Regional differences in self-reported HIV care and management in the EuroSIDA study.

INTRODUCTION: EuroSIDA has previously reported a poorer clinical prognosis for HIV-positive individuals in Eastern Europe (EE) as compared with patients from other parts of Europe, not solely explained by differences in patient characteristics. We explored regional variability in self-reported HIV management at individual EuroSIDA clinics, with a goal of identifying opportunities to reduce the apparent inequalities in health. METHODS: A survey (www.chip.dk/eurosida/csurvey) on HIV management was conducted in early 2014 in all currently active EuroSIDA clinics. Responders in EE were compared with clinics in all other EuroSIDA regions combined (non-EE). Characteristics were compared between regions using Fishers exact test. RESULTS: A total of 80/97 clinics responded (82.5%, 12/15 in EE, 68/82 in non-EE). Participating clinics reported seeing a total of 133,532 patients [a median of 1300 per clinic (IQR 700-2399)]. The majority of clinics requested viral load and CD4 measurements at least every six months for patients on as well as off ART (EE 66.7%, non-EE 75%, p=0,72). Significantly fewer EE clinics performed resistance tests before ART as well as upon treatment failure (Figure 1). Half of the EE clinics indicated following WHO guidelines (EE 50%, non-EE 7.4%, p<0.0001), whereas most non-EE clinics followed EACS guidelines (non-EE 76.5%, EE 41.7%, p=0.017). The majority of EE clinics and » non-EE clinics indicated deferral of ART initiation in asymptomatic individuals until CD4 ≤350 cells/mm(3) (Figure 1). There were no significant regional differences in screening haematology, liver or renal function, which the majority of clinics reported to do routinely. However, EE clinics reported screening significantly less for cardiovascular disease (CVD), and only about half screened for tobacco use, alcohol consumption and drug use (Figure 1). Screening for cervical cancer and for anorectal cancer was low in both regions (Figure 1). CONCLUSIONS: We found significant regional variability in self-reported HIV management across Europe, with less resistance testing, screening for CVD and substance use in EE. EE clinics indicated deferral of ART initiation for longer than non-EE clinics. Adherence to international guidelines for cervical cancer screening was poor in both regions. Whether differences in HIV management are reflected in clinical outcomes deserves further investigation.

Short- and long-term mortality and causes of death in HIV/tuberculosis patients in Europe.

Mortality of HIV/tuberculosis (TB) patients in Eastern Europe is high. Little is known about their causes of death. This study aimed to assess and compare mortality rates and cause of death in HIV/TB patients across Eastern Europe and Western Europe and Argentina (WEA) in an international cohort study. Mortality rates and causes of death were analysed by time from TB diagnosis (<3 months, 3-12 months or >12 months) in 1078 consecutive HIV/TB patients. Factors associated with TB-related death were examined in multivariate Poisson regression analysis. 347 patients died during 2625 person-years of follow-up. Mortality in Eastern Europe was three- to ninefold higher than in WEA. TB was the main cause of death in Eastern Europe in 80%, 66% and 61% of patients who died <3 months, 3-12 months or >12 months after TB diagnosis, compared to 50%, 0% and 15% in the same time periods in WEA (p<0.0001). In multivariate analysis, follow-up in WEA (incidence rate ratio (IRR) 0.12, 95% CI 0.04-0.35), standard TB-treatment (IRR 0.45, 95% CI 0.20-0.99) and antiretroviral therapy (IRR 0.32, 95% CI 0.14-0.77) were associated with reduced risk of TB-related death. Persistently higher mortality rates were observed in HIV/TB patients in Eastern Europe, and TB was the dominant cause of death at any time during follow-up. This has important implications for HIV/TB programmes aiming to optimise the management of HIV/TB patients and limit TB-associated mortality in this region.

TB meningitis in HIV-positive patients in Europe and Argentina: clinical outcome and factors associated with mortality.

