HIV epidemic in Russia and neighbouring countries.

Reports of HIV/AIDS cases attributed to sexual transmission from foreigners were published in the USSR in the mid of 80s. In the initial decade of the epidemic, the subtype B was found in men who have sex with men (MSM) population and several non-B subtypes were identified in heterosexual persons. The first case of HIV infection in intravenous drug users (IVDU) was reported in 1993 and since then a specific subtype A and its recombinants invaded the intravenous drug users (IVDU) populations of the region with the highest rate in Estonia, Russia and Ukraine. The concentrated HIV epidemic in IVDUs is still the main problem in the Eastern Europe; however, the rate of heterosexual transmission is increasing and many evidences of HIV prevalence rise in MSM are published. UNAIDS estimations for the number of HIV-positive persons living in the region range from 980,000 to 1,300,000 but distribution of HIV-cases is uneven and the prevalence rate of HIV infection in separate regions is over 1%. Mass seasonal labour migration from Central Asia and Caucasian republics to Russia transmits HIV to these countries. Prevention programs in the region are limited, and ART coverage is not more than 20% of the total HIV-positive population. The lack of concern about the epidemic, absence of effective national strategies and limited allocated resources are the main barriers to prevention and care in many countries. Local conflicts, rising religiosity and discrimination are adverse factors. The near-term forecast for the epidemic in the region is pessimistic and further international advocacy is needed to improve the situation.

Plasmacytoid Dendritic cells (pDCs) in HIV-infected and HIV/HCV-co-infected patients receiving successful treatment.

INTRODUCTION: Depletion of cellular pool and constant activation of plasmacytoid dendritic cells (pDCs) in HIV-infected persons (HIV+) are associated with disease progression and manifestation of opportunistic infections. The influence of highly-active antiretroviral treatment (HAART) and suppressed HCV-co-infection (HIV+/HCV+) on the extent of these changes remains unknown. OBJECTIVE: To study parameters of pDCs in peripheral blood of HIV+ and HIV+/HCV+ patients on HAART. METHODS: Twelve uninfected with HIV or HCV volunteers and 37 patients (12 HIV+, 9 HIV+/HCV+ and 16 HCV+) were enrolled. All HIV+ patients received HAART and had undetermined HIV viral load. All HCV+ patients had finished antiviral therapy (Pegasys/ribavirin) with sustained viral response for six months and more. The pDC population was enumerated by flow cytometry. In vitro IFN production in the whole blood in response to pDC-specific stimulus unmethylated CpG oligonucleotides was determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: The percentage of pDCs of peripheral blood mononuclear cells (PBMC) in HIV+/HCV+ was the lowest (0.08±0.02) but statistically not different from HIV+ (0.15±0.03; p=0.11) and significantly lower than HCV+ (0.17±0.015; p=0.4) and controls (0.27±0.045; p=0.03). Absolute number of pDCs in HIV+ on HAART (6.3±1.3) was not significantly lower than the control (10.25±1.75; p=0.09) but in HIV+/HCV+ (5.1±1.2; p=0.03), the difference was valid. IFN-alpha production by pDCs in patients on HAART in HIV+ (2.4±0.9 pg/µl) and in HIV+/HCV+ (3.7±1 pg/µl) patients were significantly higher than in controls (in controls IFN-alpha production by pDCs in the native plasma was below the level of detection (3 pg/µl), p=0.02 and p=0.0014). CONCLUSIONS: Absolute number of pDC in HIV-positive person on HAART with sustained viral response to treatment of HCV-co-infection was lower than in HIV-mono-infected. IFN-alpha production by pDC in HIV+ and in HIV+/HCV+ patients receiving HAART remains higher than in uninfected persons.

Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study.

