[Show abstract][Hide abstract] ABSTRACT: The aim of the study was to evaluate the spectrum of AIDS-defining malignancies (ADMs) and non-AIDS-defining malignancies (NADMs) in HIV-infected patients in Poland.
Material and methods: A retrospective observational study was conducted among HIV-infected adult patients who developed a malignancy between 1995 and 2012 in a Polish cohort. Malignancies were divided into ADMs and NADMs. Non-AIDS-defining malignancies were further categorised as virus-related (NADMs-VR) and unrelated (NADMs-VUR). Epidemiological data was analysed according to demographic data, medical history, and HIV-related information. Results were analysed by OR, EPITools package parameters and Fisher’s exact test.
Results: In this study 288 malignancies were discovered. The mean age at diagnosis was 41.25 years (IQR20-81); for ADMs 38.05 years, and for NADMs-VURs 46.42 years; 72.22% were male, 40.28% were co-infected with HCV. The risk behaviours were: 37.85% IDU, 33.33% MSM, and 24.31% heterosexual. Mean CD4+ at the diagnosis was 282 cells/mmł (for ADMs 232 and for NADMs-VUR 395). Average duration of HIV infection at diagnosis was 5.69 years. There were 159 (55.2%) ADMs and 129 (44.8%) NADMs, among whom 58 (44.96%) NADMs-VR and 71 (55.04%) NADMs-VUR. The most frequent malignancies were: NHL (n = 76; 26.39%), KS (n = 49; 17.01%), ICC (n = 34; 11.81%), HD (n = 23; 7.99%), lung cancer (n = 18; 6.25%) and HCC (n = 14; 4.86%). The amount of NADMs, NADMs-VURs in particular, is increasing at present. Male gender (OR = 1.889; 95% CI: 1.104–3.233; p = 0.024), advanced age: 50–60 years (OR = 3.022; 95% CI: 1.359–6.720; p = 0.01) and ≥ 60 years (OR = 15.111; 95% CI: 3.122–73.151; p < 0.001), longer duration of HIV-infection and successful HAART (OR = 2.769; 95% CI: 1.675–4.577; p = 0) were independent predictors of NADMs overall, respectively.
Conclusions: In a Polish cohort NHL was the most frequent malignancy among ADMs, whereas HD was the most frequent among NADMs. Increased incidence of NADMs appearing in elderly men with longer duration of HIV-infection and with better virological and immunological control was confirmed. As HIV-infected individuals live longer, better screening strategies, especially for NADMs-VUR, are needed. The spectrum of cancer diagnoses in Poland currently does not appear dissimilar to that observed in other European populations.
HIV, AIDS-defining malig- nancies, non-AIDS-defining malignancies, PLHIV, cART, cancer
[Show abstract][Hide abstract] ABSTRACT: Objectives:
INSIGHT (ClinicalTrials.gov NCT01513941) evaluated the efficacy, safety and pharmacokinetics of telaprevir-based therapy and specific antiretroviral agents in hepatitis C virus genotype 1 (HCV-1)/HIV-1-coinfected patients.
Patients and methods:
Open-label, Phase IIIb, multicentre study of telaprevir with pegylated-IFN (Peg-IFN) α2a and ribavirin in treatment-naive or -experienced HCV-1/HIV-1-coinfected patients on stable HIV HAART comprising efavirenz, atazanavir/ritonavir, darunavir/ritonavir, raltegravir, etravirine or rilpivirine with two nucleos(t)ide analogues. Patients received 750 mg telaprevir (1125 mg, if on efavirenz) every 8 h plus 180 μg/week Peg-IFNα2a and 800 mg/day ribavirin for 12 weeks, followed by Peg-IFNα2a and ribavirin alone for 12 weeks (HCV treatment naive and relapsers without cirrhosis, with extended rapid virological response) or 36 weeks (all others).
