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BACKGROUND: Typically, genotypic resistance testing is recommended at the start of antiretroviral therapy and is even mandatory in cases of virologic failure. The material of choice is plasma viral RNA. However, in patients with low viremia (viral load < 500 copies/ml), resistance testing by population-based sequencing is very difficult. OBJECTIVE: Therefore, we aimed to investigate whether next generation sequencing (NGS) from proviral DNA and RNA could be an alternative. MATERIAL AND METHODS: EDTA blood samples (n = 36) from routine clinical viral load testing were used for the study. Viral loads ranged from 96 to 390,000 copies/mL, with 100% of samples having low viremia. Distribution of subtypes; A (n = 2), B (n = 16), C (n = 4), D (n = 2), G (1), CRF02 AG (n = 5), CRF01 AE (n = 5), undefined/mixed (n = 4). The extracted consensus sequences were uploaded to the Stanford HIV Drug Resistance Data Base and Geno2pheno for online analysis of drug resistance mutations and resistance factors. RESULTS: A total of 2476 variants or drug resistance mutations (DRMs) were detected with Sanger sequencing, compared with 2892 variants with NGS. An average of 822/1008 variants were identified in plasma viral RNA by Sanger or NGS sequencing, 834/956 in cellular viral RNA, and 820/928 in cellular viral DNA. CONCLUSION: Both methods are well suited for the detection of HIV substitutions or drug resistance mutations. Our results suggest that cellular RNA or cellular viral DNA is an informative alternative to plasma viral RNA for variant detection in patients with low viremia, as shown by the high correlation of variants in the different viral pools. We show that by using UDS, a plus of two DRMs per patient becomes visible, which can make a big difference in the assessment of the expected resistance behavior of the virus.
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Fármacos Anti-HIV , Infecções por HIV , Soropositividade para HIV , HIV-1 , Animais , Fármacos Anti-HIV/uso terapêutico , DNA Viral/genética , Farmacorresistência Viral/genética , Ácido Edético/uso terapêutico , Genômica , Genótipo , Infecções por HIV/tratamento farmacológico , Soropositividade para HIV/tratamento farmacológico , HIV-1/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Leucócitos Mononucleares , Estágios do Ciclo de Vida , Mutação , Provírus/genética , RNA Viral/genética , Carga Viral , Viremia/tratamento farmacológicoRESUMO
BACKGROUND: A persistently low CD4/CD8 ratio has been reported to inversely correlate with the risk of non-AIDS defining cancer in people living with human immunodeficiency virus (HIV; PLWH) efficiently treated by combination antiretroviral therapy (cART). We evaluated the impact of the CD4/CD8 ratio on the risk of Kaposi sarcoma (KS) or non-Hodgkin lymphoma (NHL), still among the most frequent cancers in treated PLWH. METHODS: PLWH from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) were included if they achieved virological control (viral loadâ ≤â 500 copies/mL) within 9 months following cART and without previous KS/LNH diagnosis. Cox models were used to identify factors associated with KS or NHL risk, in all participants and those with CD4â ≥â 500/mm3 at virological control. We analyzed the CD4/CD8 ratio, CD4 count and CD8 count as time-dependent variables, using spline transformations. RESULTS: We included 56 708 PLWH, enrolled between 2000 and 2014. At virological control, the median (interquartile range [IQR]) CD4 count, CD8 count, and CD4/CD8 ratio were 414 (296-552)/mm3, 936 (670-1304)/mm3, and 0.43 (0.28-0.65), respectively. Overall, 221 KS and 187 NHL were diagnosed 9 (2-37) and 18 (7-42) months after virological control. Low CD4/CD8 ratios were associated with KS risk (hazard ratio [HR]â =â 2.02 [95% confidence interval {CIâ } =â 1.23-3.31]) when comparing CD4/CD8â =â 0.3 to CD4/CD8â =â 1) but not with NHL risk. High CD8 counts were associated with higher NHL risk (HRâ =â 3.14 [95% CIâ =â 1.58-6.22]) when comparing CD8â =â 3000/mm3 to CD8â =â 1000/mm3). Similar results with increased associations were found in PLWH with CD4â ≥â 500/mm3 at virological control (HRâ =â 3.27 [95% CIâ =â 1.60-6.56] for KS; HRâ =â 5.28 [95% CIâ =â 2.17-12.83] for NHL). CONCLUSIONS: Low CD4/CD8 ratios and high CD8 counts despite effective cART were associated with increased KS/NHL risks respectively, especially when CD4â ≥â 500/mm3.