OBJECTIVES: The study aimed at describing characteristics and outcome of tuberculous meningitis (TBM) in HIV-positive patients and comparing these parameters with those of extrapulmonary TB (TBEP) and pulmonary TB (TBP). METHODS: Kaplan-Meier estimation and Poisson regression models were used to assess the mortality following TB diagnosis and to evaluate potential prognostic factors for the 3 groups of TB patients separately. RESULTS: A total of 100 patients with TBM, 601 with TBEP, and 371 TBP were included. Patients with TBM had lower CD4 cell counts and only 17.0% received antiretroviral therapy (ART) at TB diagnosis. The cumulative probability of death at 12 months following TB was 51.2% for TBM (95% CI 41.4-61.6%), 12.3% for TBP (8.9-15.7%), and 19.4% for TBEP (16.1-22.6) (P<0.0001; log-rank test). For TBM, factors associated with a poorer prognosis were not being on ART (adjusted incidence rate ratio (aIRR) 4.00 (1.72-9.09), a prior AIDS diagnosis (aIRR=4.82 (2.61-8.92)), and receiving care in Eastern Europe (aIRR=5.41 (2.58-11.34))). CONCLUSIONS: TBM among HIV-positive patients was associated with a high mortality rate, especially for patients from Eastern Europe and patients with advanced HIV-infection, which urgently calls for public health interventions to improve both TB and HIV aspects of patient management.

VS411 reduced immune activation and HIV-1 RNA levels in 28 days: randomized proof-of-concept study for antiviral-hyperactivation limiting therapeutics.

BACKGROUND: A new class of antiretrovirals, AntiViral-HyperActivation Limiting Therapeutics (AV-HALTs), has been proposed as a disease-modifying therapy to both reduce Human Immunodeficiency Virus Type 1 (HIV-1) RNA levels and the excessive immune activation now recognized as the major driver of not only the continual loss of CD4(+) T cells and progression to Acquired Immunodeficiency Syndrome (AIDS), but also of the emergence of both AIDS-defining and non-AIDS events that negatively impact upon morbidity and mortality despite successful (ie, fully suppressive) therapy. VS411, the first-in-class AV-HALT, combined low-dose, slow-release didanosine with low-dose hydroxycarbamide to accomplish both objectives with a favorable toxicity profile during short-term administration. Five dose combinations were administered as VS411 to test the AV-HALT Proof-of-Concept in HIV-1-infected subjects. METHODS: Multinational, double-blind, 28-day Phase 2a dose-ranging Proof-of-Concept study of antiviral activity, immunological parameters, safety, and genotypic resistance in 58 evaluable antiretroviral-naïve HIV-1-infected adults. Randomization and allocation to study arms were carried out by a central computer system. Results were analyzed by ANOVA, Kruskal-Wallis, ANCOVA, and two-tailed paired t tests. RESULTS: VS411 was well-tolerated, produced significant reductions of HIV-1 RNA levels, increased CD4(+) T cell counts, and led to significant, rapid, unprecedented reductions of immune activation markers after 28 days despite incomplete viral suppression and without inhibiting HIV-1-specific immune responses. The didanosine 200 mg/HC 900 mg once-daily formulation demonstrated the greatest antiviral efficacy (HIV-1 RNA: -1.47 log(10) copies/mL; CD4(+) T cell count: +135 cells/mm(3)) and fewest adverse events. CONCLUSIONS: VS411 successfully established the Proof-of-Concept that AV-HALTs can combine antiviral efficacy with rapid, potentially beneficial reductions in the excessive immune system activation associated with HIV-1 disease. Rapid reductions in markers of immune system hyperactivation and cellular proliferation were obtained despite the fact that VS411 did not attain maximal suppression of HIV RNA, suggesting this effect was due to the HALT component. TRIAL REGISTRATION: ITEudraCT 2007-002460-98.

The clinical benefits of antiretroviral therapy in severely immunocompromised HIV-1-infected patients with and without complete viral suppression.

