Articles tagged as "France"

New evidence in support of opioid substitution therapy as a key HIV programme for people who inject drugs

Impact of opioid substitution therapy on antiretroviral therapy outcomes: a systematic review and meta-analysis.

Low AJ, Mburu G, Welton NJ, May MT, Davies CF, French C, Turner K, Looker KJ, Christensen H, McLean S, Rhodes T, Platt L, Hickman M, Guise A, Vickerman P. Clin Infect Dis. 2016 Jun 25. pii: ciw416. [Epub ahead of print]

Background: HIV-positive people who inject drugs (PWID) frequently encounter barriers accessing and remaining on antiretroviral treatment (ART). Some studies have suggested that opioid substitution therapy (OST) could facilitate PWID's engagement with HIV services. We conducted a systematic review and meta-analysis to evaluate the impact of concurrent OST use on ART-related outcomes among HIV-positive PWID.

Methods: We searched Medline, PsycInfo, Embase, Global Health, Cochrane, Web of Science, and Social Policy and Practice databases for studies between 1996 to November 2014 documenting the impact of OST, compared to no OST, on ART outcomes. Outcomes considered were: coverage and recruitment onto ART, adherence, viral suppression, attrition from ART, and mortality. Meta-analyses were conducted using random effects modelling, and heterogeneity assessed using Cochran's Q test and I2 statistic.

Results: We identified 4685 articles, and 32 studies conducted in North America, Europe, Indonesia and China were included. OST was associated with a 69% increase in recruitment onto ART (HR=1.69, 95% confidence interval (CI): 1.32-2.15), a 54% increase in ART coverage (OR=1.54; 95% CI: 1.17-2.03), a two-fold increase in adherence (OR=2.14, 95% CI: 1.41-3.26), and a 23% decrease in the odds of attrition (OR=0.77, 95% CI:0.63-0.95). OST was associated with a 45% increase in odds of viral suppression (OR=1.45, 95%CI:1.21-1.73), but there was limited evidence from six studies for OST decreasing mortality for PWID on ART (HR=0.91, 95% CI:0.65-1.25).

Conclusions: These findings support the use of OST, and its integration with HIV services, to improve the HIV treatment and care continuum amongst HIV-positive PWID.

Abstract access

Editor’s notes: This is a very important study contributing new evidence on how opioid substitution therapy can help in the treatment and prevention of HIV among people who inject drugs. This review provides key evidence in support of opioid substitution therapy as a cornerstone HIV treatment and prevention programme. This evidence is essential given the growing number of HIV infections among people who inject drugs globally, particularly in eastern Europe and sub-Saharan Africa. There is a wealth of evidence from systematic reviews and mathematical modelling to illustrate how the use of opioid substitution therapy decreases risk of HIV acquisition at an individual-level.  It can also reduce HIV prevalence and incidence at the population level. This review is important in that it illustrates how opioid substitution therapy can facilitate HIV treatment.  Findings illustrate that opioid substitution therapy works by increasing adherence to HIV treatment, decreasing attrition from treatment and increasing odds of viral suppression reducing the odds of onwards HIV transmission. In addition to this important review, there is also a need to understand the role opioid substitution therapy might have in increasing uptake of HIV testing. This review does not address that question. It is notable that few studies on impact of opioid substitution therapy on HIV treatment outcomes and uptake included in the review were identified in low-income countries or eastern Europe where need is greatest. This partly reflects the lack of opioid substitution therapy programmes in that region, particularly the Russian Federation. This is also the case in sub-Saharan Africa where opioid substitution therapy programmes are newly established and yet to be evaluated. Future research is necessary to understand how opioid substitution therapy might work: (1) where transmission of HIV is predominantly sexual and (2) where injecting drug use occurs within very different social and economic contexts.

Asia, Europe, Northern America
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Oral PrEP reduces risk of HIV and does not result in riskier sex

Effectiveness and safety of oral HIV pre-exposure prophylaxis (PrEP) for all populations: A systematic review and meta-analysis.

Fonner VA, Dalglish SL, Kennedy CE, Baggaley R, O'Reilly K R, Koechlin FM, Rodolph M, Hodges-Mameletzis I, Grant RM. AIDS. 2016 May 5. [Epub ahead of print]

Objective: Pre-exposure prophylaxis (PrEP) offers a promising new approach to HIV prevention. This systematic review and meta-analysis evaluated the evidence for use of oral PrEP containing tenofovir disoproxil fumarate (TDF) as an additional HIV prevention strategy in populations at substantial risk for HIV based on HIV acquisition, adverse events, drug resistance, sexual behavior, and reproductive health outcomes.

Design: Rigorous systematic review and meta-analysis.