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Infecções por HIV , Linfoma não Hodgkin , Sarcoma de Kaposi , Contagem de Linfócito CD4 , Relação CD4-CD8 , Linfócitos T CD8-Positivos , Estudos de Coortes , HIV , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Incidência , Linfoma não Hodgkin/epidemiologia , Fatores de Risco , Sarcoma de Kaposi/epidemiologiaRESUMO
Human immunodeficiency virus-2 (HIV-2) is endemic in some countries in West Africa. Due to the lower prevalence in industrialized countries, there is limited experience and knowledge on the management of individuals living with HIV-2 in Europe. Compared to HIV-1, there are differential characteristics of HIV-2 regarding diagnostic procedures, the clinical course, and, most importantly, antiretroviral therapy. We integrated the published literature on HIV-2 (studies and reports on epidemiology, diagnostics, the clinical course, and treatment), as well as expert experience in diagnosing and clinical care, to provide recommendations for a present standard of medical care of those living with HIV-2 in Western European countries, including an overview of strategies for diagnosis, monitoring, and treatment, with suggestions for effective drug combinations for first- and second-line treatments, post-exposure prophylaxis, and the prevention of mother-to-child transmission, as well as listings of mutations related to HIV-2 drug resistance and C-C motif chemokine receptor type 5 and C-X-C motif chemokine receptor type 4 coreceptor tropism.
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Fármacos Anti-HIV , Infecções por HIV , África Ocidental , Fármacos Anti-HIV/uso terapêutico , Criança , Europa (Continente) , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , HIV-2/genética , Humanos , Transmissão Vertical de Doenças Infecciosas , Padrão de CuidadoRESUMO
We compared invasive cervical cancer (ICC) incidence rates in Europe, South Africa, Latin and North America among women living with HIV who initiated antiretroviral therapy (ART) between 1996 and 2014. We analyzed cohort data from the International Epidemiology Databases to Evaluate AIDS (IeDEA) and the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord. We used flexible parametric survival models to determine regional ICC rates and risk factors for incident ICC. We included 64,231 women from 45 countries. During 320,141 person-years (pys), 356 incident ICC cases were diagnosed (Europe 164, South Africa 156, North America 19 and Latin America 17). Raw ICC incidence rates per 100,000 pys were 447 in South Africa (95% confidence interval [CI]: 382-523), 136 in Latin America (95% CI: 85-219), 76 in North America (95% CI: 48-119) and 66 in Europe (95% CI: 57-77). Compared to European women ICC rates at 5 years after ART initiation were more than double in Latin America (adjusted hazard ratio [aHR]: 2.43, 95% CI: 1.27-4.68) and 11 times higher in South Africa (aHR: 10.66, 95% CI: 6.73-16.88), but similar in North America (aHR: 0.79, 95% CI: 0.37-1.71). Overall, ICC rates increased with age (>50 years vs. 16-30 years, aHR: 1.57, 95% CI: 1.03-2.40) and lower CD4 cell counts at ART initiation (per 100 cell/µl decrease, aHR: 1.25, 95% CI: 1.15-1.36). Improving access to early ART initiation and effective cervical cancer screening in women living with HIV should be key parts of global efforts to reduce cancer-related health inequities.
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Infecções por HIV/complicações , Disparidades nos Níveis de Saúde , Neoplasias do Colo do Útero/epidemiologia , Adolescente , Adulto , Fatores Etários , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , Comparação Transcultural , Detecção Precoce de Câncer , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Humanos , Incidência , América Latina/epidemiologia , Pessoa de Meia-Idade , América do Norte/epidemiologia , Fatores de Risco , África do Sul/epidemiologia , Neoplasias do Colo do Útero/complicações , Neoplasias do Colo do Útero/prevenção & controle , Adulto JovemRESUMO
OBJECTIVE: HIV positive individuals, particularly men having sex with men (MSM), are at increased risk of sexually transmitted infections (STIs) at genital and extra-genital sites. Data on anorectal Ureaplasma infections are lacking. The aim of our study was to characterize anal Ureaplasma positivity among a cohort of HIV positive MSM and evaluate possible association with papillomavirus infection at the same site. METHODS: Anal swab samples, collected as part of routine screening for Chlamydia trachomatis and Neisseria gonorrhea, were additionally tested for HPV genotypes as well as for Ureaplasma and Mycoplasma using nucleic acid amplification method. RESULTS: Out of a total of 222 study participants, 195 (89%, 95% CI (84.9-93.2)) were positive for HPV, approximately three quarter being high-risk genotypes. Forty three individuals (19.4%, 95% CI (14.4-24.3)) harbored Ureaplasma spp. Infection with high-risk HPV types was significantly associated with co-presence of Ureaplasma with an odds ratio (95% confidence-interval) of 2.59 (1.03-6.54), P = 0.04. CONCLUSION: Besides a high predominance of HPV infection, asymptomatic HIV positive MSM had a high prevalence of anal Ureaplasma positivity. Concomitant infections with high-risk HPV genotypes were common and statistically significant. The role of this co-existence as a potential risk factor for anal carcinogenesis needs further elucidation.