BACKGROUND: The aim of this study was to determine whether there is a protective effect of combination antiretroviral therapy (cART) on the development of clinical events in patients with ongoing severe immunosuppression. METHODS: A total of 3,780 patients from the EuroSIDA study under follow-up after 2001 with a current CD4(+) T-cell count ≤200 cells/mm(3) were stratified into five groups: group 1, viral load (VL)<50 copies/ml on cART; group 2, VL 50-99,999 copies/ml on cART; group 3, VL 50-99,999 copies/ml off cART; group 4, VL≥100,000 copies/ml on cART; and group 5, VL≥100,000 copies/ml off cART. Poisson regression was used to identify the risk of (non-fatal or fatal) AIDS- and non-AIDS-related events considered together (AIDS/non-AIDS) or separately as AIDS or non-AIDS events within each group. RESULTS: There were 428 AIDS/non-AIDS events during 3,780 person-years of follow-up. Compared with group 1, those in group 2 had a similar incidence of AIDS/non-AIDS events (incidence rate ratio [IRR] 1.04; 95% CI 0.79-1.36). Groups 3, 4 and 5 had significantly higher incidence rates of AIDS/non-AIDS events compared with group 1; incidence rates increased from group 3 (IRR 1.78; 95% CI 1.25-2.55) to group 5 (IRR 2.36; 95% CI 1.66-3.40), demonstrating the increased incidence of AIDS/non-AIDS events associated with increasing viraemia. After adjustment, the use of cART was associated with a 40% reduction in the incidence of AIDS/non-AIDS events in patients with VL 50-99,999 copies/ml (IRR 0.59; 95% CI 0.41-0.85) and in those with a VL>100,000 copies/ml (IRR 0.66; 95% CI 0.44-1.00). Similar relationships were seen for non-AIDS events and AIDS events when considered separately. CONCLUSIONS: In patients with ongoing severe immunosuppression, cART was associated with significant clinical benefits in patients with suboptimal virological control or virological failure.

Benchmarking HIV health care: from individual patient care to health care evaluation. An example from the EuroSIDA study.

BACKGROUND: State-of-the-art care involving the utilisation of multiple health care interventions is the basis for an optimal long-term clinical prognosis for HIV-patients. We evaluated health care for HIV patients based on four key indicators. METHODS: Four indicators of health care were assessed: Compliance with current guidelines on initiation of: 1) combination antiretroviral therapy (cART); 2) chemoprophylaxis; 3) frequency of laboratory monitoring; and 4) virological response to cART (proportion of patients with HIV-RNA < 500copies/ml for >90% of time on cART). RESULTS: 7097 EuroSIDA patients were included from Northern (n = 923), Southern (n = 1059), West Central (n = 1290) East Central (n = 1366), Eastern (n = 1964) Europe, and Argentina (n = 495). Patients in Eastern Europe with a CD4 < 200cells/mm(3) were less likely to initiate cART and Pneumocystis jiroveci-chemoprophylaxis compared to patients from all other regions, and less frequently had a laboratory assessment of their disease status. The proportion of patients with virological response was highest in Northern, 89% vs. 84%, 78%, 78%, 61%, 55% in West Central, Southern, East Central Europe, Argentina and Eastern Europe, respectively (p < 0.0001). Compared to Northern, patients from other regions had significantly lower odds of virological response; the difference was most pronounced for Eastern Europe and Argentina (adjusted OR 0.16 [95%CI 0.11-0.23, p < 0.0001]; 0.20[0.14-0.28, p < 0.0001] respectively). CONCLUSIONS: This assessment of HIV health care utilization revealed pronounced regional differences in adherence to guidelines and can help to identify gaps and direct target interventions. It may serve as a tool for the assessment and benchmarking of the clinical management of HIV patients in any setting worldwide.

Regional differences in AIDS and non-AIDS related mortality in HIV-positive individuals across Europe and Argentina: the EuroSIDA study.

BACKGROUND: Differences in access to care and treatment have been reported in Eastern Europe, a region with one of the fastest growing HIV epidemics, compared to the rest of Europe. This analysis aimed to establish whether there are regional differences in the mortality rate of HIV-positive individuals across Europe, and Argentina. METHODS: 13,310 individuals under follow-up were included in the analysis. Poisson regression investigated factors associated with the risk of death. FINDINGS: During 82,212 person years of follow-up (PYFU) 1,147 individuals died (mortality rate 14.0 per 1,000 PYFU (95% confidence interval [CI] 13.1-14.8). Significant differences between regions were seen in the rate of all-cause, AIDS and non-AIDS related mortality (global p<0.0001 for all three endpoints). Compared to South Europe, after adjusting for baseline demographics, laboratory measurements and treatment, a higher rate of AIDS related mortality was observed in East Europe (IRR 2.90, 95%CI 1.97-4.28, p<.0001), and a higher rate of non-AIDS related mortality in North Europe (IRR 1.51, 95%CI 1.24-1.82, p<.0001). The differences observed in North Europe decreased over calendar-time, in 2009-2011, the higher rate of non-AIDS related mortality was no longer significantly different to South Europe (IRR 1.07, 95%CI 0.66-1.75, p = 0.77). However, in 2009-2011, there remained a higher rate of AIDS-related mortality (IRR 2.41, 95%CI 1.11-5.25, p = 0.02) in East Europe compared to South Europe in adjusted analysis. INTERPRETATIONS: There are significant differences in the rate of all-cause mortality among HIV-positive individuals across different regions of Europe and Argentina. Individuals in Eastern Europe had an increased risk of mortality from AIDS related causes and individuals in North Europe had the highest rate of non-AIDS related mortality. These findings are important for understanding and reviewing HIV treatment strategies and policies across the European region.