Methods: A comprehensive search strategy reviewed three electronic databases and conference abstracts through April 2015. Pooled effect estimates were calculated using random-effects meta-analysis.

Results: Eighteen studies were included, comprising data from 39 articles and six conference abstracts. Across populations and PrEP regimens, PrEP significantly reduced the risk of HIV acquisition compared to placebo. Trials with PrEP use >70% demonstrated the highest PrEP effectiveness (RR = 0.30, 95% CI: 0.21-0.45, p < 0.001) compared to placebo. Trials with low PrEP use did not show a significantly protective effect. Adverse events were similar between PrEP and placebo groups. More cases of drug-resistant HIV infection were found among PrEP users who initiated PrEP while acutely HIV-infected, but incidence of acquiring drug-resistant HIV during PrEP use was low. Studies consistently found no association between PrEP use and changes in sexual risk behavior. PrEP was not associated with increased pregnancy-related adverse events or hormonal contraception effectiveness.

Conclusion: PrEP is protective against HIV infection across populations, presents few significant safety risks, and no evidence of behavioral risk compensation. The effective and cost-effective use of PrEP will require development of best practices for fostering uptake and adherence among people at substantial HIV-risk.

Abstract access

Editor’s notes: This systematic review is the first to aggregate data from across oral pre-exposure prophylaxis (PrEP) studies, including randomized control trials and observational studies, to present clear evidence on the effectiveness of oral PrEP use. The findings confirm that oral PrEP significantly reduces the risk of acquiring HIV if taken consistently and correctly across populations, countries, and most age groups. Differences in efficacy directly correlate with adherence, which accounts for the lower efficacy seen in some subgroups. Perhaps two of the most compelling analyses presented in this paper relate to resistance and behavioural disinhibition. The risk of resistance was shown to be quite low, and study participants exhibiting resistant HIV either enrolled in the studies during an acute infection stage or acquired resistant strains during the course of the research. Regarding behavioural disinhibition, indicators measured such as rates of sexually transmitted infections revealed that PrEP use in the efficacy trials was not associated with behavioural disinhibition and in some studies, resulted in even safer sexual behaviour than what was reported at baseline. Recently completed demonstration projects have reported increased rates of STIs among gay men and other men who have sex with men. However, in the open-label extensions included in this review, where counselling was more intensive, safer sex practices were maintained, thus suggesting that counselling can be effective in preventing behavioural disinhibition. 

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High TB mortality among people living with HIV in eastern Europe: a growing concern

Tuberculosis-related mortality in people living with HIV in Europe and Latin America: an international cohort study. 

Podlekareva DN, Efsen AM, Schultze A, Post FA, Skrahina AM, Panteleev A, Furrer H, Miller RF, Losso MH, Toibaro J, Miro JM, Vassilenko A, Girardi E, Bruyand M, Obel N, Lundgren JD, Mocroft A, Kirk O, TB:HIV study group in EuroCoord. Lancet HIV. 2016 Mar;3(3):e120-31. doi: 10.1016/S2352-3018(15)00252-0. Epub 2016 Feb 2.

Background: Management of tuberculosis in patients with HIV in eastern Europe is complicated by the high prevalence of multidrug-resistant tuberculosis, low rates of drug susceptibility testing, and poor access to antiretroviral therapy (ART). We report 1 year mortality estimates from a multiregional (eastern Europe, western Europe, and Latin America) prospective cohort study: the TB:HIV study.

Methods: Consecutive HIV-positive patients aged 16 years or older with a diagnosis of tuberculosis between Jan 1, 2011, and Dec 31, 2013, were enrolled from 62 HIV and tuberculosis clinics in 19 countries in eastern Europe, western Europe, and Latin America. The primary endpoint was death within 12 months after starting tuberculosis treatment; all deaths were classified according to whether or not they were tuberculosis related. Follow-up was either until death, the final visit, or 12 months after baseline, whichever occurred first. Risk factors for all-cause and tuberculosis-related deaths were assessed using Kaplan-Meier estimates and Cox models.

Findings: Of 1406 patients (834 in eastern Europe, 317 in western Europe, and 255 in Latin America), 264 (19%) died within 12 months. 188 (71%) of these deaths were tuberculosis related. The probability of all-cause death was 29% (95% CI 26-32) in eastern Europe, 4% (3-7) in western Europe, and 11% (8-16) in Latin America (p<0.0001) and the corresponding probabilities of tuberculosis-related death were 23% (20-26), 1% (0-3), and 4% (2-8), respectively (p<0.0001). Patients receiving care outside eastern Europe had a 77% decreased risk of death: adjusted hazard ratio (aHR) 0.23 (95% CI 0.16-0.31). In eastern Europe, compared with patients who started a regimen with at least three active antituberculosis drugs, those who started fewer than three active antituberculosis drugs were at a higher risk of tuberculosis-related death (aHR 3.17; 95% CI 1.83-5.49) as were those who did not have baseline drug-susceptibility tests (2.24; 1.31-3.83). Other prognostic factors for increased tuberculosis-related mortality were disseminated tuberculosis and a low CD4 cell count. 18% of patients were receiving ART at tuberculosis diagnosis in eastern Europe compared with 44% in western Europe and 39% in Latin America (p<0.0001); 12 months later the proportions were 67% in eastern Europe, 92% in western Europe, and 85% in Latin America (p<0.0001).

