No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV-Infected Subjects.

Lopinavir-ritonavir is frequently prescribed to HIV-1-infected women during pregnancy. Decreased lopinavir exposure has been reported during pregnancy, but the clinical significance of this reduction is uncertain. This analysis aimed to evaluate the need for lopinavir dose adjustment during pregnancy. We conducted a population pharmacokinetic analysis of lopinavir and ritonavir concentrations collected from 84 pregnant and 595 nonpregnant treatment-naive and -experienced HIV-1-infected subjects enrolled in six clinical studies. Lopinavir-ritonavir doses in the studies ranged between 400/100 and 600/150 mg twice daily. In addition, linear mixed-effect analysis was used to compare the area under the concentration-time curve from 0 to 12 h (AUC0-12) and concentration prior to dosing (Cpredose) in pregnant women and nonpregnant subjects. The relationship between lopinavir exposure and virologic suppression in pregnant women and nonpregnant subjects was evaluated. Population pharmacokinetic analysis estimated 17% higher lopinavir clearance in pregnant women than in nonpregnant subjects. Lopinavir clearance values postpartum were 26.4% and 37.1% lower than in nonpregnant subjects and pregnant women, respectively. As the tablet formulation was estimated to be 20% more bioavailable than the capsule formulation, no statistically significant differences between lopinavir exposure in pregnant women receiving the tablet formulation and nonpregnant subjects receiving the capsule formulation were identified. In the range of lopinavir AUC0-12 or Cpredose values observed in the third trimester, there was no correlation between lopinavir exposure and viral load or proportion of subjects with virologic suppression. Similar efficacy was observed between pregnant women and nonpregnant subjects receiving lopinavir-ritonavir at 400/100 mg twice daily. The pharmacokinetic and pharmacodynamic results support the use of a lopinavir-ritonavir 400/100-mg twice-daily dose during pregnancy.

Immunogenicity and sustainability of the immune response in Brazilian HIV-1-infected individuals vaccinated with inactivated triple influenza vaccine.

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.

Comparative effectiveness of tenofovir in treatment-naïve HIV-infected patients: systematic review and meta-analysis.

INTRODUCTION: Benefits and harms of tenofovir disoproxil fumarate (TDF) in HIV-infected, antiretroviral treatment (ART)-naïve patients of any age have not been systematically reviewed since recent milestone trials were published. METHODS: We searched MEDLINE, EMBASE, CENTRAL, SCI, LILACS, WHO GHL, and ClinicalTrials.gov for randomized controlled trials (RCTs) comparing TDF-based treatments with any other ART-regimen (last search 01/2015). Trial characteristics and results were extracted, risks of bias systematically assessed, and treatment effects synthesized in meta-analyses using random-effects models. RESULTS: We included 22 RCTs (8297 patients). We found no differences between groups for mortality, AIDS, fractures, CD4 cell count, and virological failure; and inconclusive information due to inadequate reporting for cardiovascular events, renal failure, proteinuria, rash, and quality of life. Tenofovir disoproxil fumarate-based regimens significantly reduced total cholesterol (mean difference -18.42 mg/dl; 95% confidence interval [CI] -22.80 to -14.0), LDL-cholesterol (-9.53 mg/dl; -12.16 to -6.89), HDL-cholesterol (-2.97 mg/dl; -4.41 to -1.53), and triglycerides (-29.77 mg/dl; -38.61 to -20.92), bone mineral density (BMD) (hip: -1.41%; -1.87 to -0.94), and glomerular filtration rate (eGFR) (-3.47 ml/minute; -5.89 to -1.06) over 48 weeks of follow-up. Effects were similar in trials comparing fixed-dose TDF/FTC-based regimens with ABC/3TC-based regimens. We found no influence of baseline viral load on virological failure. DISCUSSION: Moderate-quality evidence suggests similar effects of TDF-based treatment regimens and other ART on virological failure. Tenofovir disoproxil fumarate-based regimens are associated with a more favorable lipid profile, but with increased risk of reduced BMD and eGFR. Improved reporting quality is vital to allow assessment of clinical outcomes in future trials.

Randomized clinical trial comparing the pharmacokinetics of standard- and increased-dosage lopinavir-ritonavir coformulation tablets in HIV-positive pregnant women.