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Canal Anal/microbiologia , Soropositividade para HIV/complicações , Homossexualidade Masculina , Infecções por Papillomavirus/etiologia , Ureaplasma/isolamento & purificação , Adulto , Soropositividade para HIV/microbiologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The Austrian province of Tyrol belongs to the areas where the alveolar echinococcosis (AE) caused by the fox tapeworm Echinococcus multilocularis (E. multilocularis) is highly endemic. In Central Europe and since 2011 in Austria, a growing incidence of human cases of AE has been observed, presumably linked with increasing fox populations infected by the fox tapeworm E. multilocularis. Hunting and the related activities put hunters in a high-risk group, and they are considered particularly vulnerable for the contraction of an AE. In light of this risk and the increased number of AE cases made public in Austria, the objective of the study was to investigate the prevalence of AE in hunters and to provide a possible connection to the incidence increase. In 2015 and 2016, we examined 813 serums of active hunters from all nine districts of Tyrol and serologically tested them for E. multilocularis antibodies. Twenty-one (2.58%) positive results in ELISA were detected via Western blot (WB), and only one (0.12%) serum showed a low positive reaction. No lesion in the liver parenchyma could be detected by abdominal ultrasonography in this patient so far, but the risk of developing alveolar echinococcosis remains for this WB-positive hunter. Risk factor analysis of these 813 hunters revealed that 697 (85.7%) hunted red foxes regularly and 332 (40.8%) of those skinned them as well. Three hundred and eighteen (39.1%) out of the 813 hunters were owners of hunting dogs; 89 (10.9%) and 243 (29.9%) were owners of non-hunting dogs and cats, respectively. Our results indicate that hunters do not have a greater risk of infection with E. multilocularis compared to non-hunters in Austria. The cause of the unexpected increase in AE cases in Austria remains unclear.
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OBJECTIVE: Model trajectories of CD4+ and CD8+ cell counts after starting combination antiretroviral therapy (ART) and use the model to predict trends in these counts and the CD4+â:âCD8+ ratio. DESIGN: Cohort study of antiretroviral-naïve HIV-positive adults who started ART after 1997 (ART Cohort Collaboration) with more than 6 months of follow-up data. METHODS: We jointly estimated CD4+ and CD8+ cell count trends and their correlation using a bivariate random effects model, with linear splines describing their population trends, and predicted the CD4+â:âCD8+ ratio trend from this model. We assessed whether CD4+ and CD8+ cell count trends and the CD4+â:âCD8+ ratio trend varied according to CD4+ cell count at start of ART (baseline), and, whether these trends differed in patients with and without virological failure more than 6 months after starting ART. RESULTS: A total of 39â979 patients were included (median follow-up was 53 months). Among patients with baseline CD4+ cell count at least 50 cells/µl, predicted mean CD8+ cell counts continued to decrease between 3 and 15 years post-ART, partly driving increases in the predicted mean CD4+â:âCD8+ ratio. During 15 years of follow-up, normalization of the predicted mean CD4+â:âCD8+ ratio (to >1) was only observed among patients with baseline CD4+ cell count at least 200 cells/µl. A higher baseline CD4+ cell count predicted a shorter time to normalization. CONCLUSION: Declines in CD8+ cell count and increases in CD4+â:âCD8+ ratio occurred up to 15 years after starting ART. The likelihood of normalization of the CD4+â:âCD8+ ratio is strongly related to baseline CD4+ cell count.
