Articles tagged as "Blood / body fluids and HIV prevention"

Nutrition and People Living with HIV

Serum Vitamin D concentration and potential risk factors for its deficiency in HIV positive individuals

Etminani-Esfahani M, Khalili H, Soleimani N, Jafari S, Abdollahi A, Khazaeipour Z, Gholami K. Curr HIV Res. 2012 Feb 2. [Epub ahead of print]

Human immunodeficiency virus (HIV) infected individuals are prone to malnutrition, and deficiencies of some minerals and vitamins. The aim of this study is to evaluate the frequency of vitamin D deficiency and determine the possible risk factors associated with this problem in HIV-infected individuals. This cross-sectional study was performed on 98 adult patients referred to the Emam Khomeini Hospital Complex, Tehran, Iran. The patients' serum vitamin D concentration was determined using radioimmunoassay method. The possible correlations between demographic and clinical data with the level of vitamin D were evaluated. Vitamin D levels less than 35 nmol/l was considered as deficient in this study. Eighty-five (86.7%) of patients had serum vitamin D deficiency (concentrations less than 35 nmol/l) in this study. Co-infection with hepatitis C virus was present in 54 (55.1%) of patients. Only daily intake of vitamin D (r=0.304, p=0.002), duration of sun exposure (r=0.268, p=0.009), the level of parathryroid hormone (r=-0.459, p<0.001), daily intake of calcium (r=0.239, p=0.018) and glomerular filtration rate of more than 90 ml/min (OR=1.208, CI 95%= 1.080-1.350, p=0.033) had correlation with serum vitamin D concentration. Being female (OR=7.224, CI 95%= 3.640-14.335, p<0.001), unemployed (OR= 1.627, CI 95%=1.209-2.190, p<0.001) and infected with hepatitis C virus (OR= 1.811, CI 95%= 1.331-2.465, p<0.001) were related to the severe serum vitamin D deficiency. Vitamin D deficiency is a common problem in Iranian HIV-infected patients and with concern of this vitamin's important role in health issues, early evaluation of its status and providing appropriate nutritional support seems to be important.

For abstract access click here. 

Editor’s note: This study documenting the extent of Vitamin D deficiency among Iranian HIV patients raises some important issues, given the important role of Vitamin D for human health. It influences processes as diverse as muscle function, immune regulation, protection against cancer and cardiovascular disease, and calcium and phosphorous balance, let alone bone health. Vitamin D deficiency is common in the North, particularly at the end of winter when Vitamin D stores are lowest due to lack of exposure to sunlight, affecting those of darker skin most. One would expect Iranians to be less affected but this study suggests that this is not the case for people living with HIV in Iran and elsewhere. Potential mechanisms are macronutrient and micronutrient deficiencies due to inadequate intake, nutrient loss through malabsorption and diarrhoea, and metabolic alterations. As well, some antiretroviral drugs increase the rate of Vitamin D hydroxylation to inactive compounds. Renal function is also important because the kidneys generate the active form of Vitamin D. Further, people co-infected with hepatitis C appear to be more prone to Vitamin D deficiency. Although evidence for the benefits of Vitamin D supplementation in people living with HIV is lacking, it makes sense to get more sun exposure, eat Vitamin D fortified food, and take extra units of Vitamin D, pending more information.

Iran (Islamic Republic of)
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Microbicides

Microbicides: Topical prevention against HIV

Shattock RJ, Rosenberg Z. Cold Spring Harb Perspect Med. 2012 Feb;2(2):a007385

Microbicides represent a potential intervention strategy for preventing HIV transmission. Vaginal microbicides would meet the need for a discreet method that women could use to protect themselves against HIV. Although early-generation microbicides failed to demonstrate efficacy, newer candidates are based on more potent antiretroviral products. Positive data from the CAPRISA 004 trial of tenofovir gel support use in women and represent a turning point for the field. This article reviews current progress in development of ARV-based microbicides. Shattock and Rosenberg discuss the consensus on selection criteria, the potential for drug resistance, rationale for drug combinations, and the use of pharmacokinetic (PK)/pharmacodynamic (PD) assessment in product development. The urgent need for continued progress in development of formulations for sustained delivery is emphasized. Finally, as the boundaries between different prevention technologies become increasingly blurred, consideration is given to the potential synergy of diverse approaches across the prevention landscape.