A lopinavir-ritonavir (LPV/r)-based regimen is recommended during pregnancy to reduce the risk of HIV mother-to-child transmission, but the appropriate dose is controversial. We compared the pharmacokinetics of standard and increased LPV/r doses during pregnancy. This randomized, open-label prospective study enrolled 60 pregnant women between gestational weeks 14 and 30. The participants received either the standard dose (400/100 mg twice a day [BID]) or increased dose (600/150 mg BID) of LPV/r tablets during pregnancy and the standard dose for 6 weeks after childbirth. Pharmacokinetics analysis was performed using a high-performance liquid chromatography-tandem mass spectrometry method. Adherent participants who received the standard dose presented minimum LPV concentrations of 4.4, 4.3, and 6.1 µg/ml in the second and third trimesters and postpartum, respectively. The increased-dose group exhibited values of 7.9, 6.9, and 9.2 µg/ml at the same three time points. Although LPV exposure was significantly higher in the increased-dose group, the standard dose produced therapeutic levels of LPV against wild-type virus in all adherent participants, except one patient in the third trimester; 50%, 37.5%, and 25%, and 0%, 15%, and 0% of the participants in the standard- and increased-dose groups failed to achieve therapeutic levels against resistant viruses during the second and third trimesters and after childbirth, respectively. After 12 weeks of treatment and after childbirth, all adherent participants achieved undetectable HIV viral loads, and their babies (49/54) were uninfected. No serious drug-related adverse events were observed. We conclude that the standard dose is appropriate for use during pregnancy and that an increased dose may be necessary for women harboring resistant HIV. (This study has been registered at ClinicalTrials.gov under registration no. NCT00605098.).

Ambulatory and hospitalized patients with suspected and confirmed mpox: an observational cohort study from Brazil.

Background: By October 30, 2022, 76,871 cases of mpox were reported worldwide, with 20,614 cases in Latin America. This study reports characteristics of a case series of suspected and confirmed mpox cases at a referral infectious diseases center in Rio de Janeiro, Brazil. Methods: This was a single-center, prospective, observational cohort study that enrolled all patients with suspected mpox between June 12 and August 19, 2022. Mpox was confirmed by a PCR test. We compared characteristics of confirmed and non-confirmed cases, and among confirmed cases according to HIV status using distribution tests. Kernel estimation was used for exploratory spatial analysis. Findings: Of 342 individuals with suspected mpox, 208 (60.8%) were confirmed cases. Compared to non-confirmed cases, confirmed cases were more frequent among individuals aged 30-39 years, cisgender men (96.2% vs. 66.4%; p < 0.0001), reporting recent sexual intercourse (95.0% vs. 69.4%; p < 0.0001) and using PrEP (31.6% vs. 10.1%; p < 0.0001). HIV (53.2% vs. 20.2%; p < 0.0001), HCV (9.8% vs. 1.1%; p = 0.0046), syphilis (21.2% vs. 16.3%; p = 0.43) and other STIs (33.0% vs. 21.6%; p = 0.042) were more frequent among confirmed mpox cases. Confirmed cases presented more genital (77.3% vs. 39.8%; p < 0.0001) and anal lesions (33.1% vs. 11.5%; p < 0.0001), proctitis (37.1% vs. 13.3%; p < 0.0001) and systemic signs and symptoms (83.2% vs. 64.5%; p = 0.0003) than non-confirmed cases. Compared to confirmed mpox HIV-negative, HIV-positive individuals were older, had more HCV coinfection (15.2% vs. 3.7%; p = 0.011), anal lesions (45.7% vs. 20.5%; p < 0.001) and clinical features of proctitis (45.2% vs. 29.3%; p = 0.058). Interpretation: Mpox transmission in Rio de Janeiro, Brazil, rapidly evolved into a local epidemic, with sexual contact playing a crucial role in its dynamics and high rates of coinfections with other STI. Preventive measures must address stigma and social vulnerabilities. Funding: Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz (INI-Fiocruz).

Development of the Sm14/GLA-SE Schistosomiasis Vaccine Candidate: An Open, Non-Placebo-Controlled, Standardized-Dose Immunization Phase Ib Clinical Trial Targeting Healthy Young Women.

