Counterfeit Artemisinin Derivatives and Africa: Update from Authors

Since the publication of our article on counterfeit artesunate in June 2006 [1], further information has become available which we would like to report, as it has public health significance. An additional two counterfeit artesunate “types” with distinguishing features of the packaging have been found in mainland Southeast Asia, bringing the number of physical types to at least 14. For details see “Fake Artesunate Warning Sheet Number 5a” [2], an update (dated August 2006) to that published as supplementary material to the above paper. 
 
In addition, we would like to bring readers' attention to the newspaper reports of counterfeit artesunate and dihydroartemisinin seized from ladies' handbags at Lagos airport [3].

amme wvdamme@itg.be 
Paul N Newton 
Michael D Green 
Facundo Fernandez 

University of Cape Town Cape Town
Western CapeSouth Africa


Komfo Anokye Teaching Hospital Kumasi
Ghana


University of KwaZulu-Natal
Scottsville, PietermaritzburgSouth Africa


Alzaiem Alazhari University Khartoum North
Sudan


Chris Hani Baragwanath Hospital Meyersdal
GautengSouth Africa


Tropical Institute of Community Health and Development in Africa Kisumu
Kenya


University of Malawi Blantyre
Malawi


Food and Nutrition Center Dar es Salaam
Tanzania, United Republic of Tanzania


Directorate of Public Health and Research Lusaka
Zambia


University of Yaounde Yaounde
Cameroon


Navrongo Health Research Centre Navrongo U/E Region
Ghana


Instit te for Tropical Medicine
Antwerp AntwerpBelgium


Wellcome Trust-Mahosot Hospital-Oxford University Tropical Medicine Research Collaboration
Mahosot Hospital Vientiane
Lao People's Democratic Republic Centre for Tropical Medicine
Churchill Hospital
University of Oxford Oxford
United Kingdom


Division of Parasitic Diseases
Centers for Disease Control and Prevention Atlanta
GeorgiaUnited States of America


Facundo Fernández School of Chemistry and Biochemistry
Georgia Institute of Technology Atlanta
GeorgiaUnited States of America

Research Ethics Committees in Africa: Building Capacity
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55C0989863D2E1
C4365611D10.1371/journal.pmed.0040135
Each of these programs has a different focus and both are making highly valued contributions to capacity building in international research ethics in Southern Africa.The goal of the IRENSA diploma program is to develop and nourish sustainable multidisciplinar expertise in international research ethics and bioethics in southern Africa.It prepares mid-career health and allied professionals from South Africa and other developing nations in Africa to assume positions of leadership in research ethics in their home institutions.This program is unique on the African continent in focusing exclusively on training mid-career professionals (who cannot take the time or leave to undertake full-time graduate work), in three intensive two-week modules spread throughout one year, with assignments carried out at their home institutions.In four years IRENSA trained 49 mid-career professionals (17 men, 32 women, 20 white, 29 black) drawn from 20 institutions in South Africa and from 11 institutions in eight other low-income African countries.Sixteen students serve as chairs, deputy chairs, or secretaries of RECs.Students refl ect professional training in many disciplines, including science, medicine, nursing, social sciences, law, and pharmacology.Eighteen students hold doctoral degrees and represent a broad spectrum of health organizations.In addition, our annual two-day seminars in research ethics have reached over 400 attendees.SARETI's goal is to build capacity for ethical review of health research and strengthen Africa's institutional training capacity necessary to ac ieve and sustain this aim.It offers a multidisciplinary, modular master's degree program with funding for nine trainees over four years, an advanced, non-degree program resulting in a certifi cate with funding for 16 trainees, and a training program for 40 ethics review committee members.In 2003 SARETI co-hosted, with the HIV/AIDS Vaccines Ethics Group, a two-day training workshop for over 40 members of South African RECs, and in 2004 it offered a three-week Ethics Review Committee Training Program sponsorship to nine South African applicants.A spin-off of these educational programs has been the formation of a network of Chairs of South African Human Health Research Ethics Committees.This has signifi cantly improved liaison across the country, reduced the potential for shopping around by researchers, and has enhanced the stringency with which protocols are reviewed.A newsletter from Stellenbosch University on research ethics activities in the country draws attention to current debates and events and facilitates networking [2].The re ent stand taken by the chairpersons of RECS in South Africa not to permit studies that do not provide insurance cover for researchrelated injuries is one example of how improved knowledge and coordination in South African RECs are making such a contribution [3].

