Prevalence of obesity and disturbances in glucose homeostasis in HIV-infected subjects and general population - missed diagnoses of diabetes?

OBJECTIVES: Comparative data on glucose disorders using fasting blood samples between people living with HIV (PLWH) and the general population are lacking. The objective of this study was to compare the prevalence and risk factors of obesity and disturbances in glucose homeostasis between PLWH treated with modern antiretroviral therapy and the general population. METHODS: Adjusted prevalence of obesity, features of insulin resistance (triglyceride:high-density lipoprotein cholesterol ratio and alanine aminotransferase), impaired fasting glucose (IFG), diabetes mellitus (DM) and combined dysglycaemia (presence of IFG or DM) were determined using fasting blood samples among 1041 PLWH and 7047 subjects representing the general population. RESULTS: People living with HIV had a lower prevalence of obesity [18.2%, 95% confidence interval (CI): 15.1-21.2 vs. 23.9%, 95% CI: 22.4-25.4], but a higher prevalence of insulin resistance and IFG (20.0%, 95% CI: 16.6-23.4 vs. 9.8%, 95% CI: 8.7-10.8) than the general population. Fasting glucose concentration was higher, but glycated haemoglobin (HbA1c) was lower, among PLWH. Prevalence of dysglycaemia for a given body mass index (BMI) was higher in PLWH than in the general population. The prevalence of DM did not differ between PLWH (13.2%, 95% CI: 10.2-15.9) and the general population (14.5%, 95% CI: 13.6-15.4). CONCLUSIONS: The prevalence of obesity was lower, but the risk of dysglycaemia for a given BMI was significantly higher, among PLWH, highlighting the importance of prevention and treatment of obesity among HIV-infected subjects. Regardless of the increased prevalence of insulin resistance and IFG, DM was surprisingly not more common among PLWH, raising concern about the under-diagnosis of DM, possibly due to low sensitivity of HbA1c in this patient population.

Primary resistance to integrase strand-transfer inhibitors in Europe.

OBJECTIVES: The objective of this study was to define the natural genotypic variation of the HIV-1 integrase gene across Europe for epidemiological surveillance of integrase strand-transfer inhibitor (InSTI) resistance. METHODS: This was a multicentre, cross-sectional study within the European SPREAD HIV resistance surveillance programme. A representative set of 300 samples was selected from 1950 naive HIV-positive subjects newly diagnosed in 2006-07. The prevalence of InSTI resistance was evaluated using quality-controlled baseline population sequencing of integrase. Signature raltegravir, elvitegravir and dolutegravir resistance mutations were defined according to the IAS-USA 2014 list. In addition, all integrase substitutions relative to HXB2 were identified, including those with a Stanford HIVdb score ≥ 10 to at least one InSTI. To rule out circulation of minority InSTI-resistant HIV, 65 samples were selected for 454 integrase sequencing. RESULTS: For the population sequencing analysis, 278 samples were retrieved and successfully analysed. No signature resistance mutations to any of the InSTIs were detected. Eleven (4%) subjects had mutations at resistance-associated positions with an HIVdb score ≥ 10. Of the 56 samples successfully analysed with 454 sequencing, no InSTI signature mutations were detected, whereas integrase substitutions with an HIVdb score ≥ 10 were found in 8 (14.3%) individuals. CONCLUSIONS: No signature InSTI-resistant variants were circulating in Europe before the introduction of InSTIs. However, polymorphisms contributing to InSTI resistance were not rare. As InSTI use becomes more widespread, continuous surveillance of primary InSTI resistance is warranted. These data will be key to modelling the kinetics of InSTI resistance transmission in Europe in the coming years.

Analysis of HIV-1 genetic subtypes in Finland reveals good correlation between molecular and epidemiological data.

The molecular epidemiology of HIV-1 genetic subtypes was studied in a cross-sectional sample collected from HIV-infected individuals living in Finland between 1988 and 1994 and compared with independently collected epidemiological data. Subtypes were determined by sequencing and phylogenetic analysis of the gag NCp7 and the env coding regions of PBMC provirus. Finnish viruses belonging to 7 subtypes were found. Two thirds (n = 70) of the sequences could be classified as subtype B, while others belonged to subtypes A, C, D, F and G and the circulating recombinant form AE(CM240) (n = 25). There were significant differences in gender distribution and mode-of-transmission between B-type infections and infections with the other subtypes. Most subtype B strains in Finland were associated with homosexual transmission and about half of these were acquired in Finland, while most individuals harbouring non-B infections indicated heterosexual transmission and direct or indirect contact with Africa or Southeast Asia. The heterogeneity of genetic subtypes in the country was in good agreement with the epidemiological data suggesting that a significant proportion of infections were imported. HIV-1 subtype determination may prove to be a valuable tool for providing objective epidemiological data.

An AB recombinant and its parental HIV type 1 strains in the area of the former Soviet Union: low requirements for sequence identity in recombination. UNAIDS Virus Isolation Network.