Interpretation: Patients with HIV and tuberculosis in eastern Europe have a risk of death nearly four-times higher than that in patients from western Europe and Latin America. This increased mortality rate is associated with modifiable risk factors such as lack of drug susceptibility testing and suboptimal initial antituberculosis treatment in settings with a high prevalence of drug resistance. Urgent action is needed to improve tuberculosis care for patients living with HIV in eastern Europe.

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Editor’s notes: Eastern Europe is experiencing one of the fastest growing HIV epidemics globally. Within this, the number of HIV-positive people with tuberculosis (TB) is also rising rapidly, posing a significant public health challenge. The authors have previously reported retrospective data illustrating 30% mortality at one year among HIV-positive people with TB in eastern Europe. This was noted to be at least three times higher than mortality among people from western Europe and Argentina. Within this study they go further to provide prospective data with comparison across multiple regions. They also highlight prognostic markers associated with death.

The study spans across eastern Europe, western Europe and Latin America with a cohort of 1406 people. It robustly demonstrates a significant excess of TB-associated mortality in HIV-positive people with TB receiving care in eastern Europe. The cumulative probability of TB-associated death at 12 months in eastern Europe was 23% (95% confidence interval [CI] 20 – 26), versus 1% (95% CI 0 - 3) in western Europe and 4% (95% CI 2-8) in Latin America. Prognostic markers associated with an increased risk of death included multidrug-resistant TB, disseminated TB and modifiable factors such as choice of initial anti-TB regimen and a lack of baseline drug susceptibility tests.

These findings highlight the hugely detrimental impact of the fragmented system of HIV and TB services within eastern Europe. Such inequality in outcomes emphasises the need for urgent strategic change. Co-ordinated care across HIV and TB services, alongside timely and appropriate diagnostics and treatment, is of paramount importance.

Europe, Latin America
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Tenofovir resistance – need for caution but not panic

Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study.

TenoRes Study Group. Lancet Infect Dis. 2016 Jan 28. pii: S1473-3099(15)00536-8. doi: 10.1016/S1473-3099(15)00536-8. [Epub ahead of print]

Background: Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART.

Methods: The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase (RT) gene.

Findings: We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1.50, 95% CI 1.27-1.77 for CD4 cell count <100 cells per µL). Use of lamivudine versus emtricitabine increased the risk of tenofovir resistance across regions (OR 1.48, 95% CI 1.20-1.82). Of 700 individuals with tenofovir resistance, 578 (83%) had cytosine analogue resistance (M184V/I mutation), 543 (78%) had major NNRTI resistance, and 457 (65%) had both. The mean plasma viral load at virological failure was similar in individuals with and without tenofovir resistance (145 700 copies per mL [SE 12 480] versus 133 900 copies per mL [SE 16 650; p=0.626]).

Interpretation: We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial.

Abstract  Full-text [free] access 

Editor’s notes: Global surveillance for tenofovir (TDF) resistance is important at a time of expanding use of TDF-containing regimens for treatment and prevention. This collaborative analysis used data collated from several small studies in different settings. Overall, around one in three people who had failed on TDF-containing treatment had evidence of TDF resistance, although this frequency varied between 20% in Europe to almost 60% in Africa. Mutations associated with NNRTIs and lamivudine/emtricitabine resistance were more common overall and were present in most people with TDF resistance.

The regional variation probably reflects differences in clinical practice and study inclusion criteria. All European studies involved cohorts with frequent viral load monitoring, whereas half of the African cohorts had no routine viral load monitoring. All European studies included people with virologic failure but with low-level viraemia (viral load <1000 copies/ml) whereas almost all African studies included only people with viral load >1000 copies/ml.

While these data provide useful estimates of the frequency of drug resistance mutations in people with virologic failure on first-line ART, there should be caution about extrapolating beyond this. Reports from cohort studies with an accurate denominator of all people starting TDF-containing first-line ART would be useful to give more reliable estimates of overall incidence of acquired TDF resistance. Moreover, there remains a need for representative population-based surveillance for acquired and transmitted drug resistance. So far, global surveillance has detected limited evidence of transmitted TDF-associated mutations, but this needs to be monitored closely, especially in high incidence settings.