We report the successful closure of Phase I clinical trials, comprising Phases Ia and Ib, of the vaccine candidate against human schistosomiasis: the Schistosoma mansoni 14 kDa fatty acid-binding protein (Sm14) + glucopyranosyl lipid A in squalene emulsion (GLA-SE). Shown here are the results of Phase Ib, an open, non-placebo-controlled, standardized-dose immunization trial involving 10 healthy 18-49-year-old women. Fifty micrograms of the Sm14 protein plus 10 µg GLA-SE per dose was given intramuscularly thrice at 30-day intervals. Participants were assessed clinically, biochemically, and immunologically for up to 120 days. In preambular experiments involving vaccinated pregnant female rabbits, we did not find any toxicological features in either the offspring or mothers, and the vaccine induced adaptive immunity in the animals. In women, no adverse events were observed, and vaccination induced high titers of anti-Sm14 serum IgG antibody production. Vaccination also elicited robust cytokine responses, with increased TNFα, IFNγ, and IL-2 profiles in all vaccinees on days 90 and 120. The completion of Phase I clinical trials, which were performed to the highest standards set by Good Clinical Research Practice (GCP) standards, and preclinical data in pregnant rabbits enabled the vaccine candidate to proceed to Phase II clinical trials in endemic areas.

Bridging Learning in Medicine and Citizenship During the COVID-19 Pandemic: A Telehealth-Based Case Study.

BACKGROUND: COVID-19 presented great challenges for not only those in the field of health care but also those undergoing medical training. The burden on health care services worldwide has limited the educational opportunities available for medical students due to social distancing requirements. OBJECTIVE: In this paper, we describe a strategy that combines telehealth and medical training to mitigate the adverse effects of the COVID-19 pandemic. METHODS: A toll-free telescreening service, Telecoronavirus, began operations in March 2020. This service was operated remotely by supervised medical students and was offered across all 417 municipalities (14.8 million inhabitants) in the Brazilian state of Bahia. Students recorded clinical and sociodemographic data by using a web-based application that was simultaneously accessed by medical volunteers for supervision purposes, as well as by state health authorities who conducted epidemiological surveillance and health management efforts. In parallel, students received up-to-date scientific information about COVID-19 via short educational videos prepared by professors. A continuously updated triage algorithm was conceived to provide consistent service. RESULTS: The program operated for approximately 4 months, engaging 1396 medical students and 133 physicians. In total, 111,965 individuals residing in 343 municipalities used this service. Almost 70,000 individuals were advised to stay at home, and they received guidance to avoid disease transmission, potentially contributing to localized reductions in the spread of COVID-19. Additionally, the program promoted citizenship education for medical students, who were engaged in a real-life opportunity to fight the pandemic within their own communities. The objectives of the education, organization, and assistance domains of the Telecoronavirus program were successfully achieved according to the results of a web-based post-project survey that assessed physicians' and students' perceptions. CONCLUSIONS: In a prolonged pandemic scenario, a combination of remote tools and medical supervision via telehealth services may constitute a useful strategy for maintaining social distancing measures while preserving some practical aspects of medical education. A low-cost tool such as the Telecoronavirus program could be especially valuable in resource-limited health care scenarios, in addition to offering support for epidemiological surveillance actions.

Comparative effectiveness of tenofovir in HIV-infected treatment-experienced patients: systematic review and meta-analysis.

