Search

Background Since the beginning of the COVID-19 pandemic, therapeutic options for treating COVID-19 have been investigated at different stages of clinical manifestations. Considering the particular impact of COVID-19 in the Americas, this document aims to present recommendations for the pharmacological treatment of COVID-19 specific to this population. Method Fifteen experts, members of the Brazilian Society of Infectious Diseases (SBI) and the Pan-American Association of Infectious Diseases (API) make up the panel responsible for developing this guideline. Questions were formulated regarding prophylaxis and treatment of COVID-19 in outpatient and inpatient settings. The outcomes considered in decision-making were mortality, hospitalisation, need for mechanical ventilation, symptomatic COVID-19 episodes, and adverse events. In addition, a systematic review of randomised controlled trials was conducted. The quality of evidence assessment and guideline development process followed the GRADE system. Results Nine technologies were evaluated, and ten recommendations were made, including the use of tixagevimab + cilgavimab in the prophylaxis of COVID-19, tixagevimab + cilgavimab, molnupiravir, nirmatrelvir + ritonavir, and remdesivir in the treatment of outpatients, and remdesivir, baricitinib, and tocilizumab in the treatment of hospitalised patients with severe COVID-19. The use of hydroxychloroquine or chloroquine and ivermectin was discouraged. Conclusion This guideline provides recommendations for treating patients in the Americas following the principles of evidence-based medicine. The recommendations present a set of drugs that have proven effective in the prophylaxis and treatment of COVID-19, emphasising the strong recommendation for the use of nirmatrelvir/ritonavir in outpatients as the lack of benefit from the use of hydroxychloroquine and ivermectin.

The use of antiretroviral therapy has drastically improved the life quality and prognosis of people living with the human immunodeficiency virus (HIV). The risk of acute myeloid leukemia (AML) currently does not appear to be significantly increased compared to the general population. Acute promyelocytic leukemia (APL), infrequent in people with HIV, is a distinct subtype of AML with unique molecular pathogenesis, clinical manifestations, and treatment. Herein we describe a fatal case of APL hypogranular variant in an HIV-positive patient presenting with hyperleukocytosis. Also, we conducted a literature review of the ten cases reported so far.

Background: The recent urbanization of Chagas disease (CD) has contributed to a greater risk of coexistence with human immunodeficiency virus (HIV) and AIDS. Methods: This retrospective observational study included patients who were followed at INI-Fiocruz between July 1986 and October 2021. All patients underwent an assessment protocol that included sociodemographic profile, epidemiological history, and clinical evaluation. Descriptive data analyses included reports of the medians and frequencies of variables of interest. Differences in medians between groups were tested using the Mann-Whitney U test. Differences in frequency were tested using Fisher's exact test. Results: Among 2201 patients, 11 (0.5%) were identified with Trypanosoma cruzi/HIV coinfection. Of these, 63.6% were women with a median age of 51.0 years old. Two patients had the indeterminate form of CD, six had the cardiac form, two had the digestive form and one had the cardio-digestive form. Half of the patients were undergoing antiretroviral treatment at the time of coinfection diagnosis with a median CD4+ count of 350 cells/μL and a viral load of 1500 copies/μL. Four patients underwent a xenodiagnosis test at coinfection diagnosis, which all yielded positive results; two of them presented high parasitemia under the risk of reactivation. Prophylaxis for CD reactivation was administered to four patients; two with ketoconazole and two with benznidazole. Six patients died after a median follow-up of 22.5 months, with AIDS being the most common cause of death. Only one case of reactivation was observed. Conclusions: Early diagnosis and prompt treatment of CD reactivation dramatically reduced mortality. Identification of Trypanosoma cruzi/HIV co-infection is crucial to planning a close follow-up of coinfected patients.