Overall, 162 patients (median age of 46 years, 78% male, 92% Caucasian and mean CD4 count of 687 cells/mm(3)) were treated; 13% had cirrhosis. One-hundred-and-thirty-two patients (81%) completed telaprevir; 14 (9%) discontinued due to an adverse event (AE). Sustained virological response (SVR) 12 rates (<25 IU/mL HCV RNA 12 weeks after the last planned treatment dose) in treatment-naive patients, relapsers and non-responders were 64% (41 of 64), 62% (18 of 29) and 49% (34 of 69), respectively. SVR12 rates ranged from 51% (33 of 65) (patients receiving efavirenz) to 77% (13 of 17) (patients receiving raltegravir). Most frequently reported AEs during telaprevir treatment were pruritus (43%) and rash (34%) special search categories. Anaemia special search category occurred in 15% of patients; 6% of patients reported a serious AE.
In treatment-naive/-experienced HCV-1/HIV-1 patients there were significantly higher SVR rates with telaprevir-based therapy compared with pre-specified historical controls, and safety comparable to that in HCV-monoinfected patients.
Journal of Antimicrobial Chemotherapy 10/2015; DOI:10.1093/jac/dkv323 · 5.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated the safety, efficacy, and impact of ribavirin and peginterferon dose reduction on complete early virologic response and sustained virologic response (SVR) to triple therapy with telaprevir in treatment-experienced patients with advanced liver fibrosis.Treatment was initiated for 211 patients who failed treatment with peginterferon and ribavirin, with bridging fibrosis (F3, n = 68) or cirrhosis (F4, n = 143), including 103 (49%) null-responders (NR), 30 (14%) partial responders (PR), and 78 (37%) relapsers (REL). Impaired liver function (ILF) platelets <100,000/mm or albumin <35 g/L were present in 40 patients. The distribution of hepatitis C virus subtypes was: 1a, 1b, or 1, with undetermined subtype for 10 (5%), 187 (89%), and 14 (6%) patients, respectively. Treatment was started with peginterferon alpha-2a or alpha-2b, ribavirin, and telaprevir at standard doses.The overall SVR24 rate was 56% and was lower in cirrhotic patients (NR: 35%, PR: 40%, and REL: 63%, respectively) than in patients with bridging fibrosis (NR: 50%, PR: 75%, and REL: 75%, respectively). The lowest probability of SVR24 was in NRs with ILF (26%). The SVR24 rate significantly decreased in NRs receiving <60% vs >60% of the total ribavirin dose (23% vs 44%, respectively) or <80% vs >80% of the total ribavirin dose (33% vs 48%, respectively). A significant SVR24 decrease was noted subsequent to a total peginterferon dose reduction, both when comparing patients who received <60% vs >60% of the total dose (NR: 0% vs 44%; REL: 33% vs 68%) and patients who received <80% vs >80% of the total dose (NR: 17% vs 50%; REL: 46% vs 71%).Serious adverse events were observed in 31 patients (15%). Deaths occurred in 4 patients. All of the deceased subjects were cirrhotic members of the ILF (baseline serum albumin level <35 g/L and/or platelet count <100,000/mm) group.Ribavirin dose reduction did not affect efficacy in REL but did in NR. Peginterferon dose reduction decreased the SVR24 rate for all groups, particularly in prior NR. ILF increased the risk of fatal complications with a low probability to achieve SVR24. One solution might be to provide wide and early access to novel, efficient, and safe interferon-free combinations to treatment-experienced patients, particularly those with liver cirrhosis.
Medicine 09/2015; 94(38):e1411. DOI:10.1097/MD.0000000000001411 · 5.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
In previous studies in virologically suppressed patients, protease inhibitor monotherapy has shown trends for more low-level elevations in HIV-1 RNA compared with triple therapy, but no increase in the risk of drug resistance.
A total of 273 patients with HIV-1 RNA less than 50 copies/ml on first-line antiretrovirals switched to darunavir/ritonavir (DRV/r) 800/100 mg once daily, either as monotherapy (n = 137) or as triple therapy with two nucleoside analogues (n = 136). Treatment failure was defined as HIV-1 RNA levels 50 copies/ml or above, or discontinuation of study treatment by week 48 (FDA Snapshot algorithm).