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Editor’s note: This article makes for excellent background reading In the lead up to the biannual Microbicides 2012 conference being held in Sydney, Australia April 15 to 18, 2012. The colour figures show you exactly where and how effective vaginal microbicides would work. Microbicides are topical PrEP and they come as gels, tablets, capsules, films, and intravaginal rings. The focus now is on formulations that women want to use – tenofovir gel applied before and after sex appears to have been more acceptable in CAPRISA 004 than it was in the VOICE trial’s dosing of ‘every day regardless of whether or not sex is going to or has happened’. FACTS 001 is the trial in South Africa that is testing the BAT24 (before sex, after sex, and not more than twice in 24 hours) dosing of CAPRISA 004. Choosing combinations of antiretroviral drugs and designing intravaginal formulations that can co-carry them is the next challenge, along with developing gels with fewer side effects for rectal application before anal sex. As this article underscores, principles for prioritising candidates in the pipeline include safety, efficacy, cost, acceptability, appropriate drug delivery, long-term efficacy, potential for resistance and impact on therapy, and whether a product is ‘best-in-class’. This is a dynamic active research field, spurred on by the proof of concept shown in CAPRISA 004. Expectations for tangible results in the coming years are understandably high.

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Positive health, dignity, and prevention

ABC for people with HIV: responses to sexual behaviour recommendations among people receiving antiretroviral therapy in Jinja, Uganda

Allen C, Mbonye M, Seeley J, Birungi J, Wolff B, Coutinho A, Jaffar S. Cult Health Sex. 2011 Mar 1:1

People living with HIV who are taking antiretroviral therapy are increasingly involved in 'positive prevention' initiatives. These are generally oriented to promoting abstinence, 'being faithful' (partner reduction) and condom use (ABC). Allen and colleagues conducted a longitudinal qualitative study with people living with HIV using antiretroviral therapy, who were provided with adherence education and counselling support by a Ugandan non-governmental organisation, The AIDS Support Organisation (TASO). Forty people were selected sequentially as they started antiretroviral therapy, stratified by sex, antiretroviral therapy delivery mode (clinic- or home-based) and HIV progression stage (early or advanced) and interviewed at enrolment and at 3, 6, 18 and 30 months. At initiation of antiretroviral therapy, participants agreed to follow TASO's positive-living recommendations. Initially poor health prevented sexual activity. As health improved, participants prioritised resuming economic production and support for their children. With further improvements, sexual desire resurfaced and people in relationships cemented these via sex. The findings highlight the limitations of HIV prevention based on medical care/personal counselling. As antiretroviral therapy leads to health improvements, social norms, economic needs and sexual desires increasingly influence sexual behaviour. Positive prevention interventions need to seek to modify normative and economic influences on sexual behaviour, as well as to provide alternatives to condoms.

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Editors’ note: This qualitative study of patient perspectives on life changes, relationships, and adherence challenges was nested in a trial of 1453 people living with HIV who were randomised to receive home-based care employing lay workers or standard clinic care in Jinja, Uganda provided by TASO. The results call into question standard ABC (abstinence, be faithful, condomise) counselling in the context of evolving sexuality as health improves on antiretroviral therapy and people attempt to re-establish their social position and feel ‘normal’ again. Social norms dictating that married people have sex with their spouses when they are well enough, that childless couples have a child, or that condom use should cease when a relationship transitions from a casual to a regular and committed partnership have to be navigated by people living with HIV as they regain their health. Protection from reinfection with a different HIV strain or from other sexually transmitted diseases is one aspect but the overarching objective of ‘positive health, dignity, and prevention’ strategies is to enable and empower people living with HIV to lead emotionally healthy lives with dignity. As the authors suggest, male circumcision for HIV-negative men in discordant couples and antiretroviral microbicides (when they are licensed) for HIV-negative women in discordant couples can play an important role in the future. They wrote this before HPTN 052 announced treatment for prevention.

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Genital tract susceptibility

Induction of Innate Immune Responses in the Female Genital Tract: Friend or Foe of HIV-1 Infection?