BACKGROUND: Antiretroviral therapy (ART) regimens for HIV infection are frequently changed. We conducted a systematic review of randomized trials (RCTs) on the benefits and harms of switching to tenofovir disoproxil fumarate (TDF)-based regimens in ART-experienced patients. METHODS: We included RCTs in HIV-infected adults comparing switching to a TDF-containing regimen with maintaining or switching to another regimen. We searched MEDLINE, EMBASE, CENTRAL, LILACS, SCI, and the WHO Global Health Library. We assessed bias with the Cochrane tool and synthesized data using random-effects meta-analyses and Peto's approach. For further analyses, we added data from a previous systematic review in treatment-naïve patients. RESULTS: 17 RCTs with 2210 patients were included. All but one study had a high risk of bias. There was no significant association of switching to TDF-based regimens with mortality, fractures, CD4-cell count, body fat, virological failure, LDL-, and HDL-cholesterol. TDF-based regimens decreased total cholesterol (mean difference -12.05 mg/dL; 95% CI -20.76 to -3.34), trigylcerides (-14.33 mg/dL; -23.73 to -4.93), and bone mineral density (BMD; hip: -2.46%; -3.9 to -1.03; lumbar spine -1.52%; -2.69 to -0.34). Effects on estimated glomerular filtration (eGFR) were inconsistent and depended on the measurement. Adding 22 RCTs from 8297 treatment-naïve patients gave consistent results with then significant reductions of LDL (-7.57 mg/dL; -10.37 to -4.78), HDL (-2.38 mg/dL; -3.83 to -0.93), and eGFR (-3.49 ml/min; -5.56 to -1.43). CONCLUSIONS: Switching to TDF-based regimens is associated with reductions of BMD and lipid levels and possibly lowered kidney function. The evidence is limited by the high risk of bias.

Schistosomiasis vaccine candidate Sm14/GLA-SE: Phase 1 safety and immunogenicity clinical trial in healthy, male adults.

DESIGN: Safety and immunogenicity of a recombinant 14kDa, fatty acid-binding protein(FABP) from Schistosoma mansoni (rSm14) were evaluated through an open, non-placebo-controlled, dose-standardized trial, performed at a single research site. The vaccine was formulated with glucopyranosyl lipid A (GLA) adjuvant in an oil-in-water emulsion (SE) and investigated in 20 male volunteers from a non-endemic area for schistosomiasis in the state of Rio de Janeiro, Brazil. Fifty microgram rSm14 with 10 µg GLA-SE (rSm14/GLA-SE)/dose were given intramuscularly three times with 30-day intervals. Participants were assessed clinically, biochemically and immunologically for up to 120 days. METHODS: Participants were screened for inclusion by physical examination, haematology and blood chemistry; then followed to assess adverse events and immunogenicity. Sera were tested for IgG (total and isotypes) and IgE. T cell induction of cytokines IL-2, IL-5, IL-10, IFNγ and TNFα was assessed by Milliplex kit and flow cytometry. RESULTS: The investigational product showed high tolerability; some self-limited, mild adverse events were observed during and after vaccine administration. Significant increases in Sm14-specific total IgG, IgG1 and IgG3 were observed 30 days after the first vaccination with specific IgG2 and IgG4 after 60 days. An increase in IgE antibodies was not observed at any time point. The IgG response was augmented after the second dose and 88% of all vaccinated subjects had developed high anti-Sm14 IgG titres 90 days after the first injection. From day 60 and onwards, there was an increase in CD4(+) T cells producing single cytokines, particularly TNFα and IL-2, with no significant increase of multi-functional TH1 cells. CONCLUSION: Clinical trial data on tolerability and specific immune responses after vaccination of adult, male volunteers in a non-endemic area for schistosomiasis with rSm14/GLA-SE, support this product as a safe, strongly immunogenic vaccine against schistosomiasis paving the way for follow-up Phase 2 trials. Study registration ID: NCT01154049 at http://www.clinicaltrials.gov.

HIV Infection Is Not Associated with Carotid Intima-Media Thickness in Brazil: A Cross-Sectional Analysis from the INI/ELSA-Brasil Study.

BACKGROUND: Carotid intima-media thickness (cIMT) has been used as an early marker of atherosclerotic disease in the general population. Recently its role among HIV-infected patients has been questioned. To date, no Brazilian study has compared cIMT in respect to HIV status. METHODS: We compared data from 535 patients actively followed in a prospective cohort in Rio de Janeiro (HIV group); 88 HIV-negative individuals who were nominated by patients (friend controls-FCs); and 10,943 participants of the ELSA-Brasil study. Linear regression models were used to study associations of the 3 groups and several covariables with cIMT. Propensity scores weighting (PSW) were also employed to balance data. RESULTS: Median thickness in mm (IQR) were 0.54 (0.49,0.62); 0.58 (0.52,0.68); and 0.57 (0.49,0.70), HIV, FCs and ELSA-Brasil groups, respectively (p-value<0.001). The best linear model chosen did not include the group variables, after adjusting for all the variables chosen, showing no difference of cIMT across groups. Similar results were obtained with PSW. Several traditional CVD risk factors were also significantly associated with cIMT: female gender, higher education and higher HDL were negatively associated while risk factors were older age, current/former smoker, AMI/stroke family history, CVD history, hypertension, DM, higher BMI and total cholesterol. CONCLUSIONS: We show for the first time in a middle-income setting that cIMT, is not different in HIV-infected patients in Rio de Janeiro compared with 2 different groups of non-HIV-infected individuals. Traditional CVD risk factors are associated with this outcome. Our results point out that high standards of care and prevention for CVD risk factors should always be sought both in the HIV-infected and non-infected populations to prevent CVD-related events.

