Baseline Viremia Research Articles

Case series of two persons living with HIV with detectable viral loads initiated then suppressed on cabotegravir/rilpivirine with lenacapavir.

Long-acting (LA) cabotegravir/rilpivirine (CAB/RPV) is primarily prescribed for virologically suppressed persons living with HIV (PLWH). Patients experiencing pill dysphagia or profound adherence challenges were excluded from the phase 3 studies, but recent reports demonstrate successful treatment in PWLH with baseline viremia. We describe two PLWH with detectable viral loads (VL) with multidrug resistance mutations. They were unable to sustain virologic suppression on oral therapy with historical poor adherence and dysphagia. Initiation of intramuscular CAB/RPV with subcutaneous lenacapavir (LEN) injections was necessary with baseline resistance. Due to anorexia and a low muscle mass, one patient received CAB/RPV injections in the vastus lateralis rather than the gluteal muscle with a 67-day delay between injections three and four due to health challenges. Both achieved viral suppression on monthly CAB/RPV with LEN. A return to health with a BMI increase from <14kg/m2 to almost 17kg/m2 resulted in the second patient. Injectable LA ART (CAB/RPV + LEN) in PLWH with detectable viremia results in sustained virologic suppression and a return to health and should now be considered a novel option for MDR patients with an inability to adhere to oral regimens.

Phylogenetic Network Analyses Reveal the Influence of Transmission Clustering on the Spread of HIV Drug Resistance in Quebec from 2002 to 2022.

HIV drug resistance (HIV-DR) may jeopardize the benefit of antiretroviral therapy (ART) in treatment and prevention. This study utilized viral phylogenetics to resolve the influence of transmission networks on sustaining the spread of HIV-DR in Quebec spanning 2002 to 2022. Time trends in acquired (ADR) and transmitted drug resistance (TDR) were delineated in treatment-experienced (n = 3500) and ART-naïve persons (n = 6011) with subtype B infections. Similarly, non-B-subtype HIV-DR networks were assessed pre- (n = 1577) and post-ART experience (n = 488). Risks of acquisition of resistance-associated mutations (RAMs) were related to clustering using 1, 2-5, vs. 6+ members per cluster as categorical variables. Despite steady declines in treatment failure and ADR since 2007, rates of TDR among newly infected, ART-naive persons remained at 14% spanning the 2007-2011, 2012-2016, and 2017-2022 periods. Notably, half of new infections among men having sex with men and heterosexual groups were linked in large, clustered networks having a median of 35 (14-73 IQR) and 16 (9-26 IQR) members per cluster, respectively. Cluster membership and size were implicated in forward transmission of non-nucleoside reverse transcriptase inhibitor NNRTI RAMs (9%) and thymidine analogue mutations (TAMs) (5%). In contrast, transmission of M184V, K65R, and integrase inhibitors (1-2%) remained rare. Levels of TDR reflected viral replicative fitness. The median baseline viremia in ART-naïve groups having no RAMs, NNRTI RAMs, TAMs, and M184VI were 46.088, 38,447, 20,330, and 6811 copies/mL, respectively (p < 0.0001). Phylogenetics emphasize the need to prioritize ART and pre-exposure prophylaxis strategies to avert the expansion of transmission cascades of HIV-DR.

The kinetics of SARS-CoV-2 viremia in COVID-19 patients receiving remdesivir

Detection of SARS-CoV-2 RNA in serum, viremia, has been linked to disease severity and outcome. The kinetics of viremia in patients receiving remdesivir has not been thoroughly studied and could help predict treatment response and outcome. We investigated the kinetics of SARS-CoV-2 viremia and factors associated with baseline viremia, viral clearance and 30-day mortality in patients receiving remdesivir. An observational study including 378 hospitalised patients (median age 67 years, 67% male) sampled with serum SARS-CoV-2 RT-PCR within ± 24 h of initiation of remdesivir treatment. Baseline viremia was present in 206 (54%) patients with a median Ct value of 35.3 (IQR = 33.3–37.1). In patients with baseline viremia, the estimated probability of viral clearance was 72% by day 5. Ct values decreased significantly during remdesivir treatment for viremic patients, indicating an increase in viral load. In total, 44 patients (12%) died within 30 days, and mortality was significantly associated with viremia at baseline (OR = 2.45, p = 0.01) and lack of viral clearance by day 5 (OR = 4.8, p = < 0.01). Viral clearance was not associated with any individual risk factor. Viremia appears to be a prognostic marker before and during remedesivir treatment. The resolution of viremia was similar to patients not receiving remdesivir in other studies, and the decrease in Ct values during treatment questions the antiviral capacity of remdesivir in vivo. Prospective studies are warranted to confirm our findings.