Patients were 83% male and 88% white, with mean age 42 years. In the primary efficacy analysis, HIV-1 RNA less than 50 copies/ml by week 48 [intention-to-treat (ITT)] was 118 of 137 (86%) in the DRV/r monotherapy arm versus 129 of 136 (95%) in the triple therapy arm (difference = -8.7%, 95% confidence interval -15.50, -1.80). In a post-hoc analysis, for patients with nadir CD4 cell count 200 cells/μl or above, rates of HIV-1 RNA suppression were 91 of 96 (95%) in the DRV/r monotherapy arm and 100 of 106 (94%) in the triple therapy arm. There was no difference in neurocognitive function or the risk of neuropsychiatric adverse events between DRV/r monotherapy and triple therapy. Two patients in the monotherapy arm with CD4 nadir less than 200 cells/μl developed viraemia in both cerebrospinal fluid (CSF) and plasma, with one symptomatic case.
In this study for patients with HIV-1 RNA less than 50 copies/ml at baseline, switching to DRV/r monotherapy showed lower efficacy versus triple therapy at week 48 in the primary ITT switch equals failure analysis, with two cases of viraemia in the CSF in the protease inhibitor monotherapy arm.
AIDS (London, England) 09/2015; 29(14):1811-20. DOI:10.1097/QAD.0000000000000778 · 5.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Association between hepatitis C virus (HCV) quasispecies and treatment outcome among patients with chronic hepatitis C has been the subject of many studies. However, these studies focused mainly on viral variable regions (E1 and E2) and usually did not include human immunodeficiency virus (HIV)-positive patients. The aim of the present study was to analyze heterogeneity of the 5′untranslated region (5′UTR) in HCV/HIV coinfected patients treated with interferon and ribavirin. The HCV 5′UTR was amplified from serum and peripheral blood mononuclear cells (PBMC) samples in 37 HCV/HIV coinfected patients treated for chronic hepatitis C. Samples were collected right before treatment, and at 2, 4, 6, 8, 12, 20, 24, 36, 44, 48, 60, and 72 weeks. Heterogeneity of the 5′UTR was analyzed by single strand conformational polymorphism (SSCP), cloning and sequencing. Sustained virological response (SVR) was achieved in 46% of analyzed HCV/HIV co-infected patients. Stable SSCP band pattern was observed in 22 patients (62.9%) and SVR rate among these patients was 23%. Decline in the number of bands and/or shift in band positions were found in 6 patients (17.1%), 5 (83%) of whom achieved SVR (p=0.009). A novel viral genotype was identified in all but one of these patients. In 5 of these 6 patients a new genotype was dominant. 5′UTR heterogeneity may correlate with interferon and ribavirin treatment outcome. In the analyzed group of HCV/HIV coinfected patients, viral quasispecies stability during treatment favored viral persistence, whereas decrease in the number of variants and/or emergence of new variants was associated with SVR. Among injection drug users (IDU) patients, a new genotype may become dominant during treatment, probably due to the presence of mixed infections with various strains, which have different susceptibility to treatment.
PLoS ONE 05/2015; 10(5):e0125604. DOI:10.1371/journal.pone.0125604 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract Aim To investigate epidemiology and characteristics of chronic pain in HIV-1 positive persons. Background Chronic pain is vital but still understudied problem in HIV clinical practice; therefore we have designed a study to analyse the prevalence and attributes of pain symptoms in the group of HIV-positive patients in the Out-Patient HIV Clinic in Warsaw. Materials and methods During their routine visit patients were asked to fill in a general information form and the Alcohol Use Disorders Identification Test Consumption (AUDIT-C) form. All patients reporting any pain were additionally asked to fill in the Brief Pain Inventory (BPI) form and were subject to a brief examination performed by a physician who afterwards completed a DN4 (Douleur Neuropathique en 4 Questions) form. Logistic regression models were used to identify factors associated with chronic pain occurrence. Results Forty nine patients completed the questionnaires. Nineteen patients (37.2%) reported chronic pain, occurring once daily in 39.4%, and in 42.9% lasting several hours. In univariate logistic regression analyses factors increasing the odds of chronic pain were age at the time of evaluation (OR = 1.07; 95% CI 1.02-1.08, p = 0.01), starting antiretroviral treatment with didanosine, zalcitabine and stavudine (OR = 6.75; 1.18-38.4, p = 0.03) and last CD4+ lymphocyte count (OR = 0.99; 0.99-1.00, p = 0.07). After adjusting for the three above only age at the evaluation time remained significant factor increasing the odds of experiencing chronic pain (OR = 1.07 [1.01-1.13]; p = 0.03). Conclusion Almost 40% of respondents reported chronic pain. We have found a strong correlation between age and chronic pain in the HIV infected population with the 7% increase in the odds of experiencing pain with each year of age.
