Emília Valadas

20 Years of HIV-2 Infection in Portugal: Trends and Changes in Epidemiology

To the Editor—We read with attention the letter by Lomas et al. [1] and agree that, as we stated in our article [2], some episodes of viridans group streptococci infective endocarditis in our series could have been misclassified as health care–associated infective endocarditis, rather than community-acquired infective endocarditis. In fact, 7 of 9 viridans group streptococci episodes met the criteria for health care–associated infective endocarditis only on the basis of hospital admission during the previous 6 months [3] and were associated with no other identifiable risk factor. In 1 of the 2 remaining patients, the onset of symptoms was established at 13 days after admission to the hospital for another condition (until that time, the patient had been asymptomatic); in the other patient, fever and persistent bacteremia due to Streptococcus sanguis type 2 began !24 h after a cardiac catheterization. This would support the idea that most viridans group streptococci bloodstream infections are community acquired. However, when we analyzed these 9 cases of health care–associated infective endocarditis due to viridans group streptococci in more detail, we found that the mean patient age ( SD) was 68.2 years, that 5 (55.6%) of the patients 14.4 were women, that the median Charlson score was 2 (range, 0–5), that 6 (66.7%) of the patients had a previously known valvular disease and/or prosthesis, that 6 (66.7%) of the patients had an indication for surgery (although a surgical procedure was only performed in 1 patient, because of a high surgical risk in the remaining patients; the mean [ SD] European system for cardiac operative risk evaluation score [EuroSCORE] in this subgroup of patients was points), that 5 12.8 4.3 (55.6%) of the patients died during hospitalization, and that the cumulative 1year mortality was 66.7%. All of these patient characteristics are much closer to those associated with health care–associated infective endocarditis than they are to those associated with community-acquired infective endocarditis in our series and are probably related to a poor general condition. Thus, previous hospital admission could reflect a comorbid status. In conclusion, although the true source of acquisition is questionable, the inclusion of these 9 patients in the health care–associated infective endocarditis group in our study is justified by epidemiological characteristics and by the fact that the prognosis was similar to that for other patients with health care–associated infective endocarditis.

Immunovirological Response to Triple Nucleotide Reverse-Transcriptase Inhibitors and Ritonavir-Boosted Protease Inhibitors in Treatment-Naive HIV-2–Infected Patients: The ACHIEV2E Collaboration Study Group

BACKGROUNDnTriple nucleoside reverse-transcriptase inhibitors (NRTIs) are recommended by the World Health Organization as first-line regimen in treatment-naïve HIV-2-infected patients. However, ritonavir-boosted protease inhibitor (PI/r)-containing regimens are frequently prescribed. In the absence of previous randomized trials, we retrospectively compared these regimens in observational cohorts.nnnMETHODSnHIV-2-infected patients from 7 European cohorts who started triple NRTI or PI/r since January 1998 were included. Piecewise linear models were used to estimate CD4 cell count and plasma HIV-2 RNA level slopes, differentiating an early phase (until end of month 3) and a second phase (months 4-12). On-treatment analyses censored data at major treatment modification and systematically at month 12.nnnRESULTSnForty-four patients started triple NRTI therapy and 126 started PI/r therapy. Overall, the median CD4 cell count was 191 cells/mm(3) and the median plasma HIV-2 RNA level was ≥2.7 log(10) copies/ml in 61% of the patients at combination antiretroviral therapy (cART) initiation; the median duration of the first cART was 20 months, not differing between groups. PI/r regimens were associated with better CD4 cell count and HIV-2 RNA level outcomes, compared with NRTI regimens. Estimated CD4 cell count slopes were +6 and +12 cells/mm(3)/month during the early phase (P = .22), and -60 cells/mm(3)/year versus +76 cells/mm(3)/year during the second phase (P = .002), for triple NRTI and PI/r, respectively. Estimated mean HIV-2 RNA levels at month 12 in patients with detectable viremia at cART initiation were 4.0 and 2.2 log(10) copies/ml, respectively (P = .005).nnnCONCLUSIONSnIn this observational study, PI/r-containing regimens showed superior efficacy over triple NRTI regimens as first-line therapy in HIV-2-infected patients.

PD-1 and its ligand PD-L1 are progressively up-regulated on CD4 and CD8 T-cells in HIV-2 infection irrespective of the presence of viremia.