Firoz Mian M, Ashkar AA. Am J Reprod Immunol. 2011 Mar;65(3):344-51

Heterosexual transmission of HIV-1 and HSV-2 across the genital tract epithelial tissue is one of the primary routes for dissemination of these viral infections. Mucosal innate immunity is the first line of defense against invading pathogens. A vast majority of mucosal HIV-1 exposures do not result in productive infections which may indicate that the innate mucosal immune system is highly protective. It has been shown that Toll-like receptors (TLR)-induced innate antiviral immunity in the genital mucosa lead to induction of type I and III interferon and prevention of HSV-2 infection. The innate antiviral function of type I and III interferons and other innate factors at genital mucosa against HIV-1 is not well defined. In this review, Firoz Mian and Ashkar summarize their current understanding and advances of the innate mucosal response to genital viral infections, including HIV-1 and HSV-2, focusing on those factors that may prevent or accelerate initial infection. Understanding how each of these components contributes to mucosal innate antiviral immunity may lead to the development of novel and effective strategies to use microbicides or antiviral agents to control HIV-1 acquisition and/or transmission.

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Editors’ note: Innate immunity is our first line of defence against viruses, limiting their replication until adaptive immunity steps in. However, much of the work to date on immunological responses to HIV has focused on adaptive immunity in the search for an HIV vaccine. It is important to understand whether innate immunity at the mucosal level protects against HIV and, if so, how it works. Immune mechanisms vary by site—this review focuses on the innate immune response in the female genital tract. It includes mechanical interference, immediate cytokine/chemokine and interferon responses to prevent viral replication and spread, and rapid recruitment of cellular defences. Hormones, secreted mediators (e.g. human β-defensins, secretory leukoprotease inhibitors, lactoferin, trappin-2/elafin), toll-like receptors (TLR)—all regulate the immune response in the complex female genital tract microenvironment. For example, toll-like receptors recognise conserved pathogen-associated molecular patterns (PAMPs) made by invading pathogens and link to pathogens, triggering local inflammation, recruitment of effector cells, and secretion of cytokines/chemokines and interferon (IFN). But HIV is wily, inhibiting host defence factors and evading the TLR-IFN pathway to take advantage of inflammatory responses to replicate in the cells that have responded to the call for help. In the search for effective anti-HIV microbicides, we need to take advantage of what we know about innate immunity and learn more.

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Microbicides

Female genital tract secretions and semen impact the development of microbicides for the prevention of HIV and other sexually transmitted infections

Herold BC, Mesquita PM, Madan RP, Keller MJ. Am J Reprod Immunol. 2011; 65:325-333

Pharmacologic strategies for the prevention of HIV include vaccines, post-exposure prophylaxis with antiretroviral therapy, and topical microbicides. Vaginal microbicides have the potential to augment innate defenses in the genital tract but may also disrupt endogenous protection and increase HIV acquisition risk, as observed in clinical trials of nonoxynol-9. The initially disappointing results of microbicide clinical trials stimulated the development of more sensitive and comprehensive pre-clinical safety studies, which include dual-chamber culture systems to model the epithelial barrier and post-coital studies to evaluate the effects of semen and sexual intercourse on microbicide efficacy. This review discusses the key factors that contribute to a healthy female genital tract environment, the impact of semen on mucosal defense, and how our understanding of these mediators informs the development of effective vaginal microbicides.

Abstract

Editors’ note: This article provides strong justification for conducting pharmacokinetic and pharmacodynamic studies for microbicide candidates using post-coital samples rather than ordinary cervicovaginal secretions. The female genital tract has several natural host defences that semen counteracts. It neutralises the protective acidic pH of vaginal fluid, stimulates inflammatory cytokines, and causes white cells and Langerhans cells to come into the path of HIV. More directly, semen contains prostatic acid phosphatise which forms fibrils that capture HIV and help their attachment to target cells. Semen may also interfere with defensins, SLPI (secretory leukocyte protease inhibitor), and other antimicrobial proteins found in cervicovaginal secretions. Clearly, when we are trying to measure the effects of a microbicide candidate on the multilayered squamous epithelial barrier of the vagina we have to include semen. Predictive safety assays such as those described in this article are helping us understand why microbicide candidates such as non-oxynol 9 and cellulose sulfate increased risk of HIV acquisition. We need to better understand mucosal immunity and the role of semen in order to find ways to increase women’s natural defenses. In the meantime, reading this article brings the reader right back to square one—if there is any possibility of HIV or genital herpes, use a condom if you are not trying to get pregnant!