The analysis of near full-length genome sequences of HIV type 1 subtype A viruses from Russia supports the monophyly of major intrasubtype clusters.

The HIV-1 epidemic in Russia has been insufficiently studied, with only 11 complete genome sequences from this country currently available, only three of which are of the locally predominant genetic form, the former Soviet Union (FSU) subtype A variant (A(FSU)). Here we analyze 10 newly derived A(FSU) near full-length genome sequences from Russia. Samples were selected based on phylogenetic clustering in protease-reverse transcriptase in two of the major A(FSU) clusters, V77I(PR) (n=6), widely circulating in Russia and other FSU countries, and A(SP1) (n=4), predominant in St. Petersburg. The phylogenetic analysis shows that the V77I(PR) genomes group in a monophyletic cluster together with 10 previously obtained A(FSU) genome sequences from Uzbekistan, Kazakhstan, Russia, and Cyprus, all bearing the V77I substitution in protease. Similarly, the four A(SP1) genomes group in a monophyletic cluster. These results therefore show that the monophyly of V77I(PR) and A(SP1) A(FSU) clusters is supported in near complete genomes.

Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial.

BACKGROUND: Dolutegravir (S/GSK1349572) is a new HIV-1 integrase inhibitor that has antiviral activity with once daily, unboosted dosing. SPRING-1 is an ongoing study designed to select a dose for phase 3 assessment. We present data from preplanned primary and interim analyses. METHODS: In a phase 2b, multicentre, dose-ranging study, treatment-naive adults were randomly assigned (1:1:1:1) to receive 10 mg, 25 mg, or 50 mg dolutegravir or 600 mg efavirenz. Dose but not drug allocation was masked. Randomisation was by a central integrated voice-response system according to a computer-generated code. Study drugs were given with either tenofovir plus emtricitabine or abacavir plus lamivudine. Our study was done at 34 sites in France, Germany, Italy, Russia, Spain, and the USA beginning on July 9, 2009. Eligible participants were seropositive for HIV-1, aged 18 years or older, and had plasma HIV RNA viral loads of at least 1000 copies per mL and CD4 counts of at least 200 cells per µL. Our primary endpoint was the proportion of participants with viral load of less than 50 copies per mL at week 16 and we present data to week 48. Analyses were done on the basis of allocation group and included all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00951015. FINDINGS: 205 patients were randomly allocated and received at least one dose of study drug: 53, 51, and 51 to receive 10 mg, 25 mg, and 50 mg dolutegravir, respectively, and 50 to receive efavirenz. Week 16 response rates to viral loads of at most 50 copies per mL were 93% (144 of 155 participants) for all doses of dolutegravir (with little difference between dose groups) and 60% (30 of 50) for efavirenz; week 48 response rates were 87% (139 of 155) for all doses of dolutegravir and 82% (41 of 50) for efavirenz. Response rates between nucleoside reverse transcriptase inhibitor subgroups were similar. We identified three virological failures in the dolutegravir groups and one in the efavirenz group-we did not identify any integrase inhibitor mutations. We did not identify any dose-related clinical or laboratory toxic effects, with more drug-related adverse events of moderate-or-higher intensity in the efavirenz group (20%) than the dolutegravir group (8%). We did not judge that any serious adverse events were related to dolutegravir. INTERPRETATION: Dolutegravir was effective when given once daily without a pharmacokinetic booster and was well tolerated at all assessed doses. Our findings support the assessment of once daily 50 mg dolutegravir in phase 3 trials.

Five-year trends in epidemiology and prevention of mother-to-child HIV transmission, St. Petersburg, Russia: results from perinatal HIV surveillance.

