Raffaella Ravinetto

Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea

BACKGROUND In the wake of the recent outbreak of Ebola virus disease (EVD) in several African countries, the World Health Organization prioritized the evaluation of treatment with convalescent plasma derived from patients who have recovered from the disease. We evaluated the safety and efficacy of convalescent plasma for the treatment of EVD in Guinea. METHODS In this nonrandomized, comparative study, 99 patients of various ages (including pregnant women) with confirmed EVD received two consecutive transfusions of 200 to 250 ml of ABO-compatible convalescent plasma, with each unit of plasma obtained from a separate convalescent donor. The transfusions were initiated on the day of diagnosis or up to 2 days later. The level of neutralizing antibodies against Ebola virus in the plasma was unknown at the time of administration. The control group was 418 patients who had been treated at the same center during the previous 5 months. The primary outcome was the risk of death during the period from 3 to 16 days after diagnosis with adjustments for age and the baseline cycle-threshold value on polymerase-chain-reaction assay; patients who had died before day 3 were excluded. The clinically important difference was defined as an absolute reduction in mortality of 20 percentage points in the convalescent-plasma group as compared with the control group. RESULTS A total of 84 patients who were treated with plasma were included in the primary analysis. At baseline, the convalescent-plasma group had slightly higher cycle-threshold values and a shorter duration of symptoms than did the control group, along with a higher frequency of eye redness and difficulty in swallowing. From day 3 to day 16 after diagnosis, the risk of death was 31% in the convalescent-plasma group and 38% in the control group (risk difference, -7 percentage points; 95% confidence interval [CI], -18 to 4). The difference was reduced after adjustment for age and cycle-threshold value (adjusted risk difference, -3 percentage points; 95% CI, -13 to 8). No serious adverse reactions associated with the use of convalescent plasma were observed. CONCLUSIONS The transfusion of up to 500 ml of convalescent plasma with unknown levels of neutralizing antibodies in 84 patients with confirmed EVD was not associated with a significant improvement in survival. (Funded by the European Unions Horizon 2020 Research and Innovation Program and others; ClinicalTrials.gov number, NCT02342171.).

Four Artemisinin-Based Treatments in African Pregnant Women with Malaria.

BACKGROUND Information regarding the safety and efficacy of artemisinin combination treatments for malaria in pregnant women is limited, particularly among women who live in sub-Saharan Africa. METHODS We conducted a multicenter, randomized, open-label trial of treatments for malaria in pregnant women in four African countries. A total of 3428 pregnant women in the second or third trimester who had falciparum malaria (at any parasite density and regardless of symptoms) were treated with artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate, or dihydroartemisinin-piperaquine. The primary end points were the polymerase-chain-reaction (PCR)-adjusted cure rates (i.e., cure of the original infection; new infections during follow-up were not considered to be treatment failures) at day 63 and safety outcomes. RESULTS The PCR-adjusted cure rates in the per-protocol analysis were 94.8% in the artemether-lumefantrine group, 98.5% in the amodiaquine-artesunate group, 99.2% in the dihydroartemisinin-piperaquine group, and 96.8% in the mefloquine-artesunate group; the PCR-adjusted cure rates in the intention-to-treat analysis were 94.2%, 96.9%, 98.0%, and 95.5%, respectively. There was no significant difference among the amodiaquine-artesunate group, dihydroartemisinin-piperaquine group, and the mefloquine-artesunate group. The cure rate in the artemether-lumefantrine group was significantly lower than that in the other three groups, although the absolute difference was within the 5-percentage-point margin for equivalence. The unadjusted cure rates, used as a measure of the post-treatment prophylactic effect, were significantly lower in the artemether-lumefantrine group (52.5%) than in groups that received amodiaquine-artesunate (82.3%), dihydroartemisinin-piperaquine (86.9%), or mefloquine-artesunate (73.8%). No significant difference in the rate of serious adverse events and in birth outcomes was found among the treatment groups. Drug-related adverse events such as asthenia, poor appetite, dizziness, nausea, and vomiting occurred significantly more frequently in the mefloquine-artesunate group (50.6%) and the amodiaquine-artesunate group (48.5%) than in the dihydroartemisinin-piperaquine group (20.6%) and the artemether-lumefantrine group (11.5%) (P<0.001 for comparison among the four groups). CONCLUSIONS Artemether-lumefantrine was associated with the fewest adverse effects and with acceptable cure rates but provided the shortest post-treatment prophylaxis, whereas dihydroartemisinin-piperaquine had the best efficacy and an acceptable safety profile. (Funded by the European and Developing Countries Clinical Trials Partnership and others; ClinicalTrials.gov number, NCT00852423.).