We thank Dr. Benatar [1] for pointing out that South Africa has two Fogarty-funded bioethics training programs: one that focuses primarily on providing short-term training to mid-career professionals from Southern Africa; and another that provides modular training in research ethics to professionals from t e African continent.In addition, there are now several other Fogarty-funded training programs that either target African professionals exclusively or include African professionals, among others, in their programs (see http:⁄⁄www.fi c.nih.gov/programs/training_grants/ bioethics/index.htm).All of these programs share the goal of increasing professional capacity in bioethics and research ethics on the African continent.

Our own paper demonstrated that training even a small number of individuals can make a difference in changing policy and practice regar

ng research ethics in several institutions; that so many training efforts are now ongoing is a major step forward.Again, having more peo
le teaching and discussing research ethics and starting and staffi ng research ethics committees will never itself guarantee that research with humans is more ethical, but it seems to be a critical fi rst step.Capacity development for Africa still remains a challenge and worthy of increasing investments in global health.

Nancy E. Kass


World Social Health Insurance: Strengthening Health Systems in Low-Income Countries Wim Van Damme

The paper by Ooms et al. [1] is very timely and stimulating.It launches the debate on how to fi nance globally the right to health care in low-income countries.This is a most welcome step, going beyond the usual aspirational rhetoric.I would like to contribute to the development of this idea.

First: the name.I fear that "World Health Insurance" may create confusion.Health insurance can be a pure risksharing mechanism without built-in solidarity between rich and poor, healthy and less healthy, or between old and young.But the concept of social health insurance-as the statutory health insurance systems in much of continental Europe are usually referred to-is intrinsically based on such solidarity, which certainly is one of the values underpinning Ooms' proposal.I therefore propose the name "World Social Health Insurance."

Second: the contribution by low-income countries.Ooms et al. propose 15% of government budget as a fair contribution, the so-called Abuja target.I fear, however, that this target does not create the right incentive for governments in lowincome countries, many of whom are reluctant or unable to tax their citizens, even the richer ones, and fail to create a decent tax basis.Consequently, some governments have extremely lean budgets, even below 20% of gross domestic product (GDP) [2], while the World Bank estimates that at least some 30% of GDP is needed to sustain a well-functioning state.I therefore think that calculating the contribution of low-income countries to their countries' health system as 4% or 5% of GDP would constitute a fairer burden sharing mechanism.

Third: the contribution of high-income countries.Ooms et al. propose that rich countries adopt a burden sharing similar to their contribution to World Bank's IDA 14 (the 14th replenishment of the International Development Association).This normalizes the low commitment of donors such as the United States, contributing in absolute terms hardly more than the United Kingdom or Japan, while its total GDP is much larger.I therefore think that for high-income countries, a contribution linked to total GDP would be fairer: e.g., 0.15%, which would be a bit more than on -fi fth of the 0.7% target that most OECD countries have committed to as total overseas development assistance.Alternatively, and more in line with the concept of social health insurance, high-income countries could dedicate a share of domestic health expenditure (e.g., 1%) to world social health insurance.With total health expenditure in the United States now reaching US$2,000 billion [3], this modest 1% would already come close to the total needs as estimated by Ooms.Lastly: operationalization.How to operationalize the massive scale-up of services pro osed, given present human resource constraints and institutional capacities, is still a huge challenge.Whether it is best to take inspiration from the experience with rounds of competitive proposals, followed by performance-related disbursement, as the Global Fund uses, or whether the proposal of the Global Alliance for Vaccines and Immunisation (GAVI) to link disbursement to strategic government plans and sector-wide approaches would be more successful, remains to be explored.

We sincerely hope that the idea launched by Ooms et al. catches on, so that health services in low-income countries can rapidly expand.This can be seen, as Garrett convincingly argues [4], as an expression of a moral duty, as a form of public diplomacy, or as an investment in selfprotection.Whatever the drive, there are enough reasons to start preparing it backed by long-term reliable funding, fairly shared between all stakeholders, according to their purchasing power.


Funding

The author received no specifi c funding for th
s article.

Competing Interests: The author has declared that no competing interests exist.