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Abacavir: a safe first line drug for children

Adverse events associated with abacavir use in HIV-infected children and adolescents: a systematic review and meta-analysis.

Jesson J, Dahourou DL, Renaud F, Penazzato M, Leroy V. Lancet HIV. 2016 Feb;3(2):e64-75. doi: 10.1016/S2352-3018(15)00225-8. Epub 2015 Dec 7.

Background: Concerns exist about the toxicity of drugs used in the implementation of large-scale antiretroviral programmes, and documentation of antiretroviral toxicity is essential. We did a systematic review and meta-analysis of adverse events among children and adolescents receiving regimens that contain abacavir, a widely used antiretroviral drug.

Methods: We searched bibliographic databases and abstracts from relevant conferences from Jan 1, 2000, to March 1, 2015. All experimental and observational studies of HIV-infected patients aged 0-18 years who used abacavir, were eligible. Incidence of adverse outcomes in patients taking abacavir (number of new events in a period divided by population at risk at the beginning of the study) and relative risks (RR) compared with non-abacavir regimens were pooled with random effects models.

Findings: Of 337 records and 21 conference abstracts identified, nine studies (eight full-text articles and one abstract) collected information about 2546 children, of whom 1769 (69%) were on abacavir regimens. Among children and adolescents taking abacavir, hypersensitivity reactions (eight studies) had a pooled incidence of 2.2% (95% CI 0.4-5.2); treatment switching or discontinuation (seven studies) pooled incidence was 10.9% (2.1-24.3); of grade 3-4 adverse events (six studies) pooled incidence was 9.9% (2.4-20.9); and adverse events other than hypersensitivity reaction (six studies) pooled incidence was 21.5% (2.8-48.4). Between-study inconsistency was significant for all outcomes (p<0.0001 for all inconsistencies). Incidence of death (four studies) was 3.3% (95% CI 1.5-5.6). In the three randomised clinical trials with comparative data, no increased risk of hypersensitivity reaction (pooled RR 1.08; 95% CI 0.19-6.15), grade 3 or 4 events (0.79 [0.44-1.42]), or death (1.72 [0.77-3.82]) was noted for abacavir relative to non-abacavir regimens. None of the reported deaths were related to abacavir.

Interpretation: Abacavir-related toxicity occurs early after ART initiation and is manageable. Abacavir can be safely used for first-line or second-line antiretroviral regimens in children and adolescents, especially in sub-Saharan Africa where HLA B5701 genotype is rare.

Abstract access

Editor’s notes: Abacavir is a nucleoside reverse transciptase inhibitor (NRTI), available as a paediatric formulation. Abacavir in combination with lamivudine is the preferred NRTI backbone for children aged three to ten years and for adolescents weighing under 35 kilograms. It is thus part of both first- and second-line antiretroviral therapy (ART) regimens recommended for children by World Health Organization (WHO), American and European guidelines.  

In the context of implementation of large-scale ART programmes where abacavir is recommended as the NRTI of choice, understanding its toxicity is crucial. In adults the main concern is the increased risk of hypersensitivity reactions, particularly among people with the HLA B5701 genotype, and of myocardial infarction. Children have specific characteristics that affect both the pharmacokinetic profiles of drugs, and also drug tolerability in the short and the long term. Despite the widespread use of abacavir, there has been no systematic evaluation of the toxicity profile of abacavir in children. 

This systematic review of nine studies conducted between 2000 and 2015 demonstrates that there is a low risk of hypersensitivity reactions, especially for children living in sub-Saharan Africa, where 90% of children with HIV live. This is consistent with studies in adults which illustrates that the frequency of the HLAB5701 allele genotype in African populations is low, estimated to be less than two percent.

Other adverse events such as gastrointestinal symptoms and laboratory abnormalities were common. Rates of adverse events should be interpreted with caution as these could depend on factors such as other drugs in the regimen, adherence and so on. Furthermore, data on adverse events were obtained from cohort studies that were not blinded and selection or recall bias cannot be excluded.

Notwithstanding this, most adverse events occurred early after initiation of abacavir, were no more common than with other NRTI regimens, and were manageable. Importantly, there were no deaths associated with abacavir in any of the reported studies. This study supports the use of abacavir as a preferred drug in the NRTI backbone for treatment of children living with HIV. 

HIV Treatment
Africa, Europe, Latin America
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High adherence to on-demand PrEP and no increase in sexual risk behaviours

Uptake of PrEP and condom and sexual risk behavior among MSM during the ANRS IPERGAY trial.