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Plasma donation and HIV

HIV-infected former plasma donors in rural central China: from infection to survival outcomes, 1985-2008

Dou Z, Chen RY, Wang Z, Ji G, Peng G, Qiao X, Fu J, Meng X, Bulterys M, Ma Y, Zhao Y, Wang N, Zhang F. PLoS One. 2010 Oct 29; 5(10):e13737.

The HIV epidemic among former plasma donors in rural central China in the early-mid 1990s is likely the largest known HIV-infected cohort in the world related to commercial plasma donation but has never been fully described. The objectives of this study are to estimate the timing and geographic spread of HIV infection in this cohort and to demonstrate the impact of antiretroviral therapy on survival outcomes. HIV-infected former plasma donors were identified using the national HIV epidemiology and treatment databases. Locations of subjects were mapped. Dates of infection and survival were estimated using the midpoint date between initial-final plasma donation dates from 1985-2008 among those with plasma donation windows ≤2 years. Among 37084 former plasma donors in the two databases, 36110 were included. 95% were located in focal areas of Henan province and adjacent areas of surrounding provinces. Midpoint year between initial-final plasma donation dates was 1994 among former plasma donors with known donation dates. Median survival from infection to AIDS was 11.8 years and, among those not treated, 1.6 years from AIDS to death. Among those on treatment, 71% were still alive after five years. Using Cox proportional hazard modelling, untreated AIDS patients were 4.9 times (95% confidence interval 4.6-5.2) more likely to die than those on treatment. The epidemic of HIV-infected former plasma donors in China was not widespread throughout China but rather was centred in Henan Province and the adjacent areas of surrounding provinces. Even in these areas, infections were concentrated in focal locations. Overall, HIV infections in this cohort peaked in 1994, with median survival of 13.4 years from infection to death among those not treated. Among AIDS patients on treatment, 71% were still alive after five years.

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Editors’ note: These survival figures are biased upwards because many people had likely died by 2004 when mass HIV screening identified tens of thousands of former plasma donors with HIV infection across central China. Commercial plasma collection had already been stopped for many years (1996). The full story from 1990 to 2004 remains to be told but the Chinese government responded to the 2004 screening results by setting up a free treatment programme for former plasma donors that eventually scaled up to the national level. Why did these primarily poor male farmers come to commercial plasma donation stations in the first place? Plasma donation involved giving blood and receiving pooled blood cells back from blood-type matched donors. The payment they got in return supplemented meagre farming incomes while the blood cell transfusion back, combined with drinking fluids to replace the plasma, meant that the farmer felt strong for work. Why were commercial plasma donation centres set up in rural Henan province and surrounding areas? Risk factors for blood-transmitted infections such as hepatitis B and HIV were low – there was almost no injecting drug use or sex work in these communities. Donations were screened for hepatitis B which can be transmitted perinatally but not for HIV. The Chinese plasma donor HIV epidemic demonstrates graphically what happens if strict blood-borne pathogen precautions are not followed – beyond the donors, many spouses and children also became infected with HIV.

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Blood transfusion risk

Estimate of the residual risk of transfusion-transmitted human immunodeficiency virus infection in sub-Saharan Africa: a multinational collaborative study

Lefrère JJ, Dahourouh H, Dokekias AE, Kouao MD, Diarra A, Diop S, Tapko JB, Murphy EL, Laperche S, Pillonel J. Transfusion. 2010 Sep 28. doi: 10.1111/j.1537-2995.2010.02886.x. [Epub ahead of print]

Sub-Saharan Africa remains the epicenter of the human immunodeficiency virus (HIV) pandemic. However, there is a lack of multicentre data on the risk of transfusion-transmitted HIV from blood centres in sub-Saharan Africa. The incidence of HIV infections in blood donations collected in the main blood banks of five countries (Burkina Faso, Congo, Ivory Coast, Mali, and Senegal) was determined to estimate the current transfusion risk of HIV infection using the incidence rate/window period model. The risk of transfusion-transmitted HIV infections associated with the window period varied from 1 in 90,200 donations (Senegal) to 1 in 25,600 (Congo). Considering the five participating blood centres as a whole, the incidence rate of HIV-positive donors per 100,000 person-years was 56.6 (95% confidence interval [CI], 47.1-67.9); the residual risk was 34.1 (95% CI, 7.8-70.7) per 1 million donations, which represents 1 in 29,000 donations (95% CI, 1/128,000-1/14,000). Residual risk estimates varied according to the country. This is potentially due to a lower incidence of HIV infection in the general population or to a more efficient selection of blood donors in the countries with the lowest risk. The estimates of the transfusion risk of HIV infection in each country are important, both to assess the impact of current preventative strategies and to contribute data to policy decisions to reinforce transfusion safety.