Circumcision for HIV Prevention: Failure to Fully Account for Behavioral Risk Compensation


Seth Kalichman, Lisa Eaton, Steven Pinkerton

Three randomized controlled trials (RCTs) of male circumcision (MC) have been halted when interim analyses showed signifi cant reductions in HIV infection among men who received this interventi n [1][2][3].Modeling suggests that increased MC coverage in southern Africa could prevent as many as 2 million HIV infections over ten years [4].Moreover, the cost-effectiveness analysis by Kahn et al. recently published in PLoS Medicine indicates that MC could be cost-saving [5].However, the protection of MC may be partially offset by increased HIV risk behavior, or "risk compensation," especially reduction in condom use or increases in numbers of sex partners.Risk compensation occurs when individua s adjust their behavior in response to perceived changes in their vulnerability to a disease [6].Risk compensation may be especially important for MC because avoiding the sexual dissatisfactions of condom use and the desire to have more sex partners are likely to be signifi cant motivations for men to seek circumcision [7].In South Africa, 73% of men between the ages of 15 and 24 report using condoms during the last time they had sex [8].It is diffi cult to imagine a convincing public health message that effectively infl uences men to undergo circumcision and continue to co sistently use condoms.

Circumcised men in the ANRS 1265 trial reported 18% more sexual contacts at follow-up than did uncircumcised men, but no other sexual behavior differences were obtained [1].However, for ethical reasons all men in MC RCTs receive ongoing risk-reduction counseling and free condoms, which reduces the utility of these trials for estimating the potential behavioral impact of MC when implemented in a natural setting.One model of the potential impact of MC did not take into account risk compensation [4], but noted that "increases in risk-taking behaviour among circumcised men could reduce the benefi t of MC." Based on the 18% difference in sexual contacts for circumcised and uncircumcised men in the ANRS 1265 trial and the assumption that "risk compensation might be higher in a nonresearch program scale-up," Kahn et al. [5] adjusted the 60% effectiveness estimate obtained in this RCT downward to 50% to refl ect a 25% increase in sexual risk behaviors among circumcised men.Although Kahn et al.'s model explicitly incorporated the increased risk of HIV acquisition associated with risk compensation, it did not consider the impact of risk compensation on the HIV transmission risk of HIV-infected circumcised men, or on circumcised men's risk for non-HIV sexually transmitted infections (STIs).

There is no evidence that circumcision increases or decreases the risk of HIV transmission by HIV-infected men.However, risk compensation by HIV-infected circumcised men will substantially increase the risk of transmission to their sex partners.This suggests that, in the short term at least, circumcision would reduce the incidence of HIV among men, but increase the incidence among women, translating to increased prevalence among women, which in turn translates to greater risk to men.Epidem

lcerative an
nonulcerative STIs account for at least some of the rapid increases in HIV transmission in southern Africa [9].Non-HIV STIs are associated with a 2-to 5-fold increase in HIV transmission risk in countries with low and high rates of MC [9].In areas with prevalent STIs, the relative increase in men's STI-associated HIV risk can be as high as 60% to 340% [10].Circumcision likely reduces the risk of acquiring a non-HIV STI and may be partially responsible for the decreased HIV risk observed in circumcision RCTs [1].Nevertheless, the failure of models to account for increased STI risk due to risk compensation likely infl ates estimates of averted HIV infections.Estimates of HIV risks resulting from increased exposure to STIs that coincide with reductions in condom use have been included in previous models of the cost-effectiv ness of HIV prevention interventions [11] and should be included in MC models.Competing Interests: The authors have declared that no competing interests exist.


Circumcision for HIV Prevention: Authors' Reply

The issues regarding risk compensation raised by Kalichman et al. [1] are cogent for refi ning modeled estimates of the impact of male circumcision (MC).Even more important is to empirically monitor risk compensation during the scale-up of male circumcision.As Kalichman et al. note, we included in our modeling of MC impact a risk compensation level for men susceptible to HIV above that observed in the Orange Farm trial.

However, we did not incorporate risk compensation among the HIV infected, an adjustment which would have lessened the estimated benefi t of male circumcision.These two biases are offsetting.Another conservative bias in our an

ysis is that we used
the per-randomization protective effect of 0.60, rather than the per-clinical protocol protective effect of 0.70.Arguably, effectiveness in practice is better captured by the latter, and this would increase the estimated benefi ts of male circumcision.

The inclusion of the effects of non-HIV sexually transmitted infections (STIs) as risk co-factors would add a useful dimension to our analysis.The net effect could be to decrease or increase MC impact.As Kalichman et al. note, increased STIs associated with risk compensation in newly circumcised HIV-infected men would likely lessen MC impact.However, in a concentrated epidemic setting where STIs play a greater role in HIV transmission than in South Africa, the STI-reducing effects of MC in HIV-susceptible men could further incr ase the benefi ts of MC in preventing HIV.