BACKGROUND: The HIV epidemic in Russia has increasingly involved reproductive-aged women, which may increase perinatal HIV transmission. METHODS: Standard HIV case-reporting and enhanced perinatal HIV surveillance systems were used for prospective assessment of HIV-infected women giving birth in St. Petersburg, Russia, during 2004-2008. Trends in social, perinatal, and clinical factors influencing mother-to-child HIV transmission stratified by history of injection drug use, and rates of perinatal HIV transmission were assessed using two-sided χ2 or Cochran-Armitage tests. RESULTS: Among HIV-infected women who gave birth, the proportion of women who self-reported ever using injection drugs (IDUs) decreased from 62% in 2004 to 41% in 2008 (P<0.0001). Programmatic improvements led to increased uptake of the following clinical services from 2004 to 2008 (all P<0.01): initiation of antiretroviral prophylaxis at ≤28 weeks gestation (IDUs 44%-54%, non-IDUs 45%-72%), monitoring of immunologic (IDUs 48%-64%, non-IDUs 58%-80%) and virologic status (IDUs 8%-58%, non-IDUs 10%-75%), dual/triple antiretroviral prophylaxis (IDUs 9%-44%, non-IDUs 14%-59%). After initial increase from 5.3% (95% confidence interval [CI] 3.5%-7.8%) in 2004 to 8.5% (CI 6.1%-11.7%) in 2005 (P<0.05), perinatal HIV transmission decreased to 5.3% (CI 3.4%-8.3%) in 2006, and 3.2% (CI 1.7%-5.8%) in 2007 (P for trend<0.05). However, the proportion of women without prenatal care and without HIV testing before labor and delivery remained unchanged. CONCLUSIONS: Reduced proportion of IDUs and improved clinical services among HIV-infected women giving birth were accompanied by decreased perinatal HIV transmission, which can be further reduced by increasing outreach and HIV testing of women before and during pregnancy.

Fatal and nonfatal AIDS and non-AIDS events in HIV-1-positive individuals with high CD4 cell counts according to viral load strata.

BACKGROUND: This study compared the incidence of fatal and nonfatal AIDS and non-AIDS events in HIV-positive individuals with a CD4 cell count more than 350  cells/µl among viral load strata: low (<500  copies/ml), intermediate (500-9999.9  copies/ml) and high (≥ 10000  copies/ml). METHODS: Individuals contributed person-years at risk if their most recent CD4 cell count was more than 350  cells/µl. Follow-up was censored if their CD4 cell count dropped below 350  cells/µl. Poisson regression analysis investigated the relationship between viraemia and the incidence of AIDS and non-AIDS events. RESULTS: Three hundred and fifty-four AIDS events occurred during 51 732  person-years of follow-up (PYFU), crude incidence rate of AIDS across the three strata was 0.53, 0.90 and 2.12 per 100 PYFU, respectively. After adjustment, a higher rate of AIDS was observed in individuals with moderate [incidence rate ratio (IRR) 1.44, 1.02-2.05, P = 0.03] and high viraemia had a higher rate (IRR 3.91, 2.89-5.89, P < 0.0001) compared with low viraemia. Five hundred and seventy-two non-AIDS events occurred during 43 784 PYFU, the crude incidence rates were 1.28, 1.52, and 1.38 per 100 PYFU, respectively. After adjustment, particularly for age, region of Europe and starting combination antiretroviral therapy, there was a 61% (IRR 1.61, 1.21-2.14, P = 0.001) and 66% (IRR 1.66, 1.17-2.32, P = 0.004) higher rate of non-AIDS in individuals with intermediate and high viraemia compared with low viraemia. CONCLUSION: In individuals with a CD4 cell count more than 350  cells/µl, an increased incidence of AIDS and a slightly increased incidence of non-AIDS was found in those with uncontrolled viral replication. The association with AIDS was clear and consistent. However, the association with non-AIDS was only apparent after adjustment and no differences were observed between intermediate and high viraemia.

Tuberculosis among HIV-positive patients across Europe: changes over time and risk factors.