In the former Soviet Union (SU) increasing numbers of HIV-1 infections among injecting drug users (IDU) have been reported, especially in the Ukraine. The main subtype transmitted among the IDUs seems to be subtype A, but limited numbers of subtype B cases have also been reported. In Kaliningrad, Russia, an AB recombinant strain was earlier shown to be responsible for the local outbreak. Here we describe the genetic relationship of HIV-1 strains circulating among IDUs in the former SU. For subtype A and the AB recombinant strains nearly full-length genomes were sequenced, and for one subtype B strain the entire envelope gene was cloned. The relationship between the AB recombinant strain and the subtype A and subtype B strains and the mosaic structure of the recombinant was studied by phylogenetic analysis. Ukrainian A and B strains were shown to be the probable parental viruses of the Kaliningrad AB recombinant strain. In the envelope gene the recombination breakpoint could also be precisely mapped to a region of similarity of only 14 base pairs. This suggests that only short stretches of absolute sequence identity may be needed for efficient RNA recombination between HIV-1 subtypes.

Virtually full-length subtype F and F/D recombinant HIV-1 from Africa and South America.

For reliable classification of HIV-1 strains appropriate reference sequences are needed. The HIV-1 genetic subtype F has a wide geographic spread, causing significant epidemics in South America, Africa, and some regions of Europe. Previously only two full-length sequences of each of the HIV-1 subtype F subclusters F1 and F2 have been described. To extend the knowledge of subtype F variation on a complete genome level, three new virtually full-length F1 sequences were cloned and sequenced, two from Africa and one from South America. Comparison of the new and previously described sequences showed that monophyletic clustering of the subcluster F1 of subtype F is consistent and highly supported in all genome regions. Two additional full-length strains were shown to be mosaics of subtypes F and D. These epidemiologically unrelated F/D sequences showed similar chimeric structure, suggesting that they may represent a previously undescribed circulating recombinant form (CRF). This was supported by partial sequences from three additional unlinked F/D recombinants. Genetic distances in the phylogenetic trees suggest that the recombination event leading to the putative CRF occurred relatively long ago, close to the divergence of the F1 and F2 subclusters. Furthermore, all five F/D recombinants are linked to the Democratic Republic of Congo, suggesting that the original recombination event took place in central Africa.

[A recombinant HIV-1 strain causing an epidemic among injection drug addicts in Kaliningrad]. / Rekombinantnyi shtamm VICh-1, vyzvavshii épidemiiu sredi in''ektsionnykh narkomanov v Kaliningrade.

The analysis of the genetic structure of HIV causing the epidemic in Kaliningrad Province. A new recombinant virus of subtype A/B was detected with the use of the polymerase chain reaction, the cloning of amplified fragments, sequencing and the phylogenetic analysis of the obtained data. The results thus obtained indicate that the epidemic in Kaliningrad was caused by a recombinant strain, and not due to co-infection caused by two HIV strains of different subtypes. The study of HIV-1 DNA revealed the divergence between the samples was extremely low, which was characteristic of epidemics connected with the transmission of the virus in the process of the intravenous use of narcotic drugs.

HIV-1 genetic subtype A/B recombinant strain causing an explosive epidemic in injecting drug users in Kaliningrad.

OBJECTIVES: To investigate the molecular epidemiology and genetic structure of the virus strain(s) causing an outbreak of HIV-1 infection in the Kaliningrad province of the Russian Federation and to investigate the relationship of this outbreak to some other emerging HIV-1 epidemics in the countries of the former Soviet Union. DESIGN: A molecular epidemiological investigation was conducted in the city of Kaliningrad amongst individuals recently diagnosed as HIV-1-positive. Samples were also collected from neighbouring Lithuania and from the Ukraine. METHODS: Incident and population data was collected from official health statistics in Kaliningrad. A standardized questionnaire was administered to newly diagnosed individuals to assess risk factors for HIV-1 infection. For genotyping, two regions of the virus (env C2-V3 and gag NCp7) were directly sequenced. RESULTS: The number of newly diagnosed individuals testing seropositive for HIV-1 infection in Kaliningrad rose from less than one per month to more than 100 per month during the period of July-October 1996. A total of 1335 new infections were identified between 1 July 1996 and 30 June 1997. The main reported risk factor for HIV-1 infection (80%) was injecting drug use, in particular with a locally produced opiate. Sequence analysis of patient viruses in Kaliningrad (n = 50) showed that the epidemic was caused by a highly homogenous HIV-1 strain, recombinant between the genetic subtypes A and B. Comparison with subtype A strains prevalent amongst injecting drug users (IDU) in the Ukraine showed that one of these strains was the direct subtype A parent of the epidemic A/B recombinant strain in Kaliningrad. CONCLUSIONS: The HIV-1 epidemic in Kaliningrad probably started from a single source, with rapid spread of the virus through the IDU population. The origin of the epidemic strain is a recombination event occurring between the subtype A strain virus prevalent among IDU in some southern CIS countries, and a subtype B strain of unknown origin.

