Articles tagged as "Spain"

If approved, once-daily dolutegravir could form part of an effective new option for treatment of HIV-1 in treatment-naive patients

Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study.

Raffi F, Rachlis A, Stellbrink HJ, Hardy WD, Torti C, Orkin C, et al. SPRING-2 Study Group. Lancet. 2013 Mar 2;381(9868):735-43. doi: 10.1016/S0140-6736(12)61853-4. Epub 2013 Jan 8.

BACKGROUND: Dolutegravir (S/GSK1349572) is a once-daily HIV integrase inhibitor with potent antiviral activity and a favourable safety profile. We compared dolutegravir with HIV integrase inhibitor raltegravir, as initial treatment for adults with HIV-1.

METHODS: SPRING-2 is a 96 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began on Oct 19, 2010, at 100 sites in Canada, USA, Australia, and Europe. Treatment-naive adults (aged ≥ 18 years) with HIV-1 infection and HIV-1 RNA concentrations of 1000 copies per mL or greater were randomly assigned (1:1) via a computer-generated randomisation sequence to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily). Study drugs were given with coformulated tenofovir/emtricitabine or abacavir/lamivudine. Randomisation was stratified by screening HIV-1 RNA (≤ 100,000 copies per mL or >100,000 copies per mL) and nucleoside reverse transcriptase inhibitor backbone. Investigators were not masked to HIV-1 RNA results before randomisation. The primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies per mL at 48 weeks, with a 10% non-inferiority margin. Main secondary endpoints were changes from baseline in CD4 cell counts, incidence and severity of adverse events, changes in laboratory parameters, and genotypic or phenotypic evidence of resistance. Our primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01227824.

FINDINGS: 411 patients were randomly allocated to receive dolutegravir and 411 to receive raltegravir and received at least one dose of study drug. At 48 weeks, 361 (88%) patients in the dolutegravir group achieved an HIV-1 RNA value of less than 50 copies per mL compared with 351 (85%) in the raltegravir group (adjusted difference 2·5%; 95% CI -2·2 to 7·1). Adverse events were similar between treatment groups. The most common events were nausea (59 [14%] patients in the dolutegravir group vs 53 [13%] in the raltegravir group), headache (51 [12%] vs 48 [12%]), nasopharyngitis (46 [11%] vs 48 [12%]), and diarrhoea (47 [11%] in each group). Few patients had drug-related serious adverse events (three [<1%] vs five [1%]), and few had adverse events leading to discontinuation (ten [2%] vs seven [2%] in each group). CD4 cell counts increased from baseline to week 48 in both treatment groups by a median of 230 cells per μL. Rates of graded laboratory toxic effects were similar. We noted no evidence of treatment-emergent resistance in patients with virological failure on dolutegravir, whereas of the patients with virologic failure who received raltegravir, one (6%) had integrase treatment-emergent resistance and four (21%) had nucleoside reverse transcriptase inhibitors treatment-emergent resistance.

INTERPRETATION: The non-inferior efficacy and similar safety profile of dolutegravir compared with raltegravir means that if approved, combination treatment with once-daily dolutegravir and fixed-dose nucleoside reverse transcriptase inhibitors would be an effective new option for treatment of HIV-1 in treatment-naive patients.

FUNDING: ViiV Healthcare.

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Editor’s notes: Integrase inhibitors are a novel and potent class of antiretroviral drug, however their role in first line therapy has yet to be clearly defined. Use of the two FDA approved integrase inhibitors, raltegravir and elvitegravir, has been limited by the need for twice-daily dosing and the requirement for boosting respectively. Dolutegravir, evaluated in the SPRING-2 study, has a very favourable pharmacokinetic profile which allows once-daily dosing without the need for boosting. Planned co-formulation with ABC/3TC further increases the attractiveness of dolutegravir as a treatment option in treatment-naive patients. In this head to head study dolutegravir was non-inferior to raltegravir in terms of the primary endpoint (viral suppression at 48 weeks), and was well tolerated. Additionally, no evidence of drug resistance was found in the small number of patients with virological failure on dolutegravir treatment, in keeping with prior evidence suggesting a high genetic barrier to resistance. But as the accompanying Lancet editorial noted, some important questions remain unanswered. The study population of predominantly white males and the fact that most study participants had non-advanced disease, with a median baseline CD4 count of 359 cells/µL, makes extrapolation of the results to the areas of the world with the highest disease burdens difficult. Further studies in populations more representative of the global HIV epidemic are needed, but the results of the SPRING study suggest that dolutegravir will be a useful addition to the ART repertoire.