We evaluated in-hospital mortality and outcomes incidence after hospital discharge due to COVID-19 in a Brazilian multicenter cohort.This prospective multicenter study (RECOVER-SUS, NCT04807699) included COVID-19 patients hospitalized in public tertiary hospitals in Brazil from June 2020 to March 2021. Clinical assessment and blood samples were performed at hospital admission, with post-hospital discharge remote visits. Hospitalized participants were followed-up until March 31, 2021. The outcomes were in-hospital mortality and incidence of rehospitalization or death after hospital discharge. Kaplan-Meier curves and Cox proportional-hazard models were performed.1589 participants [54.5% male, age=62 (IQR 50-70) years; BMI=28.4 (IQR,24.9-32.9) Kg/m² and 51.9% with diabetes] were included. A total of 429 individuals [27.0% (95%CI,24.8-29.2)] died during hospitalization (median time 14 (IQR,9-24) days). Older age [vs40 years; age=60-69 years-aHR=1.89 (95%CI,1.08-3.32); age=70-79 years-aHR=2.52 (95%CI,1.42-4.45); age≥80-aHR=2.90 (95%CI 1.54-5.47)]; noninvasive or mechanical ventilation at admission [vs facial-mask or none; aHR=1.69 (95%CI 1.30-2.19)]; SAPS-III score≥57 [vs57; aHR=1.47 (95%CI 1.13-1.92)] and SOFA score≥10 [vs10; aHR=1.51 (95%CI 1.08-2.10)] were independently associated with in-hospital mortality. A total of 65 individuals [6.7% (95%CI 5.3-8.4)] had a rehospitalization or death [rate=323 (95%CI 250-417) per 1000 person-years] in a median time of 52 (range 1-280) days post-hospital discharge. Age ≥ 60 years [vs60, aHR=2.13 (95%CI 1.15-3.94)] and SAPS-III ≥57 at admission [vs57, aHR=2.37 (95%CI 1.22-4.59)] were independently associated with rehospitalization or death after hospital discharge.High in-hospital mortality rates due to COVID-19 were observed and elderly people remained at high risk of rehospitalization and death after hospital discharge.Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Programa INOVA-FIOCRUZ.

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.

Despite widespread availability of direct-acting antivirals including generic formulations, limited progress has been made in the global adoption of hepatitis C virus (HCV) treatment. Barriers to treatment scale-up include availability and access to diagnostic and monitoring tests, health-care infrastructure, and requirement for frequent visits during treatment.ACTG A5360 was a phase 4, open-label, single-arm trial across 38 sites in Brazil, South Africa, Thailand, Uganda, and the USA. Key inclusion criteria were age of 18 years or older, evidence of active HCV infection (HCV RNA1000 IU/mL) and HCV treatment-naive; patients with compensated cirrhosis and HIV/HCV co-infection were included but their enrolment was capped. All participants received a fixed dose combination of oral sofosbuvir (400 mg) and velpatasvir (100 mg) once daily for 12 weeks. The minimal monitoring (MINMON) approach consisted of four components: (1) there was no pre-treatment genotyping; (2) the entire treatment course (84 tablets) was dispensed at entry; (3) there were no scheduled visits or laboratory monitoring; and (4) there were two points of remote contact, at week 4 for adherence and week 22, to schedule outcome assessment at week 24 (-2 weeks to +4 weeks). Participants who missed the week 24 window could return for a visit to assess treatment response any time before week 72. Unplanned visits for any reason were permissible before the week 24 visit. The primary efficacy outcome was sustained virological response (SVR), defined as HCV RNA less than the lower limit of quantification measured at least 22 weeks post-treatment initiation; the primary safety outcome was serious adverse events. The primary efficacy analysis included all participants who initiated treatment, using a missing=failure approach. The primary safety analysis included all participants who initiated treatment and had at least one post-treatment assessment. This trial is registered at ClinicalTrials.gov, NCT03512210.Between Oct 22, 2018, and July 19, 2019, 400 participants were enrolled across all 38 sites; 399 initiated treatment. At the SVR assessment visit, 355 (89%) of 397 participants reported taking 100% of the trial medication during the 12-week treatment period; two patients did not have any follow-up visits after the entry visit and were excluded from the safety analyses. Overall, 379 of the 399 who initiated treatment had an SVR (95·0%, 95% CI 92·4-96·7). 14 (4%) of 397 participants reported serious adverse events between treatment initiation and week 28; none were treatment related or led to treatment discontinuation or death. 15 (4%) of 399 participants had unplanned visits; none were related to treatment.In this diverse global population of people with HCV, the MINMON approach with sofosbuvir-velpatasvir treatment was safe and achieved SVR comparable to standard monitoring observed in real-world data. Coupled with innovative case finding strategies, this strategy could be crucial to the global HCV elimination agenda.US National Institutes of Health and Gilead Sciences.