HIV and AIDS Review 03/2015; 14(3). DOI:10.1016/j.hivar.2015.02.003
[Show abstract][Hide abstract] ABSTRACT: Background:
Human immunodeficiency virus type 1 (HIV-1) subtype CRF01_AE originated in Africa and then passed to Thailand, where it established a major epidemic. Despite the global presence of CRF01_AE, little is known about its subsequent dispersal pattern.
We assembled a global data set of 2736 CRF01_AE sequences by pooling sequences from public databases and patient-cohort studies. We estimated viral dispersal patterns, using statistical phylogeographic analysis run over bootstrap trees estimated by the maximum likelihood method.
We show that Thailand has been the source of viral dispersal to most areas worldwide, including 17 of 20 sampled countries in Europe. Japan, Singapore, Vietnam, and other Asian countries have played a secondary role in the viral dissemination. In contrast, China and Taiwan have mainly imported strains from neighboring Asian countries, North America, and Africa without any significant viral exportation.
The central role of Thailand in the global spread of CRF01_AE can be probably explained by the popularity of Thailand as a vacation destination characterized by sex tourism and by Thai emigration to the Western world. Our study highlights the unique case of CRF01_AE, the only globally distributed non-B clade whose global dispersal did not originate in Africa.
The Journal of Infectious Diseases 12/2014; 211(11). DOI:10.1093/infdis/jiu666 · 6.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction
We report the SVR12 final analysis of a phase 3 study of telaprevir in combination with peginterferon (P)/ribavirin (R) in HCV-genotype 1, treatment-naïve and -experienced patients with HCV/HIV co-infection (INSIGHT).
Materials and Methods
Patients receiving stable, suppressive HIV antiretroviral (ARV) therapy, containing atazanavir/ritonavir, efavirenz, darunavir/ritonavir, raltegravir, etravirine or rilpivirine, received telaprevir 750 mg q8h (1125 mg q8h if on efavirenz) plus P (180 µg once-weekly) and R (800 mg/day) for 12 weeks, followed by an additional 12 weeks (non-cirrhotic HCV treatment-naïve and relapse patients with extended rapid viral response [eRVR]) or 36 weeks (all others) of PR alone. Analysis was performed when all patients had completed the follow-up visit of 12 weeks after last planned dose.
One hundred sixty-two patients were enrolled and treated (65 efavirenz, 59 atazanavir/ritonavir, 17 darunavir/ritonavir, 17 raltegravir, 4 etravirine). Mean age was 45 years, 78% were male, 92% were Caucasian; mean CD4 count was 687 cells/mm3. Sixty four patients (40%) were HCV treatment-naïve and 98 (60%) were treatment experienced (29 relapsers, 18 partial responders and 51 null responders). 64% were subtype 1a. 30% had bridging fibrosis (17%) or cirrhosis (13%). 19% of patients discontinued telaprevir, including 9% due to an adverse event (AE), 8% reaching a virologic endpoint and 2% for other reasons (non compliance or not defined). Treatment responses are shown in Table 1. There were no HIV RNA breakthroughs. Most frequently reported (≥20% patients) AEs were pruritus 43%; fatigue 27%; rash 34%, anorectal events 30% and influenza-like illness (25%). Anemia was reported in 15% of patients; grade ≥3 haemoglobin decrease occurred in 2.5% of patients. 6% of patients experienced serious AEs.