OBJECTIVE: To describe temporal changes in the incidence rate of tuberculosis (TB) (pulmonary or extrapulmonary) among HIV-positive patients in western Europe and risk factors of TB across Europe. METHODS: Poisson regression models were used to determine temporal changes in incidence rate of TB among 11,952 patients from western Europe (1994-2010), and to assess risk factors for TB among 12,673 patients from across Europe with follow-up after 2001. RESULTS: Two hundred and seventy-seven TB events occurred during 84,221 person-years of follow-up (PYFU) in western Europe. The incidence rate declined from 1.91 [95% confidence interval (CI) 1.51-2.37)] in 1994-1995 to 0.12 (0.07-0.21)/100 PYFU in 2002-2003, and remained stable thereafter. After January 2001, 159 TB events were diagnosed; 65 cases in western Europe and 94 cases in eastern Europe; resulting in incidence rates of 0.12 (0.09-0.14) and 0.65 (0.52-0.79)/100 PYFU, respectively. In multivariable analysis, incidence rate of TB was approximately four-fold higher in eastern Europe compared with western Europe [incidence rate ratio (IRR) 4.25 (2.78-6.49), P < 0.001]. There were no significant temporal changes after 2001 and risk factors did not differ significantly between eastern Europe and western Europe. Lower CD4 cell counts, higher HIV-RNA levels, male sex, intravenous drug usage and African origin were all associated with higher risk of TB. CONCLUSION: Incidence rates of TB in western Europe remained at a very low and stable level since 2001. After 2001, patients in eastern Europe were at substantially higher risk of TB than in western Europe. TB is of great concern in HIV-positive patients, especially in areas with high TB prevalence, high levels of immigration from TB-endemic regions, and with suboptimal access to combination antiretroviral therapy.

Construction and phenotypic characterization of HIV type 1 functional envelope clones of subtypes G and F.

Subtype G has been estimated to represent the fourth most prevalent clade in the HIV-1 pandemic and subtype F is widely circulating in parts of South America (frequently within BF recombinant forms) and in Romania. However, functional envelope clones of these subtypes are lacking, which are needed for studies on antibody-mediated neutralization, coreceptor usage, and efficiency of viral entry inhibitor drugs. Here we report the construction, neutralization properties, and coreceptor usage of HIV-1 functional envelope clones of subtypes G (n = 15) and F (n = 7). These clones were obtained through RT-PCR amplification of HIV-1 gp160 from plasma RNA, and were used for pseudovirus production. All 15 subtype G-enveloped pseudoviruses were resistant to neutralization by gp120-targeted broadly neutralizing monoclonal antibodies (MAbs) b12 and 2G12, while a majority were neutralized by gp41-targeted MAbs 2F5 and 4E10. With regard to the subtype F envelopes, all seven pseudoviruses were resistant to 2F5 and b12, six were resistant to G12, and six were neutralized by 4E10. Coreceptor usage testing revealed that 21 of 22 envelopes were CCR5-tropic, including all 15 subtype G envelopes, seven of which were from patients with CD4(+) T cell counts <200/ml. These results confirm the broadly neutralizing activity of 4E10 on envelope clones across all tested group M clades, including subtypes G and F, reveal the resistance of most subtype F-enveloped pseudoviruses to broadly neutralizing MAbs b12, 2G12, and 2F5, and suggest that, similarly to subtype C, CXCR4 tropism is uncommon in subtype G, even at advanced stages of infection.

Serious fatal and nonfatal non-AIDS-defining illnesses in Europe.

BACKGROUND: Little is known about the incidence and risk factors for serious non-AIDS-defining events. METHODS: The incidence of non-AIDS events (malignancies, end-stage renal disease, liver failure, pancreatitis, cardiovascular disease), and AIDS after January 1, 2001, was calculated; Poisson regression was used to investigate factors associated with non-AIDS and AIDS. RESULTS: Among 12,844 patients, 1058 were diagnosed with a non-AIDS event [incidence 1.77 per 100 person-years of follow-up; 95% confidence interval (CI): 1.66 to 1.87]; 462 patients (43.7%) died. The incidence of AIDS (1025 diagnoses; 339 deaths, 33.1%) was 1.72 per 100 person-years of follow-up (1.61 to 1.83). After adjustment, older age [incidence rate ratio (IRR): 1.71 per 10 years older, 95% CI: 1.60 to 1.83], diabetes (IRR: 1.49, 95% CI: 1.22 to 1.82) and hypertension (IRR: 1.63, 95% CI: 1.43 to 1.87) were associated with non-AIDS events. Compared with patients without an event, there was a 4-fold increased risk of death after an AIDS event (relative hazard: 4.14; 95% CI 3.47 to 4.94) and almost a 7-fold increased risk of death after a non-AIDS event (relative hazard: 6.72; 95% CI: 5.61 to 8.05). CONCLUSIONS: Non-AIDS events were common in the combination antiretroviral therapy era and associated with considerably mortality. Evidence on the impact of modifying immunodeficiency and lifestyle-related factors on the risk of non-AIDS events in HIV-infected persons is an important but unmet research need.