Europe, Northern America, Oceania
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HIV infection increases mortality among HIV-positive pregnant women

The contribution of HIV to pregnancy-related mortality: a systematic review and meta-analysis.

Calvert C, Ronsmans PC. AIDS. 2013 Feb 25. [Epub ahead of print]

Whilst much is known about the contribution of HIV to adult mortality, remarkably little is known about the mortality attributable to HIV during pregnancy. In this paper the proportion of pregnancy-related deaths attributable to HIV based on empirical data was estimated from a systematic review of the strength of association between HIV and pregnancy-related mortality. Studies comparing mortality during pregnancy and the postpartum in HIV-infected and uninfected women were included. Summary estimates of the relative and attributable risks for the association between HIV and pregnancy-related mortality were calculated through meta-analyses. Varying estimates of HIV prevalence were used to predict the impact of the HIV epidemic on pregnancy-related mortality at the population level. 23 studies were included (17 from sub-Saharan Africa). Meta-analysis of the risk ratios (RR) indicated that HIV-infected women had eight times the risk of a pregnancy-related death compared with HIV-uninfected women (pooled RR: 7.74, 95% CI 5.37-11.16). The excess mortality attributable to HIV among HIV-infected pregnant and postpartum women was 994 per 100,000 pregnant women. We predict that 12% of all deaths during pregnancy and up to one year postpartum are attributable to HIV/AIDS in regions with a prevalence of HIV among pregnant women of 2%. This figure rises to 50% in regions with a prevalence of 15%.  The substantial excess of pregnancy-related mortality associated with HIV highlights the importance of integrating HIV and reproductive health services in areas of high HIV prevalence and pregnancy-related mortality.

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Editor’s notes: Millennium Development Goals include commitments to reduce maternal mortality. While HIV is a leading cause of death among women of reproductive age in sub-Saharan Africa, the contribution of HIV infection to overall maternal mortality is Africa has been less described. This analysis of this study indicates that a significant proportion of maternal deaths is due to HIV. While the contribution of HIV to maternal mortality is high in relatively low prevalence settings, it is remarkably and tragically high in high prevalence countries such as is seen in southern Africa: with an estimated 50% of maternal deaths due to HIV infection when prevalence is 15%. This modeling highlights the ongoing essential need to prevent new HIV infections if the MDGs will be met.

Epidemiology, Gender
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Comparing adverse effects of nevirapine and efavirenz

Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis.

Shubber Z, Calmy A, Andrieux-Meyer I, Vitoria M, Renaud-Thery F, Shaffer N, Hargreaves S, Mills EJ, Ford N. AIDS. 2013 Jan 22. [Epub ahead of print]

Since 2002, the World Health Organization has recommended either nevirapine (NVP) or efavirenz (EFV) as part of first-line antiretroviral therapy. These two drugs are known to have differing toxicity profiles, but the clinical importance of these toxicities overall is not well established. The authors systematically reviewed adverse events among treatment-naïve HIV-positive adults and children receiving either NVP or EFV as part of first-line antiretroviral therapy. The primary outcome was drug discontinuation as a result of any adverse event; specific toxicities were evaluated as secondary outcomes. Point estimates and 95% confidence intervals (95% CI) were calculated and proportions and odds ratios (OR) pooled using fixed-effects meta-analysis. Data was reviewed on 26446 adult and 3975 children from 8 randomized trials and 26 prospective cohorts. Overall, adults on NVP were more than two times more likely to discontinue treatment due to any adverse event compared to patients on EFV (OR 2.2, 95%CI 1.9-2.6). Severe hepatotoxicity (OR 3.3, 95%CI 2.5-4.2), severe skin toxicity (OR 3.9, 95%CI 2.5-5.4), and severe hypersensitivity reactions (OR 2.4, 95%CI 1.9-2.9) were more likely to occur among patients on NVP. Patients receiving EFV were more likely to experience severe CNS-events (OR 3.4, 95%CI 2.1-5.4). Similar associations were seen in children. Compared to NVP, EFV is associated with a lower frequency of severe adverse events, in particular treatment discontinuations. This finding supports a move towards efavirenz-based therapy as the preferred first-line treatment regimen for HIV treatment within a public health approach.