HDV RNA Levels and Progression of Hepatitis Delta Infection: A 14 Year Follow Up Experience in Italy

Background: Identification of outcome predictors is one of the unmet needs in chronic HDV infection. Until recently, no reliable quantitative assays for HDV RNA were available. Aims: To evaluate the impact of baseline viremia on natural history of HDV infection in a cohort of patients whose serum samples were stored at their first visit 15 years ago. Methods: Quantitative HBsAg, HBeAg, HBeAb, HBV DNA, HDV RNA, genotypes, and liver disease severity were assessed at baseline. Patients who were no longer on active follow-up were recalled and re-evaluated in August 2022. Results: The majority of patients were male (64.9%); the median age was 50.1 years; and all patients were Italian, with only three born in Romania. All were HBeAg negative with HBV genotype D infection. Patients were subdivided three groups: 23 were in active follow-up (Group 1), 21 were recalled due to no longer being in follow-up (Group 2), and 11 died (Group 3). Liver cirrhosis was diagnosed in 28 subjects at the first visit; 39.3% of diagnosed patients were in Group 3, 32.1% were in Group 1 and 28.6% were in Group 2 (p = 0.001). Baseline HBV DNA IU/mL Log10 were 1.6 (1.0–5.9) in Group 1, 1.3 (1.0–4.5) in Group 2, and 4.1 (1.5–4.5) in Group 3; median baseline HDV RNA Log10 levels were 4.1 (0.7–6.7) in Group 1, 3.2 (0.7–6.2) in Group 2, and 5.2 (0.7–6.7) in Group 3, resulting significantly higher rates among patients in Group 3 compared to the other groups (p = 0.038). Eighteen patients in Group 2, as compared to 7 in Group 1, had undetectable HDV RNA at the follow-up evaluation (p = 0.001). Conclusions: HDV chronic infection is a heterogeneous disease. It may not only progress but also improve over time in patients, who eventually become HDV RNA-undetectable. HDV RNA levels may help identify the subgroup of patients with less progressive liver disease.

Клинико-вирусологическая характеристика хронического гепатита в и ответ на противовирусную терапию

Chronic hepatitis B (CHB) is a common infectious disease that represents one of the main causes of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). CHB is still difficult to treat due to the lack of drugs that completely eliminate hepatitis B virus (HBV) from hepatocytes. The study was aimed to describe the CHB clinical and laboratory features, assess the efficiency of antiviral therapy and identify the factors associated with the response to antiviral therapy. The results of clinical and laboratory assessment, instrumental examination, serological and molecular testing of the patients (n = 201) followed up between 2007–2021 in the Viral Hepatitis Diagnosis and Treatment Center at the Clinical Hospital No. 85 of FMBA of Russia were assessed based on primary sources. Most of the patients in the group were males (56.7%); the HBeAg-negative patients predominated (93%). LC was diagnosed in nine patients (4.5%), among them one patient had HCC. The HBV D genotype was determined in 95.4% of cases, А genotype in 3.1% of cases, and С genotype in 1.5% of cases. After a year of treatment with the nucleos(t)ide analogues (entecavir or tenofovir) 88% of patients showed no viremia and their biochemical parameters were back to normal (88%). The overall seroconversion rate was 41.7% for HBeAg and 3% for HBsAg. Thus, high rates of virological response and enzyme activity normalization were obtained. Low baseline viremia level is an independent prognostic factor of achieving a virological response. The HBsAg level in the end of therapy makes it possible to predict relapse after the treatment cessation.

Elimination of Herpes Simplex Virus-2 and Epstein-Barr Virus With Seraph 100 Microbind Affinity Blood Filter and Therapeutic Plasma Exchange: An Explorative Study in a Patient With Acute Liver Failure

