Background We evaluated efficacy, pharmacokinetics (PK), and safety of clofazimine (CFZ) in HIV-infected patients with cryptosporidiosis. Methods We performed a randomized, double-blind, placebo-controlled study. Primary outcomes in Part A were reduction in Cryptosporidium shedding, safety, and PK. Primary analysis was according to protocol (ATP). Part B of the study compared CFZ PK in matched HIV-infected individuals without cryptosporidiosis. Results Twenty Part A and 10 Part B participants completed the study ATP. Almost all Part A participants had high viral loads and low CD4 counts, consistent with failure of antiretroviral (ARV) therapy. At study entry, the Part A CFZ group had higher Cryptosporidium shedding, total stool weight, and more diarrheal episodes compared to the placebo group. Over the inpatient period, compared to those who received placebo, the CFZ group Cryptosporidium shedding increased by 2.17 log2Cryptosporidium per gram stool (95% upper confidence limit: 3.82), total stool weight decreased by 45.3 g (p=0.37), and number of diarrheal episodes increased by 2.32 (p=0.87). The most frequent solicited adverse effects were diarrhea, abdominal pain, and malaise. Three CFZ and 1 placebo subjects died during the study. Plasma levels of CFZ in participants with cryptosporidiosis were 2-fold lower than Part B controls. Conclusion Our findings do not support the efficacy of CFZ for the treatment of cryptosporidiosis in a severely immunocompromised HIV population. However, this trial demonstrates a pathway to assess the therapeutic potential of drugs for cryptosporidiosis treatment. Screening persons with HIV for diarrhea, and especially Cryptosporidium infection, may identify those failing ARV therapy.

Background: An effective drug to treat cryptosporidial diarrhea in HIV-infected individuals is a global health priority. Promising drugs need to be evaluated in endemic areas which may be challenged by both lack of resources and experience to conduct International Committee of Harmonisation-Good Clinical Practice (ICH-GCP)compliant clinical trials. Methods: We present the challenges and lessons learned in implementing a phase 2A, randomized, double-blind, placebo-controlled trial of clofazimine, in treatment of cryptosporidiosis among HIV-infected adults at a single site in Malawi. Results: Primary challenges are grouped under study initiation, study population, study implementation, and cultural issues. The lessons learned primarily deal with regulatory system and operational barriers, and recommendations can be applied to other human experimental trials in low-and middle-income countries, specifically in sub-Saharan Africa. Conclusion: This study demonstrated that initiating and implementing human experimental trials in sub-Saharan Africa can be challenging. However, solutions exist and successful execution requires careful planning, ongoing evaluation, responsiveness to new developments, and oversight of all trial operations.

BackgroundAcute seizures are common in pediatric cerebral malaria (CM), but usual care with phenobarbital risks respiratory suppression. We undertook studies of enteral levetiracetam (eLVT) to evaluate pharmacokinetics (PK), safety and efficacy including an open-label, randomized controlled trial (RCT) comparing eLVT to phenobarbital.MethodsChildren 24–83 months old with CM were enrolled in an eLVT dose-finding study starting with standard dose (40 mg/kg load, then 30 mg/kg Q12 hours) titrated upward until seizure freedom was attained in 75% of subjects.The RCT that followed randomized children to eLVT vs. phenobarbital for acute seizures and compared the groups on minutes with seizures based upon continuous electroencephalogram. Due to safety concerns, midway through the study children allocated to phenobarbital received the drug only if they continued to have seizures (either clinically or electrographically) after benzodiazepine treatment. Secondary outcomes were treatment failure requiring cross over, coma duration and neurologic sequelae at discharge. PK and safety assessments were also undertaken.ResultsAmong 30 comatose CM children, eLVT was rapidly absorbed and well-tolerated. eLVT clearance was lower in patients with higher admission serum creatinine (SCr), but overall PK parameters were similar to prior pediatric PK studies. Within 4 h of the first dose, 90% reached therapeutic levels (> 20 μg/mL) and all were above 6 μg/mL. 7/7 children achieved seizure freedom on the initial eLVT dose.Comparing 23 eLVT to 21 phenobarbital patients among whom 15/21 received phenobarbital, no differences were seen for minutes with seizure, seizure freedom, coma duration, neurologic sequelae or death, but eLVT was safer (p = 0.019). Phenobarbital was discontinued in 3/15 due to respiratory side effects.ConclusionEnteral LVT offers an affordable option for seizure control in pediatric CM and is safer than phenobarbital.Trial registrationNCT01660672.NCT01982812.

Background: Human infection studies (HIS) involve deliberately infecting healthy volunteers with a pathogen in a controlled environment to understand infection and support the development of effective vaccines or treatments. HIS research is expanding to many low and middle-income settings to accelerate vaccine development. Given the implementation of the first HIS research to establish the experimental human pneumococcal carriage model’s feasibility, we sought to understand the participant’s opinions and experiences. Methods: We used a qualitative, descriptive approach to understand participants perceptions and experiences on HIS participation. Sixteen healthy adult participants were invited to participate in in-depth exit interviews to discuss their experiences, motivations and concerns. Results: Our findings showed that the likelihood of participation in HIS research rests on three essential conditions: motivation to participate, compensation and advocacy. The motivation and decision to participate was based on reasons including altruism, patriotism, monetary and material incentives, and while compensation was deemed appropriate, concerns about unanticipated research-related risks were raised. Participant advocate groups were recommended for increasing awareness and educating others in the broader community about HIS research. Conclusions: Participants’ experiences of HIS in Malawi provide the basis of what can be acceptable in HIS research in lower-income countries and areas where study procedures could be adjusted.