Effectiveness of first-wave protease inhibitors in hepatitis C virus genotype 1 infection: a multicenter study in Brazil

Abstract INTRODUCTION: In 2013, combination therapy using peginterferon, ribavirin, and boceprevir or telaprevir was introduced to treat hepatitis C virus genotype 1 infection in Brazil. The effectiveness of this therapy in four Brazilian regions was evaluated. METHODS: Clinical and virological data were obtained from patients of public health institutions in five cities, including sustained virological response (SVR) and side effects. Patients with advanced fibrosis (F3/4), moderate fibrosis (F2) for > 3 years, or extra-hepatic manifestations were treated according to Ministry of Health protocol. Treatment effectiveness was verified by using bivariate and multivariate analysis; p-values of < 0.05 were considered significant. RESULTS: Of 275 patients (64.7% men; average age, 57 years old), most (61.8%) were treatment-experienced; 53.9% had subgenotype 1a infection, 85.1% had advanced fibrosis, and 85.5% were treated with telaprevir. SVR was observed in 54.2%. Rapid virological response (RVR) was observed in 54.6% of patients (data available for 251 patients). Overall, 87.5% reported side effects and 42.5% did not complete treatment. Skin rash, severe infection, and death occurred in 17.8%, 2.5%, and death in 1.4% of cases, respectively. SVR was associated with treatment completion, RVR, and anemia. CONCLUSIONS: The effectiveness of hepatitis C virus triple therapy was lower than that reported in phase III clinical trials, possibly owing to the prioritized treatment of patients with advanced liver fibrosis. The high frequency of side effects and treatment interruptions observed supported the decision of the Brazilian authorities to suspend its use when safer and more effective drugs became available in 2015.

Consensus of the Brazilian Society of Infectious Diseases and Brazilian Society of Clinical Oncology on the management and treatment of Kaposi's sarcoma

Kaposi's sarcoma is a multifocal vascular lesion of low-grade potential that is most often present in mucocutaneous sites and usually also affects lymph nodes and visceral organs. The condition may manifest through purplish lesions, flat or raised with an irregular shape, gastrointestinal bleeding due to lesions located in the digestive system, and dyspnea and hemoptysis associated with pulmonary lesions. In the early 1980s, the appearance of several cases of Kaposi's sarcoma in homosexual men was the first alarm about a newly identified epidemic, acquired immunodeficiency syndrome. In 1994, it was finally demonstrated that the presence of a herpes virus associated with Kaposi's sarcoma called HHV-8 or Kaposi's sarcoma herpes virus and its genetic sequence was rapidly deciphered. The prevalence of this virus is very high (about 50%) in some African populations, but stands between 2% and 8% for the entire world population. Kaposi's sarcoma only develops when the immune system is depressed, as in acquired immunodeficiency syndrome, which appears to be associated with a specific variant of the Kaposi's sarcoma herpes virus. There are no treatment guidelines for Kaposi's sarcoma established in Brazil, and thus the Brazilian Society of Clinical Oncology and the Brazilian Society of Infectious Diseases developed the treatment consensus presented here.

Fatores determinantes para modificações da terapia antirretroviral inicial / Factors determining changes in initial antiretroviral therapy

OBJETIVO: Investigar os fatores determinantes das mudanças da terapia antirretroviral (TARV) inicial dos pacientes assistidos em hospital de referência em AIDS do Ceará. MÉTODOS: O estudo descritivo e exploratório utilizou a análise dos formulários de solicitação de início ou modificação de tratamento do ano de 2008, acompanhando as mudanças de terapia durante o primeiro ano de tratamento. Os dados foram analisados nos programas Statistical Package for the Social Sciences (SPSS) e Epi Info, utilizando ANOVA e teste exato do coeficiente de contingência, com significância de p < 0,05. RESULTADOS: Dos 301 pacientes que iniciaram TARV, 22,1% (n = 68) realizaram troca no primeiro ano. Os pacientes eram, na maioria, do sexo masculino, de idade entre 20 e 39 anos, e fizeram apenas uma mudança da TARV (86,8%; n = 59). Registros de duas ou três mudanças de esquema foram observados. A zidovudina foi o fármaco mais substituído, seguido por lopinavir/ritonavir e efavirenz. Existiu associação significante entre as trocas dos esquemas iniciais com o relato de ocorrência de reações adversas (p < 0,001). CONCLUSÃO: O principal fator determinante para as mudanças de TARV inicial foi o relato de ocorrência de reações adversas. A maioria dos pacientes fez somente uma mudança na TARV inicial durante o primeiro ano de tratamento. O monitoramento da TARV contribuiu para melhor controle da farmacoterapia específica.