OBJECTIVES:Herpes simplex virus (HSV)-2 is a rare cause of hepatitis that can lead to acute liver failure (ALF) and often death. The earlier the initiation of acyclovir treatment the better the survival. With regard to ALF, controlled randomized data support the use of therapeutic plasma exchange (TPE) both as bridge to recovery or transplantation—possibly by modulating the systemic inflammatory response and by replacing coagulation factors. Seraph 100 Microbind Affinity Blood Filter (Seraph; Ex Thera Medical, Martinez, CA), a novel extracorporeal adsorption device, removes living pathogens by binding to a heparin-coated surface was shown to efficiently clear HSV-2 particles in vitro. Here, we tested the combination of Seraph with TPE to reduce a massive HSV-2 viral load to reach a situation in that liver transplantation would be feasible.DESIGN:Explorative study.SETTING:Academic tertiary care transplant center.PATIENT:Single patient with HSV-2–induced ALF.INTERVENTIONS:TPE + Seraph 100 Microbind Affinity Blood Filter.MEASUREMENTS AND MAIN RESULTS:We report Seraph clearance data of HSV-2 and of Epstein-Barr virus (EBV) in vivo as well as total viral elimination by TPE. Genome copies/mL of HSV-2 and EBV in EDTA plasma were measured by polymerase chain reaction every 60 minutes over 6 hours after starting Seraph both systemically and post adsorber. Also, HSV-2 and EBV were quantified before and after TPE and in the removed apheresis plasma. We found a total elimination of 1.81 × e11 HSV-2 copies and 2.11 × e6 EBV copies with a single TPE (exchange volume of 5L; 1.5× calculated plasma volume). Whole blood clearance of HSV-2 in the first 6 hours of treatment was 6.64 mL/min (4.98–12.92 mL/min). Despite much lower baseline viremia, clearance of EBV was higher 36.62 mL/min (22.67–53.48 mL/min).CONCLUSIONS:TPE was able to remove circulating HSV-2 copies by 25% and EBV copies by 40% from the blood. On the other hand, clearance of HSV-2 by Seraph was clinically irrelevant, but Seraph seemed to be far more effective of removing EBV, implicating a possible use in EBV-associated pathologies, but this requires further study.

Cytomegalovirus viremia and risk of disease progression and death in HIV-positive patients starting antiretroviral therapy.

The aim of this study was to assess the prevalence of cytomegalovirus (CMV) viremia in HIV-positive patients starting antiretroviral therapy (ART) and to evaluate its impact on clinical outcomes. A retrospective analysis of four clinical trials (INSIGHT FIRST, SMART, START, and ANRS REFLATE TB). Stored plasma samples from participants were used to measure CMV viremia at baseline prior to initiating ART and at visits through 1 year of follow-up after ART initiation. CMV viremia was measured centrally using a quantitative PCR assay. Within FIRST, associations of CMV viremia at baseline and through 8 months of ART were examined with a composite clinical outcome of AIDS, serious non-AIDS events, or death using Cox proportional hazards regression. Samples from a total of 3176 participants, 1169 from FIRST, 137 from ANRS REFLATE TB, 54 from SMART, and 1816 from START were available with baseline CMV viremia prevalence of 17, 26, 0, and 1%, respectively. Pooled across trials, baseline CMV viremia was associated with low CD4 + T-cell counts and high HIV RNA levels. In FIRST, CMV viremia was detected in only 5% of participants between baseline and month 8. After adjustment for CD4 + T-cell count and HIV RNA levels, hazard ratios for risk of clinical outcomes was 1.15 (0.86-1.54) and 2.58 (1.68-3.98) in FIRST participants with baseline and follow-up CMV viremia, respectively. Baseline CMV viremia in HIV-positive patients starting ART is associated with advanced infection and only persistent CMV viremia after ART initiation is associated with a higher risk of morbidity and mortality.

Improved Viral Suppression With Streamlined Care in the SEARCH Study.

HIV differentiated service delivery (DSD) models are scaling up in resource-limited settings for stable patients; less is known about DSD outcomes for patients with viremia. We evaluated the effect on viral suppression (VS) of a streamlined care DSD model implemented in the SEARCH randomized universal test and treat trial in rural Uganda and Kenya (NCT:01864603). We included HIV-infected adults at baseline (2013) who were country guideline antiretroviral therapy (ART) eligible (prior ART experience or CD4 ≤ 350) with ≥1 HIV clinic visit between 2013 and 2017 in SEARCH communities randomized to intervention (N = 16) or control (N = 16). We assessed the effect of streamlined care in intervention community clinics (patient-centered care, increased appointment spacing, improved clinic access, reminders, and tracking) on VS at 3 years. Analysis was stratified by the baseline care status: ART-experienced with viremia, ART-naïve with CD4 ≤ 350, or ART-experienced with VS. Among 6190 ART-eligible persons in care, year 3 VS was 90% in intervention and 87% in control arms (RR 1.03, 95% CI: 1.01 to 1.06). Among ART-experienced persons with baseline viremia, streamlined care was associated with higher VS (67% vs 47%, RR 1.41, 95% CI: 1.05 to 1.91). Among ART-naïve persons, VS was not significantly higher with streamlined care (83% vs 79%, RR 1.05, 95% CI: 0.95 to 1.16). Among ART-experienced persons with baseline VS, nearly all remained virally suppressed in both arms (97% vs 95%, RR 1.01, 95% CI: 1.00 to 1.03). Streamlined care was associated with higher viral suppression among ART-experienced patients with viremia in this randomized evaluation of ART-eligible patients who were in care after universal HIV testing.