Hongchao Pan (University of Oxford. Nuffield Department of Population Health. Medical Research Council Population Health Research Unit. Oxford, United Kingdom); Richard Peto (University of Oxford. Nuffield Department of Population Health. Medical Research Council Population Health Research Unit. Oxford, United Kingdom); Ana-Maria Henao-Restrepo (World Health Organization. Geneva, Switzerland); Marie-Pierre Preziosi (World Health Organization. Geneva, Switzerland); Vasee Sathiyamoorthy (World Health Organization. Geneva, Switzerland); Quarraisha Abdool Karim (Centre for the AIDS Programme of Research in South Africa. Durban, South Africa); Marissa M. Alejandria (University of the Philippines. National Institutes of Health. Institute of National Epidemiology. Manila, Philippines); Cesar Hernandez Garcia (Spanish Agency of Medicines and Medical Devices. Madrid, Spain / Hospital Clinico San Carlos. Madrid, Spain); Marie-Paule Kieny (Institut National de la Sante et de la Recherche Medicale. Paris, France); Reza Malekzadeh (Tehran University of Medical Sciences. Digestive Disease Research Institute. Tehran, Iran); Srinivas Murthy (University of British Columbia. Vancouver, Canada); K. Srinath Reddy (Public Health Foundation of India. New Delhi, India); Mirta Roses Periago (National Academy of Sciences of Buenos Aires. Buenos Aires, Argentina); Pierre Abi Hanna (Rafic Hariri University Hospital. Beirut, Lebanon); Florence Ader (Hospices Civils de Lyon. Lyon, France); Abdullah M. Al-Bader (Ministry of Health. Kuwait City, Kuwait); Almonther Alhasawi (Infectious Diseases Hospital. Kuwait City, Kuwait); Emma Allum (University of Bristol. Bristol, United Kingdom); Athari Alotaibi (Ministry for Preventive Health. Riyadh, Saudi Arabia); Carlos A. Alvarez-Moreno (Universidad Nacional de Colombia. Bogota, Colombia / Clinica Colsanitas. Bogota, Colombia); Sheila Appadoo (University of Bern. Bern, Switzerland); Abdullah Asiri (Ministry for Preventive Health. Riyadh, Saudi Arabia); Pal Aukrust (Oslo University Hospital. Oslo, Norway); Andreas Barratt-Due (Oslo University Hospital. Oslo, Norway); Samir Bellani (University of Bristol. Bristol, United Kingdom); Mattia Branca (University of Bern. Bern, Switzerland); Heike B.C. Cappel-Porter (University of Bristol. Bristol, United Kingdom); Nery Cerrato (Secretaria de Salud de Honduras. Tegucigalpa, Honduras); Ting S. Chow (Penang Hospital. Penang, Malaysia); Najada Como (University Hospital Center "Mother Teresa". Tirana, Albania); Joe Eustace (University College Cork. HRB Clinical Research Facility. Cork, Ireland); Patricia J. Garcia (Universidad Peruana Cayetano Heredia. Lima, Peru); Sheela Godbole (Indian Council of Medical Research. New Delhi, India / National AIDS Research Institute. Pune, Maharashtra, India); Eduardo Gotuzzo (Universidad Peruana Cayetano Heredia. Lima, Peru); Laimonas Griskevicius (Vilnius University Hospital Santaros Klinikos. Vilnius, Lithuania); Rasha Hamra (Ministry of Public Health. Beirut, Lebanon); Mariam Hassan (Shaukat Khanum Memorial Cancer Hospital and Research Centre. Lahore, Pakistan); Mohamed Hassany (National Hepatology and Tropical Medicine Research Institute. Cairo, Egypt); David Hutton (University of Bristol. Bristol, United Kingdom); Irmansyah Irmansyah (National Institute of Health Research and Development. Jakarta, Indonesia); Ligita Jancoriene (Vilnius University. Faculty of Medicine. Institute of Clinical Medicine. Vilnius, Lithuania); Jana Kirwan (University of Bristol. Bristol, United Kingdom); Suresh Kumar (Sungai Buloh Hospital. Selangor, Malaysia / Jalan Hospital. Selangor, Malaysia); Peter Lennon (Department of Health and Children. Dublin, Ireland); Gustavo Lopardo (Fundacion del Centro de Estudios Infectologicos. Buenos Aires, Argentina); Patrick Lydon (World Health Organization. Geneva, Switzerland); Nicola Magrini (Italian Medicines Agency. Rome, Italy); Teresa Maguire (Department of Health and Children. Dublin, Ireland); Suzana Manevska (Ministry of Health. Skopje, North Macedonia); Oriol Manuel (Lausanne University Hospital. Lausanne, Switzerland); Sibylle McGinty (University of Bern. Bern, Switzerland); Marco T. Medina (Universidad Nacional Autonoma de Honduras. Tegucigalpa, Honduras); Maria L. Mesa Rubio (Ministry of Health. Bogota, Colombia); Maria C. Miranda-Montoya (World Health Organization. Geneva, Switzerland); Jeremy Nel (University of the Witwatersrand. Johannesburg, South Africa); Estevao Portela Nunes (Fundacao Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil); Markus Perola (National Institute for Health and Welfare of Finland. Helsinki, Finland / University of Finland. Helsinki, Finland); Antonio Portoles (Universidade Complutense de Madrid. Madrid, Spain / Spanish Clinical Research Network. Madrid, Spain / Hospital Clinico San Carlos. Instituto de Investigacion Sanitaria San Carlos. Madrid, Spain); Menaldi R. Rasmin (Rumah Sakit Umum Pusat Persahabatan. Jakarta, Indonesia); Aun Raza (Shaukat Khanum Memorial Cancer Hospital and Research Centre. Lahore, Pakistan); Helen Rees (Wits Reproductive Health and HIV Institute. Johannesburg, South Africa); Paula P. S. Reges (Fundacao Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil); Chris A. Rogers (University of Bristol. Bristol, United Kingdom); Kolawole Salami (World Health Organization. Geneva, Switzerland); Marina I. Salvadori (Public Health Agency of Canada. Ottawa, Canada); Narvina Sinani (National Agency for Medicines and Medical Devices. Tirana, Albania); Jonathan A. C. Sterne (University of Bristol. Bristol, United Kingdom); Milena Stevanovikj (University Clinic of Infectious Diseases and Febrile Conditions. Skopje, North Macedonia); Evelina Tacconelli (University of Verona. Verona, Italy); Kari A. O. Tikkinen (Helsinki University Hospital. Helsinki, Finland / South Karelian Central Hospital. Lappeenranta, Finland); Sven Trelle (University of Bern. Bern, Switzerland); Hala Zaid (Ministry of Health and Population. Cairo, Egypt); John-Arne Rottingen (Research Council of Norway. Oslo, Norway); Soumya Swaminathan (World Health Organization. Geneva, Switzerland).