In this phase 3 study of HIV-infected, HCV treatment-naïve and -experienced patients, 49% achieved eRVR and 57% reached SVR12. In patients with an eRVR, SVR12 rates were >80%, irrespective of prior treatment history.
Journal of the International AIDS Society 11/2014; 17(4 Suppl 3):19626. DOI:10.7448/IAS.17.4.19626 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction
With increased usage of antiretroviral drugs (ARVs) in HIV uninfected persons proper reporting on suspected unexpected serious adverse reactions (SUSARs) and continued insight into serious adverse events (SAEs) is needed for adequate information on ARVs safety in such populations.
We have evaluated medical documentation of persons receiving ARVs after non-occupationally HIV exposure (nPEP) during five concomitant years (2009–2013). SAEs and SUSARs were evaluated by two HIV physicians and defined according to international standards. In statistical methods, Kaplan Meier survival analysis was used to estimate the probability of SAE and Cox proportional hazard models to identify independent predictors of developing SAE. Only the first SAE was included in these analyses.
In total, 375 persons received nPEP. The most common reason was needle stick (43%), followed by unprotected sexual intercourse (17%), rape (10%) and first aid (10%). In 84 (22%) cases, the source patient was either known to be HIV positive or within a high risk group (active injecting drug user). In total, 170 SAEs were reported, 139 persons had only one SAE and majority developed it within first two weeks. The most frequent first SAEs were gastrointestinal disorders (22%), followed by general symptoms (9%), hypersensitivity reactions (1.6%) and CNS symptoms (1.3%). The remaining events were laboratory abnormalities of liver and kidney function, haematological disorders, other and unknown, each contributing to less than 1% of all patients. 8 (2.1%) patients have developed a SUSAR (bradycardia, vivid dreams, lymphadenopathy of the neck, increased platelet count, swelling and pain of large joints, swelling of lower limbs, peripheral oedema and loss of concentration). 22 (5.9%) persons discontinued nPEP due to adverse event and 19 (5.1%) required a paid sick leave from work. In multivariate analyzes, only age was independent predictor of developing SAE (HR 1.17; [95% CI 1.03–1.34]; p=0.02).
In our observation, SAEs in reaction to nPEP were frequent yet usually mild events, mostly occurring in first two weeks and rarely causing discontinuation. The only significant factor increasing the risk of SAE was age. SUSARs were rare and moderately significant. More insight into this important area is required in order to ascertain proper pharmacovigilance of ARVs usage in HIV uninfected persons.
Journal of the International AIDS Society 11/2014; 17(4(Suppl 3)):19733. DOI:10.7448/IAS.17.4.19733 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background & aims:
We evaluated the antiviral response of Asian or Pacific Islander (API) patients with chronic hepatitis B (CHB) who had baseline high viral load (HVL), defined as pre-treatment hepatitis B virus (HBV) DNA ≥9 log10 copies/ml, following up to 288 weeks of tenofovir disoproxil fumarate (TDF) treatment.
A total of 205 HBeAg-negative and HBeAg-positive self-described API patients received 48 weeks of TDF 300 mg (HVL n = 18) or adefovir dipivoxil 10 mg (HVL n = 15) in a blinded fashion, followed by open-label TDF for an additional 240 weeks. The proportions of HVL vs. non-HVL patients with HBV DNA <400 copies/ml were compared. Mean declines in HBV DNA were evaluated in API vs. non-API patients.
Throughout the first 72 weeks of treatment, a smaller proportion of HVL API patients reached HBV DNA <400 copies/ml than non-HVL API patients. However, after this timepoint similar proportions of HVL and non-HVL API patients achieved HBV DNA <400 copies/ml (100% vs. 97%, respectively), which was maintained through week 288, where 92% of HVL patients and 99% of non-HVL API patients on treatment had HBV DNA <400 copies/ml. During the 288 weeks of treatment, API patients had similar mean HBV DNA declines as non-API patients, regardless of whether patients were HVL or non-HVL. No API HVL patient had persistent viremia at week 288. No resistance was detected among HVL or non-HVL patients.