HIV-1 integrase resistance associated mutations and the use of dolutegravir in Sub-Saharan Africa: a systematic review and meta-analysis protocol

BackgroundSub-Saharan Africa carries the greatest burden of HIV-infection with increasing drug resistance burden, which requires improved patient management and monitoring. Current WHO recommendations suggest transitioning to dolutegravir-based (adults) or raltegravir-based-regimens (neonates) for initial antiretroviral therapy (ART) and as a suitable alternative in cases of multi-resistance in resource-limited settings. This review aims at synthesizing the current knowledge on dolutegravir use and integrase resistance-associated mutations found before the wide use of dolutegravir-based regimens.MethodsThis systematic review will include randomized and non-randomized trials, cohort, and cross-sectional studies published on dolutegravir use or integrase resistance-associated mutations in Sub-Saharan Africa. Searches will be conducted (from 2007 onwards) in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Latin American and Caribbean Health Sciences Literature (LILAC), Web of Science, African Journals Online, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases. Hand searching of the reference lists of relevant reviews and trials will be conducted and we will also look for conference abstracts. We will include studies of adults and/or children exposed to integrase inhibitors-based therapies; especially dolutegravir or raltegravir (which is our intervention of interest as compared to other antiretroviral regimens). We will exclude studies of patients with specific co-morbidities such as tuberculosis or opportunistic infections. Primary outcomes will be “the rate of viral suppression” and “the level of drug resistance” on integrase inhibitor-based regimens among patients in Sub-Saharan Africa. Secondary outcomes will be “the effect of baseline viremia on viral suppression,” “the effect of treatment duration on viral suppression,” “the proportion of patients with immune recovery,” “the rate of non-adherence,” “rate of adverse events;” “drug resistance according to different integrase inhibitor-based regimens,” and “drug resistance according to viral subtypes/recombinants.” Two reviewers will independently screen titles and abstracts, assess the full texts for eligibility, and extract data. If data permits, random effects models will be used where appropriate. Subgroup and additional analyses will be conducted to explore the potential sources of heterogeneity (e.g., age, sex, baseline viremia, CD4 following treatment, treatment duration, and adherence level).DiscussionThis review will help to strengthen evidence on the effectiveness of integrase strand transfer inhibitors by contributing to current knowledge on the use of dolutegravir and/or raltegravir (especially for neonates) in Sub-Saharan Africa. Results will therefore help in setting-up baseline data for an optimal management of people living with HIV as Sub-Saharan African countries are transitioning to dolutegravir-based regimens. Evidence will also support HIV/AIDS programs in identifying gaps and actions to be undertaken for improved long-term care and treatment of people living with HIV in Sub-Saharan Africa.Systematic review registrationPROSPERO CRD42019122424

Association of Prophylactic Anti-Hepatitis B Virus Therapy With Improved Long-term Survival in Patients With Hepatocellular Carcinoma Undergoing Transarterial Therapy.

The effect of prophylactic antiviral therapy (AVT) on survival of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains unknown. This study aimed to determine whether prophylactic AVT could improve long-term survival in patients undergoing transarterial chemotherapy (TAC). Between 2002 and 2016, 2860 newly diagnosed HBV-related patients with HCC treated with TAC were screened to analyze 2 groups based on prophylactic use of antivirals. Treatment effects were analyzed using propensity score (PS) matching (1:1) separately for the entire cohort and each subgroup. The primary endpoint was overall survival. A total of 1547 patients met the inclusion criteria and 1084 were PS matched for the 2 groups. Median follow-up duration was 16.55 months. In the entire unmatched cohort, patients receiving prophylactic AVT survived significantly longer than those who did not. Among AVT-untreated patients, baseline high viremia and HBV reactivation during treatment were significantly associated with shorter survival. Regarding types of antivirals, survival was significantly longer for patients receiving high-potency antivirals than those receiving low-potency antivirals. Survival differed with antiviral response. In the PS-matched cohort, the prophylactic AVT group survived significantly longer than the nonprophylactic group, irrespective of viral status or tumor stage. Prophylactic AVT remained an independent factor for survival. The association of prophylactic AVT with decreased risk of mortality persisted in patient subgroups after adjusting for baseline risk factors. Sensitivity analyses also confirmed estimated treatment effects. Prophylactic AVT is associated with significantly improved long-term survival among patients undergoing TAC. High-potency antivirals are indicated for this approach.Hepatitis B virus-associated morbidity is a well-known complication during transarterial chemotherapy (TAC). Our large-scale study demonstrated that prophylactic therapy with high-potency antivirals provides a significantly better survival in TAC-treated patients, irrespective of baseline viremia status or tumor stage.