BACKGROUND AND AIM Few studies have evaluated sustained virological response (SVR) rates by direct-acting agents (DAAs) and liver stiffness measurement (LSM) changing post-SVR in limited-resource settings. We aimed to describe the effectiveness of DAAs for hepatitis C virus treatment and to assess the changing of LSM post-SVR. METHODS This retrospective study analyzed data of consecutive hepatitis C virus-infected patients treated by DAAs from 2015 to 2017 in two tertiary centers in Brazil. SVR rates were reported by intention-to-treat and per-protocol analyses. LSM by transient elastography performed before treatment and post-SVR was compared, and logistic regression models were performed. RESULTS Six hundred seventy-one patients (63% female, 62 years [55-68], 89% genotype 1, 8% HIV co-infected, and 64% with cirrhosis) were included. Most patients were treated by sofosbuvir/daclatasvir ± ribavirin (74%) and sofosbuvir/simeprevir ± ribavirin (21%). SVR rates (95% confidence interval [CI]) were 94.6% (92.7-96.1) and 97.8% (96.4-98.7) for intention-to-treat and per-protocol analyses, respectively. The leading adverse event was anemia (9.6% [95% CI 7.6-12.1]). Pretreatment and post-SVR12 LSM were available in 400 patients. LSM had significantly decreased after SVR (13.6 kPa [interquartile range, 10.0-21.6] vs 10.2 kPa [7.0-17.6], P