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Antirretrovirais/uso terapêutico , Relação CD4-CD8 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Adolescente , Adulto , Contagem de Linfócito CD4 , Estudos de Coortes , Feminino , Seguimentos , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Carga ViralRESUMO
Outcome of HIV-infected patients with AIDS-related lymphomas has improved during recent years. However, data on incidence, risk factors, and outcome of relapses in AIDS-related lymphomas after achieving complete remission are still limited. This prospective observational multicenter study includes HIV-infected patients with biopsy- or cytology-proven malignant lymphomas since 2005. Data on HIV infection and lymphoma characteristics, treatment and outcome were recorded. For this analysis, AIDS-related lymphomas patients in complete remission were analyzed in terms of their relapse- free survival and potential risk factors for relapses. In total, 254 of 399 (63.7%) patients with AIDS-related lymphomas reached a complete remission with their first-line chemotherapy. After a median follow up of 4.6 years, 5-year overall survival of the 254 patients was 87.8% (Standard Error 3.1%). Twenty-nine patients relapsed (11.4%). Several factors were independently associated with a higher relapse rate, including an unclassifiable histology, a stage III or IV according to the Ann Arbor Staging System, no concomitant combined antiretroviral therapy during chemotherapy and R-CHOP-based compared to more intensive chemotherapy regimens in Burkitt lymphomas. In conclusion, complete remission and relapse rates observed in our study are similar to those reported in HIV-negative non-Hodgkin lymphomas. These data provide further evidence for the use of concomitant combined antiretroviral therapy during chemotherapy and a benefit from more intensive chemotherapy regimens in Burkitt lymphomas. Modifications to the chemotherapy regimen appear to have only a limited impact on relapse rate.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Linfoma Relacionado a AIDS/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Recidiva Local de Neoplasia/induzido quimicamente , Recidiva Local de Neoplasia/epidemiologia , Adulto , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Incidência , Linfoma Relacionado a AIDS/patologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Indução de Remissão , Fatores de Risco , Taxa de SobrevidaRESUMO
The p53 tumor suppressor is inactivated in most cancers, thus suggesting that loss of p53 is a prerequisite for tumor growth. Therefore, its reintroduction through different means bears great clinical potential. After a brief introduction to current knowledge of p53 and its regulation by the ubiquitin-ligases MDM2/MDMX and post-translational modifications, we will discuss small molecules that are able to reactivate specific, frequently observed mutant forms of p53 and their applicability for clinical purposes. Many malignancies display amplification of MDM genes encoding negative regulators of p53 and therefore much effort to date has concentrated on the development of molecules that inhibit MDM2, the most advanced of which are being tested in clinical trials for sarcoma, glioblastoma, bladder cancer and lung adenocarcinoma. These will be discussed as will recent findings of MDMX inhibitors: these are of special importance as it has been shown that cancers that become resistant to MDM2 inhibitors often amplify MDM4. Finally, we will also touch on gene therapy and vaccination approaches; the former of which aims to replace mutated TP53 and the latter whose goal is to activate the body's immune system toward mutant p53 expressing cells. Besides the obvious importance of MDM2 and MDMX expression for regulation of p53, other regulatory factors should not be underestimated and are also described. Despite the beauty of the concept, the past years have shown that many obstacles have to be overcome to bring p53 reactivation to the clinic on a broad scale, and it is likely that in most cases it will be part of a combined therapeutic approach. However, improving current p53 targeted molecules and finding the best therapy partners will clearly impact the future of cancer therapy.
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Neoplasias/genética , Proteína Supressora de Tumor p53/genética , Animais , Proteínas de Ciclo Celular , Modelos Animais de Doenças , Terapia Genética , Humanos , Neoplasias/diagnóstico , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND: Hemeoxygenase-1 (HO-1) has recently been identified as a major driver of metaflammation and obesity-related insulin resistance (IR). Drug-induced IR increases cardiovascular risk within the HIV-1-infected population receiving antiretroviral therapy (ART). We therefore investigated a possible role of HO-1 in ART-induced IR. METHODS: Effects of HIV-1 protease inhibitor ritonavir and integrase inhibitor raltegravir (RAL) on expression levels of HO-1 and proinflammatory cytokines, including interleukin 1ß (IL-1ß), IL-6, IL-8, tumor necrosis factor-α (TNFα), chemokine (C-C motif) ligand 5 (CCL5), and monocyte chemotactic protein 1 (MCP-1), were studied in monocyte and hepatocyte cell lines. Plasma levels of HO-1 and inflammatory markers were measured in insulin-resistant and insulin-sensitive HIV-1-infected patients under ART and seronegative controls. RESULTS: We show that, in contrast to RAL, ritonavir treatment significantly increases mRNA expression levels of HO-1, IL-8, TNFα, CCL5, and MCP-1 in vitro in a dose-dependent manner. HO-1 plasma levels were significantly higher in insulin-resistant compared to insulin-sensitive patients on ritonavir-boosted ART (lopinavir/ritonavir group: 3.90 ± 1.15 vs 2.56 ± 1.07 ng/mL, P < 0.005 and darunavir/ritonavir group: 3.16 ± 1.37 vs 2.28 ± 1.23 U/mL, P < 0.05) and were correlated with expression levels of TNFα in individuals on ritonavir-boosted ART (lopinavir/ritonavir group: r = 0.108, P < 0.05 and darunavir/ritonavir group: r = 0.221, P < 0.05) but not in HIV-1-infected individuals receiving RAL or in seronegative controls. IMPLICATIONS: HIV-1-infected patients on stable ART are often faced with non-AIDS-related metabolic comorbidities, increasing their individual cardiovascular risk. Here, we provide insight into a novel mechanism of ritonavir-induced IR involving proinflammatory properties of HO-1. Our initial observations might also provide prognostic value in the future to identify patients at risk for the development type 2 diabetes mellitus.