Objective:Hyper-immune activation is a main determinant of HIV disease progression, potentially counter-acted by T-cell inhibitory pathways. Here we investigated, for the first time, inhibitory molecules in HIV-2 infection, a naturally occurring attenuated form of HIV disease, associated with reduced viremia and very slow rates of CD4 T-cell decline. Design:Programmed death (PD)-1/PD-L1, an important pathway in limiting immunopathology, and its possible relationship with T-cell immunoglobulin and mucin-domain containing molecule-3 (TIM-3), a recently identified inhibitory molecule, were studied in untreated HIV-2 and HIV-1 cohorts, matched for degree of CD4 T-cell depletion, and noninfected individuals. Methods:Flow cytometric analysis of T-cell expression of PD-1, PD-L1 and TIM-3, combined with markers of cell differentiation, activation, cycling and survival. Statistical analysis was performed using ANOVA, Mann–Whitney/Wilcoxon tests, Spearmans correlations, multiple linear regressions and canonical correlation analysis. Results:T-cell expression of PD-1 and PD-L1 was tightly associated and directly correlated with CD4 T-cell depletion and immune activation in HIV-2 infection. No such correlation was found for PD-L1 expression in HIV-1-positive patients. Central memory and intermediate memory cells, rather than terminally differentiated T-cells, expressed the highest levels of both PD-1 and PD-L1 molecules. Conversely, TIM-3 expression was independent of T-cell differentiation and dissociated from cell cycling, suggesting distinct induction mechanisms. Importantly, in contrast with HIV-1, no significant increases in TIM-3 expression were found in the HIV-2 cohort. Conclusions:Our data suggest that PD-1/PD-L1 molecules, rather than markers of T-cell exhaustion, may act as modulators of T-cell immune activation, contributing to the slower course of HIV-2 infection. These data have implications for the design of antiretroviral therapy-complementary immune-based strategies.

Monocyte and Myeloid Dendritic Cell Activation Occurs Throughout HIV Type 2 Infection, an Attenuated Form of HIV Disease

Monocytes and myeloid dendritic cells (mDCs) are important orchestrators of innate and human immunodeficiency virus (HIV)-specific immune responses and of the generalized inflammation that characterizes AIDS progression. To our knowledge, we are the first to investigate monocyte and mDC imbalances in HIV type 2 (HIV-2)-positive patients, who typically feature reduced viremia and slow disease progression despite the recognized ability of HIV-2 to establish viral reservoirs and overcome host restriction factors in myeloid cells. We found a heightened state of monocyte and mDC activation throughout HIV-2 infection (characterized by CD14(bright)CD16(+) expansion, as well as increased levels of soluble CD14, HLA-DR, and CD86), together with progressive mDC depletion. Importantly, HIV-2-positive patients also featured overexpression of the inhibitory molecule PD-L1 on monocytes and mDCs, which may act by limiting the production of proinflammatory molecules. These data, from patients with a naturally occurring form of attenuated HIV disease, challenge current paradigms regarding the role of monocytes in HIV/AIDS and open new perspectives regarding potential strategies to modulate inflammatory states.

Tuberculosis with malaria or HIV co-infection in a large hospital in Luanda, Angola

INTRODUCTIONnThree major public health problems, tuberculosis, malaria and HIV/AIDS, are widespread in Angola, often as co-infections in the same individual. In 2009, it was assumed that 44,151 new cases of TB occurred in Angola. Interestingly, interventions such as treatment/prevention of malaria appear to reduce mortality in HIV-infected and possibly TB co-infected patients. However, despite the seriousness of the situation, current data on TB and co-infection rates are scarce. This study aimed to characterize all TB cases seen at the Hospital Sanatório de Luanda, and to determine the co-infection rate with HIV and/or malaria.nnnMETHODOLOGYnThis retrospective study collected demographic, diagnostic and clinical data from all patients admitted during 2007.nnnRESULTSnA total of 4,666 patients were admitted, of whom 1,906 (40.8%) were diagnosed with TB. Overall, 1,111 patients (58.3%) were male and most patients (n=1302, 68.3%) were adults (≥ 14 years). The rate of HIV co-infection was 37.4% (n=712). Malaria was diagnosed during admission and hospital stay in 714 patients (37.5%), with Plasmodium falciparum the predominant species. Overall mortality was 15.2% (n=290).nnnCONCLUSIONSnBecause Luanda does not have the infrastructure to perform culture-based diagnosis of TB, confirmation of TB is problematic. The HIV-co-infection rate is high, with 37.4% of patients requiring integrated approaches to address this problem. With more than 1/3 of the TB patients co-infected with malaria, even during the hospital stay, the prevention of malaria in TB patients appears to be an effective way to reduce overall mortality.

Mutations selected in HIV-2-infected patients failing a regimen including atazanavir

OBJECTIVESnTo investigate mutations selected in viruses from HIV-2-infected patients failing a highly active antiretroviral treatment (HAART) regimen including atazanavir/ritonavir.nnnMETHODSnTwenty-eight HIV-2-infected patients previously exposed to atazanavir/ritonavir and failing therapy were studied. The protease (PR) gene was amplified and sequenced, and mutations emerging under atazanavir/ritonavir selective pressure were reported.nnnRESULTSnThe I50L mutation emerged in 4 out of 28 HIV-2-infected patients failing a HAART regimen including atazanavir/ritonavir. Besides I50L, four PR mutations previously associated with protease inhibitor resistance (I54L, I64V, V71I and I82F) and six PR mutations of unknown impact (V10I, E37D, S43T, K45R, I75V and F85L) in HIV-2 were also identified in this small group of patients.nnnCONCLUSIONSnSeveral mutations were associated with virological failure of a regimen including atazanavir/ritonavir in HIV-2-infected patients, including I50L for the first time. It should be included in HIV-2 algorithms for interpretation of genotypic resistance data, and taken into account when making therapeutic decisions for HIV-2-infected patients.