Contribution of the CCR5 and MBL genes to susceptibility to HIV type 1 infection in the Finnish population.

Homozygosity for a variant of a chemokine receptor gene (CCR5) has been shown to protect from HIV-1 infection. Variants of the mannose-binding lectin (MBL) gene have been suggested to predispose to HIV-1 infection. These genetic variants and their possible role in susceptibility to HIV-1 infection were studied in sample material from more than 300 Finnish HIV-infected and control individuals. The genotyping was carried out efficiently using a novel, primer extension assay in a miniaturized oligonucleotide array format. Homozygotes for the protective deletion allele of the CCR5 gene were found only in the control group, and the frequency of the allele was high in the Finnish population. Homozygosity for the MBL variant alleles was enriched significantly in the HIV-1-infected group, thus providing further evidence for the harmfulness of MBL variant homozygosity in HIV-1 transmission.

[The identification of the genetic subtypes of HIV-1 circulating on the territory of Russia]. / Identifikatsiia geneticheskikh subtipov VICh-1, tsirkuliruiushchikh na territorii Rossii.

In this work the results of the genotyping of HIV strains obtained from 12 patients residing in Russia are presented. Proviral DNA from lysates of mononuclear cells was amplified with the use of primers, complementary to the conservative site of gene gag p7/p9 with the subsequent sequencing of the amplified material and phylogenetic analysis. 9 strains were classified with subtype B (most frequently occurring in Western countries), 2 of them being found closely related (probably, of African origin). In 2 patients infected from the same source the virus of unusual subtype F/1 was identified. This is the second case of the detection of this subtype in the world. One strain belonged to subtype G. in spite of the fact that in accordance with the epidemiological history only 3 patients got infection outside Russia, molecular epidemiological studies showed the genetic heterogeneity of the circulating strains and suggested the diversity of sources of the penetration of HIV infection to Russia.

HIV-1 D subtype viruses in Finland.

BACKGROUND: Human immunodeficiency virus (HIV)-1 strains are divided into seven genetic subtypes based on their gag sequences (A, B, C, D, F, G and H). Strains that have appeared in Finland show unusual heterogeneity compared to most industrialized countries, up to 25% of the strains belong to non-B subtypes (Liitsola et al., 1996). Three D subtype viruses have so far been identified in Finland. All patients were men, one Kenyan immigrant and two Finnish men, who had been infected in Africa. Here we describe some of the characteristics of the genomic diversity of these strains. METHOD: The genotype was determined by direct solid-phase sequencing of the p7 gag region. Phylogenetic analysis was done using standard methods. RESULTS: The analysis showed that the D subtype sequences clustered clearly distinctly from the other non-B strains, but did not suggest any transmission links between the three cases. From one case both cerebrospinal fluid (CSF) and blood leukocyte virus isolates were studied. The analysis revealed significant differences between the blood and CSF viruses. A four amino acid duplication and other differences were observed between the strains. CONCLUSION: The results confirm that D subtype viruses do indeed occur in Finland and they represent quite heterogenic strains within the D cluster.

Genetic characterization of HIV-1 strains in the Baltic countries and Russia.

Proviral nucleotide sequences from the p7 region of the gag gene were compared among 40 Baltic and Russian HIV-1 strains. 33 of the infected persons carried a virus belonging to subtype B. Thus subtype B, which is most prevalent in Western Europe, was the most common subtype in all 3 Baltic countries (Estonia, Latvia and Lithuania) and Russia, and was associated with homosexual transmission. It also seemed that viruses of the same origin have been circulating in these countries; most of the subtype B viruses studied (n = 22) belonged to a closely related virus pool with average inter-nucleotide sequence distances of 2.7%. In 7 cases, viruses of non-B subtypes were found (1 subtype D from Estonia, 1 subtype C from Latvia, 1 subtype A from Lithuania and 1 subtype G from Russia). Three closely related viruses (1 from Lithuania and 2 from Russia) remained unclassified.

Molecular epidemiology of HIV-1 based on phylogenetic analysis of in vivo gag p7/p9 direct sequences.

Viruses of different geographical origin are circulating in Finland. We wanted to test whether phylogenetic analysis of patient lymphocyte proviral quasispecies sequences could be used to group different strains into genetic lineages. The gag p7/p9 coding region was analyzed using solid-phase direct sequencing from 30 patients in Finland and Estonia. Proviral sequences were found to represent at least four, possibly even five, different, highly diverged major lineages. Different methods of phylogenetic analysis resulted in the same conclusion. Serial samples from the same patients, taken over a period of several years showed limited variation over time. Cases of potential patient-to-patient transmission or common source of infection were identified based on the sequence analysis. Compared to similar analyses of longer genome segments, the gag p7/p9 nucleic acid binding protein coding region produces analogous results in phylogenetic analysis. The method can be used as a rapid way of determining the genetic subtype of HIV-1 strains circulating in populations.