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Summary Background and aims Treatment for hepatitis C has evolved significantly with the licensing of direct-acting antiviral drugs (DAAs). However, one of the limiting factors of the effectiveness of antiviral therapy with protease inhibitors (PIs) is the emergence of resistance caused by point mutations. The aim of this study was to determine the prevalence of resistance-associated substitutions (RASs) in HCV NS3 gene in patients infected with genotype 1 before therapy with simeprevir. Methods A total of 73 serum samples from 15 treatment-experienced patients with boceprevir/telaprevir and 58 DAA-naive patients were collected before therapy with DAAs simeprevir, daclatasvir and/or sofosbuvir. Presence of baseline resistance-associated substitutions (RAS) in the serine protease domain of HCV NS3 was analyzed by nucleotide sequencing followed by amino acid deduction. Results Overall RAS prevalence in this study was 13.7% (10/73). RAS prevalence for HCV subtype 1b was 17.4% (4/23) while for HCV subtype 1a was 12% (6/50). Primary mutations V36M/L and R155K were observed only in HCV subtype 1a, whereas T54S and Q80K were identified only in HCV subtype 1b. RAS V36M, which is related to reduction of susceptibility to second-generation PIs, was the most frequent in the study (6.9%; 5/73). Conclusions Our results indicated that Brazilian isolates of HCV present a distinct pattern of RAS depending on the infecting viral subtype. In contrast to data from other countries, RAS Q80K prevalence in Brazil is low in HCV subtype 1a. This study improves the knowledge of genetic barrier for resistance to PIs involving RASs in chronically infected patients and its possible impact on an unsuccessful treatment outcome, information that might be crucial to upcoming decisions of incorporation of new DAAs in Brazilian guidelines of antiviral therapy against HCV infection.

Background: Development of drug-resistance mutations is the main cause of failure in antiretroviral therapy. In Brazil, there is scarce information on resistance pattern for patients failing antiretroviral therapy. Objectives: To define the HIV mutational profile associated with drug resistance in Brazilian patients from 5 large cities, after first, second or further failures to antiretroviral therapy. Methods: We reviewed genotyping results of 1520 patients failing therapy in five Brazilian cities. Frequency of mutations, mean number of active drugs, viral susceptibility to each antiretrovirals drug, and regional differences were assessed. Results: Mean time of antiretrovirals use was 22.7 ± 41.1 months. Mean pre-genotyping viral load was 4.2 ± 0.8 log (2.1 ± 2.0 after switching antiretrovirals). Mean number of remaining active drugs was 9.4, 9.0, and 7.9 after 1st, 2nd, and 3rd failure, respectively. We detected regional variations in drug susceptibility: while BA and RS showed the highest (∼40%) resistance level to ATV/r, FPV/r and LPV/r, in the remaining cities it was around half of this rate. We detected 90% efavirenz/nevirapine resistance in SP, only 45% in RS, and levels between 25% and 30% in the other cities. Regarding NRTI, we found a similar pattern, with RJ presenting the highest, and CE the lowest susceptibility rates for all NRTI. Zidovudine resistance was detected in only 3% of patients in RJ, against 45–65% in the other cities. RJ and RS showed 3% resistance to tenofovir, while in CE it reached 55%. DRV/r (89–97%) and etravirine (61–85%) were the most active drugs, but again, with a wide variation across cities. Conclusions: The resistance mutational profile of Brazilian patients failing antiretroviral therapy is quite variable, depending on the city where patients were tested. This variation likely reflects distinctive choice of antiretrovirals drugs to initiate therapy, adherence to specific drugs, or circulating HIV-1 strains. Overall, etravirine and DRV/r remain as the most active drugs. Keywords: HIV, Resistance, Brazil, Mutations