Hepatitis B and C Virus Reactivation Patterns in a Romanian Cohort of Patients with Chronic Lymphoproliferative Disorders.

Hepatitis B and C virus (HBV and HCV) reactivations have become more common following the intensive use of biological therapies for the treatment of chronic lymphoproliferative disorders (CLD). We evaluate risk factors for virus reactivation and exitus in patients diagnosed with CLD and HBV or HCV infection, undergoing rituximab-chemotherapy (R-chemo). A prospective, observational study in two tertiary-care Romanian hospitals, between December 2007 and May 2010, of patients diagnosed with CLD undergoing R-chemo. HBV and HCV serological markers, viral load, fibrosis and necroinflammation were assessed at baseline and every 3-6 months. We screened 502 patients diagnosed with CLDs (77.2% non-Hodgkin lymphomas) and enrolled 57 patients with HBV and/or HCV infection with a mean age of 61.35 ± 11.1 years. The replicative virus was HBV in 23 patients (40.3%), HCV in 33 patients (57.9%). HCV reactivation rate (15.6%) was lower than for HBV (45.5%) (p = 0.02). In univariate analysis, viral reactivation was associated with aggressive CLD (p = 0.01), HBV (p = 0.01) and lymphopenia (p = 0.02). Death was associated with aggressive CLD (p = 0.01), viral reactivation (p = 0.001) and high baseline viremia (p = 0.05). In multivariate analysis, viral reactivation was associated with lymphopenia (OR 0.05, 95% CI 0.003-0.85, p = 0.03). Risk of death was 10times higher for patients with viral reactivation (95% CI 1.54-65.5, p = 0.01). A quarter of the infected patients were diagnosed with viral reactivation. While hepatitis C was more prevalent than hepatitis B in patients with CLD, viral reactivation was found 3times more frequently in patients with hepatitis B than C.

Brief Report: Declining Baseline Viremia and Escalating Discordant HIV-1 Confirmatory Results Within South Africa's Early Infant Diagnosis Program, 2010–2016

To describe baseline HIV-1 RNA viral load (VL) trends within South Africa's Early Infant Diagnosis program 2010-2016, with reference to prevention of mother-to-child transmission guidelines. HIV-1 total nucleic acid polymerase chain reaction (TNA PCR) and RNA VL data from 2010 to 2016 were extracted from the South African National Health Laboratory Service's central data repository. Infants with a positive TNA PCR and subsequent baseline RNA VL taken at age <7 months were included. Descriptive statistics were performed for quantified and lower-than-quantification limit (LQL) results per annum and age in months. Trend analyses were performed using log likelihood ratio tests. Multivariable linear regression was used to model the relationship between RNA VL and predictor variables, whereas logistic regression was used to identify predictors associated with LQL RNA VL results. Among 13,606 infants with a positive HIV-1 TNA PCR linked to a baseline RNA VL, median age of first PCR was 57 days and VL was 98 days. Thirteen thousand one hundred ninety-five (97.0%) infants had a quantified VL and 411 (3.0%) had an LQL result. A significant decline in median VL was observed between 2010 and 2016, from 6.3 log10 (interquartile range: 5.6-6.8) to 5.6 log10 (interquartile range: 4.2-6.5) RNA copies per milliliter, after controlling for age (P < 0.001), with younger age associated with lower VL (P < 0.001). The proportion of infants with a baseline VL <4 Log10 RNA copies per milliliter increased from 5.4% to 21.8%. Subsequent to prevention of mother-to-child transmission Option B implementation in 2013, the proportion of infants with an LQL baseline VL increased from 1.5% to 6.1% (P < 0.001). Between 2010 and 2016, a significant decline in baseline viremia within South Africa's Early Infant Diagnosis program was observed, with loss of detectability among some HIV-infected infants.