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Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/efeitos adversos , Heme Oxigenase-1/análise , Resistência à Insulina , Ritonavir/efeitos adversos , Linhagem Celular , Citocinas/análise , Perfilação da Expressão Gênica , Infecções por HIV/virologia , Inibidores da Protease de HIV/administração & dosagem , HIV-1/isolamento & purificação , Hepatócitos/enzimologia , Hepatócitos/imunologia , Humanos , Monócitos/enzimologia , Monócitos/imunologia , Ritonavir/administração & dosagemRESUMO
Background. Viral loads (VLs) detectable at low levels are not uncommon in patients on combination antiretroviral therapy (cART). We investigated whether a single quantifiable VL predicted virological failure (VF). Methods. We analyzed patients receiving standard regimens with at least 1 VL measurement below the limit of quantification (BLQ) in their treatment history. The first VL measurement after 6 months of unmodified cART served as baseline VL for the subsequent analyses of the time to reach single VL levels of ≥200, ≥400, and ≥1000 copies/mL. Roche TaqMan 2.0 was used to quantify human immunodeficiency virus-1 ribonucleic acid. Factors associated with VF were determined by Cox proportional hazards models. Results. Of 1614 patients included in the study, 68, 44, and 34 experienced VF ≥200, ≥400, and ≥1000 copies/mL, respectively. In multivariable analyses, compared with patients who were BLQ, a detectable VL ≤ 50 and VL 51-199 copies/mL predicted VF ≥ 200 copies/mL (hazards ratio [HR] = 2.19, 95% confidence interval [CI] = 1.06-4.55 and HR = 4.21, 95% CI = 2.15-8.22, respectively). In those with VL 51-199 copies/mL, a trend for an increased risk of VF ≥400 and VF ≥1000 copies/mL could be found (HR = 2.13, 95% CI = 0.84-5.39 and HR = 2.52, 95% CI = 0.96-6.60, respectively). Conclusions. These findings support closer monitoring and adherence counseling for patients with a single measurement of quantifiable VL <200 copies/mL.
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INTRODUCTION: Because of the diagnostic complexity and potential pitfalls in interpreting test results, HIV-vacuolar myelopathy (HIVM) is far more often diagnosed postmortem than in vivo. In the era of highly active antiretroviral therapy (HAART), the topic of neuro-AIDS has become increasingly important. This case report covers some of the diagnostic problems encountered in vacuolar myelopathy based on magnetic resonance imaging (MRI) fiber-tracking pictures of the spine in a patient with HIVM, including a 1-year follow-up. CASE PRESENTATION: A 49-year-old man felt progressive weakness, and difficulties while walking, and he suffered from incomplete voiding. A week before admission, follicles appeared on the right side of his neck and shoulder. His medical history included a chronic HIV infection treated with HAART and a B-cell lymphoma in complete remission after chemotherapy. The initial exam revealed thoracic hyposensitivity level distal to dermatome Th9, spastic paraparesis of the lower limbs and herpes zoster infection in dermatome C3/C4. A lesion of the thoracic myelon could be ruled out in the MRI scan, chemotherapy-induced polyneuropathy was stable, and no acute opportunistic infection of the CNS was found. HIV load in cerebrospinal fluid (CSF) was markedly elevated. An HIV-associated vacuolar myelopathy was diagnosed, revealing the HIV itself as etiology. DISCUSSION: A negative or unspecific MRI scan excludes possible other causes, but by no means rules out HIV-related myelopathy. Furthermore, peripheral and central viral load should always be assessed to avoid missing a possible 'CSF HIV-escape'.