Sagaon-Teyssier L, Suzan-Monti M, Demoulin B, Capitant C, Lorente N, Preau M, Mora M, Rojas Castro D, Chidiac C, Chas J, Meyer L, Molina JM, Spire B, Group AIS. AIDS Care. 2016 Feb 17:1-8. [Epub ahead of print]

The double-blind phase of the randomized ANRS IPERGAY trial, evaluating sexual activity-based oral HIV pre-exposure prophylaxis (PrEP), was conducted among high-risk men who have sex with men (MSM). Results showed an 86% (95% CI: 40-98) relative reduction in HIV incidence among participants with tenofovir disoproxil fumarate-emtricitabine vs. placebo. The present pooled analysis aimed to analyze (i) participants' adherence to the prescribed treatment and/or condom use during sexual intercourse and (ii) sexual behavior during the double-blind phase of the study. Four hundred MSM were enrolled in the trial. Every 2 months they completed online questionnaires collecting sexual behavior and PrEP adherence data regarding their most recent sexual intercourse. A total of 2232 questionnaires (M0-M24) were analyzed. Changes over time were evaluated using a mixed model accounting for multiple measures. Irrespective of sexual partner and practice type, on average, 42.6% (min: 32.1-max: 45.8%) reported PrEP use only during their most recent episode of sexual intercourse; 29% (22.9-35.6%) reported both PrEP and condom use; 11.7% (7.2-18.9%) reported condom-use only, and 16.7% (10.8-29.6%) reported no PrEP or condom use with no significant change during the study. Scheduled (i.e., correct) PrEP use was reported on average by 59.0% (47.2-68.5%) of those reporting PrEP use during their most recent sexual intercourse. Overall, 70.3% (65.3-79.4%) and 69.3% (58.3-75.4%) of participants reported, respectively, condomless anal and condomless receptive anal intercourse during their most recent sexual encounter without significant change during follow-up. Overall, on average 83.3% (min: 70.4-max: 89.2%) of participants protected themselves by PrEP intake or condom use or both during the trial, and no increase in at-risk sexual practices was observed. None of these indicators showed significant trend during the follow-up, although we found a tendency toward decrease (p = .19) of the median number of sexual partners strengthening the absence of behavioral disinhibition. On-demand PrEP within a comprehensive HIV prevention package could improve prevention in MSM.

Abstract access

Editor’s notes: HIV pre-exposure prophylaxis (PrEP) is an effective method of HIV prevention, and it is now recognised as a key element of combination prevention strategies in key populations. The IPERGAY trial evaluated the intermittent use of oral PrEP, timed around sexual activity, in gay men and other men who have sex with men. The investigators hypothesised that taking PrEP ‘on demand’, i.e. at the time of sexual activity rather than daily, would improve adherence and therefore its effectiveness. The reduction in HIV incidence in the trial is one of the highest reported at 86%.

This analysis of trial participants in the double-blind phase of the trial demonstrated that PrEP and/or condom use at the most recent sexual intercourse was reported at 80% of visits, and there was no evidence of a change over time. Adherence remained quite high over the 24 months of follow-up, with 60% reporting correct use of PrEP at each visit, although numbers were small owing to early stopping of the placebo arm. As with other studies of PrEP, there was no evidence of an increase in reported sexual risk behaviours over time. In addition, there was some suggestion of a trend towards a decreased number of partners. However, as trial participants were offered a comprehensive care package (including regular adherence and risk reduction counselling), it is difficult to separate the effects of the intensive support from the effects of the PrEP regimen itself.

The successful integration of PrEP into HIV combination prevention programmes will require an understanding of factors that facilitate its uptake and who is most likely to benefit from its use, as well as ensuring regular HIV testing and adequate support services are available.

Europe, Northern America
Canada, France
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TB still responsible for large proportion of admissions and in-patient deaths among people living with HIV

TB as a cause of hospitalization and in-hospital mortality among people living with HIV worldwide: a systematic review and meta-analysis.

Ford N, Matteelli A, Shubber Z, Hermans S, Meintjes G, Grinsztejn B, Waldrop G, Kranzer K, Doherty M, Getahun H. J Int AIDS Soc. 2016 Jan 12;19(1):20714. doi: 10.7448/IAS.19.1.20714. eCollection 2016.

Introduction: Despite significant progress in improving access to antiretroviral therapy over the past decade, substantial numbers of people living with HIV (PLHIV) in all regions continue to experience severe illness and require hospitalization. We undertook a global review assessing the proportion of hospitalizations and in-hospital deaths because of tuberculosis (TB) in PLHIV.

Methods: Seven databases were searched to identify studies reporting causes of hospitalizations among PLHIV from 1 January 2007 to 31 January 2015 irrespective of age, geographical region or language. The proportion of hospitalizations and in-hospital mortality attributable to TB was estimated using random effects meta-analysis.

