Pharmacogenetic considerations in the treatment of co-infections with HIV/AIDS, tuberculosis and malaria in Congolese populations of Central Africa

Background: HIV-infection, tuberculosis and malaria are the big three communicable diseases that plague sub-Saharan Africa. If these diseases occur as co-morbidities they require polypharmacy, which may lead to severe drug-drug-gene interactions and variation in adverse drug reactions, but also in treatment outcomes. Polymorphisms in genes encoding drug-metabolizing enzymes are the major cause of these variations, but such polymorphisms may support the prediction of drug efficacy and toxicity. There is little information on allele frequencies of pharmacogenetic variants of enzymes involved in the metabolism of drugs used to treat HIV-infection, TB and malaria in the Republic of Congo (ROC). The aim of this study was therefore to investigate the occurrence and allele frequencies of 32 pharmacogenetic variants localized in absorption distribution, metabolism and excretion (ADME) and non-ADME genes and to compare the frequencies with population data of Africans and non-Africans derived from the 1000 Genomes Project. Results: We found significant differences in the allele frequencies of many of the variants when comparing the findings from ROC with those of non-African populations. On the other hand, only a few variants showed significant differences in their allele frequencies when comparing ROC with other African populations. In addition, considerable differences in the allele frequencies of the pharmacogenetic variants among the African populations were observed. Conclusions: The findings contribute to the understanding of pharmacogenetic variants involved in the metabolism of drugs used to treat HIV-infection, TB and malaria in ROC and their diversity in different populations. Such knowledge helps to predict drug efficacy, toxicity and ADRs and to inform individual and population-based decisions

Implementation of co-trimoxazole preventive therapy policy for malaria in HIV-infected pregnant women in the public health facilities in Tanzania

Appolinary AR Kamuhabwa, Richard Gordian, Ritah F Mutagonda Department of Clinical Pharmacy and Pharmacology, School of Pharmacy, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania Background: In 2011, Tanzania adopted a policy for provision of daily co-trimoxazole prophylaxis to HIV-infected pregnant women for prevention of malaria and other opportunistic infections. As per the policy, HIV-infected pregnant women should not be given sulfadoxine-pyrimethamine (SP) for intermittent preventive therapy. The challenges associated with this policy change and the extent to which the new policy for prevention of malaria in pregnant women coinfected with HIV was implemented need to be assessed. Aim: To assess the implementation of malaria-preventive therapy policy among HIV-infected pregnant women in the public health facilities in Dar es Salaam, Tanzania. Methodology: The study was conducted in Kinondoni Municipality, Dar es Salaam, Tanzania, from January 2015 to July 2015. Three hundred and fifty-three HIV-infected pregnant women who were attending antenatal clinics (ANCs) and using co-trimoxazole for prevention of malaria were interviewed. Twenty-six health care workers working at the ANCs were also interviewed regarding provision of co-trimoxazole prophylaxis to pregnant women. A knowledge scale was used to grade the level of knowledge of health care providers. Focus group discussions were also conducted with 18 health care workers to assess the level of implementation of the policy and the challenges encountered. Results: Twenty-three (6.5%) pregnant women with known HIV serostatus were using co-trimoxazole for prevention of opportunistic infections even before they became pregnant. Out of the 353 HIV-infected pregnant women, eight (2.5%) were coadministered with both SP and co-trimoxazole. Sixty (16.7%) pregnant women had poor adherence to co-trimoxazole prophylaxis. Out of the 26 interviewed health care providers, 20 had high level of knowledge regarding malaria-preventive therapy in HIV-infected pregnant women. Lack of adequate supply of co-trimoxazole in health facilities and inadequate training of health care providers were among the factors causing poor implementation of co-trimoxazole prophylaxis for prevention of malaria in HIV-infected pregnant women. Conclusion: There is a need to continue sensitization of pregnant women and communities about the importance of early attendance to the ANCs for testing of HIV and provision of co-trimoxazole prophylaxis. Availability of co-trimoxazole in the health facilities, regular training, and sensitization of health care providers are necessary for effective implementation of this policy. Keywords: SP, policy change, ANCs, health care providers, IPT

Intermittent Preventive Therapy and Treatment of Malaria during Pregnancy: A Study of Knowledge among Pregnant Women in Rufiji District, Southern Tanzania

Purpose: To assess the knowledge and awareness of pregnant women regarding the use of sulfadoxinepyrimethamine (SP) for intermittent preventive therapy (IPT) and artemether-lumefantrine (ALu) for treatment of malaria during pregnancy. Methods: The study was conducted in Rufiji district, southern Tanzania from March 2011 to September 2011. Four hundred and seventy (470) pregnant women in their second and third trimesters were interviewed when attending antenatal clinics at the selected hospitals, health centers and dispensaries. Focus group discussions (FGDs) were also conducted with 46 pregnant women at the health facilities in the district. Results: More than half (54.3 %) of pregnant women did not know if SP it was used for IPT. Most women (76.6 %) did not know the use of SP for IPT in relationship with gestation age. Overall, the results show that most women had very low knowledge about the use of SP for IPT. Forty three (9.1 %) pregnant women reported to have had malaria during their current pregnancies. The antimalarials reported to be used by pregnant women were quinine 18(42.9 %), SP (23.8 %), ALu (21.4%) and sulphamethoxyprazinepyrimethamine (2.4%). Irrespective of the gestation age of pregnancy, almost all (98.3 %) pregnant women perceived ALu as unsafe drug to be used during pregnancy. Conclusion: Most pregnant women had minimum knowledge about the use and benefits of SP for IPT and ALu for treatment of malaria during pregnancy. Some erroneous beliefs about the safety of ALu during pregnancy were also identified among pregnant women. For effective implementation of IPT policy and treatment of malaria during pregnancy, pregnant women should be sensitized and educated on the use and benefits of antimalarial drugs