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Editors’ note: This is this first published study estimating the residual risk of transfusion-related HIV transmission after standard blood screening using HIV incidence among repeat donors in five sub-Saharan African countries. The result – 1 in 29,000 donations in Burkina Faso, Congo, Ivory Coast, Mali, and Senegal – contrasts markedly with the estimate for South Africa of 1 in 479,000. South Africa uses nucleic acid testing (NAT), the more expensive but efficacious option employed for blood donation screening in industrialised countries. NAT identifies donors with HIV infection who are in the pre-seroconversion window period, after infection and before HIV antibodies appear. WHO estimated in 2005 that up to 5% of HIV transmissions in sub-Saharan Africa were transfusion-related. NAT would improve transfusion safety significantly in this highest prevalence region in the world, with a cheaper interim option being some form of combination antigen/antibody testing. Regardless, it is important to strengthen donor selection by restricting donation to volunteer, unpaid, regular donors at low risk of blood-borne infections and sexually transmitted infections. Upstream prevention of blood transfusion-related HIV transmission entails avoiding unnecessary transfusions, along with prevention and timely management of anaemia caused by obstetrical haemorrhage, nutritional deficiencies, and malaria and other infections.



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Basic science

HIV-1 populations in semen arise through multiple mechanisms

Anderson JA, Ping L-H, Dibben O, Jabara CB, Arney L, Kincer L, Tang Y, Hobbs M, Hoffman I, Kazembe P, Jones CD, Borrow P, Fiscus S, Cohen MS, Swanstrom R. PLoS Pathogens. 2010;6: e1001053

HIV-1 is present in anatomical compartments and bodily fluids. Most transmissions occur through sexual acts, making virus in semen the proximal source in male donors. Anderson and colleagues find three distinct relationships in comparing viral RNA populations between blood and semen in men with chronic HIV-1 infection, and they propose that the viral populations in semen arise by multiple mechanisms including: direct import of virus, oligoclonal amplification within the seminal tract, or compartmentalization. In addition, they find significant enrichment of six out of nineteen cytokines and chemokines in semen of both HIV-infected and uninfected men, and another seven further enriched in infected individuals. The enrichment of cytokines involved in innate immunity in the seminal tract, complemented with chemokines in infected men, creates an environment conducive to T cell activation and viral replication. These studies define different relationships between virus in blood and semen that can significantly alter the composition of the viral population at the source that is most proximal to the transmitted virus.

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Editors’ note: This groundbreaking work reveals that the disconnect sometimes observed between HIV-1 in blood plasma and semen is not just a quantitative one, e.g. undetectable viral load in plasma when virus is detectable in semen. It can also be a qualitative one, with different virus populations found in semen in some individuals. This study used single genome amplification to generate viral sequences from blood plasma and semen specimens from chronically infected men. In some men, the viral populations were the same, i.e. they were equilibrated as if they had been directly transferred from the blood. In others, there was evidence of clonal amplification, meaning that although the same sequences were seen as in the blood, their proportional representation was different suggesting that certain viral sequences had duplicated themselves in the semen. In yet others, there were viral sequences with no match in the blood – they were following a distinct evolutionary pathway. We need to better understand how immune modulators (cytokines and chemokines) may be shaping an environment that keeps activated target cells at the ready for HIV infection – this virus is one step ahead of us.