Results: From an initial screen of 9049 records, 66 studies were identified, providing data on 35 845 adults and 2792 children across 42 countries. Overall, 17.7% (95% CI 16.0 to 20.2%) of all adult hospitalizations were because of TB, making it the leading cause of hospitalization overall; the proportion of adult hospitalizations because of TB exceeded 10% in all regions except the European region. Of all paediatric hospitalizations, 10.8% (95% CI 7.6 to 13.9%) were because of TB. There was insufficient data among children for analysis by region. In-hospital mortality attributable to TB was 24.9% (95% CI 19.0 to 30.8%) among adults and 30.1% (95% CI 11.2 to 48.9%) among children.

Discussion: TB remains a leading cause of hospitalization and in-hospital death among adults and children living with HIV worldwide.

Abstract  Full-text [free] access

Editor’s notes: The last 30 years have seen radical improvements in outcomes for many people living with HIV. This study reminds us that in some parts of the world HIV-associated infections, tuberculosis (TB) in particular, still have a devastating effect on thousands of lives.

The importance of TB is widely recognised. WHO aim to reduce deaths due to TB by 75% over the next 10 years.  The question remains: do we really know how many people die due to TB?  Death certification has repeatedly been shown to be unreliable, particularly in the parts of the world where TB is most prevalent. Verbal autopsy is used to estimate cause of death in areas with poor notification systems, but poorly differentiates deaths due to TB and other HIV-associated conditions. Similar challenges are faced when counting and classifying morbidity and hospitalisations. Data are sparse, and determining the cause of an admission is not straightforward, even with access to well-maintained hospital records.  

This review, a sub-analysis of data from a broader study of HIV-associated hospital admissions, is by far the largest of its kind. The authors have been rigorous, given the heterogeneity of the studies included, and their findings are sobering. Among adults living with HIV, in all areas except Europe and South America, TB was the cause of 20-33% of admissions, and some 30% of adults and 45% of children who were admitted with TB were thought to have died from it. These findings are limited by the fact that not all reviewed studies reported on mortality and very few stated how causes of death were assigned.

This paper raises more questions than it answers, but they are important questions.  We are left in no doubt that TB is a major contributor to global morbidity and mortality in HIV-positive people, but we need to look closely at how we count and classify ‘TB deaths’ and ‘TB-associated admissions’. The recent systematic review of autopsy studies cited by the authors also found that almost half the TB seen at autopsy was not diagnosed before death. Global autopsy rates are in decline. Without access to more accurate data, how will we know if we’re winning or losing in our efforts to end TB deaths?

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A pill for HIV prevention: to take when you need it

On-demand preexposure prophylaxis in men at high risk for HIV-1 infection.

Molina JM, Capitant C, Spire B, Pialoux G, Cotte L, Charreau I, Tremblay C, Le Gall JM, Cua E, Pasquet A, Raffi F, Pintado C, Chidiac C, Chas J, Charbonneau P, Delaugerre C, Suzan-Monti M, Loze B, Fonsart J, Peytavin G, Cheret A, Timsit J, Girard G, Lorente N, Preau M, Rooney JF, Wainberg MA, Thompson D, Rozenbaum W, Dore V, Marchand L, Simon MC, Etien N, Aboulker JP, Meyer L, Delfraissy JF, Group AIS. N Engl J Med. 2015 Dec 3;373(23):2237-46. doi: 10.1056/NEJMoa1506273. Epub 2015 Dec 1.

Background: Antiretroviral preexposure prophylaxis has been shown to reduce the risk of human immunodeficiency virus type 1 (HIV-1) infection in some studies, but conflicting results have been reported among studies, probably due to challenges of adherence to a daily regimen.

Methods: We conducted a double-blind, randomized trial of antiretroviral therapy for preexposure HIV-1 prophylaxis among men who have unprotected anal sex with men. Participants were randomly assigned to take a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) or placebo before and after sexual activity. All participants received risk-reduction counseling and condoms and were regularly tested for HIV-1 and HIV-2 and other sexually transmitted infections.

Results: Of the 414 participants who underwent randomization, 400 who did not have HIV infection were enrolled (199 in the TDF-FTC group and 201 in the placebo group). All participants were followed for a median of 9.3 months (interquartile range, 4.9 to 20.6). A total of 16 HIV-1 infections occurred during follow-up, 2 in the TDF-FTC group (incidence, 0.91 per 100 person-years) and 14 in the placebo group (incidence, 6.60 per 100 person-years), a relative reduction in the TDF-FTC group of 86% (95% confidence interval, 40 to 98; P=0.002). Participants took a median of 15 pills of TDF-FTC or placebo per month (P=0.57). The rates of serious adverse events were similar in the two study groups. In the TDF-FTC group, as compared with the placebo group, there were higher rates of gastrointestinal adverse events (14% vs. 5%, P=0.002) and renal adverse events (18% vs. 10%, P=0.03).