Poor Accuracy of Rapid Diagnostic Tests and Misdiagnosis of Imported Malaria: Are PCR-Based Reference Laboratories the Answer?

The recent article by Rubio et al. reports poor accuracy of rapid malaria diagnostic tests (RDTs) and promotes PCR-based reference laboratories to avoid potential misdiagnosis ([6][1]). Both points deserve comment.nnThe authors reported low sensitivity is mainly due to poor detection of Plasmodium

Acute Q fever in Portugal. Epidemiological and clinical features of 32 hospitalized patients.

INTRODUCTIONnQ fever is a worldwide zoonosis caused by Coxiella burnetii. The main characteristic of acute Q fever is its clinical polymorphism, usually presenting as a febrile illness with varying degrees of hepatitis and/or pneumonia. Q fever is endemic in Portugal, and it is an obligatory notifiable disease since 1999. However, its epidemiological and clinical characteristics are still incompletely described.nnnMETHODSnWe performed a retrospective study of 32 cases admitted in the Infectious Diseases Department, Santa Marias University Hospital, from January 2001 to December 2010, in whom acute Q fever was diagnosed by the presence of antibodies to phase II Coxiella burnetii antigens associated with a compatible clinical syndrome.nnnRESULTSnOut of the 32 cases recorded, 29 (91%) were male, with a male:female ratio of 9.7:1. Individuals at productive age were mainly affected (88%, n=28, with ages between 25 and 64 years). Clinically, the most common manifestation of acute Q fever was hepatic involvement (84%, n=27), which occurred isolated in 53% (n=17) of the cases. Hepatitis was more severe, presenting with higher values of liver function tests, in patients presenting both pulmonary and hepatic involvement. Additionally, we report one case of myocarditis and another one with neurological involvement. Empiric but appropriate antibiotic therapy was given in 66% (n=21) of the cases. There was a complete recovery in 94% (n=30) of the patients, and one death. We confirmed the sub-notification of this disease in Portugal, with only 47% (n=15) of the cases notified.nnnCONCLUSIONnIn Portugal further studies are needed to confirm our results. From the 32 cases studied, acute Q fever presented more frequently as a febrile disease with hepatic involvement affecting mainly young male individuals. Furthermore, acute Q fever is clearly underdiagnosed and underreported in Portugal, which suggests that an increased awareness of the disease is needed, together with a broader use of serological testing.

The demise of multidrug-resistant HIV-1: the national time trend in Portugal

Objectives Despite a decreasing mortality and morbidity in treated HIV-1 patients, highly active antiretroviral treatment (HAART) can still fail due to the development of drug resistance. Especially, multidrug-resistant viruses pose a threat to efficient therapy. We studied the changing prevalence of multidrug resistance (MDR) over time in a cohort of HIV-1-infected patients in Portugal. Patients and methods We used data of 8065 HIV-1-infected patients followed from July 2001 up to April 2012 in 22 hospitals located in Portugal. MDR at a specific date of sampling was defined as no more than one fully active drug (excluding integrase and entry inhibitors) at that time authorized by the Portuguese National Authority of Medicines and Health Products (INFARMED), as interpreted with the Rega algorithm version 8.0.2. A generalized linear mixed model was used to study the time trend of the prevalence of MDR. Results We observed a statistically significant decrease in the prevalence of MDR over the last decade, from 6.9% (95% CI: 5.7–8.4) in 2001–03, 6.0% (95% CI: 4.9–7.2) in 2003–05, 3.7% (95% CI: 2.8–4.8) in 2005–07 and 1.6% (95% CI: 1.1–2.2) in 2007–09 down to 0.6% (95% CI: 0.3–0.9) in 2009–12 [ORu200a=u200a0.80 (95% CI: 0.75–0.86); Pu200a<u200a0.001]. In July 2011 the last new case of MDR was seen. Conclusions The prevalence of multidrug-resistant HIV-1 is decreasing over time in Portugal, reflecting the increasing efficiency of HAART and the availability of new drugs. Therefore, in designing a new drug, safety and practical aspects, e.g. less toxicity and ease of use, may need more attention than focusing mainly on efficacy against resistant strains.

Hypovitaminosis D in HIV-infected patients in Lisbon: a link with antiretroviral treatment.

Recent data indicates that low vitamin D (25(OH)D) levels can lead to a worst prognosis in HIV‐infected individuals, even in those on successful antiretroviral therapy (ART) [1]. Portugal is the European country that has the largest average sun exposure time but prevalence of hypovitaminosis D is mostly unknown. Our aim was to determine the prevalence of hypovitaminosis D in HIV patients in Lisbon and the possible association with ART.