API patients with HVL CHB achieve HBV DNA <400 copies/ml with long-term TDF treatment; however, achieving viral suppression may take longer for HVL patients relative to non-HVL API patients.
Liver international: official journal of the International Association for the Study of the Liver 10/2014; 35(2). DOI:10.1111/liv.12694 · 4.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background & AimsPredictors of response to treatment with peginterferon plus ribavirin are well established. In these post-hoc analyses of the REALIZE study we sought to identify predictors of response for telaprevir-based triple therapyMethods
Patients from the REALIZE study with baseline data for all predictors evaluated (including baseline disease characteristics and demographics, prior treatment response, and baseline laboratory assessments) were included in the post-hoc analyses (n = 465). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes.ResultsSustained viral response (SVR) rates were 86% in prior relapsers, 63% in prior partial responders, and 32% in prior null responders. In the final multivariate analysis, baseline factors predicting SVR were prior response to treatment (Odds ratio [OR] = 2.80; 95% confidence interval [CI], 2.13–3.69), low density lipoprotein (LDL) (≥2.6 mmol/L) (OR = 2.11; 95% CI, 1.52–2.93), HCV genotype (OR = 0.58; 95% CI, 0.36–0.93), and maximum alanine amino transferase and aspartate amino transferase (OR = 0.62; 95% CI, 0.40–0.97).Conclusions
Prior response to peginterferon plus ribavirin treatment and LDL levels are the main independent predictive markers of response with telaprevir-based triple therapy.This article is protected by copyright. All rights reserved.
Liver international: official journal of the International Association for the Study of the Liver 10/2014; 35(2). DOI:10.1111/liv.12703 · 4.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction and objective:
In June 2009 the World Health Organization announced influenza pandemic caused by A/H1N1/v virus. It became crucial to recognize new cases of A/H1N1/v infection. An effective screening diagnostic procedure was needed for patients suffering from influenza-like symptoms for making an initial diagnosis and analyzing epidemiological pattern of infection. We used a strip test for influenza A/B as a screening diagnostic procedure for patients suffering from influenza-like symptoms for making an initial diagnosis. For comparison, RT PCR for detecting A/H1N1/v was performed. The aim of this study was to assess the efficacy and sensitivity of the strip test and its value for making initial diagnosis of influenza A/H1N1/v.
Material and methods:
Strip testing for the influenza A/B infection was performed on 1123 patients with influenza-like symptoms in the Admission Unit of the Regional Infectious Diseases Hospital in Warsaw. Strip test results were analyzed according to the age of patients and season of the year. For 97 patients strip test results for detecting A/H1N1 infection were compared with those obtained by RT PCR.
There were no statistically significant differences found between the methods and strip testing demonstrated sensitivity of 61% and specificity of 71%.
No statistically significant differences were found between the two methods, however, strip test had low sensitivity and specificity.
[Show abstract][Hide abstract] ABSTRACT: Purpose
This prospective, randomized, single-centre study compared peginterferons alfa-2a and alfa-2b, combined with ribavirin, in treating patients infected with hepatitis C virus (HCV) genotype 1.
Hundred-and-one patients received 48 weeks of open-label treatment with peginterferon alfa-2a (180 μg/week) and 111 patients received peginterferon alfa-2b (1.5 μg/kg/week). All patients received the same dose of ribavirin 1000/1200 mg/day, depending on weight. The primary efficacy endpoint was sustained virologic response (SVR), defined as undetectable HCV RNA (<50 IU/mL) 24 weeks after the end of treatment.
Early virologic response (EVR), defined as at least 2 log10 IU/mL reduction of viral load at 12 weeks, was more common in patients treated with peginterferon alfa-2a (88% vs. 74.8%; p = 0.04). However, the difference in SVR was not statistically significant (49.5% vs. 44.1%; p = 0.43).