Conclusions: The use of TDF-FTC before and after sexual activity provided protection against HIV-1 infection in men who have sex with men. The treatment was associated with increased rates of gastrointestinal and renal adverse events.

Abstract Full-text [free] access

Editor’s notes: The IPERGAY trial is the first trial to assess ‘on demand’ HIV pre-exposure prophylaxis (PrEP). It had a ‘take it when you need it’ approach, rather than a daily dosing approach where a pill is taken every day, regardless of sexual activity. In 2010, the iPrEx Trial of daily pills among gay men and other men who have sex with men reported a 42% relative reduction in HIV incidence. In participants with detectable drug in their blood (meaning that they had been taking the pills), the reduction was 92%. The IPERGAY researchers set out to prove or disprove the hypothesis that men would be more likely to take pills if pill-taking was associated with having sex. The hypothesis was that this might improve adherence and hence reduce the risk of HIV acquisition compared with daily dosing. Participants were randomly assigned to take a dose of two pills of TDF/FTC (tenofovir disoproxil fumarate/emtricitabine) or placebo with food between two and 24 hours before sex. A third pill was taken 24 hours after sex and a fourth pill 24 hours after that. If they continued to be sexually active, they were told to take one pill a day while sexually active and then the two post-exposure doses 24 hours apart. When the striking results of the PROUD trial in the United Kingdom, among gay men and other men who have sex with men, were made public [see HIV This Month February 2015], IPERGAY’s Data Safety and Monitoring Board (DSMB) asked for an unblinded interim analysis of the IPERGAY data. The results were so convincing (an 86% relative risk reduction) that the DSMB recommended that the trial be unblinded so that men in the placebo arm could be offered active drug. The next question was whether this highly effective preventive measure could be made available outside the trial setting. The Food and Drug Administration of the United States of America had approved TDF/FTC for HIV PrEP in 2012 but no country had followed suit. On November 23, 2015, France’s Minister for Social Affairs, Health, and Women’s Rights announced a temporary recommendation for the use of TDF/FTC HIV prophylaxis, opening the way to the authorisation of PrEP in other European countries. Before any other European country responded, South Africa’s Medicines Control Council announced on December 3, 2015 its approval of the fixed-dose combination of TDF/FTC for pre-exposure prophylaxis of HIV. Kenya’s Pharmacy & Poisons Board also approved once-daily use of TDF/FTC for HIV prevention on December 23, 2015. The scientific evidence has been building for years. Clearly it is time to act now to make this highly effective HIV prevention choice available to people at highest risk of HIV exposure.

Europe, Northern America
Canada, France
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Large multi-centre study finds few differences between mortality in migrant and native populations in western Europe

Mortality in migrants living with HIV in western Europe (1997-2013): a collaborative cohort study.

Migrants Working Group on behalf of COHERE in EuroCoord. Lancet HIV. 2015 Dec;2(12):e540-9. doi: 10.1016/S2352-3018(15)00203-9. Epub 2015 Nov 18.

Background: Many migrants face adverse socioeconomic conditions and barriers to health services that can impair timely HIV diagnosis and access to life-saving treatments. We aimed to assess the differences in overall mortality by geographical origin in HIV-positive men and women using data from COHERE, a large European collaboration of HIV cohorts from 1997 to 2013.

Methods: In this observational cohort study, we included HIV-positive, antiretroviral-naive people accessing care in western Europe from COHERE. Individuals were eligible if enrolled in a cohort that collected information on geographical origin or ethnic origin from Jan 1, 1997, to March 19, 2013, aged 18-75 years, they had available information about sex, they were not infected perinatally or after the receipt of clotting factor concentrates, and were naive to combination antiretroviral therapy at cohort entry. Migrants' origins were grouped into seven regions: western Europe and similar countries (Australia, Canada, New Zealand, and the USA); eastern Europe; North Africa and the Middle East; sub-Saharan Africa; Latin America; the Caribbean; and Asia and the rest of Oceania (excluding Australia and New Zealand). Crude and adjusted mortality rate ratios were calculated by use of Poisson regression stratified by sex, comparing each group with the native population. Multiple imputation with chained equations was used to account for missing values.