OBJECTIVE: To investigate factors determining changes in initial antiretroviral therapy (ART) in patients attended to in an AIDS tertiary care hospital in Ceará, Brazil. METHODS: This descriptive and exploratory study used the analysis of request to initiate or change treatment forms in the year of 2008, and the changes in therapy were followed through the first year of treatment. Data were analyzed with SPSS and EpiInfo by using ANOVA and the exact test of the coefficient of contingency, with significance at p < 0.05. RESULTS: From 301 patients initiating ART, 22.1% (n = 68) needed a change in the first year. These patients were mostly males, aged 20 to 39 years; with only one ART changed needed in 86.8% of the cases (n = 59). Reports of two or three changes in regimen were observed. Zidovudine was the drug most often changed, followed by lopinavir/ritonavir and efavirenz. A significant association was found between changes in initial regimens and the report of adverse reactions (p < 0.001). Conclusion: The main factor determining changes in the initial ART was an adverse reaction report. Most patients had one change in the initial ART over the first year of treatment. ART monitoring contributed to a better control of the specific drug therapy.

Impact of the number of failed therapeutic regimes on the development of resistance mutations to HIV-1 in northeast Brazil

Highly-potent antiretroviral therapy is necessary to avoid viral replication in HIV patients; however, it can favor the appearance of resistance mutations. The mutations 41L, 67N, 70R, 210W, 215Y/F, 219E/Q, 44D and 118I are defined as nucleoside analogous mutations (NAMs), because they affect the efficacy of all nucleoside reverse transcriptase inhibitors (NRTI). The mutation most frequently associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) is 103N. 33W/F, 82A/F/L/T, 84V and 90M are called protease inhibitor resistance-associated mutations (PRAM), because they are associated with resistance to several protease inhibitors (PI). This study evaluated the development of resistance mutations and examine the susceptibility of HIV with these mutations to antiretrovirals in HIV-1 patients who have failed one or more therapy regimes. Analyses were made of 101 genotypic tests of patients with therapeutic failure to 2 or 3-drug regimens with NRTI, NNRTI or PI. We used the Stanford database to define the susceptibility profile of the viruses. The samples were divided into three treatment-failure groups: first (F), second (S) and multi-failure (MF) to antiretroviral regimens, and we correlated these groups with resistance profiles and principal mutations. There was a significant increase in resistance mutations V82A/F/L/T, I84V, L90M, M41L, K70R, L210W, T215Y/F and K219Q/E in MF. We also found significantly higher resistance to zidovudine, didanosine, stavudine and abacavir in MF. There was no increase in resistance to tenofovir (p=0.28) and lopinavir (p=0.079) in MF. A high degree of resistance to NNRTIs was observed in all groups. Increased resistance mutations will affect future therapeutic options for HIV patients in Brazil because it results in a significant increase in resistance to antiretroviral drugs.

Genotype testing and antiretroviral resistance profiles from HIV-1 patients experiencing therapeutic failure in northeast Brazil

Genotype testing for HIV-1 drug resistance is useful for selecting antiretroviral drug regimens for patients experiencing therapeutic failure, but the optimal means for interpreting the test results is unknown because many HIV-1 protease and reverse transcriptase (RT) mutations contribute to drug resistance. This study identified common combinations of resistance mutations related to antiretroviral resistance profiles. From April 2002 to March 2004, 101 protease and RT sequences were determined for HIV-1 isolates from patients who were failing antiretroviral therapy. The resistance profile was evaluated using the Stanford Database program. Male patients predominated (76.2 percent), the median age was 38 years, the average CD4 count was 279.21 cells/mm³ and the average viral load was 4.49 log. In relation to protease inhibitors (IP) 31 mutation patterns were detected, 49 mutation patterns were detected in Nucleoside RT Inhibitors (NRTI), and 17 patterns were found in the Non Nucleoside RT Inhibitors (NNRTI). K65R was detected in 5.9 percent of the isolates. The most frequent mutations were: L90M, M184V and K103N related to PI's, NRTI's and NNRTI's, respectively. The best antiretroviral susceptibility was found to be Lopinavir in the PI class and Tenofovir in the NRTI class. The top six mutation patterns accounted for 49 percent of the resistance to PI's, for 38.5 percent of NRTI resistance, and the top two mutation patterns accounted for 40.9 percent of resistance to NNRTI's.