Short communication: Molecular epidemiology of HIV type 1 in the Republic of Dagestan, Russian Federation: virtually uniform circulation of subtype A, former Soviet Union variant, with predominance of the V77I(PR) subvariant.

We examine the distribution of viral genetic forms and the presence of antiretroviral drug resistance mutations in HIV-1 infections in the Republic of Dagestan, in the North Caucasus area of Russia, where a recent large increase in HIV-1 infections has been documented. Samples were collected from 41 HIV-1-infected individuals from Dagestan, most of them from the cities of Derbent (n = 21) and Mahachkala (n = 18). Thirty six were injecting drug users and five were infected by heterosexual contact. None was on antiretroviral drug treatment. HIV-1 protease and a segment of reverse transcriptase were amplified by RT-PCR from plasma RNA and sequenced, and phylogenetic trees were constructed via maximum likelihood. Forty (97.6%) of 41 samples were of subtype A, former Soviet Union variant (A(FSU)), of which 27 (67.5%) clustered with the subvariant containing the V77I substitution in protease (V77I(PR)). Within this cluster, 13 viruses formed a local subcluster, 10 of which were from Derbent. Four viruses clustered with the A(SP2) subcluster, recently identified in St. Petersburg, two with a virus from Georgia and one with a virus from Azerbaijan. No mutations associated with antiretroviral drug resistance were detected. The results, therefore, show the relationship of the HIV-1 epidemic in Dagestan with that of other areas of Russia and of neighboring countries, and reveal the spread of the A(FSU) V77I(PR) variant in the North Caucasus area.

Antiretroviral prophylaxis to prevent perinatal HIV transmission in St. Petersburg, Russia: too little, too late.

BACKGROUND: We evaluated the influence of type and timing of prophylaxis on perinatal HIV transmission in St. Petersburg, Russia. METHODS: We linked surveillance data for 1498 HIV-infected mothers delivering from 2004 to 2007 with polymerase chain reaction data for 1159 infants to determine predictors of transmission. RESULTS: The overall perinatal transmission rate was 6.3% [73 of 1159, 95% confidence interval (CI) 4.9% to 7.7%]. Among the 12.8% (n = 149) of mother-infant pairs receiving full course (antenatal, intrapartum, postnatal) dual/triple antiretroviral prophylaxis, the transmission rate was 2.7%. Among the 1010 receiving less complete regimens (full course zidovudine, single-dose nevirapine, or incomplete), transmission ranged from 4.1% to 12.2%. Among the 28.9% (330) of mothers initiating antiretroviral drugs or=29 weeks (or not at all) had increased transmission odds (adjusted odds ratio: 4.9, 95% CI: 1.8 to 12.9; odds ratio: 5.1, 95% CI: 2.0 to 13.1, respectively). CONCLUSIONS: In St. Petersburg, the potential for further reductions in perinatal transmission is evident, given low transmission among women receiving early combination prophylaxis.

Near full-length genome characterization of a newly identified HIV type 1 subtype F variant circulating in St. Petersburg, Russia.

We report the near full-length genome characterization of an HIV-1 subtype F virus (D88_845) collected in St. Petersburg, Russia, from a 25-year-old Russian woman perinatally infected in 1982. In a Bayesian phylogenetic analysis, the genome sequence branched basally to the subsubtype F1 clade. In partial sequences, D88_845 clustered with 13 other subtype F sequences from Russia, corresponding to gag (n = 2), pol (n = 3), and env (n = 8) segments. At least 11 of these sequences are from samples collected in St. Petersburg from heterosexually infected Russian individuals. In each of these segments, the Russian viruses formed a monophyletic cluster that branched as a sister clade of the F1 subsubtype. One sequence from Belgium branched with D88_845 with a posterior probability of 0.99. This is the first report on the identification and near full-length genome characterization of the subtype F variant circulating in St. Petersburg, which is closely related to, but distinct from, the F1 subsubtype.

Mortality from HIV and TB coinfections is higher in Eastern Europe than in Western Europe and Argentina.