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BACKGROUND: In human immunodeficiency virus treatment adequate virological suppression is warranted, nevertheless for some patients it remains a challenge. We investigated factors associated with low-level viraemia (LLV) and virological failure (VF) under combined antiretroviral therapy (cART). MATERIALS AND METHODS: We analysed patients receiving standard regimens between 1st July 2012 and 1st July 2013 with at least one viral load (VL) measurement below the quantification limit (BLQ) in their treatment history. After a minimum of 6 months of unmodified cART, the next single VL measurement within 6 months was analysed. VF was defined as HIV RNA levels ≥ 200 copies/mL and all other quantifiable measurements were classified as LLV. Factors associated with LLV and VF compared to BLQ were identified by logistic regression models. RESULTS: Of 2276 participants, 1972 (86.6%) were BLQ, 222 (9.8%) showed LLV and 82 (3.6%) had VF. A higher risk for LLV and VF was shown in patients with cART interruptions and in patients with boosted PI therapy. The risk for LLV and VF was lower in patients from centres using the Abbott compared to the Roche assay to measure VL. A higher risk for LLV but not for VF was found in patients with a higher VL before cART [for >99.999 copies/mL: aOR (95% CI): 4.19 (2.07-8.49); for 10.000-99.999 copies/mL: aOR (95% CI): 2.52 (1.23-5.19)] and shorter cART duration [for <9 months: aOR (95% CI): 2.59 (1.38-4.86)]. A higher risk for VF but not for LLV was found in younger patients [for <30 years: aOR (95% CI): 2.76 (1.03-7.35); for 30-50 years: aOR (95% CI): 2.70 (1.26-5.79)], people originating from high prevalence countries [aOR (95% CI): 2.20 (1.09-4.42)] and in male injecting drug users [aOR (95% CI): 2.72 (1.38-5.34)]. CONCLUSIONS: For both VF and LLV, factors associated with adherence play a prominent role. Furthermore, performance characteristics of the diagnostic assay used for VL quantification should also be taken into consideration.
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Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , Áustria , Feminino , HIV-1 , Humanos , Modelos Logísticos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , RNA Viral/sangue , Estudos Retrospectivos , Fatores de Risco , Abuso de Substâncias por Via Intravenosa , Falha de Tratamento , Carga Viral , Viremia/virologiaRESUMO
INTRODUCTION: For some patients, it remains a challenge to achieve complete virological suppression which is the goal of antiretroviral therapy (ART). Identifying factors associated with low-level viraemia (LLV) and virological failure (VF) under ART might help to optimize management of these patients. MATERIALS AND METHODS: We investigated patients from the Austrian HIV Cohort Study receiving unmodified ART for >6 months with two nucleoside reverse-transcriptase inhibitors (NRTIs) with either a non-nucleoside reverse-transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (PI) or an integrase inhibitor (INSTI) between 1 July 2012 and 1 July 2013 with at least one viral load (VL) measurement below the limit of detection (BLD) or below level of quantification (BLQ) in their treatment history. VF was defined as HIV-RNA levels ≥200 copies/mL and all other quantifiable measurements were classified as LLV. Factors associated with LLV and VF compared to BLD and BLQ were identified by using logistic regression models. RESULTS: Of the 2,276 patients analyzed, 1,972 (86.6%) were BLD or BLQ, 222 (9.8%) showed LLV and 82 (3.6%) had VF. A higher risk for LLV and VF was found in patients with ART interruptions and in patients with boosted PI therapy. The risk for LLV and VF was lower in patients from a centre which uses Abbott RealTime HIV-1 assay compared to the other centres measuring VL by the Roche Cobas AmpliPrep/Cobas TaqMan 2.0. A higher risk for LLV but not for VF was found in patients with a higher VL before ART and shorter ART duration. A higher risk for VF but not for LLV was found in patients of younger age, originating from a high prevalence country, with a lower CD4 count and in male injecting drug users. CONCLUSIONS: This study of well-defined patients on stable ART over a period of more than six months gives insights into the different factors associated with LLV and VF. In patients with VF, factors associated with adherence play a prominent role, whereas in patients with LLV, the biology of viral replication comes additionally into effect. Despite its observational design, it has implications for patient management and forms the basis for future outcome studies.