Cryptococcal meningitis is a several disease common in late stage of HIV infection. Detection of cryptococcal antigen (CrAg) is an important for early diagnosis of this invasive mycosis. The pre-emptive treatment for isolated antigenemia prevents the onset of meningoencephalitis. Screening CrAg in patients with low CD4 count is cost-effective in countries with prevalence of antigenemia above 3%. However, in Brazil, the number of prevalence studies on cryptococcosis and HIV is insufficient. The objective of this study is to estimate the prevalence of CrAg and describe clinical characteristics from a cohort of patients followed at a reference center in Brazil. CrAg screening was performed in 89 inpatients with CD4 count ≤200 cells/mm3 or WHO stage III/IV from the National Institute of Infecttious Disease, Rio de Janeiro. Patients with isolated antigenemia received pre-emptive therapy with fluconazole and patients with meningoencephalitis were treated with Amphotericin B. Individuals were followed up for 12 months. Prevalence of serum CrAg was 11.23%, cryptococcal meningoencephalitis 6.74% and isolated antigenemia 4.81%. None of the patients with isolated antigenemia developed meningoencephalitis during the follow up. Signs and symptoms of meningoencephalitis were unspecific or absent. Our study suggests the need of CrAg screening in Brazil and highlights that lumbar puncture is mandatory in all individuals CrAg positive to exclude asymptomatic meningoencephalitis.

Treatment of HIV infection in developing countries, particularly those in Africa, is still a major challenge to healthcare systems with limited laboratory resources. While drug costs have fallen to levels where antiretroviral therapy is now possible in these countries, and results suggest that adherence is as good as in developed countries, questions remain regarding the effect of scarce laboratory resources on treatment monitoring and, hence, outcome. The DART trial aimed to measure the effect of laboratory monitoring. This randomized controlled trial evaluated the differences between routine laboratory monitoring and monitoring driven by clinical events, and was conducted between January 2003 and December 2008 at sites in Uganda and Zimbabwe. The results indicate that clinically driven monitoring is likely to be more cost-effective in this resource-limited situation.

Sporotrichosis is a fungal disease usually restricted to the cutaneous and lymphatic systems. Visceral involvement is unusual. To date, only 21 cases of sporotrichosis meningitis have been reported, some of these associated with immunosuppression. According to the reported cases, difficulty establishing the correct diagnosis is almost the rule which, undoubtedly, is associated with a worse prognosis. In this report, two HIV infected patients are described who developed meningitis due to Sporothrix schenckii associated with immune reconstitution inflammatory syndrome. This is the first report of sporotrichosis meningitis associated with immune reconstitution inflammatory syndrome in AIDS patients.

SETTING Human immunodeficiency virus (HIV) infected patients followed in a large cohort in Rio de Janeiro, Brazil. OBJECTIVE To evaluate the association of tuberculosis (TB) and other covariables with non-TB-related (NTR) causes of death (CODs). DESIGN Patients aged >18 years were followed from 1997 to 2009, until death or 31 December 2009, whichever was earlier. CODs were ascertained using a standardised algorithm. TB diagnosis and prophylaxis followed Brazilian guidelines. Poisson models were used to calculate adjusted rate ratios (aRRs). RESULTS Of 2887 patients included in the study, 761 had TB (26.4%). NTR death rates were twice as high among patients with TB (4/100 vs. 2.09/100 patient-years). TB was associated with NTR deaths (aRR 1.4, 95%CI 1.05-1.86, P = 0.01). Highly active antiretroviral treatment (HAART) was protective against NTR (aRR 0.46, 95%CI 0.34-0.61, P < 0.001). Among patients who had never had active TB, prophylaxis was also protective against NTR (aRR 0.45, P = 0.04). The CD4 cell count increase was very modest for both TB and NTR CODs compared to those who did not die (0 vs. 249 cells, P < 0.001). CONCLUSIONS TB was significantly associated with increased NTR CODs, indicating rapid progression of disease and increased long-term risk of mortality, probably related to persistent immunodeficiency or incomplete immune recovery. Our results confirm the benefits of HAART and TB prophylaxis.