Peginterferon alfa-2a treated patients were also more likely to be HCV RNA negative at the end of treatment (67.3% vs. 57.7%), but this difference did not reach statistical significance. Multivariate logistic regression analysis found that SVR was associated with low fibrosis stage (F1–2 by Scheuer; p = 0.001) and low serum HCV RNA level (<400,000 IU/L; p = 0.023). While both forms of peginterferon showed similar efficacy as measured by SVR, use of peginterferon alfa-2b could lower the number of patients receiving unnecessary treatment beyond 12 weeks.
Advances in Medical Sciences 09/2014; 59(2). DOI:10.1016/j.advms.2014.01.005 · 1.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
One out of ten newly diagnosed patients in Europe was infected with a virus carrying a drug resistant mutation. We analysed the patterns over time for transmitted drug resistance mutations (TDRM) using data from the European Spread program.
Clinical, epidemiological and virological data from 4317 patients newly diagnosed with HIV-1 infection between 2002 and 2007 were analysed. Patients were enrolled using a pre-defined sampling strategy.
The overall prevalence of TDRM in this period was 8.9% (95% CI: 8.1-9.8). Interestingly, significant changes over time in TDRM caused by the different drug classes were found. Whereas nucleoside resistance mutations remained constant at 5%, a significant decline in protease inhibitors resistance mutations was observed, from 3.9% in 2002 to 1.6% in 2007 (p = 0.001). In contrast, resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) doubled from 2.0% in 2002 to 4.1% in 2007 (p = 0.004) with 58% of viral strains carrying a K103N mutation. Phylogenetic analysis showed that these temporal changes could not be explained by large clusters of TDRM.
During the years 2002 to 2007 transmitted resistance to NNRTI has doubled to 4% in Europe. The frequent use of NNRTI in first-line regimens and the clinical impact of NNRTI mutations warrants continued monitoring.
[Show abstract][Hide abstract] ABSTRACT: Background and Aim
In areas of the world where tenofovir disoproxil fumarate is not marketed, adefovir (ADV) + lamivudine (LAM) is recommended and widely used for LAM-resistant chronic hepatitis B (CHB). This study hypothesizes that entecavir (ETV) + ADV, where both components are active against LAM-resistant hepatitis B virus (HBV), will provide greater antiviral potency than ADV+LAM where only ADV is active.
Open-label, randomized trial in HBeAg(+) LAM-experienced CHB patients with LAM resistance treated with ETV 1 mg + ADV 10 mg (N=138 ), ADV+LAM 100 mg (N=137), or ETV (N=140).
At Week 48, there was no significant difference in the primary endpoint of HBV DNA <50 IU/mL between the treatment groups (25.4% [ETV+ADV] vs 19.7% [ADV+LAM], P=0.2619; vs 16.4% [ETV], P=0.1336). However, at Week 96, rates of HBV DNA <50 IU/mL were significantly greater with ETV+ADV than with ADV+LAM (43.5% vs 28.5%; P=0.0095). Rates of virologic breakthrough and resistance to ETV or ADV were low through Week 96 with both combinations. The delayed benefit of ETV+ADV is likely related to the high baseline viremia in this cohort relating to continued LAM exposure after treatment failure. All three therapies had favourable safety profiles.
In patients with LAM-resistant HBV, ETV+ADV demonstrated greater antiviral efficacy than ADV+LAM and comparable safety over 2 years, and may therefore be a preferable treatment option for LAM-resistant CHB, especially in regions where alternative rescue therapies are not available. In highly viremic patients, the benefit of ETV+ADV became apparent after a longer treatment duration.
Journal of Gastroenterology and Hepatology 07/2014; 29(7):1485-1493. DOI:10.1111/jgh.12567 · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Hypervariable region 1 (HVR1) contained within envelope protein 2 (E2) gene is the most variable part of HCV genome and its translation product is a major target for the host immune response. Variability within HVR1 may facilitate evasion of the immune response and could affect treatment outcome. The aim of the study was to analyze the impact of HVR1 heterogeneity employing sensitive ultra-deep sequencing, on the outcome of PEG-IFN-α (pegylated interferon α) and ribavirin treatment.