BACKGROUND: Dolutegravir has been shown to be non-inferior to an integrase inhibitor and superior to a non-nucleoside reverse transcriptase inhibitor (NNRTI). In FLAMINGO, we compared dolutegravir with darunavir plus ritonavir in individuals naive for antiretroviral therapy. METHODS: In this multicentre, open-label, phase 3b, non-inferiority study, HIV-1-infected antiretroviral therapy-naive adults with HIV-1 RNA concentration of 1000 copies per mL or more and no resistance at screening were randomly assigned (1:1) to receive either dolutegravir 50 mg once daily or darunavir 800 mg plus ritonavir 100 mg once daily, with investigator-selected tenofovir-emtricitabine or abacavir-lamivudine. Randomisation was stratified by screening HIV-1 RNA (≤100,000 or >100,000 copies per mL) and nucleoside reverse transcriptase inhibitor (NRTI) selection. The primary endpoint was the proportion of patients with HIV-1 RNA concentration lower than 50 copies per mL (Food and Drug Administration [FDA] snapshot algorithm) at week 48 with a 12% non-inferiority margin. This trial is registered with ClinicalTrials.gov, NCT01449929. FINDINGS: Recruitment began on Oct 31, 2011, and was completed on May 24, 2012, in 64 research centres in nine countries worldwide. Of 595 patients screened, 484 patients were included in the analysis (242 in each group). At week 48, 217 (90%) patients receiving dolutegravir and 200 (83%) patients receiving darunavir plus ritonavir had HIV-1 RNA of less than 50 copies per mL (adjusted difference 7·1%, 95% CI 0·9-13·2), non-inferiority and on pre-specified secondary analysis dolutegravir was superior (p=0·025). Confirmed virological failure occurred in two (<1%) patients in each group; we recorded no treatment-emergent resistance in either group. Discontinuation due to adverse events or stopping criteria was less frequent for dolutegravir (four [2%] patients) than for darunavir plus ritonavir (ten [4%] patients) and contributed to the difference in response rates. The most commonly reported (≥10%) adverse events were diarrhoea (dolutegravir 41 [17%] patients vs darunavir plus ritonavir 70 [29%] patients), nausea (39 [16%] vs 43 [18%]), and headache (37 [15%] vs 24 [10%]). Patients receiving dolutegravir had significantly fewer low-density lipoprotein values of grade 2 or higher (11 [2%] vs 36 [7%]; p=0·0001). INTERPRETATION: Once-daily dolutegravir was superior to once-daily darunavir plus ritonavir. Once-daily dolutegravir in combination with fixed-dose NRTIs represents an effective new treatment option for HIV-1-infected, treatment-naive patients. FUNDING: ViiV Healthcare and Shionogi & Co.

Body fat and other metabolic effects of atazanavir and efavirenz, each administered in combination with zidovudine plus lamivudine, in antiretroviral-naive HIV-infected patients.

BACKGROUND: Protease inhibitor treatment of human immunodeficiency virus (HIV)-infected individuals has been linked to the development of lipodystrophy. The effects of atazanavir on body fat distribution and related metabolic parameters were examined in antiretroviral-naive patients. METHODS: HIV-positive patients with CD4 cell counts > or = 100 cells/mm3 were randomized to 1 of 2 treatment arms: (1) atazanavir, 400 mg given once daily, plus efavirenz placebo; or (2) efavirenz, 600 mg given once daily, plus atazanavir placebo; each drug was administered with fixed-dose zidovudine (300 mg) and lamivudine (150 mg) given twice daily, and patients were treated for at least 48 weeks. Fat distribution measurements (visceral adipose tissue [VAT], subcutaneous adipose tissue [SAT], and total adipose tissue [TAT], as measured by computed tomography; and appendicular fat, truncal fat, and total fat levels, as measured by dual-energy x-ray absorptiometry), metabolic measurements (cholesterol and fasting triglyceride levels), and measurements of insulin resistance (fasting glucose and fasting insulin levels) were made at baseline and at week 48 of treatment for a subgroup of 111 atazanavir recipients and 100 efavirenz recipients. RESULTS: Atazanavir and efavirenz treatments resulted in minimal to modest increases in fat accumulation, as measured by VAT, SAT, TAT, appendicular fat, truncal fat, and total fat levels; results were comparable in both arms. In addition, atazanavir was associated with none of the metabolic abnormalities seen with many other protease inhibitors. CONCLUSIONS: Use of atazanavir for 48 weeks neither resulted in abnormal fat redistribution in antiretroviral-naive patients nor induced other metabolic disturbances commonly associated with HIV-related lipodystrophy. Longer-term assessments (e.g., at 96 weeks) will be important to confirm these findings.

Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV.

BACKGROUND: Atazanavir, an azapeptide protease inhibitor (PI), has pharmacokinetics that allow once-daily dosing, and it is not associated with significant PI-associated dyslipidemia. METHODS: A randomized, double-blind, double-dummy, active-controlled, 2-arm study comparing the antiviral efficacy and safety of atazanavir 400 mg administered once daily with efavirenz 600 mg administered once daily in combination with open-label fixed-dose zidovudine plus lamivudine twice daily. The 810 treatment-naive patients were stratified by HIV RNA level. The primary efficacy end point was the proportion of treated patients with HIV RNA levels <400 copies/mL through week 48. RESULTS: At week 48, HIV RNA levels were <400 copies/mL in 70% of patients receiving atazanavir and 64% of patients receiving efavirenz (intent-to-treat, difference; 95% confidence interval: 5.2%; -1.2%, 11.7%). Median CD4 cell counts increased at comparable magnitudes and rates in the 2 treatment arms (mean change at week 48: 176 cells/mm with atazanavir, 160 cells/mm with efavirenz). Atazanavir-treated patients relative to comparator-treated patients did not demonstrate significant increases in total cholesterol, fasting low-density lipoprotein cholesterol, or fasting triglycerides over 48 weeks of therapy. Atazanavir-linked bilirubin elevations infrequently resulted in treatment discontinuation (<1%). Atazanavir treatment did not increase fasting glucose or insulin levels. CONCLUSIONS: For initial HIV treatment, a highly active antiretroviral therapy regimen of atazanavir/zidovudine/lamivudine is as efficacious and well tolerated as the combination of efavirenz/zidovudine/lamivudine.

Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir.

The purpose of the study was to determine long-term efficacy, safety, and tolerability of atazanavir plus stavudine/lamivudine in 346 HIV-infected patients previously treated with atazanavir or nelfinavir. BMS AI424-044 is an ongoing, multicenter, international, open-label, rollover/switch study initiated in June 2001. Patients completing >or=48 weeks in trial BMS AI424-008 with a plasma HIV RNA viral load <10,000 copies/mL were eligible to continue on atazanavir (400 or 600 mg) or to switch from nelfinavir to atazanavir (400 mg) once daily. Antiviral efficacy, change in CD4 cell counts, and effect on lipid parameters were measured. After 24 weeks of atazanavir use in BMS AI424-044, 83%, 85%, and 87% of the atazanavir 400-mg, atazanavir 600-mg, and nelfinavir-to-atazanavir-switched patients, respectively, had HIV RNA levels <400 copies/mL compared with 76%, 76%, and 63%, respectively, at week 48 of BMS AI424-008. Atazanavir-treated patients showed minimal changes in lipid levels compared with baseline. Patients switched from nelfinavir to atazanavir showed significant mean percent decreases in total cholesterol (-16%), fasting low-density lipoprotein cholesterol (-21%), and fasting triglycerides (-28%) (P<0.0001) by week 12 of atazanavir treatment. No new safety issues were identified, and the overall incidence of treatment-emergent adverse events during BMS AI424-044 was comparable across treatment groups. Atazanavir was safe, tolerable, and effective during extended use and in patients switched from nelfinavir. Extended atazanavir use resulted in continued viral suppression and lipid changes that were not clinically relevant. In virologically suppressed nelfinavir-treated patients switched to atazanavir, virologic improvement continued, whereas nelfinavir-induced lipid elevations were reversed within 12 weeks, approaching pretreatment values.