Access to health care for undocumented migrants in Italy

www.thelancet.com Vol 373 June 20, 2009 2111 1 Cometto G, Ooms G, Starrs A, Zeitz P. A global fund for the health MDGs? Lancet 2009; 373: 1500–02. 2 Marchal B, Cavalli A, Kegels G. Global health actors claim to support health system strengthening—is this reality or rhetoric? PLoS Med 2009; 6: 1–5. 3 Sheier R. African graft stings donors. Christian Science Monitor June 1, 2006. 4 Armstrong Schellenberg JR, Adam T, Mshinda H, et al. Eff ectiveness and cost of facility-based Integrated Management of Childhood Illness (IMCI) in Tanzania. Lancet 2004; 364: 1583–94. 5 Gilroy K. Debriefi ng on the external retrospective evaluation of ACSD. http://www. who.int/immunization/newsroom/190209_ K_Gilroy.pdf (accessed May 6, 2009). support for primary health, including AIDS and other disorders. The Commission called for donor support of 0·1% of donor gross national product (roughly US

Use of Pentamidine As Secondary Prophylaxis to Prevent Visceral Leishmaniasis Relapse in HIV Infected Patients, the First Twelve Months of a Prospective Cohort Study

36 billion in current dollars). Actual donor aid lags at around 0·04% (

Could the Decision of Trial Participation Precede the Informed Consent Process? Evidence From Burkina Faso

12 billion). We are not overspending on AIDS but underspending on the rest. These needed sums are paltry relative to military spending or the bank bailouts. The Global Fund off ers an eff ective fi nancing mechanism. The choice is not between AIDS, health systems, and other Millennium Development Goals. We can and must support them all.

Quality of medical devices and in vitro diagnostics in resource-limited settings

Background Visceral leishmaniasis (VL) has become an important opportunistic infection in persons with HIV-infection in VL-endemic areas. The co-infection leads to profound immunosuppression and high rate of annual VL recurrence. This study assessed the effectiveness, safety and feasibility of monthly pentamidine infusions to prevent recurrence of VL in HIV co-infected patients. Methods A single-arm, open-label trial was conducted at two leishmaniasis treatment centers in northwest Ethiopia. HIV-infected patients with a VL episode were included after parasitological cure. Monthly infusions of 4mg/kg pentamidine-isethionate diluted in normal-saline were started for 12months. All received antiretroviral therapy (ART). Time-to-relapse or death was the primary end point. Results Seventy-four patients were included. The probability of relapse-free survival at 6months and at 12 months was 79% and 71% respectively. Renal failure, a possible drug-related serious adverse event, occurred in two patients with severe pneumonia. Forty-one patients completed the regimen taking at least 11 of the 12 doses. Main reasons to discontinue were: 15 relapsed, five died and seven became lost to follow-up. More patients failed among those with a CD4+cell count ≤ 50cells/μl, 5/7 (71.4%) than those with counts above 200 cells/μl, 2/12 (16.7%), (p = 0.005). Conclusion Pentamidine secondary prophylaxis led to a 29% failure rate within one year, much lower than reported in historical controls (50%-100%). Patients with low CD4+cell counts are at increased risk of relapse despite effective initial VL treatment, ART and secondary prophylaxis. VL should be detected and treated early enough in patients with HIV infection before profound immune deficiency installs.

