HIV-1 transmission between MSM and heterosexuals, and increasing proportions of circulating recombinant forms in the Nordic Countries.

Increased knowledge about HIV-1 transmission dynamics in different transmission groups and geographical regions is fundamental for assessing and designing prevention efforts against HIV-1 spread. Since the first reported cases of HIV infection during the early 1980s, the HIV-1 epidemic in the Nordic countries has been dominated by HIV-1 subtype B and MSM transmission. HIV-1 pol sequences and clinical data of 51 per cent of all newly diagnosed HIV-1 infections in Sweden, Denmark, and Finland in the period 2000-2012 (N = 3,802) were analysed together with a large reference sequence dataset (N = 4,537) by trend analysis and phylogenetics. Analysis of the eight dominating subtypes and CRFs in the Nordic countries (A, B, C, D, G, CRF01_AE, CRF02_AG, and CRF06_cpx) showed that the subtype B proportion decreased while the CRF proportion increased over the study period. A majority (57 per cent) of the Nordic sequences formed transmission clusters, with evidence of mixing both geographically and between transmission groups. Detailed analyses showed multiple occasions of transmissions from MSM to heterosexuals and that active transmission clusters more often involved single than multiple Nordic countries. The strongest geographical link was between Denmark and Sweden. Finally, Denmark had a larger proportion of heterosexual domestic spread of HIV-1 subtype B (75 per cent) compared with Sweden (49 per cent) and Finland (57 per cent). We describe different HIV-1 transmission patterns between countries and transmission groups in a large geographical region. Our results may have implications for public health interventions in targeting HIV-1 transmission networks and identifying where to introduce such interventions.

Drug resistance in HIV patients with virological failure or slow virological response to antiretroviral therapy in Ethiopia.

BACKGROUND: The ongoing scale-up of antiretroviral therapy (ART) in sub-Saharan Africa has prompted the interest in surveillance of transmitted and acquired HIV drug resistance. Resistance data on virological failure and mutations in HIV infected populations initiating treatment in sub-Saharan Africa is sparse. METHODS: HIV viral load (VL) and resistance mutations pre-ART and after 6 months were determined in a prospective cohort study of ART-naïve HIV patients initiating first-line therapy in Jimma, Ethiopia. VL measurements were done at baseline and after 3 and 6 months. Genotypic HIV drug resistance (HIVDR) was performed on patients exhibiting virological failure (>1000 copies/mL at 6 months) or slow virological response (>5000 copies/mL at 3 months and <1000 copies/mL at 6 months). RESULTS: Two hundred sixty five patients had VL data available at baseline and at 6 months. Virological failure was observed among 14 (5.3%) participants out of 265 patients. Twelve samples were genotyped and six had HIV drug resistance (HIVDR) mutations at baseline. Among virological failures, 9/11 (81.8%) harbored one or more HIVDR mutations at 6 months. The most frequent mutations were K103N and M184VI. CONCLUSIONS: Our data confirm that the currently recommended first-line ART regimen is efficient in the vast majority of individuals initiating therapy in Jimma, Ethiopia eight years after the introduction of ART. However, the documented occurrence of transmitted resistance and accumulation of acquired HIVDR mutations among failing patients justify increased vigilance by improving the availability and systematic use of VL testing to monitor ART response, and underlines the need for rapid, inexpensive tests to identify the most common drug resistance mutations.

The origin and emergence of an HIV-1 epidemic: from introduction to endemicity.

OBJECTIVES: To describe, at patient-level detail, the determining events and factors involved in the development of a country's HIV-1 epidemic. DESIGN: Clinical information for all recorded Greenlandic HIV-1 patients was analysed and correlated with both novel and previously analysed pol sequences, representing more than half of the entire Greenlandic HIV-1 epidemic. Archival blood samples were sequenced to link early infection chain descriptions to the subsequent epidemic. METHODS: In-depth phylogenetic analyses were used in synergy with clinical information to assess number of introductions of HIV-1 into Greenland, the source of geographic origin, time of epidemic introduction and its epidemiological characteristics such as initial transmission chain, geographic dispersal within Greenland, method of infection, cluster size, sociological and behavioural factors. RESULTS: Despite its small population size and isolated geographic location, data support at least 25 introductions of HIV-1 into Greenland. Only a single of these led to an epidemic. This introduction occurred between 1985 and 1986, and the epidemic cluster is still active. Facilitating factors for the emergence and spread of the epidemic cluster include a rapid transition from MSM to heterosexual spread, high prevalence of other sexually transmitted diseases, rapid dispersal to larger cities and early emergence in a distinct subpopulation with high-risk behaviour including disregard for condomizing. CONCLUSIONS: The synergistic use of disparate data categories yields such unique detail, that the Greenland epidemic now serves as a model example for the epidemic emergence of HIV-1 in a society. This renders it suitable for testing of present and future sequence-based epidemiological methodologies.

Phylogenetics of the Danish HIV epidemic: the role of very late presenters in sustaining the epidemic.