Findings: Between Oct 25, 1979, and March 19, 2013, we recruited 279 659 individuals to the COHERE collaboration in EuroCoord. Of these 123 344 men and 45 877 women met the inclusion criteria. Our data suggested effect modification by transmission route (pinteraction=0.12 for men; pinteraction=0.002 for women). No significant difference in mortality was identified by geographical origin in men who have sex with men. In heterosexual populations, most migrant men had mortality lower than or equal to that of native men, whereas no group of migrant women had mortality lower than that in native women. High mortality was identified in heterosexual men from Latin America (rate ratio [RR] 1.46, 95% CI 1.00-2.12, p=0.049) and heterosexual women from the Caribbean (1.48, 1.29-1.70, p<0.0001). Compared with that in the native population, mortality in injecting drug users was similar or low for all migrant groups.

Interpretation: Characteristics of and risks faced by migrant populations with HIV differ for men and women and for populations infected heterosexually, by sex between men, or by injecting drug use. Further research is needed to understand how inequalities are generated and maintained for the groups with higher mortality identified in this study.

Abstract access 

Editor’s notes: This topical analysis on migrant health from the large COHERE collaboration examined mortality in people living with HIV who are treatment-naïve and enrolling for care in 11 western European countries. Routinely collected data were analysed to explore differences in mortality by region of origin. Overall, few differences in mortality were seen between migrant and native populations, with a general trend of similar or lower mortality among migrants than native populations.  However, diversity within migrant groups even from the same region makes it challenging to interpret summary data. The authors provide interesting insights into these difficulties. For example, the reasons for migration are likely to result in different socio-economic conditions in the host country, but heterogeneity in mortality between sub-groups may be masked when looking at overall mortality in migrants compared with the native population. The authors discuss both the “healthy migrant effect” (the fact that it is often healthier, younger populations who are able to migrate), and the “salmon bias” (the fact people who are ill often return to their place of origin). Both of these effects can lead to an observed lower disease burden in migrants than native populations. At a time when immigration is a hotly debated issue in western Europe this study highlights the challenges in assessing migrant health and the need for further empirical and methodological research in this area.

Europe
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Effective pre-conception ART eliminates mother-to-child transmission

No perinatal hiv-1 transmission from women with effective antiretroviral therapy starting before conception.

Mandelbrot L, Tubiana R, Le Chenadec J, Dollfus C, Faye A, Pannier E, Matheron S, Khuong MA, Garrait V, Reliquet V, Devidas A, Berrebi A, Allisy C, Elleau C, Arvieux C, Rouzioux C, Warszawski J, Blanche S, Group A-ES. Clin Infect Dis. 2015 Dec 1;61(11):1715-25. doi: 10.1093/cid/civ578. Epub 2015 Jul 21.

Background: The efficacy of preventing perinatal transmission (PT) of human immunodeficiency virus type 1 (HIV-1) depends on both viral load (VL) and treatment duration. The objective of this study was to determine whether initiating highly active antiretroviral therapy (ART) before conception has the potential to eliminate PT.

Methods: A total of 8075 HIV-infected mother/infant pairs included from 2000 to 2011 in the national prospective multicenter French Perinatal Cohort (ANRS-EPF) received ART, delivered live-born children with determined HIV infection status, and did not breastfeed. PT was analyzed according to maternal VL at delivery and timing of ART initiation.

Results: The overall rate of PT was 0.7% (56 of 8075). No transmission occurred among 2651 infants born to women who were receiving ART before conception, continued ART throughout the pregnancy, and delivered with a plasma VL <50 copies/mL (upper 95% confidence interval [CI], 0.1%). VL and timing of ART initiation were independently associated with PT in logistic regression. Regardless of VL, the PT rate increased from 0.2% (6 of 3505) for women starting ART before conception to 0.4% (3 of 709), 0.9% (24 of 2810), and 2.2% (23 of 1051) for those starting during the first, second, or third trimester (P < .001). Regardless of when ART was initiated, the PT rate was higher for women with VLs of 50-400 copies/mL near delivery than for those with <50 copies/mL (adjusted odds ratio, 4.0; 95% CI, 1.9-8.2).

Conclusions: Perinatal HIV-1 transmission is virtually zero in mothers who start ART before conception and maintain suppression of plasma VL.

Abstract access 

Editor’s notes: The risk of HIV transmission from mother-to-child is around 15-45% in the absence of maternal antiretroviral therapy (ART). This study illustrates that the risk of mother-to-child transmission is virtually eliminated when ART is started prior to conception and plasma viral load (VL) is undetectable at delivery. These findings provide further evidence supporting the implementation of Option B+ (lifelong ART as early as possible in all HIV-positive pregnant women regardless of CD4 count and VL) in low-income countries. In these settings, effectiveness of pre-conception ART will be dependent on retention in care so that women remain virologically suppressed for subsequent pregnancies. Robust surveillance data of pregnancy outcomes and other short-term and long-term risks of ART on the foetus, such as congenital malformations, and on the infant, such as pre-term birth, are also necessary to confirm that the benefit of pre-conception ART outweighs any harm.

Europe
France
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