Regarding the magnitude of risk compensation, we are encouraged by recent data suggesting that MC does not increase risky behavior, and may lead to a transient decrease [2].However, we, like Kalichman et al. and others are eager to see the favorable experience in clinical trials carried over to routine and widely operating programs.Thus, the current efforts to plan MC scale-up emphasize the need for an MC procedure that incorporates effective risk reduction counseling.In the context of a medicalized adult male circumcision model, and a clear public health message, risk compensation can be minimized.Thus, a great value of MC scale-up is the opportunity to directly deliver a strong behavioral prevention message.A similar risk reduction message has worked well with antiretroviral herapy in Africa [3].

The ultimate and critical test is monitoring risk behaviors in communities where MC is scaled up.If risk compensation is higher than expected, redoubled risk reduction methods will be imperative.


Funding:

The authors received no specifi c funding for this article.


Competing Interests:

The authors have declared that no competing interests exist.


Children Born to HIV-Infected Mothers in Côte d'Ivoire: Methodological Clarifi cations Needed Moussa Sarr

In their recently published paper, Becquet et al. [1] found that the 2- ears rates of adverse health outcomes were similar among short-term breast-fed and formula-fed children.Mortality rates also did not differ signifi cantly between these two groups and, after adjustment for pediatric HIV status, were similar to those observed among long-term breast-fed children.These results confi rm the fi ndings of two previous trials in Kenya [2] and in Botswana [3], highlighting the fact that with adequate support, alternatives to prolonged breastfeeding can be safe options for mothers to prevent motherto-child transmission of HIV in African settings.HIV-infected mothers who opt for lternatives to breast-feeding to protect their children from HIV infection should be provided the necessary support to make their choice feasible.

There are, however, some methodological clarifi cations that need to be made regarding the incidence rates of diarrhea, acute respiratory infection, and malnutrition.It was not clear if all repeated episodes of diarrhea and acute respiratory infection were taken into account to compute the incidence rates.A number of epidemiologists have also been advocatin the use of longitudinal prevalence instead of incidence for the longitudinal measure of morbidity associated with childhood diarrhea [4].The longitudinal prevalence is defi ned by the number of days of diarrhea divided by the total number of days of observation for each child.Longitudinal prevalence was found to be a better predictor of long-term health outcome in relationship to childhood diarrhea [4].

Moussa Sarr (moussasarr@westat.com)


Funding:

The author received no specifi c funding for this article.

Competing Interests: The author has declared that no competing interests exist.
Placental Malaria: Hypertension, VEGF, and Prolactin


Roy Douglas Pearson

The fi ndings by Muehlenbachs et al. [1] that placental malaria (PM) is associated with hypertension in fi rst-time mothers aged 18 -20 years is signifi cant, and not to be explained at this time of writing.The authors also provide data suggesting that the maternal-fetal confl ict, during chronic PM and hypertension in fi rst-time mothers, involves the VEGF pathway.

Previou ly [2][3][4][5], I have posited that prolactin might have a role in PM and these new fi ndings might provide further indirect evidence for such a role.It should be emembered that there is an extensive and decades-old literature (see Horrobin's chapter 23 in [6]) on the role of prolactin in hypertension; and more specifi cally, the relationship between prolactin and pregnancy-related hypertension [7,8].

Regarding the VEGF pathway, Malaguarnera et al. [9] have recently shown that prolactin induces VEGF production in human macrophages.It is conceivable that hyperprolactinemia (pituitary and/or placental) could upregulate placental macrophage production of VEGF.

Space does not permit a discussion of the well known fact of increased pregnancy-related prolactin in fi rst-time mothers, but this has been noted elsewhere [2] concerning maternal malaria.

Although there has been controversy of late [2,10], regarding y "prolactin hypothesis" in maternal malaria, it is time defi nitive experiments be conducted to ascertain if prolactin is playing a role in PM, and in other infectious diseases as well.

Roy Douglas Pearson (r.pearson@utoronto.ca)University of Toronto, Gerstein Science Information Centre Toronto, Ontario, Canada


Pollution and Tuberculosis: Outdoor Sources Aaron Cohen, Sumi Mehta

The meta-analysis by Lin and colleagues [1] is important for two reasons.It evaluates the evidence concerning exposure to combustion-derived air pollution and tuberculosis (TB), and it quantifi es the risk of TB associated with three important sources of exposure: tobacco smoking, environmental tobacco smoke, and indoor burning of solid f