Viral Decay Dynamics and Mathematical Modeling of Treatment Response: Evidence of Lower in vivo Fitness of HIV-1 Subtype C.

Despite the high prevalence of HIV-1 subtype C (HIV-1C) worldwide, information on HIV-1C viral dynamics and response to antiretroviral therapy (ART) is limited. We sought to measure viral load decay dynamics during treatment and estimate the within-host basic reproductive ratio, R0, and the critical efficacy, εc, for successful treatment of HIV-1C infection. Individuals initiated on first-line ART in India and monitored for 6 months of treatment were considered. Viral load, CD4 count, and adherence data were collected at baseline, 4, 12, 16 and 24 weeks after ART initiation. Drug resistance genotyping was performed at baseline. R0 and εc were estimated using a mathematical model. Among 257 patients with complete data, mean baseline viral load was 5.7 log10 copies per milliliter and median CD4 count was 165 cells per cubic millimeter. Primary drug resistance was present in 3.1% at baseline. At 6 months, 87.5% had undetectable viral load, indicating excellent response to ART despite high baseline viremia. After excluding those with transmitted resistance, suboptimal adherence and viral rebound, data from 112 patients were analyzed using a mathematical model. We estimated the median R0 to be 5.3. The corresponding εc was ∼0.8. These estimates of R0 and εc are smaller than current estimates for HIV-1B, suggesting that HIV-1C exhibits lower in vivo fitness compared with HIV-1B, which allows successful treatment despite high baseline viral loads. The lower fitness, and potentially lower virulence, together with high viral loads may underlie the heightened transmission potential of HIV-1C and its growing global spread.

Virological response and resistance profile in HIV-1-infected patients starting darunavir-containing regimens.

We evaluated the virological response in patients starting a regimen based on darunavir/ritonavir (DRV/r), which is currently the most widely used ritonavir-boosted protease inhibitor. Data from 206 drug-naïve and 327 PI-experienced patients starting DRV/r 600/100mg twice daily (DRV600) or 800/100mg once daily (DRV800) were examined. The probabilities of virological success (VS) and virological rebound (VR) were evaluated in survival analyses. Baseline DRV/r resistance and its evolution at failure were also examined. DRV600 was preferentially administered in patients with complex requirements (older age, higher viraemia, lower CD4 cell count and DRV/PI resistance) compared with DRV800. By 12months, the probability of achieving VS was 93.2% and 84.3% in drug-naïve and PI-experienced patients, respectively. The higher the baseline viraemia, the longer was the time required to achieve VS, both in drug-naïve patients [>500000 HIV-1 RNA copies/mL: median [interquartile range (IQR)] 6.1 (5.1-10.3) months; 100000-500000 copies/mL: median (IQR) 4.9 (3.8-6.1) months; <100000 copies/mL: median (IQR) 3.9 (3.5-4.8) months; P<0.001] and in PI-experienced patients [≥100000 copies/mL: median (IQR) 7.2 (5.7-11.6) months; <100000 copies/mL: median (IQR) 2.8 (2.4-3.3) months; P<0.001]. In PI-experienced patients, the probability of VR was higher for higher viraemia levels (22.3% for ≥100000 copies/ml vs. 9.7% for <100000 copies/mL; P=0.007). Baseline resistance did not affect the virological response. At failure, a high percentage of patients maintained virus susceptible to all PIs (drug-naïve: 95%; PI-experienced: 80%). Despite being used more often in patients with more complex requirements, DRV600 performed as well as DRV800. In clinical practice, use of DRV/r (with its flexible dosage) results in high rates of virological response. These data support the use of PI/r in patients whose characteristics require potent drugs with a high genetic barrier.

Salvage therapy or simplification of salvage regimens with dolutegravir plus ritonavir-boosted darunavir dual therapy in highly cART-experienced subjects: an Italian cohort.