Background: Cardiovascular events (CVEs) have emerged as an important cause of morbimortality in people living with HIV/AIDS (PLHA). We aimed to investigate factors associated with incident CVE and compare the observed incidence with the predicted CVE risk by three different equations. Methods: Among the 649 active participants of the INI-ELSA cohort, we analysed data of 644 individuals free of CVE at baseline examinations. We used Cox regression models to study factors associated with CVE and to assess the equation's performance we compared the observed incidence with the overall 5-year predicted risks. Results: Over a median follow-up of 6.26-years (interquartile range [IQR] 6.01-6.47), there were 18 CVE, four deaths. Overall, 57.92% were male, median age was 43.4 years (35.82-50.73), most were on cART (88.65%). Participants who had CVE were older, had poorer renal function, higher proportion of dyslipidemia and higher levels of systolic blood pressure and triglycerides. The observed CVE rate was 2.90% (1.60-4.90%) whereas their overall cardiovascular disease (CVD) risk differed depending on which score was used: 0.91 (0.42-20), 1.16 (0.38-2.78) and 1.68 (0.60-3.87), according to Framingham, ASCVD and DAD, respectively. In the multivariable Cox analysis black race, smoking 10+ packs years, dyslipidemia, current CD4 cell count x101, cumulative viral load and time on NNRTI were independent predictors of CVE. Conclusion: Both traditional and HIV-related factors were associated with incident CVE. Risk scores were inconsistent in classifying patients who had CVE as high risk, indicating that validation studies are required to improve risk assessment of PLHA in Brazil.

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.

HIV-infected individuals have a higher risk of serious illnesses following infection by infection with influenza. Although anti-influenza vaccination is recommended, immunosuppression may limit their response to active immunization. We followed-up a cohort of HIV-infected individuals vaccinated against influenza to assess the immunogenicity and sustainability of the immune response to vaccination. Individuals were vaccinated 2011 with inactivated triple influenza vaccine (TIV), and they had received in 2010 the monovalent anti-A(H1N1)pdm09 vaccine. The sustainability of the immune response to A(H1N1)pdm09 at 12 months after monovalent vaccination fell, both in individuals given two single or two double doses. For these individuals, A(H1N1)pdm09 component from TIV acted as a booster, raising around 40% the number of seroprotected individuals. Almost 70% of the HIV-infected individuals were already seroprotected to A/H3N2 at baseline. Again, TIV boosted over 90% the seroprotection to A/H3N2. Anti-A/H3N2 titers dropped by 20% at 6 months after vaccination. Pre-vaccination seroprotection rate to influenza B (victoria lineage) was the lowest among those tested, seroconversion rates were higher after vaccination. Seroconversion/protection after TIV vaccination did not differ significantly across categories of clinical and demographic variables. Anti-influenza responses in Brazilian HIV-infected individuals reflected both the previous history of virus circulation in Brazil and vaccination.

Scientific Reports 7: Article number: 40920; published online 18 January 2017; updated on 24 April 2017 The Competing Financial Interests section in this Article is incorrect and should read: “Dr. Karin Brüning is a member of the BMK consortium, able to produce sofosbuvir”.

