Inge Derdelinckx

Tracing the HIV-1 subtype B mobility in Europe: a phylogeographic approach

BackgroundThe prevalence and the origin of HIV-1 subtype B, the most prevalent circulating clade among the long-term residents in Europe, have been studied extensively. However the spatial diffusion of the epidemic from the perspective of the virus has not previously been traced.ResultsIn the current study we inferred the migration history of HIV-1 subtype B by way of a phylogeography of viral sequences sampled from 16 European countries and Israel. Migration events were inferred from viral phylogenies by character reconstruction using parsimony. With regard to the spatial dispersal of the HIV subtype B sequences across viral phylogenies, in most of the countries in Europe the epidemic was introduced by multiple sources and subsequently spread within local networks. Poland provides an exception where most of the infections were the result of a single point introduction. According to the significant migratory pathways, we show that there are considerable differences across Europe. Specifically, Greece, Portugal, Serbia and Spain, provide sources shedding HIV-1; Austria, Belgium and Luxembourg, on the other hand, are migratory targets, while for Denmark, Germany, Italy, Israel, Norway, the Netherlands, Sweden, Switzerland and the UK we inferred significant bidirectional migration. For Poland no significant migratory pathways were inferred.ConclusionSubtype B phylogeographies provide a new insight about the geographical distribution of viral lineages, as well as the significant pathways of virus dispersal across Europe, suggesting that intervention strategies should also address tourists, travellers and migrants.

Molecular footprint of drug-selective pressure in a human immunodeficiency virus transmission chain.

ABSTRACT Known human immunodeficiency virus (HIV) transmission histories are invaluable models for investigating the evolutionary and transmission dynamics of the virus and to assess the accuracy of phylogenetic reconstructions. Here we have characterized an HIV-1 transmission chain consisting of nine infected patients, almost all of whom were treated with antiviral drugs at later stages of infection. Partial pol and env gp41 regions of the HIV genome were directly sequenced from plasma viral RNA for at least one sample from each patient. Phylogenetic analyses in pol using likelihood methods inferred an evolutionary history not fully compatible with the known transmission history. This could be attributed to parallel evolution of drug resistance mutations resulting in the incorrect clustering of multidrug-resistant virus. On the other hand, a fully compatible phylogenetic tree was reconstructed from the env sequences. We were able to identify and quantify the molecular footprint of drug-selective pressure in pol using maximum likelihood inference under different codon substitution models. An increased fixation rate of mutations in the HIV population of the multidrug-resistant patient was demonstrated using molecular clock modeling. We show that molecular evolutionary analyses, guided by a known transmission history, can reveal the presence of confounding factors like natural selection and caution should be taken when accurate descriptions of HIV evolution are required.

Rising prevalence of HIV-1 non-B subtypes in Belgium: 1983-2001.

This study documented the HIV-1 subtype distribution in 2 Belgian hospitals and determined predictive demographics for non-B subtypes. Overall, subtype B was the most prevalent subtype in this population, followed by subtypes A and C. Several recombinants were detected, circulating recombinants as well as new ones. We found a rise in non-B subtypes from 0% in 1983 to 57% in 2001. The Cochran-Armitage trend test (P < 0.001) as well as the correlation analysis (R = 0.71, P = 0.0006) was highly significant. Recombinants were also increasing in this patient population from 0% in 1983 to 10% in 2001, with good support from the statistical analyses (trend test P < 0.001; correlation analysis R = 0.67, P = 0.0016). Heterosexual route of infection, black African race, African origin of the virus, and year of diagnosis were predictors for infection with non-B subtypes in multivariate analysis. This analysis indicates that the prevalence of non-B subtypes and recombinants in this patient population is high and increasing. Gathering demographic and sequence information from newly diagnosed patients could be useful to further follow the spread of non-B subtypes in Belgium and Europe, but subtyping based on sequence information still remains the most reliable method.

Value of Standard Laboratory Tests for the Early Recognition of Group A β-Hemolytic Streptococcal Necrotizing Fasciitis

The laboratory data for 17 patients with group A beta-hemolytic streptococcal necrotizing fasciitis (GAS NF) were compared with data for 145 patients hospitalized for cellulitis during the same period. Admission values of C-reactive protein and creatine kinase were higher for patients in the group with GAS NF than for patients in the group with cellulitis (P<.001), suggesting that standard laboratory tests may be useful for the early differential diagnosis of GAS NF and cellulitis.

Prevalence and epidemiology of HIV type 1 drug resistance among newly diagnosed therapy-naive patients in Belgium from 2003 to 2006.

This study is the first prospective study to assess the prevalence, epidemiology, and risk factors of HIV-1 drug resistance in newly diagnosed HIV-infected patients in Belgium. In January 2003 it was initiated as part of the pan-European SPREAD program, and continued thereafter for four inclusion rounds until December 2006. Epidemiological, clinical, and behavioral data were collected using a standardized questionnaire and genotypic resistance testing was done on a sample taken within 6 months of diagnosis. Two hundred and eighty-five patients were included. The overall prevalence of transmitted HIV-1 drug resistance in Belgium was 9.5% (27/285, 95% CI: 6.6-13.4). Being infected in Belgium, which largely coincided with harboring a subtype B virus, was found to be significantly associated with transmission of drug resistance. The relatively high rate of baseline resistance might jeopardize the success of first line treatment as more than 1 out of 10 (30/285, 10.5%) viruses did not score as fully susceptible to one of the recommended first-line regimens, i.e., zidovudine, lamivudine, and efavirenz. Our results support the implementation of genotypic resistance testing as a standard of care in all treatment-naive patients in Belgium.