HVR1 sequences were amplified from pretreatment serum samples of 25 patients infected with genotype 1b HCV (12 responders and 13 non-responders) and were subjected to pyrosequencing (GS Junior, 454/Roche). Reads were corrected for sequencing error using ShoRAH software, while population reconstruction was done using three different minimal variant frequency cut-offs of 1%, 2% and 5%. Statistical analysis was done using Mann–Whitney and Fisher’s exact tests.
Complexity, Shannon entropy, nucleotide diversity per site, genetic distance and the number of genetic substitutions were not significantly different between responders and non-responders, when analyzing viral populations at any of the three frequencies (≥1%, ≥2% and ≥5%). When clonal sample was used to determine pyrosequencing error, 4% of reads were found to be incorrect and the most abundant variant was present at a frequency of 1.48%. Use of ShoRAH reduced the sequencing error to 1%, with the most abundant erroneous variant present at frequency of 0.5%.
While deep sequencing revealed complex genetic heterogeneity of HVR1 in chronic hepatitis C patients, there was no correlation between treatment outcome and any of the analyzed quasispecies parameters.
[Show abstract][Hide abstract] ABSTRACT: Hepatitis C virus (HCV) highly conserved IRES (internal ribosome entry site) sequence, localized within the 5(')-untranslated region (5(')UTR), may determine viral properties like replication efficiency and cell tropism. The aim of the present study was to characterize newly emerging 5(')UTR variants in serum and peripheral blood mononuclear cells (PBMC) in chronic hepatitis C patients treated with interferon (IFN) and ribavirin and to identify their effect on IRES secondary structures. The study group consisted of 87 patients infected with genotype 1b from whom serum and PBMC samples were collected at 9 time points (before, during, and after treatment). New 5(')UTR variants developed in 9 patients. Out of the overall 14 new variants, 9 (64%) were found in PBMC. HCV variants with decreased thermodynamic stability were identified only in PBMC and C183U mutation was the most common one in this compartment. In conclusion, antiviral treatment may favor emergence of new 5(')UTR variants both in blood and in PBMC compartments. However, variants developing in the latter compartment were predicted to have lower thermodynamic stability of the IRES secondary structures compared to serum strains. C-U change in position 183, which has not been described previously, might indicate viral adaptation to lymphoid cells.
BioMed Research International 07/2014; 2014:175405. DOI:10.1155/2014/175405 · 1.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Despite an increase in number of new drugs in the last few years, the clinical options are limited due to cross resistance and adverse effects of cART. We explored reasons for treatment discontinuation and effectiveness of first-line LPV/r containing regimen.
The study is a retrospective analysis of data collected in POLCA cohort study. Patients were cART naïve and continued LPV/r based regimen for 24 months. Effectiveness analyses included CD4 count and proportion of patients with durable HIV VL suppression. Safety analyses included changes in selected parameters: metabolic (total cholesterol, LDL, HDL, triglycerides, glucose), hepatic (ALT, AST, GGT, total bilirubin) and renal (creatinine, urea).
The median CD4 count increased at all time points till 24 months and the largest difference was in group with CD4 < 100 cells/μl at baseline. After 24 months from starting cART 60.8% of patients achieved HIV RNA below 40 copies/ml. Twenty patients (10.6%) developed virological failure.
Substantial part of patients had abnormal lipid tests results: TCh, HDL-ch, LDL-ch, TG before starting cART (21%, 29%, 40%, 46%, respectively). An increasing proportion of abnormal results of TCh and TG have been observed during cART with only 41% and 46% of normal results at 24 months. Serum creatinine level was normal in approximately 91% patients at baseline and proportion decreased to 86% between 12 and 24 months of treatment.
In POLCA cohort 24 months treatment with LPV/r-based regimen was safe and effective. Gastrointestinal side effects and lipids disorders were quite common but rarely led to treatment discontinuation.
HIV and AIDS Review 07/2014; 13(4). DOI:10.1016/j.hivar.2014.06.001