In Brazil, hepatitis C treatment has been evolving significantly with the licensing of direct-acting antivirals (DAAs). However, viral determinants (amino acid substitutions in hepatitis C virus (HCV) genome and infective genotype) associated with host factors (hepatic condition and prior HCV therapy) might limit the achievement of sustained virologic response (SVR). Here, we described two case reports in which the occurrence of HCV NS5A mutations A30K (subtype 3a) and Y93N (subtype 1a) might have influenced daclatasvir (DCV)/sofosbuvir (SOF) combined therapy non-response. Despite high response rates for DAA combined therapies in Brazil, these case reports stated the importance of an investigation about how to manage a DAA treatment failure since a combination of factors, especially the occurrence of resistance substitutions, could impact a rescue therapy with new available antivirals in clinical routine.

Zika virus (ZIKV) is a member of the Flaviviridae family, along with other agents of clinical significance such as dengue (DENV) and hepatitis C (HCV) viruses. Since ZIKV causes neurological disorders during fetal development and in adulthood, antiviral drugs are necessary. Sofosbuvir is clinically approved for use against HCV and targets the protein that is most conserved among the members of the Flaviviridae family, the viral RNA polymerase. Indeed, we found that sofosbuvir inhibits ZIKV RNA polymerase, targeting conserved amino acid residues. Sofosbuvir inhibited ZIKV replication in different cellular systems, such as hepatoma (Huh-7) cells, neuroblastoma (SH-Sy5y) cells, neural stem cells (NSC) and brain organoids. In addition to the direct inhibition of the viral RNA polymerase, we observed that sofosbuvir also induced an increase in A-to-G mutations in the viral genome. Together, our data highlight a potential secondary use of sofosbuvir, an anti-HCV drug, against ZIKV.

Lopinavir/ritonavir approval for use in antiretroviral treatment 10 years ago was very important for the recognition of boosted protease inhibitor (PI)-based therapy as an attractive option for first-line therapy. Being coformulated with ritonavir and having less toxicity than former PIs it allowed for effective and durable virologic suppression with less impact on quality of life. It soon became the standard of care for salvage therapy in its class. Since then, however, its central role has been challenged by new PIs with a more favorable impact on lipid profile, better gastrointestinal tolerability or that are more active in the setting of multidrug resistance. This article summarizes the main clinical studies with lopinavir and discusses its particular characteristics as well as its possible current role in antiretroviral therapy.

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.

In the last 5 years there have been important achievements in the field of HIV therapy with the availability of new classes of antiretrovirals together with a new generation of old classes. Among them, the development of raltegravir, the first commercially available component of integrase inhibitors, brought an extraordinary improvement in salvage therapy for HIV-infected patients, allowing for virologic suppression even in multi-experienced subjects, who until recently had limited treatment options. It was subsequently approved for initial treatment combined with a nucleoside/nucleotide backbone, and also became an interesting option for naive HIV-infected populations. Its unique characteristics, the limited potential for significant pharmacokinetic interactions with other drugs and excellent safety profile have increased interest in its use in different settings.

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.

Both multicentric Castleman disease and Kaposi sarcoma are more frequently observed in HIV infected patients. The coexistence of these Human herpesvirus 8 related lesions, in the same tissue, has been observed, but literature reports are scant. On the other hand, the expression of HHV-8-LANA-1 is easily demonstrable by immunohistochemistry. This has been shown to be a powerful tool for the diagnosis of these entities. The aim of this report is to communicate our experience with a case of multicentric Castleman disease occurring in the setting of HIV infection, which demonstrated microscopic Kaposi sarcoma in the same lymph node during the pathological work-up.

Despite the unprecedented pace of development of drugs for the treatment of a viral disease and the unquestionable efficacy of antiretroviral therapy, there is a need for less toxic and cheaper regimens that could simplify the treatment of HIV infection without sacrificing efficacy. The favorable pharmacokinetic profile and the high genetic barrier of boosted protease inhibitors make them ideal candidates for use as monotherapy. Given the encouraging results of available studies on lopinavir/ritonavir monotherapy in patients with no prior failure with protease inhibitors, it may be warranted to conduct trials to investigate the cost-effectiveness of lopinavir/ritonavir monotherapy as second-line therapy in resource-constrained settings where virologic monitoring is not feasible. In addition, larger trials with longer follow up, with particular attention to the potential consequences of viral replication in sites where the penetration of protease inhibitors may be poor, are needed before this strategy can be considered for routine use.

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.

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.

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.