BACKGROUND AND OBJECTIVES: Tuberculosis (TB) is a leading cause of death in HIV-infected patients worldwide. We aimed to study clinical characteristics and outcome of 1075 consecutive patients diagnosed with HIV/TB from 2004 to 2006 in Europe and Argentina. METHODS: One-year mortality was assessed in patients stratified according to region of residence, and factors associated with death were evaluated in multivariable Cox models. RESULTS: At TB diagnosis, patients in Eastern Europe had less advanced immunodeficiency, whereas a greater proportion had a history of intravenous drug use, coinfection with hepatitis C, disseminated TB, and infection with drug-resistant TB (P < 0.0001). In Eastern Europe, fewer patients initiated TB treatment containing at least rifamycin, isoniazid, and pyrazinamide or combination antiretroviral therapy (P < 0.0001). Mortality at 1 year was 27% in Eastern Europe, compared with 7, 9 and 11% in Central/Northern Europe, Southern Europe, and Argentina, respectively (P < 0.0001). In a multivariable model, the adjusted relative hazard of death was significantly lower in each of the other regions compared with Eastern Europe: 0.34 (95% confidence interval 0.17-0.65), 0.28 (0.14-0.57), 0.34 (0.15-0.77) in Argentina, Southern Europe and Central/Northern Europe, respectively. Factors significantly associated with increased mortality were CD4 cell count less than 200 cells/microl [2.31 (1.56-3.45)], prior AIDS [1.74 (1.22-2.47)], disseminated TB [2.00 (1.38-2.85)], initiation of TB treatment not including rifamycin, isoniazid and pyrazinamide [1.68 (1.20-2.36)], and rifamycin resistance [2.10 (1.29-3.41)]. Adjusting for these known confounders did not explain the increased mortality seen in Eastern Europe. CONCLUSION: The poor outcome of patients with HIV/TB in Eastern Europe deserves further study and urgent public health attention.

Molecular epidemiology of HIV-1 in St Petersburg, Russia: predominance of subtype A, former Soviet Union variant, and identification of intrasubtype subclusters.

OBJECTIVES: To examine HIV-1 genetic diversity in St. Petersburg. METHODS: Partial HIV-1 pol sequences from 102 plasma samples collected in 2006 were analyzed with a Bayesian phylogeny inference method. RESULTS: Subtype A, former Soviet Union (FSU) variant (AFSU), was the predominant clade (89.3%); other clades were subtypes B (9.7%) and F1 (1%). AFSU was predominant both among injecting drug users (98.2%) and heterosexually infected individuals (91.4%), whereas subtype B was more prevalent among homosexual men (75%). Within the AFSU variant, most sequences (93.5%) branched within 1 of 4 strongly supported subclusters. The largest comprised 63% AFSU viruses and was uncommon outside St Petersburg. A second subcluster (17.4% AFSU viruses) corresponds to the variant with the V77I substitution in protease, which is widely circulating in different FSU countries. Two minor subclusters comprised 8.7% and 6.5% AFSU viruses, respectively. There was no correlation between risk exposure and AFSU subclusters. Six of 8 subtype B sequences, 4 of them from homosexual men, grouped in a monophyletic subcluster. CONCLUSIONS: The results of this study show a great predominance of AFSU viruses in St Petersburg and point to a few phylogenetically identifiable introductions as the origin of most current HIV-1 AFSU infections in the city.

Rapid HIV testing and prevention of perinatal HIV transmission in high-risk maternity hospitals in St. Petersburg, Russia.

OBJECTIVE: The purpose of this study was to evaluate the effectiveness of a human immunodeficiency virus (HIV) rapid testing (RT) program. STUDY DESIGN: From April 13, 2004, to April 13, 2005, pregnant women at 2 high-risk maternity hospitals with no or incomplete HIV testing results (negative tests at <34 weeks, none thereafter) were offered point-of-care RT, with antiretroviral prophylaxis for RT-positive women and their infants. RESULTS: Overall, 89.2% of eligible women (3671/4117) underwent RT, of whom 90.4% received results before delivery. HIV seroprevalence among all women who underwent RT was 2.7% (100/3671 women); among previously untested women, seroprevalence was 6.5% (90/1375 women); the incidence of HIV seroconversion among women with previous negative tests during pregnancy was 0.4% (10/2296 women). After adjustment, the main predictor of receiving RT results after delivery was late admission. Among HIV-exposed infants, 97.9% (92/94) received prophylaxis; 61.7% (58/94) had available follow-up data, and 8.6% (5/58) met criteria for definitive or presumptive HIV infection. CONCLUSION: The RT program achieved timely detection of HIV-infected women in labor with unknown HIV status and effectively prevented perinatal HIV transmission.