Dolutegravir plus darunavir provide a high genetic barrier to HIV-1 resistance and are suitable for simple salvage regimens. All HIV-1-infected subjects treated with dolutegravir plus boosted darunavir dual therapy between March 2011 and September 2015 were included in an observational cohort. Data were collected at baseline and at weeks 4, 12, 24 and 48. We enrolled 113 subjects. After week 24, one was lost at follow-up, one dropped out for grade 2 elevation of liver enzymes, one died from illicit drug abuse and one from cancer-related sepsis. The mean age was 51, 26.5% were female and 9.7% were non-Caucasian. Twenty had never experienced failure. A total of 99 had reverse-transcriptase (RT) mutations, 87 had protease inhibitor mutations and 12 had integrase strand transfer inhibitor (INSTI) mutations. Viraemic patients declined from baseline to week 24 from 43.4% to 6.2%, the remainder being due to high baseline viraemia or adherence issues. The proportion of subjects with viraemia 1-49 copies/ml remained at 20.4% while those in whom no virus was detected (NVD) increased from 36.3% to 73.5% by week 24. All the 47 subjects who had a 48-week follow-up had <50 copies/ml and 42 (89.4%) had NVD. 18 subjects had reduced sensitivity to darunavir (Stanford median score 15, range 15-40), but none rebounded, 6 having a 24-week and 7 a 48-week follow-up. The median variation in serum creatinine was -0.01 (range +0.2 to -0.21) mg/dl. This dual regimen provides a simple salvage regimen and proved safe and effective in this cohort.

High treatment modification rates with lamivudine therapy in HBV-infected patients with low baseline viremia and early virological response: A multicenter study.

Low baseline viremia and an early treatment response predict the best outcomes in hepatitis B virus (HBV)-infected patients treated with nucleoside analogues with low barriers to resistance. The aim of this study was to assess the long-term results and effectiveness of lamivudine in patients with low baseline viremia and early virological treatment response. In this multicenter, real-life setting study, 111 antiviral-naive patients with low baseline viremia (HBV DNA <10(7) copies/mL) plus an early virological response (HBV DNA <300 copies/mL at week 24) treated with lamivudine were enrolled. The primary end-point was treatment failure, defined as the re-emergence of detectable viremia or at least a 1 log increase in HBV DNA, resulting in a titer of ≥ 300 copies/mL with lamivudine treatment after week 24, which required treatment modification. Altogether 111 patients, including 78 non-cirrhotic and 33 cirrhotic patients, were included in the study. Treatment failure occurred in 30.8% of the non-cirrhotic patients over a median follow-up period of 32.5 months, and the 1-, 2-, 3-, 4- and 5-year treatment failure rates were 6.5%, 14.0%, 31.4%, 39.6% and 43.1%, respectively. Treatment failure occurred in 28.8% of the whole group. There were no differences between the cirrhotic and non-cirrhotic patients. Lamivudine treatment had a high treatment modification rate in patients with low baseline viremia and early virological response over a long-term follow-up in a real-life setting. The pretreatment and on-treatment favorable characteristics found in the studies with telbivudine appeared to be inapplicable to lamivudine.

Interleukin 28B polymorphisms as predictors of sustained virological response in chronic hepatitis C: systematic review and meta-analysis.

Polymorphism of interleukin 28B gene represents a powerful outcome predictor for interferon-based regimens in hepatitis C virus infection. However, some studies report conflicting results. The predictive value of interleukin 28B genotype over the outcome interferon-α/ribavirin treatment was thoroughly evaluated and compared with virological predictors of response. Literature revision was performed on PubMed. Pooled odds ratios (ORs) were calculated by fixed- or random-effects models. Heterogeneity and publication bias were also assessed. Sixty-two eligible papers including 20 290 patients were retrieved. Both polymorphisms (rs12979860 and rs8099917) were strongly associated with response (OR=4.09 and 4.00, respectively), however, the association was weaker for subjects infected with viral genotypes 2 and 3 (OR=1.52 and 1.49, respectively). Compared with interleukin 28B genotype, the association with response was lower for baseline viremia (OR=2.15) and higher for rapid virological response (OR=13.86). These results provide a critical evaluation of interleukin 28B genotype as a pharmacogenetic predictor in hepatitis C patients.

Anti-E1E2 antibodies do predict response to triple therapy in treatment-experienced Hepatitis C Virus-cirrhosis cases

We previously showed that pre-treatment serum anti-E1E2 predicted hepatitis C virus (HCV) RNA viral kinetics (VKs) and treatment outcome in patients with chronic hepatitis C receiving pegylated interferon/ribavirin (Peg-IFN/RBV) double therapy. Here, we determined whether baseline anti-E1E2 was correlated with the on-treatment VK and could predict virological outcome in treatment-experienced HCV-infected cirrhotic patients receiving protease inhibitor-based triple therapy. Sera from 19 patients with HCV genotype 1 infection and compensated cirrhosis who failed to respond to a prior course of Peg-IFN/RBV were selected at time 0 before starting triple therapy with boceprevir or telaprevir. We assessed patients with sustained viral response 12 weeks after the end of triple therapy (SVR12) by analyzing VKs at weeks 4, 12, 24, 36, 48 (end of treatment) and 60. Patients baseline characteristics were similar to the well-defined CUPIC cohort (age, HCV subtype, baseline viremia, and treatment history). Among the 19 patients, 11 achieved an SVR12. Fifteen patients were positive for pre-treatment anti-E1E2 and all of them achieved SVR12. Moreover, anti-E1E2 and SVR12 correlated with prior response to IFN/RBV therapy (relapse, partial or null response). Baseline anti-E1E2 could be considered as a new biomarker to predict SVR12 after triple therapy in this most difficult-to-treat population. These results warrant further validation on larger cohorts including patients receiving highly effective direct-acting antivirals to explore whether this test could help in better defining treatment duration for these very costly molecules.