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INTRODUCTION: While antiretroviral therapy (ART) has increased the survival of HIV patients and turned HIV infection into a chronic condition, treatment modifications and poor adherence might limit this therapeutic success. METHODS: Patients from the Austrian HIV Cohort Study, who started their first ART after Rilpivirine became available in February 2011, were analyzed for factors associated with treatment modification which could be either a change of drugs or a stop of the regimen. A drug was considered as stopped when the regimen was interrupted for more than eight days. Drugs of particular interest were Darunavir (DRV), Atazanavir (ATV), Raltegravir (RAL), Rilpivirine (RPV) and Efavirenz (EFV). RPV and EFV were analyzed only when taken as single tablet regimen. Other drugs were summarized as "other." Proportional hazards regression methods were used to identify predictors of discontinuation and Kaplan-Meier estimates were used to calculate probabilities of discontinuation. Patients who died were censored at the date of death. RESULTS: 965 patients started ART, 282 with DRV, 161 with ATV, 96 with RAL, 108 with RPV and 118 with EFV. Median time for taking initial ART is 11.6 months. 322 (33.4%) patients modified their initial ART. The overall probability of modification at one year was 28.7%, at two years 40.0% and at three years 49.8%. In a multivariable proportional hazards regression analysis, AIDS diagnosis at baseline and injecting drug use (IDU) of men compared with men who have sex with men (MSM) have a higher risk of switch/stop. Compared with DRV, RPV showed a much lower and ATV and particularly "other" a higher risk for discontinuation (Table 1). CONCLUSION: Rates of modification and interruption were still high in recent years, particularly in the first year of ART. The decreased rate of modification found in patients treated with Rilpivirine may be attributed to selection of patients according to guidelines.
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BACKGROUND: With the advent of the protease inhibitors boceprevir and telaprevir a novel therapy approach for HCV genotype 1 infected subjects has become standard of care. Quantification of HCV viral load (VL) represents an important predictor of treatment response. METHODS: Two different real-time PCR platforms, the COBAS Ampliprep/COBAS TaqMan v2.0 (CAP-CTM v2.0) and the Abbott RealTime (ART) HCV assay are most widely used. We performed a comparative evaluation of both systems focusing on genotype 1 HCV quantification using clinical specimens, the fourth WHO International Standard for HCV and the Paul Ehrlich National Standard, respectively. RESULTS: The HCV VL assays showed an excellent overall agreement in the clinical specimens studied (R(2)=0.912). Discrepant results were obtained at the low VL end. Four samples tested negative with CAP-CTM v2.0 but were detectable with ART and two samples were undetectable with ART but tested positive with CAP-CTM v2.0. The coefficient of variation in replicate measurements of both reference materials was higher for CAP-CTM v2.0 as compared with ART at the clinical decision point for boceprevir (≥100 IU/ml), but was similar for the two assays at the clinical decision point for telaprevir (≥1,000 IU/ml). The tendency for underestimation of the diluted standards was higher for ART than for CAP-CTM v2.0. CONCLUSIONS: Although both assays allowed accurate determination of VL levels in clinical samples, careful interpretation of results at the low VL end is essential. Furthermore, discontinuation of therapy based on single HCV RNA measurement should be carefully reconciled, unless the issue of assay variability has been addressed adequately.
Assuntos
Hepacivirus/genética , Hepatite C/diagnóstico , Hepatite C/virologia , Reação em Cadeia da Polimerase/métodos , Reação em Cadeia da Polimerase/normas , Kit de Reagentes para Diagnóstico , Antivirais/farmacologia , Antivirais/uso terapêutico , Genótipo , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Humanos , Prognóstico , Resultado do Tratamento , Carga ViralRESUMO
INTRODUCTION: The first case of human immunodeficiency virus type 2 (HIV-2) seropositivity in Austria was confirmed in 1993 in a dually human immunodeficiency virus type 1 (HIV-1)- and HIV-2-infected patient from Ghana, who died in 2001. Before this investigation, no further HIV-2 infection was published. METHODS: The aim of this study was to describe HIV-2 epidemiology in Austria, using serological and molecular techniques, and to perform a sequence analysis of the circulating viral strains. RESULTS: Six additional cases of HIV-2 were identified from 2000 to 2009. All patients originated from high-prevalence areas. In one patient, the HIV-2 infection was revealed 11 years after initial HIV-1 diagnosis, and further analysis confirmed a dual infection. CONCLUSION: The HIV-2 epidemic has its epicentre in West Africa, but sociocultural issues, especially migration, are contributing to the low but continuous worldwide spread of HIV-2. Diagnosis of HIV-2 implies a different therapeutical management to avoid treatment failure and clinical progression. Differential diagnosis of HIV-1 and HIV-2 is complicated due to antibody cross-reactivity, and paradoxical findings (e.g. declining CD4 cell count despite HIV-1 suppression) may require careful reassessment, especially in patients from endemic countries.