Traditional risk factors are more relevant than HIV-specific ones for carotid intima-media thickness (cIMT) in a Brazilian cohort of HIV-infected patients.

BACKGROUND: Combination antiretroviral therapy (cART) had a dramatic impact on the mortality profile in human immunodeficiency virus (HIV) infected individuals and increased their life-expectancy. Conditions associated with the aging process have been diagnosed more frequently among HIV-infected patients, particularly, cardiovascular diseases. METHODS: Patients followed in the Instituto de Pesquisa Clínica Evandro Chagas (IPEC) prospective cohort in Rio de Janeiro were submitted to the general procedures from the Brazilian Longitudinal Study of Adult Health, comprising several anthropometric, laboratory and imaging data. Carotid intima-media thickness (cIMT) was measured by ultrasonography, following the Mannheim protocol. Linear regression and proportional odds models were used to compare groups and covariables in respect to cIMT. The best model was chosen with the adaptive lasso procedure. RESULTS: A valid cIMT exam was available for 591 patients. Median cIMT was significantly larger for men than women (0.56mm vs. 0.53mm; p = 0.002; overall = 0.54mm). In univariable linear regression analysis, both traditional risk factors for cardiovascular diseases (CVD) and HIV-specific characteristics were significantly associated with cIMT values, but the best multivariable model chosen included only traditional characteristics. Hypertension presented the strongest association with higher cIMT terciles (OR = 2.51; 95%CI = 1.69-3.73), followed by current smoking (OR = 1,82; 95%CI = 1.19-2.79), family history of acute myocardial infarction or stroke (OR = 1.60; 95%CI = 1.10-2.32) and age (OR per year = 1.12; 95%CI = 1.10-1.14). CONCLUSIONS: Our results show that traditional cardiovascular disease (CVD) risk factors are the major players in determining increased cIMT among HIV infected patients in Brazil. This finding reinforces the need for thorough assessment of those risk factors in these patients to guarantee the incidence of CVD events remain under control.

Adverse drug reactions associated with antiretroviral therapy during pregnancy.

INTRODUCTION: Antiretroviral (ARV) drug use during pregnancy significantly reduces mother-to-child HIV transmission, delays disease progression in the women and reduces the risk of HIV transmission to HIV-serodiscordant partners. Pregnant women are susceptible to the same adverse reactions to ARVs as nonpregnant adults as well as to specific pregnancy-related reactions. In addition, we should consider adverse pregnancy outcomes and adverse reactions in children exposed to ARVs during intrauterine life. However, studies designed to assess the safety of ARV in pregnant women are rare, usually with few participants and short follow-up periods. AREAS COVERED: In this review, we discuss studies reporting adverse reactions to ARV drugs, including maternal toxicity, adverse pregnancy outcomes and the consequences of exposure to ARV in infants. We included results of observational studies, both prospective and retrospective, as well as randomized clinical trials, systematic reviews and meta-analyses. EXPERT OPINION: The benefits of ARV use during pregnancy outweigh the risks of adverse reactions identified to date. More studies are needed to assess the adverse effects in the medium- and long term in children exposed to ARVs during pregnancy, as well as pregnant women using lifelong antiretroviral therapy and more recently available drugs.

Incidence of antiretroviral adverse drug reactions in pregnant women in two referral centers for HIV prevention of mother-to-child-transmission care and research in Rio de Janeiro, Brazil.

Mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) infection remains an important cause of new HIV infections worldwide, especially in low and middle-resource limited countries. Safety data from studies involving pregnant women and prenatal antiretroviral (ARV) exposure are still needed once these studies are often small and with a limited duration to assess adverse drug reactions (ADR). The aim of this study was to estimate the incidence of ADR related to the use of antiretroviral therapy (ART) in pregnant women in two referral centers in Rio de Janeiro State. A prospective study was carried out from February 2005 to May 2006. Women were classified according to their ART status during pregnancy diagnosis: ARV-experienced (ARTexp) or ARV-naïve (ARTn). Two hundred fourteen HIV-infected pregnant women were included: 36 ARTexp and 178 ARTn. ARTexp women have not experienced ADR. Among ARTn, 20.2% presented ADR. Incidence rate of ADR was 70.8 per 1000 person-months and the most common ADRs observed were: gastrointestinal (belly or abdominal cramps, diarrhea, nausea and vomit) in 16.3%, cutaneous (pruritus and rash) in 6.2%, anemia (2.2%) and hepatitis (1.7%). The frequency of obstetrical complications, pre-term delivery, low birth weight and birth abnormalities was low in this population. ADRs ranged from mild to moderate intensity, none of them being potentially fatal. Only in a few cases it was necessary to discontinue ART. In conclusion, the high effectiveness of ARV for HIV prevention of MTCT (PMTCT) overcomes the risk of ADR.

Factors associated with tobacco smoking and cessation among HIV-infected individuals under care in Rio de Janeiro, Brazil.

Worldwide the prevalence of smoking among people living with HIV/AIDS is elevated compared to the general population. This probably reflects the cluster of individual characteristics that have shared risk factors for HIV infection and smoking. A cross-sectional study, enrolling a convenience sample from a Brazilian HIV clinical cohort was conducted to evaluate the prevalence of tobacco smoking and the factors associated with current smoking and abstinence. A total of 2,775 HIV-infected individuals were interviewed: 46.2% have never smoked, 29.9% were current smokers and 23.9% were former smokers. Current smokers had a higher prevalence of alcohol and illicit drug use when compared to the other two groups. A higher proportion of heterosexual individuals were former smokers or never smokers while among men who have sex with men (MSM) a higher proportion were current smokers. Former smokers had been more frequently diagnosed with high blood pressure, diabetes mellitus, cardiovascular diseases and depression, while for current smokers lung diseases were more frequent. Former smokers and current smokers were more likely to have had any hospital admission (42.0% and 41.2%, respectively) than participants who never smoked (33.5%) (p<0.001). Multivariate model results showed that current smokers (versus never smokers) were more likely to be less educated, to report the use of alcohol, crack and cocaine and to present clinical comorbidities. Former smokers (versus current smokers) were more likely to be older, to have smoked for a shorter amount of time and to have smoked >31 cigarettes/day. MSM (compared to heterosexuals) and cocaine users (versus non-users) had lower odds of being former smokers. Considering our results, smoking cessation interventions should be tailored to younger individuals, MSM and substance users.

Raltegravir for the treatment of patients co-infected with HIV and tuberculosis (ANRS 12 180 Reflate TB): a multicentre, phase 2, non-comparative, open-label, randomised trial.