Molecular testing of multiple HIV-1 transmissions in a criminal case.

Objective:To test the a priori hypothesis of HIV-1 transmission from one suspect to six recipients in a criminal case. Methods:Partial pol and/or env sequences were obtained for at least two samples of the suspect and the victims. Appropriate local controls were sampled based on epidemiological and subtype criteria. Phylogenetic testing was performed using different reconstruction methods. Results:Phylogenetic analyses consistently inferred a monophyletic cluster for the suspect and victim samples in both genome regions. This was highly supported by parametric and non-parametric bootstrapping techniques. Moreover, the controls most closely related to the suspect–victim cluster had a similar geographical origin to the suspect. Conclusions:Taking into account the limitations on the conclusions that can be drawn from molecular investigations we could infer that our molecular data is consistent with a scenario of multiple HIV transmission between suspect and victims.

Current levels of drug resistance among therapy-naive HIV-infected patients have significant impact on treatment response

Resistant HIV can be transmitted from one patient t o another. 1 Recent large-scale European research found onetenth of viruses from untreated patients showing at least 1 resistance-related mutation. 2 Such investigations are mainly driven by the concern that resistant virus c ould at some point hamper optimal treatment response. However, the impact of baseline drug resistance on treatment response is not well studied. Various gen otypic interpretation methods are used to assess resistanc e in drug-naive patients. When transmitted resistan ce is the topic of interest, irrespective of treatment, prima ry mutations are considered most indicative. Second ary mutations could also be the result of natural varia tion. However, when interpreting resistance in view of the response to the installed treatment, all positions possibly contributing to the selective advantage of the virus in the presence of drug should be taken into account.

Circulating HIV Type 1 Drug Resistance Will Have Limited Impact on the Effectiveness of Preexposure Prophylaxis among Young Women in Zimbabwe

BACKGROUNDnPreexposure prophylaxis (PrEP) with antiretroviral drugs may prevent transmission of human immunodeficiency virus (HIV). Our objective was to predict whether PrEP, in the presence of circulating drug resistance, will reduce the risk of infection with HIV.nnnMETHODSnWe used risk equations to calculate the monthly risk of infection with HIV before and after the introduction of PrEP. Uncertainty and sensitivity analyses were performed for 2 ranges of PrEP effectiveness (40%-60% and 60%-80%). Circulating drug resistance was assumed to reduce the effectiveness of PrEP by 50%-90% and the transmissibility of HIV by 0%-30%. Parameter ranges were chosen for women 17-29 years of age from publications on HIV in Manicaland in Zimbabwe.nnnRESULTSnPrEP would decrease the median risk of HIV transmission by 21%-33% (effectiveness of PrEP, 40%-60% and 60%-80%). If 50% of HIV strains are drug resistant, then the median risk reduction would be 19%-26% if drug-resistant strains were less transmissible than wild-type HIV and 12%-19% if they were equally transmissible. The risk would increase if condoms were frequently replaced with PrEP. Use of PrEP for sexual acts for which no protection is currently used would be beneficial.nnnCONCLUSIONnThe public health impact of PrEP will depend on its effectiveness and on risk behavior. Circulating drug resistance will have only a small impact on the effectiveness of PrEP.

Performance of the VERSANT® HIV-1 Resistance Assays (LiPA) for detecting drug resistance in therapy-naive patients infected with different HIV-1 subtypes

In this study we evaluated the performance of the VERSANT HIV-1 Resistance Assays (LiPA) in detecting drug resistance in therapy-naive HIV-infected patients diagnosed in Belgium in 2000. We compared the results with population sequencing and found concordance to be in line with previous studies in treatment-experienced patients (86.87% for reverse transcriptase (RT); 92.77% for protease (PRO)). Discordance was mainly due to indeterminate reactions on LiPA (8.45% for RT; 6.85% for PRO) and minor discordances (4.13% for RT; 0.25% for PRO). Major discordances were rare (0.46% for RT; 0.12% for PRO). Indeterminate reactions were significantly associated with strains belonging to non-B subtypes.

Clinical presentation, causes and outcome of febrile episodes in a prospective cohort of HIV-infected patients

Abstract Background: Fever was frequently caused by opportunistic conditions in HIV-patients in the early years of the epidemic. Little is known about diagnostic spectrum and outcome of febrile episodes in patients with good access to antiretroviral therapy. Methods: We prospectively studied clinical presentation, diagnosis and outcome of febrile episodes in a contemporary cohort of HIV-patients with good access to antiretroviral therapy. Fever was defined as temperature 38.3u2009°C or higher, measured by a health care provider. Results: We found 220 febrile episodes in 146 patients. In 25.9% of episodes the patient had a CD4 less than 200/mm³ and in 78.6% the patient was on antiretroviral therapy. There were multiple episodes in 44 patients. A diagnosis was established in 91.8%. Infection accounted for 82.3%, mainly respiratory tract infections, viral syndromes and abdominal infections. Malignancy, drug reactions and inflammatory conditions accounted together for less than 12% of episodes. Fifteen percent were attributed to opportunistic conditions. Episodes in patients with CD4 less than 200 were less likely to be caused by infection, but more likely to be caused by malignancy, drug reactions and opportunistic conditions. In 6.4% the patient died within six months after the onset of fever. Risk factors for death at six months in multivariable analysis were higher age and lower CD4. Conclusions: HIV-patients with access to antiretroviral therapy present with fever mostly due to conditions common in the general population. HIV-patients with low CD4 remain at risk for fever due to opportunistic conditions and death.