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Blood safety

Progress in Global Blood Safety for HIV

Takei T, Abu Amin N, Schmid G, Dhingra-Kumar N, and Rugg D, J Acquir Immune Defic Syndr, 2009;52(S2)

The aim of the report was to assess progress towards ensuring a globally safe blood supply. The authors examined 2 global databases for blood safety: that of the United Nations General Assembly Special Session on HIV/AIDS (UNGASS) blood safety indicator; and that of the Global Database on Blood Safety (GDBS), a database developed by the World Health Organization. The UNGASS data were collected through the Ministry of Health based on the GDBS data, followed by a reconciliation and cross-checking of the data by World Health Organization and United Nations Programme on AIDS (UNAIDS). They found that the proportion of United Nations member countries reporting UNGASS data for blood safety is among the highest of all UNGASS indicators: 147 of 192 United Nations Member States participated in UNGASS reporting in 2008 and 125 of them (85%) submitted data on blood safety. Ninety-one of the 125 countries (73%) reported that 100% of collected blood units were screened in a quality assured manner, but 34 countries did not screen all collected blood units in accordance with minimum quality standards. GDBS data showed that 80.7 million blood units were collected globally in 167 countries during 2004–2005, of which 77.3 million were tested for HIV and at least 0.6 million of the remaining 3.4 million donations went untested. In conclusion, progress has been made toward eliminating blood transfusion as a significant cause of HIV infection globally. Screening all donated blood for HIV in accordance with minimum quality standards remains vital, however, as health care systems should, at a minimum, do no harm. This goal is achievable and would assist in reaching Millennium Development Goals by 2015.

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Editors’ note: Because receiving HIV-infected blood leads to HIV infection in 95 to 100 per cent of people who are transfused with it, ensuring the safety of blood transfusion is a highly cost-effective prevention measure at an estimated 18$ per HIV infection averted. The fact that screening all donated blood in accordance with standardised procedures in a quality assured manner is still not universal around the world is disturbing. Gaps in blood supply in some settings are endangering lives and 50% of transfusions are unnecessary in others, but it is of immediate concern that so many countries are failing to ensure safe blood for their citizens when they are in dire need. Achieving this goal is not beyond reach and will save lives.  

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Blood donor referral

Vamvakas EC. Scientific background on the risk engendered by reducing the lifetime blood donation deferral period for men who have sex with men. Transfus Med Rev. 2009 Apr;23(2):85-102.

The lifetime deferral for men who have sex with men has not been harmonized with the 12-month deferral for similar-risk activities through heterosexual contacts. This occurs primarily because of fears of increased transfusion transmission of known sexually and transfusion-transmitted viruses for which donor blood is (eg, HIV) or is not (eg, human herpesvirus 8 [HHV-8]) tested and also of fears of novel agents that may share the epidemiology and long asymptomatic phase of HIV. A 12-month men who have sex with men deferral could result in release of 1 HIV-infectious donation every 11 years in the United States. This risk is smaller than the risk from allowing the continued use of pooled whole blood-derived platelets (release of 1 infectious platelet dose every 1.67 years), a risk that is considered “tolerable.” Provided that measures to reduce the number of allogeneic-donor exposures to novel pathogens (which may be vector- or food-borne rather than sexually transmitted) are implemented, and the deferral for similar-risk activities through heterosexual contacts is extended to 5 years, a 5-year men who have sex with men deferral could be justified because of the interval between emergence of a novel pathogen and introduction of measures to protect the blood supply. Also, provided that measures to protect the blood supply from HHV-8 are implemented, a lifetime men who have sex with men deferral could be justified because of the uncertainty about the clinical consequences of transfusion transmission of HHV-8. Because such alternate measures, which would have had a greater impact on safety than the men who have sex with men deferral, have not been implemented to demonstrate a consistent approach to safety, maintenance of the current men who have sex with men deferral appears to be selectively precautionary and cannot be justified.

Editors’ note: Arguments have been advanced to harmonise the deferral periods for men who have sex with men with those for heterosexuals with similar-risk activities. Argentina, Brazil, Japan, Hungary, New Zealand, Russia, and South Africa have substituted a 1-, 5-, or 10-year deferral for the lifetime deferral of men who have sex with men. The USA, Canada, and the 19-nation European Blood Alliance maintain their current positions. This article argues cogently for a scientifically based, consistent approach to blood safety. It highlights the ramifications for blood safety of inconsistencies in national policies, arguing that the men who have sex with men lifetime deferral is selectively precautionary. More can be achieved by interventions to protect the blood supply against HHV-8 and by prohibiting the use of pooled whole blood-derived platelets. On balance, arguments can be made that extending the heterosexual deferral from 1 year to 5 years and harmonising the men who have sex with men deferral to 5 years would reasonably protect against an ‘HIV-like’ agent that could emerge in the future.

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