Quality assurance of drugs used in clinical trials: proposal for adapting guidelines

Background Over the last years, the number of clinical trials carried out in low-income countries with poor medical infrastructure and limited access to health care has increased. In these settings, the decision of participating in a clinical study may be influenced by factors related to participants’ vulnerability that limit the efficacy of the informed consent. Methods A mixed methods social science study, based on the triangulation of qualitative and quantitative data, was carried out in a socio-economically disadvantaged and semi-urban area of Bobo Dioulasso, Burkina Faso. The study aimed at assessing the relevance of the informed consent procedure on the decision-making process of the parents and/or guardians of potential participants in a pediatric malaria trial. Results For most parents (70.4%), the decision of participating had already been taken before undergoing the informed consent process and was based on the information conveyed through the community. Access to free and good quality health care often inspired this decision. In addition, the parents’ willingness to have their child included in the trial made them develop active strategies to achieve this purpose. Discussion In a context of socio-economic vulnerability and poor access to free health care, the process of informed consent does not always accomplish its goal of informing people and enabling them to make a free and informed decision. This information role is somehow anticipated by the community and trial participation becomes a strategic action to secure otherwise unavailable health resources leading community members to decide on participation even prior to the informed consent process.

Innovations in research ethics governance in humanitarian settings

The phenomenon of poor‐quality medicines in resource‐limited settings is well documented, and field observations reveal similar problems with medical devices (MDs) and in vitro diagnostics (IVDs). In scientific literature, however, there are only scarce reports and documents providing evidence of quality problems of MDs or IVDs in resource‐limited settings. This discrepancy may be ascribed to (i) the poor regulatory oversight of MDs/IVDs in resource‐limited settings, (ii) a general lack of awareness of the problem of poor‐quality MDs/IVDs amongst the scientific community and decision‐makers, and (iii) poor quality assurance in diagnostic laboratories in resource‐poor settings, precluding tracing quality problems of IVDs from the other potential causes of diagnostic inaccuracy. The problem of poor‐quality MDs/IVDs in resource‐limited settings is a complex one to address. Firstly, operational definitions for substandard and counterfeit MDs/IVDs are required, as well as ad hoc field surveys, to ensure proper appraisal of the real extent of the problem. Investments are needed to reinforce the national regulatory oversights on MDs/IVDs in resource‐limited settings, and to encourage a proactive and transparent exchange of information between Northern and Southern regulatory authorities. Industrialized countries can play a role by expanding and strengthening their regulatory oversight and quality labels to those MDs/IVDs that are frequently used in resource‐poor settings. Hopefully, the combination of these measures will result in better protection of patients in resource‐poor countries from the effects of being exposed to poor‐quality MDs and IVDs.

Double ethical review of North-South collaborative clinical research: hidden paternalism or real partnership?

Paul Newton and colleagues propose that clinical trial guidelines should include a requirement to assess and state the quality of the drugs and other medical products used

Challenges of non-commercial multicentre North-South collaborative clinical trials

BackgroundMédecins Sans Frontières (MSF) is one of the world’s leading humanitarian medical organizations. The increased emphasis in MSF on research led to the creation of an ethics review board (ERB) in 2001. The ERB has encouraged innovation in the review of proposals and the interaction between the ERB and the organization. This has led to some of the advances in ethics governance described in this paper.DiscussionWe first update our previous work from 2009 describing ERB performance and then highlight five innovative practices:• A new framework to guide ethics review• The introduction of a policy exempting a posteriori analysis of routinely collected data• The preapproval of “emergency” protocols• General ethical approval of “routine surveys”• Evaluating the impact of approved studiesThe new framework encourages a conversation about ethical issues, rather than imposing quasi-legalistic rules, is more engaged with the specific MSF research context and gives greater prominence to certain values and principles. Some of the innovations implemented by the ERB, such as review exemption or approval of generic protocols, may run counter to many standard operating procedures. We argue that much standard practice in research ethics review ought to be open to challenge and revision. Continued interaction between MSF researchers and independent ERB members has allowed for progressive innovations based on a trustful and respectful partnership between the ERB and the researchers. In the future, three areas merit particular attention. First, the impact of the new framework should be assessed. Second, the impact of research needs to be defined more precisely as a first step towards being meaningfully assessed, including changes of impact over time. Finally, the dialogue between the MSF ERB and the ethics committees in the study countries should be enhanced.SummaryWe hope that the innovations in research ethics governance described may be relevant for other organisations carrying out research in fragile contexts and for ethics committees reviewing such research.