BACKGROUND: Concurrent treatment of HIV and tuberculosis is complicated by drug interactions. We explored the safety and efficacy of raltegravir as an alternative to efavirenz for patients co-infected with HIV and tuberculosis. METHODS: We did a multicentre, phase 2, non-comparative, open-label, randomised trial at eight sites in Brazil and France. Using a computer-generated randomisation sequence, we randomly allocated antiretroviral-naive adult patients with HIV-1 and tuberculosis (aged ≥18 years with a plasma HIV RNA concentration of >1000 copies per mL) to receive raltegravir 400 mg twice a day, raltegravir 800 mg twice daily, or efavirenz 600 mg once daily plus tenofovir and lamivudine (1:1:1; stratified by country). Patients began study treatment after the start of tuberculosis treatment. The primary endpoint was virological suppression at 24 weeks (HIV RNA <50 copies per mL) in all patients who received at least one dose of study drug (modified intention-to-treat analysis). We recorded death, study drug discontinuation, and loss to follow-up as failures to achieve the primary endpoint. We assessed safety in all patients who received study drugs. This study is registered in ClinicalTrials.gov, number NCT00822315. FINDINGS: Between July 3, 2009, and June 6, 2011, we enrolled and randomly assigned treatment to 155 individuals; 153 (51 in each group) received at least one dose of the study drug and were included in the primary analysis. 133 patients (87%) completed follow-up at week 48. At week 24, virological suppression was achieved in 39 patients (76%, 95% CI 65-88) in the raltegravir 400 mg group, 40 patients (78%, 67-90) in the raltegravir 800 mg group, and 32 patients (63%, 49-76) in the efavirenz group. The adverse-event profile was much the same across the three groups. Three (6%) patients allocated to efavirenz and three (6%) patients allocated to raltegravir 800 mg twice daily discontinued the study drugs due to adverse events. Seven patients died during the study (one in the raltegravir 400 mg group, four in the raltegravir 800 mg group, and two in the efavirenz group): none of the deaths was deemed related to study treatment. INTERPRETATION: Raltegravir 400 mg twice daily might be an alternative to efavirenz for the treatment of patients co-infected with HIV and tuberculosis. FUNDING: French National Agency for Research on AIDS and Viral Hepatitis (ANRS), Brazilian National STD/AIDS Program-Ministry of Health.

Aging with HIV: a practical review.

The worldwide elderly population is expected to grow by an additional 694 million people by 2025. By that time, there will be approximately two billion elderly people in the world, most of whom (80%) will be living in developing countries. Based on recent estimates, this population will number over 40 million in 2030 in Brazil and a consequent increase in governmental spending for this population can be expected. Since highly active antiretroviral therapy became available in the mid-1990s, the life expectancy of people living with HIV has increased significantly. Approximately 12 million life years were added to the world between 1996 and 2008 as a consequence of wider access to highly active antiretroviral therapy. In Brazil, the incidence of AIDS among the population aged ≥50 years doubled between 1996 and 2006. The development of antiretroviral therapy has allowed individuals diagnosed at a younger age to live longer, which partially explains the aging tendency associated with the HIV/AIDS epidemic. It is estimated that by 2015, subjects aged ≥50 years will represent 50% of the people living with HIV undergoing clinical treatment. This scenario presents some challenges, including the fact that the diagnosis of HIV tends to be delayed in older patients compared to younger patients because the symptoms of HIV can be confused with those of other common diseases among the elderly and also because healthcare professionals do not consider this population to be at high risk for HIV infection. In regard to the individuals diagnosed with HIV, a further challenge is presented by the morbidity normally associated with aging. Finally, the elderly also exhibit higher susceptibility to the toxic effects and pharmacological interactions of medications. The present article reviews the literature regarding the profile of HIV infection among individuals aged ≥50 years focusing on practical features related to the clinical approach and long-term follow-up of this population.

Safety and immunovirologic outcomes with maraviroc combination regimens in patients with a history of past treatment failures and virologic resistance in Brazil: an open-label, multicenter phase 3b study.

Maraviroc is a first-in-class chemokine coreceptor type-5 (CCR5) antagonist with demonstrated immunovirologic activity in treatment-experienced (TE) patients with CCR5 (R5)-tropic HIV-1; however, experience in regimens containing newer antiretroviral agents is limited. The primary objective of this 96-week open-label, noncomparative, multicenter Phase 3b study (NCT00478231) was to assess the safety of maraviroc in combination with optimized background therapy (OBT), which could include recently introduced agents such as darunavir and raltegravir in TE patients in Brazil with R5 HIV-1 and limited therapeutic options. Immunovirologic activity was a secondary endpoint. Of 638 patients screened, 206 were treated and 125 completed the study. Approximately 70% were male; the mean age was 43.2 years. Most patients (65.0%) received an OBT combination of protease inhibitor plus nucleoside reverse transcriptase inhibitor. Adverse event (AE) and treatment-related AE incidence was 91.3% and 36.9%, respectively. The most common AEs were diarrhea, nasopharyngitis, and headache. Serious AEs and treatment-related serious AEs occurred in 16.5% and 4.4% of patients. Only eight patients (3.9%) discontinued due to AEs. Few AIDS-defining events were observed (4.9%). The proportion of patients with viral load <400 copies/ml increased from 2.4% at baseline to 43.9% at week 8, remaining >40% until week 48. At the end of treatment, 26.7% of patients had a viral load <400 copies/ml. Median CD4(+) cell count increased throughout the study; the mean change from baseline to end of treatment was 174.1 cells/µl. In conclusion, maraviroc, combined with different agents from multiple classes, was well tolerated in highly TE patients. Maraviroc plus OBT was associated with an immunovirologic response in this population.