INTRODUCTION: We describe temporal trends in the mortality rates and factors associated with AIDS and non-AIDS related mortality at the Evandro Chagas Clinical Research Institute (IPEC), Oswaldo Cruz Foundation (FIOCRUZ). METHODS: Adult patients enrolling from 1986 through 2009 with a minimum follow up of 60 days were included. Vital status was exhaustively checked using patients' medical charts, through active contact with individuals and family members and by linkage with the Rio de Janeiro Mortality database using a previously validated algorithm. The CoDe protocol was used to establish the cause of death. Extended Cox proportional hazards models were used for multivariate modeling. RESULTS: A total of 3530 individuals met the inclusion criteria, out of which 868 (24.6%) deceased; median follow up per patient was 3.9 years (interquartile range 1.7-9.2 years). The dramatic decrease in the overall mortality rates was driven by AIDS-related causes that decreased from 9.19 deaths/100PYs n 1986-1991 to 1.35/100PYs in 2007-2009. Non-AIDS related mortality rates remained stable overtime, at around 1 death/100PYs. Immunodeficiency significantly increased the hazard of both AIDS-related and non-AIDS-related causes of death, while HAART use was strongly associated with a lower hazard of death from either cause. CONCLUSIONS: Our results confirm the remarkable decrease in AIDS-related mortality as the HIV epidemic evolved and alerts to the conditions not traditionally related to HIV/AIDS which are now becoming more frequent, needing careful monitoring.

Background Since human immunodeficiency virus (HIV)-infected individuals are at increased risk of severe disease from pandemic influenza A (H1N1pdm09), vaccination was recommended as a prevention strategy. The aim of the present study was to evaluate the safety, immunogenicity and persistence of the immune response after vaccination against pandemic influenza A (H1N1pdm09) with an adjuvanted vaccine in human immunodeficiency virus (HIV)-infected adults using two single and two double doses. Methodology/Principal Findings Open label, randomized trial to evaluate the immune response following H1N1pdm09 vaccination in HIV-infected participants compared to HIV-negative controls (NCT01155037). HIV-infected participants were randomized to receive 2 single (3.75 µg hemagglutinin) or 2 double (7.5 µg hemagglutinin) doses of the vaccine, 21 days apart. Controls received one dose of the vaccine. The primary endpoint was seroconversion as measured by hemagglutination inhibition assay. Two hundred fifty six HIV-infected participants (129 and 127 randomized to single and double doses, respectively) and 71 HIV-negative controls were enrolled. Among HIV-infected participants, seroconversion increased from 46.7% and 51.7% after the first dose to 77.2% and 83.8% after the second dose of the vaccine using single and double doses, respectively. Participants aged >40 years showed higher seroconversion compared to younger participants. Seroconversion among HIV-infected women and those with nadir CD440 years or with nadir CD4

Long-term adverse events and expenses associated with HAART have led to an interest in simplified therapy. Lopinavir/ritonavir monotherapy is attractive due to its potency and high genetic barrier.This is a 96-week, open-label, randomized study to assess the feasibility of using LPV/r monotherapy in patients with undetectable viral load after being on successful HAART for at least 6 months. Subjects were randomized (1:1) to either switch from HAART to LPV/r monotherapy or to maintain their previous regimen.60 patients were enrolled. Baseline characteristics were similar in both groups. At Week 96, by intention-to-treat analysis, 24/30 (80.0%) subjects in monotherapy group and 26/30(86.6%) in the control group had a plasma viral load of80 copies/mL. There was one virologic failure (defined as VL not greater-than 500 copies/mL) in each arm. Genotyping testing identified no resistance-associated mutations. The patient on the monotherapy arm was successfully resuppressed to80 copies/mL after intensification with tenofovir and lamivudine. No statistically significant differences were found with regard to changes in CD4 counts. One subject in the monotherapy group discontinued due to diarrhea. Five subjects in the control group underwent regimen changes due to drug-related toxicities. Viral load from semen samples collected at the end of follow-up was undetectable on 14/15 patients randomized to monotherapy.Switching from various HAART regimens to LPV/r monotherapy in patients who were virologically suppressed and without a history of previous virologic failure was effective, safe, and well tolerated through 96 weeks.

