 and 3 as in mono-infected patients. HCV-RNA negativity at 4 weeks has a positive predictive value for SVR. Aggressive treatment of adverse effects to avoid dose reduction, consent withdrawal or drop-out is crucial to increase the rate of SVR, especially when duration of treatment is 48 weeks. Sixty-one percent of HIV-HCV co-infected patients with genotypes 1 and 4 did not complete the study against 4% with genotypes 2 and 3.

Hepatocellular apoptosis plays a major role in the pathogenesis of chronic hepatitis C. It can be measured noninvasively by determining the circulating levels of cytokeratin-18 fragments. We hypothesized that the effect of antiviral therapy on this parameter will be different in patients with a sustained virological response, relapse (REL) and nonresponse (NR). We quantified cytokeratin-18 fragments in plasma of patients participating in the Swiss Hepatitis C cohort, who received antiviral therapy without stopping because of sides effects. A total of 315 patients were included, 183 with a sustained response, 64 with NR and 68 who relapsed. Mean levels +/-SD of circulating cytokeratin-18 fragments before therapy were 174 +/- 172 U/L for responsders, 188 +/- 145 for nonresponders and 269 +/- 158 U/L for patients who relapsed. The values were significantly higher in the REL group (ANOVA P < 0.006). A sustained response was associated with a significant improvement of the plasma levels (94 +/- 92 U/L, paired test P < 0.000001), whereas there was no improvement in the nonresponder group (183 +/- 158 U/L) and in the relapser group (158 +/- 148 U/L). There was a weak correlation between alanine aminotransferase (ALT) and cytokeratin-18 fragment levels (r(2) = 0.35, P < 0.000001) before therapy but not after therapy and none with hepatitis C virus (HCV) viremia. Successful antiviral therapy results in a significant decrease in circulating levels of cytokeratin-18 fragments arguing for a reduction in hepatocellular apoptosis after clearance of the HCV. Baseline cytokeratin-18 fragment levels are higher in relapsers. Correlations with ALT are weak, suggesting that these two tests measure different but related processes.

BACKGROUND: Yellow fever vaccine (17DV) has been investigated incompletely in human immunodeficiency virus (HIV)-infected patients, and adequate immunogenicity and safety are of concern in this population. METHODS: In the Swiss HIV Cohort Study, we identified 102 patients who received 17DV while they were HIV infected. We analyzed neutralization titers (NTs) after 17DV administration using the plaque reduction neutralization test. NTs of 1:>or=10 were defined as reactive, and those of 1

BACKGROUND: Enfuvirtide was shown to be highly effective in treatment- experienced patients. Data on discontinuation of enfuvirtide and switch to new antiretroviral drugs are scarce. We aimed to evaluate the efficacy and the impact of discontinuing and/or switching enfuvirtide on virologic and clinical parameters in clinical practice. METHODS: All HIV-infected individuals participating in the Swiss HIV Cohort Study who were treated with enfuvirtide for at least 4 weeks in combination with an optimized background antiretroviral regimen were included in this study. RESULTS: A total of 151 patients were analyzed. The median baseline CD4 cell count was 108 cells/microL (interquartile range [IQR] 50-206) and HIV RNA was 4.7 log10 copies/mL (IQR 4.1-5.2). Virologic suppression, defined as a viral load below 50 copies/mL at 12 months, was achieved by 57.6% of patients. Overall, a median CD4 cell increase of 121 cells/microL (IQR 50-189) from baseline was noted. Up to 50% of patients discontinued enfuvirtide within the first year of treatment, mainly because of the patient's choice. After discontinuation of enfuvirtide, high rates of virologic failure and clinical progression were observed, notably when CD4 cell count at stopping enfuvirtide was below 100 cells/microL and no switch to new potent antiretroviral drugs such as darunavir, maraviroc, or raltegravir was performed. CONCLUSIONS: Enfuvirtide provides high virologic and immunologic response in treatment-experienced patients in the setting of clinical practice. Enfuvirtide should not be discontinued but should be replaced by new potent antiretrovirals, particularly in case of severe immunosuppression.