H1N1pdm09 adjuvanted vaccination in HIV-infected adults: a randomized trial of two single versus two double doses.

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 CD4<200 cells/mm(3) was significantly higher with double doses. Persistence of protective antibodies six months after vaccination was achieved by 80% and 89.9% of the HIV-infected participants who received single and double doses, respectively. CONCLUSIONS/SIGNIFICANCE: Our results support the recommendation of two double doses of adjuvanted H1N1pdm09 vaccine for HIV-infected individuals, particularly women, and those aged >40 years or with nadir CD4<200 cells/mm(3), to achieve antibody levels that are both higher and more sustained. TRIAL REGISTRATION: ClinicalTrials.gov NCT01155037.

Incidence of antiretroviral adverse drug reactions in pregnant women in two referral centers for HIV prevention of mother-to-child-transmission care and research in Rio de Janeiro, Brazil

Mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) infection remains an important cause of new HIV infections worldwide, especially in low and middle-resource limited countries. Safety data from studies involving pregnant women and prenatal antiretroviral (ARV) exposure are still needed once these studies are often small and with a limited duration to assess adverse drug reactions (ADR). The aim of this study was to estimate the incidence of ADR related to the use of antiretroviral therapy (ART) in pregnant women in two referral centers in Rio de Janeiro State. A prospective study was carried out from February 2005 to May 2006. Women were classified according to their ART status during pregnancy diagnosis: ARV-experienced (ARTexp) or ARV-naïve (ARTn). Two hundred fourteen HIV-infected pregnant women were included: 36 ARTexp and 178 ARTn. ARTexp women have not experienced ADR. Among ARTn, 20.2% presented ADR. Incidence rate of ADR was 70.8 per 1000 person-months and the most common ADRs observed were: gastrointestinal (belly or abdominal cramps, diarrhea, nausea and vomit) in 16.3%, cutaneous (pruritus and rash) in 6.2%, anemia (2.2%) and hepatitis (1.7%). The frequency of obstetrical complications, pre-term delivery, low birth weight and birth abnormalities was low in this population. ADRs ranged from mild to moderate intensity, none of them being potentially fatal. Only in a few cases it was necessary to discontinue ART. In conclusion, the high effectiveness of ARV for HIV prevention of MTCT (PMTCT) overcomes the risk of ADR.

Aging with HIV: a practical review

The worldwide elderly population is expected to grow by an additional 694 million people by 2025. By that time, there will be approximately two billion elderly people in the world, most of whom (80%) will be living in developing countries. Based on recent estimates, this population will number over 40 million in 2030 in Brazil and a consequent increase in governmental spending for this population can be expected. Since highly active antiretroviral therapy became available in the mid-1990s, the life expectancy of people living with HIV has increased significantly. Approximately 12 million life years were added to the world between 1996 and 2008 as a consequence of wider access to highly active antiretroviral therapy. In Brazil, the incidence of AIDS among the population aged >50 years doubled between 1996 and 2006. The development of antiretroviral therapy has allowed individuals diagnosed at a younger age to live longer, which partially explains the aging tendency associated with the HIV/AIDS epidemic. It is estimated that by 2015, subjects aged >50 years will represent 50% of the people living with HIV undergoing clinical treatment. This scenario presents some challenges, including the fact that the diagnosis of HIV tends to be delayed in older patients compared to younger patients because the symptoms of HIV can be confused with those of other common diseases among the elderly and also because healthcare professionals do not consider this population to be at high risk for HIV infection. In regard to the individuals diagnosed with HIV, a further challenge is presented by the morbidity normally associated with aging. Finally, the elderly also exhibit higher susceptibility to the toxic effects and pharmacological interactions of medications. The present article reviews the literature regarding the profile of HIV infection among individuals aged >50 years focusing on practical features related to the clinical approach and long-term follow-up of this population.