The widespread use of highly active antiretroviral therapy (HAART) has led to marked decreases in death rates in Brazil in HIV-infected individuals. Nonetheless, there are scarce data on specific causes of death.Death rates from a cohort of HIV-infected patients in Rio de Janeiro, Brazil, were analyzed in 2-year periods, from 1997 to 2006. Poisson models and survival models accounting for competing risks were used to assess association of covariables. A standardized validated algorithm was used to ascertain specific causes of death.Of the 1538 eligible patients, 226 (14.7%) died during the study period, corresponding to a mortality rate of 3.2 per 100 person-years. The median follow-up time was 4.61 years (interquartile range = 5.63 years) and the loss to follow-up rate was 2.4 per 100 person-years. Overall, 98 (43.4%) were classified as non-AIDS-related causes. Although opportunistic infections were the leading causes of death (37.6%), deaths due to AIDS-related causes declined significantly over time (P0.01). In the most recent period (2005-2006), the rate of non-AIDS-related causes of deaths was higher than that of AIDS-related causes of death.In the HAART era, there has been a significant change in causes of death among HIV-infected patients in Rio de Janeiro. As access to HAART improves, integration with other public programs will become critically important for the long-term success of HIV/AIDS programs in developing countries.

Cat scratch disease (CSD) is a self limited condition characterized by fever, lymph node enlargement and less often eye involvement. Central nervous system involvement by Bartonella henselae infection is possibly an important cause of morbidity; its role as an agent of aseptic meningitis is unknown. We report a case of a 40 years-old man with CSD accompanied by aseptic meningitis and neuroretinitis. Serum indirect immmunofluorescence (IFI) assays for B. henselae were positive and the cerebrospinal fluid (CSF) analysis showed mononuclear pleocytosis and increased level of protein. Serological tests for other etiologies were negative. The patient responded well to antibiotic therapy with oral doxycicline plus rifampin and in the 12th day of hospitalization evolved to total regression of the headache and partial regression of the visual loss. Clinicians should consider CSD as a differential diagnosis when assessing previously healthy patients with aseptic meningitis associated with regional lymphadenopathy and epidemiological history of feline contact.

In Brazil, HIV-infected individuals receive drugs (including non-brand name drugs which comprise locally produced generics and drugs that have not been tested in bioequivalence trials) free of charge from the government. The objective of the present study was to evaluate the effectiveness of highly active antiretroviral therapy (HAART) in Rio de Janeiro, Brazil, where non-brand drugs are widely used. For this purpose, we estimated the proportion of subjects with virologic failure (plasma HIV viral load greater than 400 copies/mL at 6 months after initiation of treatment). This was a retrospective cohort study of drug-naive HIV-infected subjects who initiated HAART. Subjects were included in the analysis if they were 18 years of age or older, were treatment naive, started HAART with a minimum of 3 drugs, and had available information on blood plasma HIV-1 viral load after 6 months on therapy. All subjects used antiretrovirals in dosing regimens recommended by the Brazilian National Advisory Committee for Antiretroviral Therapy. Chart reviews were conducted in three settings: at two public health outpatient units, at one clinical trial unit and at one private office. No comparisons of the effectiveness of non-brand name with the effectiveness of brand name drugs were made. We present results for 485 patients; of these, 354 (73%), 55 (11%), and 76 (16%) were seen at the public health outpatient units, private office, and clinical trial unit, respectively. Virologic failure was observed in 119 (25%) of the subjects. This study demonstrates the effectiveness of HAART in a setting where non-brand name drugs are widely used.