Dermatite Seborreica da Face Tratada com Pimecrolimus Creme em Quatro Pacientes HIV positivos / Facial Seborrheic Dermatitis Treated with Pimecrolimus Cream in four patients HIV positive

Quatro pacientes HIV positivos com perfil imunologico diferente e portadores de dermatite seborreica(DS) da face forma tratados exclusivamente com pimecrolimus creme, um imunomodulador macrolactamico. O pimecrolimus inibe a calcineurina atraves do complexo droga-macrofilina-12 e desta maneira inibe a ativacao e maturacao das celulas T, bloqueia a ativacao da transccricao dos genes das linfocinas, evita a degranulacao mastocitaria e iniube a funcao das celulas de Langerhans. Nao promove atrofia, estria, foliculite, exacerbacao de acne/rosacea, telangiectasia ou toxicidade ocular permitindo o uso seguro em areas criticas com a face. Os pacientes usaram na face o pimecrolimus 1,0porcento creme duas vezes por dia por sete dias consecuti9vos havendo desaparecimento total das lesoes apos este periodo.

Comparacao da resposta terapeutica na "Vida Real" entre esquemas de resgate contendo RTV/SQV versus NVP/NFV / Comparison of therapeutic response to salvage therapy with RTV/SQV and NVP/NFV

A terapia anti-retroviral para pacientes que falham a esquemas iniciais e menos efetiva, devido a menor sensibilidade do virus aos medicamentos e a maior complexidade dos esquemas propostos, que acarretam menor adesao. Com o objetivo de comparar a resposta terapeutica na "vida real" entre esquemas de resgate contendo RTV/SQV (400/400BID) e NVP/NFV (200BID/750TID) analisamos, retrospectivamente, prontuarios de 64 pacientes (35 em uso de RTV/SQV - grupo 1 e 29 em uso de NVP/NFV - grupo 2). Os grupos nao diferiram quanto a sexo, idade, media de CD4 e Carga Viral (NASBA) basal, tempo medio de exposicao a terapia anti-retroviral previa e tempo de tratamento com o esquema de resgate (p>0,05). Nao houve diferenca significativa na melhora imunologica (aumento de CD4), que ocorreu em 37, 1 porcento no grupo 1 e 41,4 porcento no grupo 2, nem no ganho medio de CD4 que foi de 85,7 cel. e 52,9 cel., respectivamente(p>0,05). Da mesma forma, em relacao a resposta virologica, nao houve diferenca significativa na comparacao entre os grupos. Esse beneficio foi evidenciado em 54,3 porcento e 48,3 porcento dos pacientes nos grupos 1 e 2 (p>0,05). Tambem nao houve diferenca em relacao a magnitude da diminuicao de Carga Viral (1,5 log e 1,1 log) nem no numero de pacientes com Carga Viral indetectavel apos inicio do Resgate (17 porcento e 3,5 porcento) nos grupos 1 e 2 (p>0,05). Neste estudo nao houve diferenca quanto a resposta terapeutica entre os esquemas de resgate com RTV/SQV e NVP/NFV

Resposta terapeutica a esquema anti-retroviral inicial contendo efavirenz ou nelfinavir, na "Vida Real" / Therapeutic response in inicial antiretroviral therapy with efavirenz or nelfinavir