BACKGROUND: In Denmark, 300 new individuals are diagnosed with HIV every year, despite decades of public health campaigns aimed to raise awareness of potential risk behavior for HIV transmission. It is important to identify the driving forces of the epidemic, to enable more targeted campaigns. The role of very late presenters (VLPs, defined by a CD4 T-cell count of <200 cells/µL at the time of diagnosis) in driving the epidemic is currently not known and was investigated in this study. METHODS: We performed phylogenetic analysis to identify potential transmission clusters. One thousand five hundred fifteen partial polymerase sequences from 1515 newly diagnosed individuals in Denmark for whom clinical and epidemiological data existed were included in the study. RESULTS: We identified 46 epidemic clusters, including a total of 502 patients. Median cluster size was 7 patients (range, 4-82). Of the 460 VLPs, 20% were included in a cluster. Through multivariate analysis, it was found that the clusters mainly consisted of Danish individuals with homosexual and intravenous drug use risk behavior, infected in Denmark with subtype B. Large clusters contained significantly more homosexual transmission events, characterized by primary infections, younger age, higher CD4 cell count, and lower viral load compared with the small clusters that contained mostly heterosexual transmission events and VLP. CONCLUSION: Danish HIV epidemic is driven mainly by younger homosexual men diagnosed during primary HIV infection. VLPs appear more frequently in smaller clusters or as single branches in the phylogeny. The VLP contribution is not of significant importance from a transmission standpoint.

Molecular phylogenetics of transmitted drug resistance in newly diagnosed HIV Type 1 individuals in Denmark: a nation-wide study.

Highly active antiretroviral treatment is compromised by viral resistance mutations. Transmitted drug resistance (TDR) is therefore monitored closely, but follow-up studies of these patients are limited. Virus from 1405 individuals diagnosed with HIV-1 in Denmark between 2001 and 2009 was analyzed for TDR, and molecular-epidemiological links and progression of the infection were described based on data from standardized questionnaires, the prospective Danish HIV Cohort Study, and by phylogenetic analysis. Eighty-five individuals were found to be infected with virus harboring mutations resulting in a prevalence of 6.1%, with no changes over time. The main resistance mutations were nucleoside reverse transcriptase inhibitor (NRTI) mutation 215 revertants, as well as nonnucleoside reverse transcriptase inhibitor (NNRTI) mutation 103N/S and protease inhibitor (PI) mutations 90M and 85V. Phylogenetic analysis confirmed 12 transmission chains involving 37 TDR individuals. Of these 21 were also documented epidemiologically. The virus included in the transmission chain carried similar resistance mutations to the TDR index case, whereas controls chains from index cases without TDR were generally without resistance mutations. We observed no difference in progression of the infection between individuals infected with TDR and individuals infected with wild-type HIV-1. The prevalence of TDR is low in Denmark and transmission of dual-drug-resistant HIV-1 is infrequent. The TDR isolates were shown to originate from local patients failing therapy.

Clinical, virological and immunological responses in Danish HIV patients receiving raltegravir as part of a salvage regimen.

BACKGROUND: Raltegravir is the first integrase inhibitor approved for treatment of HIV-infected patients harboring multiresistant viruses. METHODS: From a Danish population-based nationwide cohort of HIV patients we identified the individuals who initiated a salvage regimen including raltegravir and a matched cohort of HIV-infected patients initiating HAART for the first time. We compared these two cohorts for virological suppression, gain in CD4 count, and time to first change of initial regimen. RESULTS: We identified 32 raltegravir patients and 64 HIV patients who initiated HAART for the first time in the period 1 January 2006 to 1 July 2009. The virological and immunological responses in the raltegravir patients were comparable to those seen in the control cohort. No patients in the two cohorts died and no patients terminated raltegravir treatment in the observation period. Time to first change of initial regimen was considerably shorter for HAART-naïve patients. CONCLUSION: We conclude that salvage regimens including raltegravir have high effectiveness in the everyday clinical setting. The effectiveness of the regimens is comparable to that observed for patients initiating HAART for the first time. The risk of change in the salvage regimens after initiation of raltegravir is low.

The incidence rate of HIV type-1 drug resistance in patients on antiretroviral therapy: a nationwide population-based Danish cohort study 1999-2005.

BACKGROUND: Newer antiretroviral treatment regimens for HIV carry a lower risk of inducing drug resistance mutations. We estimated changes in incidence rates (IRs) of new mutations in HIV-infected individuals receiving highly active antiretroviral therapy (HAART). METHODS: Population-based data were obtained from the Danish HIV Cohort Study and the Danish HIV Sequence Database. We included treatment-naive patients initiating HAART after December 1997 and computed time to first drug resistance mutation, identified as new mutations detected within 1 year after a 60-day period of treatment failure (HIV RNA>1,000 copies/ml). We estimated annual IRs of new resistance mutations towards nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs) and protease inhibitors (PI), and of new specific resistance mutations. RESULTS: A total of 1,829 individuals were observed for 7,294 person-years at risk (PYR). The IR of NRTI resistance decreased from 13.1 per 1,000 PYR (95% confidence interval [CI] 4.9-35.0) in 1999 to 3.7 (1.9-7.2) in 2004-2005 (test for trend P=0.024). The IR of NNRTI resistance decreased from 15.4 (2.2-109.6) in 1999 to 7.9 (4.6-13.6) in 2004-2005 (P=0.077). The IR of PI resistance decreased from 7.5 (1.4-21.8) in 1999 to 2.9 (0.7-11.4) in 2002-2003 (P=0.148). The IRs were low for specific resistance mutations, except for M184V (IR 5.6 [4.0-7.9]) and K103N (IR 8.2 [5.6-12.0]). CONCLUSIONS: The incidence of acquired drug resistance has decreased among HIV-infected patients treated with HAART in Denmark during 1999-2005.

Follow-up of a multi-drug resistant HIV-1 infected patient successfully treated with darunavir and etravirine.

A multi-drug-resistant, non-compliant HIV-1 patient was treated successfully with a combination of the drugs darunavir and etravirine for more than 8 months. The patient experienced an immunoreconstitution syndrome due to improved compliance. Examining previous resistance tests for this type of patient is valuable when assigning new medication.