Assuntos
Emigração e Imigração/estatística & dados numéricos , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , HIV-2/genética , HIV-2/isolamento & purificação , Adulto , Áustria/epidemiologia , Feminino , Gâmbia , Gana , Infecções por HIV/diagnóstico , HIV-2/classificação , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: High-sensitive real-time PCR assays are routinely used to monitor HIV-1 infected subjects. Inter-assay discrepancies have been described at the low viral load (VL) end, where clinical decisions regarding possible virological rebound are based. METHODS: A retrospective study was performed to analyze frequencies of viral blips after transition to the COBAS Ampliprep/COBAS TaqMan v2.0 HIV-1 assay (Taqman v2.0) in patients with prior undetectable VLs as measured with the Roche Cobas Ampliprep Amplicor HIV-1 Monitor Test, v1.5 (Amplicor) and was evaluated in comparison to a group of patients monitored with the Abbott Real-time HIV-1 assay (Abbott RT) during the same period of time. RESULTS: 85 of 373 patients with VLs below the limit of quantification with Amplicor had VLs >50 copies/mL after transition to the TaqMan v2.0 assay. Among these 74.1% had VLs ranging from 50-499 copies/mL, 22.9% had VLs >500 copies/mL. From 22 patients with initial Taqman v2.0 based VLs exceeding 500 copies/mL, 6 patients had VLs <20 copies/mL after novel VL measurement on a next visit. In our control group with VL quantification using the Abbott RT assay, only 1 patient became detectable and showed a VL of <40 copies/mL after new measurement. CONCLUSIONS: Transition to the Taqman v2.0 assay was accompanied by an increase of quantifiable HIV-1 VLs in patients with long term viral suppression under antiretroviral therapy that might be attributed to technical shortcomings of the Taqman v2.0 assay. A high test variability at the low VL end but also beyond was observed, making meaningful clinical interpretation of viral blips derived from different assays difficult.
Assuntos
HIV-1/genética , HIV-1/isolamento & purificação , Kit de Reagentes para Diagnóstico , Reação em Cadeia da Polimerase em Tempo Real/métodos , Taq Polimerase/metabolismo , Terapia Antirretroviral de Alta Atividade , Estudos de Coortes , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Fatores de Tempo , Carga Viral/genéticaAssuntos
Infecções por HIV/complicações , Hepatite C/complicações , Receptores Fc/uso terapêutico , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/uso terapêutico , Trombocitopenia/tratamento farmacológico , Trombopoetina/uso terapêutico , Adulto , Fármacos Anti-HIV/uso terapêutico , Antivirais/uso terapêutico , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Hepatite C/sangue , Hepatite C/tratamento farmacológico , Humanos , Interferon-alfa/uso terapêutico , Masculino , Contagem de Plaquetas , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , Trombocitopenia/sangue , Trombocitopenia/etiologiaRESUMO
INTRODUCTION: Peripheral T-cell lymphomas (PTCLs) and natural killer (NK) or T-cell non-Hodgkin's lymphomas (NHLs) are a rare and heterogeneous class of diseases with generally poor prognosis. This work intends to provide a focused primer on clinical diagnosis, current treatment regimens, and novel therapeutic approaches. The recent WHO classification has defined 18 different subtypes of PTCL and NK T-cell lymphomas. Diagnosis is mainly based on histology, flow-cytometric analysis of surface molecules in the blood and bone marrow, cytogenetics/fluorescence in situ hybridization (FISH), and T-cell receptor (TCR) rearrangement. Staging as well as follow-up diagnostic procedures rely on imaging techniques such as computerized tomography (CT) and positron emission tomography (PET). Current chemotherapeutic regimens such as CHOP result in a 60 - 70% response rate; however, 5-year survival is only around 30%. Therefore, new treatment strategies are urgently needed. Currently, different drug classes are under scrutiny. AREAS COVERED: The authors discuss substances that directly target the tumor cells. The article includes such substances as antimetabolites, antibodies, histone deacetylase inhibitors, tyrosine kinase inhibitors, and immunomodulatory substances such as lenalidomide. EXPERT OPINION: In the future a close collaboration of geneticists, biochemists, and clinicians together with new technologies such as deep sequencing will allow the refinement of treatment strategies in many diseases including PTCLs and NHLs. This refinement will allow treatments to be prepared according to the need of the individual patient.