HCV genotype 1 subtypes (1a and 1b): similarities and differences in clinical features and therapeutic outcome.

To evaluate similarities and differences in HCV-1 subtypes 1a and 1b in the presenting clinical features and the response to peg-interferon and ribavirin (Peg/RIBA). A total of 1,233 naïve patients with HCV genotype-1 infection, 159 (13%) with subtype 1a and 1,074 (87%) with subtype 1b were treated with Peg-IFN/RIBA at 12 Italian centers. Covariates included in the logistic model were age, gender, BMI, serum alanine aminotransferase, serum gamma-glutamiltranspeptidase (γGT), platelets counts, liver fibrosis, the occurrence of type 2 diabetes, baseline viremia, and IL28B genotype. At multivariate analysis, baseline characteristics differentiating patients with HCV-1a versus HCV-1b were young age, male gender, no F4 fibrosis, and no diabetes. SVR was achieved by 37% of patients with subtype 1b and 45% of those with subtype 1a, a nonsignificant difference of 8% (p = 0.069). In patients with subtype 1a, predictors of SVR were IL28B CC (OR 5.78, CI 1.98-16.83), RVR (OR 4.18, CI 1.66-10.55), female gender (OR 2.83, CI 1.83-6.78), and HCVRNA (OR 0.55, CI 0.32-0.96). In patients with subtype 1b, the ranking of predictors was levels RVR (OR 6.49, CI 4.32-9.73), IL28B CC (OR 3.32, CI 2.15-4.58), γGT (OR 1.59, CI 0.14-2.22), HCVRNA (OR 0.61, CI 0.47-0.79), and age (OR 0.01, CI 0.02-0.42). In Italy HCV-1 subtype 1a prevails in young male patients with less advanced liver damage, findings that imply a more recent spreading of the infection with this viral strain. The two HCV-1 subtypes appear equally responsive to Peg-IFN/RIBA, with IL28B genotyping and monitoring of RVR mostly influencing the therapeutic response.

Evolution of HIV-1 tropism at quasispecies level after 5 years of combination antiretroviral therapy in patients always suppressed or experiencing episodes of virological failure.

Tropism evolution of HIV-1 quasispecies was analysed by ultra-deep pyrosequencing (UDPS) in patients on first-line combination antiretroviral therapy (cART) always suppressed or experiencing virological failure episodes. Among ICONA patients, two groups of 20 patients on cART for ≥5 years, matched for baseline viraemia and therapy duration, were analysed [Group I, patients always suppressed; and Group II, patients experiencing episode(s) of virological failure]. Viral tropism was assessed by V3 UDPS on plasma RNA before therapy (T0) and on peripheral blood mononuclear cell proviral DNA before-after therapy (T0-T1), using geno2pheno false positive rate (FPR) (threshold for X4: 5.75). For each sample, quasispecies tropism was assigned according to X4 variant frequency: R5, <0.3% X4; minority X4, 0.3%-19.9% X4; and X4, ≥20% X4. An R5-X4 switch was defined as a change from R5/minority X4 in plasma/proviral genomes at T0 to X4 in provirus at T1. At baseline, mean FPR and %X4 of viral RNA were positively correlated with those of proviral DNA. After therapy, proviral DNA load significantly decreased in Group I; mean FPR of proviral quasispecies significantly decreased and %X4 increased in Group II. An R5-X4 switch was observed in five patients (two in Group I and three in Group II), all harbouring minority X4 variants at T0. UDPS analysis reveals that the tropism switch is not an 'on-off' phenomenon, but may result from a profound re-shaping of viral quasispecies, even under suppressive cART. However, episodes of virological failure seem to prevent reduction of proviral DNA and to accelerate viral evolution, as suggested by decreased FPR and increased %X4 at T1 in Group II patients.