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Editor’s notes: As increased progress is being made towards universal access to treatment, increased attention is being addressed towards retention in care and on treatment. Simpler, less toxic regimens have been a cornerstone of the Treatment 2.0 initiative of UNAIDS and WHO. Nevirapine has been widely utilized as an essential component of three drug antiretroviral therapy, in part due to low cost and safety at a population level. While efavirenz does have a greater incidence of central nervous system side effects (many of them manageable with supportive treatment), the overall discontinuation rate is significantly lower than with nevirapine. This data in combination with the continued reduction in efavirenz price, and incorporation into combination pill form, supports the move towards increased use of efavirenz for first line antiretroviral therapy.

HIV Treatment
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Persons left behind: transgender women

Worldwide burden of HIV in transgender women: a systematic review and meta-analysis.

Baral SD, Poteat T, Strömdahl S, Wirtz AL, Guadamuz TE, Beyrer C. Lancet Infect Dis. 2012 Dec 20. pii: S1473-3099(12)70315-8. [Epub ahead of print]

Background: Previous systematic reviews have identified a high prevalence of HIV infection in transgender women in the USA and in those who sell sex (compared with both female and male sex workers). However, little is known about the burden of HIV infection in transgender women worldwide. We aimed to better assess the relative HIV burden in all transgender women worldwide.

Methods: We did a systematic review and meta-analysis of studies that assessed HIV infection burdens in transgender women that were published between Jan 1, 2000, and Nov 30, 2011. Meta-analysis was completed with the Mantel-Haenszel method, and random-effects modelling was used to compare HIV burdens in transgender women with that in adults in the countries for which data were available.

Findings: Data were only available for countries with male-predominant HIV epidemics, which included the USA, six Asia-Pacific countries, five in Latin America, and three in Europe. The pooled HIV prevalence was 19·1% (95% CI 17·4-20·7) in 11 066 transgender women worldwide. In 7197 transgender women sampled in ten low-income and middle-income countries, HIV prevalence was 17·7% (95% CI 15·6-19·8). In 3869 transgender women sampled in five high-income countries, HIV prevalence was 21·6% (95% CI 18·8-24·3). The odds ratio for being infected with HIV in transgender women compared with all adults of reproductive age across the 15 countries was 48·8 (95% CI 21·2-76·3) and did not differ for those in low-income and middle-income countries compared with those in high-income countries.

Interpretation: Our findings suggest that transgender women are a very high burden population for HIV and are in urgent need of prevention, treatment, and care services. The meta-analysis showed remarkable consistency and severity of the HIV disease burden among transgender women.

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Editor’s notes: This paper systematically reviews studies on the prevalence of HIV infection among transgender women in different countries from three continents. Results unfortunately show that there is a dramatic consistency in HIV prevalence data, which reach peaks often above 20%, irrespective of the financial context of the countries where transgenders live. In addition, there is a common theme: risk factors including stigma, discrimination and marginalisation are all factors which dramatically increase the risk of becoming infected by HIV. Not only are transgender women probably the group with the highest risk of acquiring the infection, but they are also in urgent need of prevention, possibly including pre- and post-exposure prophylaxis, and of tailored support and care. But these might not be enough, if marginalisation is supported in some countries with a legal environment contradicting international human rights frameworks.

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