Comparameos resposta terapeutica, virologica e imunologica, em estudo na "vida real" entre esquemas de terapia inicial contendo ITRNN - Efavirenz (EFV) ou IP - Nelfinavir (NFV), por analise retrospectiva de 58 prontuarios (32 com EFV e 26 com NFV), de janeiro/1999 a outubro/2001. Os grupos nao diferiram quanto a sexo, idade media, tempo entre o diagnostico do HIV e inicio da terapia, tempo de avaliacao com a terapia em estudo e media de carga viral (CV) inicial. A media de CD4 inicial foi 258,6 cel/mm3 para EFVe 156,7 cel/mm3 para NFV (p=0,038). Dos pacientes com CD4 inicial <100 cel/mm3 (31 porcento do total), 27,7 porcento pertenciam ao grupo do EFV e 72 porcento ao do NFV(p=0,005). Apenas 25 porcento dos pacientes em EFV e 11,5 porcento com NFV apresentaram CV indetectavel durante a terapia. Resposta virologica foi percebida em 94,4 porcento no grupo EFV e 61,9 porcento no NFV(p=0,029), com diminuicao media da CV de 3,11 log para o grupo EFV e 1,85 log para NFV(p=0,02). Resposta imunologica foi alcancada em 96,8 porcento no grupo EFV e 79,1 porcento no NFV (p=0,033) com ganho medio de CD4 = 75 cel/mm3 para EFV e 96 cel/mm3 para NFV (p=0,0019). Nosso estudo evidenciou diferenca quanto a resposta virologicae imunologica entre os grupos EFV e NFV, em beneficio da primeira droga; assim como o grupo EFV apresentou maior numero de pacientes com Carga Viral indetectavel durante a terapia (25 porcento contra 11,5 porcento)

Clinical evaluation of the efficacy and tolerability of ritonavir in combination with two reverse transcriptase inhibitors

A retrospective study of 76 patients was carried out using ritonavir in an antiretroviral regimen combined with two reverse transcriptase inhibitors to treat outpatients from July, 1996, to April, 1998, with the objective of evaluating clinical efficacy and tolerability,. Seventy-six percent of the patients had been diagnosed with AIDS, an average number of CD4 cells =233.7 cells/mmü and viral load = 144,084 RNA copies/mmü. The majority of patients (76.3 percent) were antiretroviral treatment-experienced, 21.4 percent having taken protease inhibitors. A positive clinical response was found in 86.7 percent (including an average weight gain of 4.41kg in 58.5 percent), an average CD4 count increase of 169.5 cells/mmü in 83.3 percent and an average viral load decrease of approximately 2.28 log in 75 percent of patients. A high percentage of adverse effects (76.3 percent) was detected, with most slight or moderate, but they significantly impacted adherence to treatment as 31.6 percent stopped taking the drug as a result. We conclude that this antiretroviral regimen has good clinical efficacy, but relatively poor tolerability.

Central venous catheter-related infections in intensive care units

Objective: To determine the rates of colonization and infection related to central venous catheter (CVC), the causative microorganisms, and the influence of various factors. Methods: From June to August 1993, all CVC in 4 Intensive Care Units were evaluated from their insertion to removal. Data were collected, by 3 nurses. Blood and catheter tips were cultured. Results: Of 84 catheters, 29.8 percent were colonized, 9.5 percent of patients showed evidence of local infection, and 4.8 percent had primary bloodstream infections. The internal jugular vein was the most commun site for catheter insertion (81 percent). Causes of removal were: end of need (48.3 percent), suspected infection (23.3 percent), malfunction (20 percent), routine change (8.3 percent). Among removals because of suspected infection 50 percent presented evidence of local infection, 43 percent were colonized (>15cfu), but there were no bloodstream infections. The average time of catheter use for those which became colonized was longer than for catheters that did not become colonized (p=0.008). The average time of catheter use associated with removal for infection (local and bloodstream) was longer than for removal for other reasons (p=0.042). Among colonized catheters, 16 percents developed bloodstream infection and 20 percent local infection. Immunosupressive drugs, cancer, diabets mellitus, HIV-infection, and neutropenia were not associated with infection or colonization. The most common microorganisms were gram-negative rods and S.aureus. Conclusions: The duration of venous catheter use increased the risk of colonization and infection. The observation suggests that physicians must strive for the shortest time of use of venous catheters, but it does not indicate a need for routine central venous catheter removal.