Comparison of malaria treatment outcome of generic and innovator’s anti-malarial drugs containing artemether–lumefantrine combination in the management of uncomplicated malaria amongst Tanzanian children

Abstract Background In 2006, artemether–lumefantrine (ALU), specifically Coartem® (Novartis Pharma AG, Basel Switzerland), was approved as the first-line drug for treatment of uncomplicated malaria in Tanzania. Due to poor availability and affordability of the innovator’s product, the government of Tanzania in 2013 prequalified the use of generic anti-malarial drugs, whereby Artefan® (Ajanta, Pharma Ltd, India) was the first to be approved. Methods This was an equivalence prospective study that aimed to determine the effectiveness of anti-malarial generic Artefan® in comparison with innovator’s product Coartem®. Patients aged 6 to 59 months with uncomplicated malaria were recruited and randomized to either receive Artefan® or Coartem® as a control. Participants were required to revisit clinic five times as follow up to monitor treatment outcome as per World Health Organization recommendations. On each visit, thick and thin blood smears, dried blood spot (DBS), haemoglobin concentrations and auxiliary temperature were performed and documented. Results Out of 230 recruited participants, 200 met inclusion criteria and were randomized equally to receive Artefan® and Coartem®. The overall PCR uncorrected cure rate were 80% for Artefan® and 75% for Coartem® (p = 0.44). Adequate clinical and parasitological response were 82.1% for Artefan® and 74.7% for Coartem®, and there was no early treatment failure (ETF) observed in both arms of treatment. Both drugs showed excellent early parasite clearance, whereby no participants had peripheral parasitaemia on day 3. Late clinical failures (LCF) were 3.6% for Artefan® and 1.3% for Coartem® (p = 0.31), and late parasitological failure (LPF) were 15.4% for Artefan® and 22.7% for Coartem® (p = 0.32). Mean haemoglobin (g/dl) concentrations observed on day 28 were higher compared to day 0 for both drugs, although not statistically significant. Only one (1.3%) participant on Artefan® had temperature ≥ 37.5 °C on day 3. Conclusion The findings of this study indicate that both Artefan® and Coartem® are equivalent and effective in the management of uncomplicated malaria amongst children in the Coast part of Tanzania

A decade since sulfonamide-based anti-malarial medicines were limited for intermittent preventive treatment of malaria among pregnant women in Tanzania

Abstract Background Despite the development of resistance to Plasmodium falciparum malaria, sulfadoxine–pyrimethamine is still effective for intermittent preventive treatment of malaria in pregnancy (IPTp). In Tanzania, more than 10 years have passed since sulfadoxine–pyrimethamine and sulfamethopyrazine–pyrimethamine (SPs) were reserved for IPTp only. However, the retail pharmaceutical outlet dispensers’ knowledge and their compliance with the policies have not been recently explored. Therefore, this study was designed to investigate dispensers’ knowledge about these medications together with their actual dispensing practices, a decade since they were limited for IPTp use only. Methods This descriptive cross-sectional study was conducted between February and July 2017 in all municipalities of Dar-es-Salaam city. Data were collected by direct interviews using a structured questionnaire to assess knowledge and a simulated client approach was used to assess the actual practice of medicine dispensers. Data analysis was done by using SPSS version 20 and Chi square test was used to test significant differences in proportions between different categorical variables. A p-value of less than 0.05 was considered to be statistically significant. Results A random sample of 422 medicine dispensers participated in this study whereby 185 (43.8%) were from community pharmacies and 237 (56.2%) from accredited drug dispensing outlets. The study revealed that SPs were available in 76% of the community pharmaceutical outlets in Dar es Salaam. In general majority of the dispensers (64%) had moderate to high knowledge about SPs and their indication. About 80% of the dispensers were aware that SP is reserved for IPTp. However, irrespective of the level of knowledge, almost all dispensers (92%) were willing to dispense the medicines for the purpose of treating malaria, contrary to the current Tanzania malaria treatment guideline. Conclusion Majority of the medicine dispensers in the community pharmaceutical outlets were knowledgeable about SPs and their indications. Disappointingly, almost all dispensers irrespective of their levels of knowledge were willing to dispense SPs for treatment of malaria contrary to the available treatment guidelines

Effect of pharmacogenetics on plasma lumefantrine pharmacokinetics and malaria treatment outcome in pregnant women

Abstract Background Pregnancy has considerable effects on the pharmacokinetic properties of drugs used to treat uncomplicated Plasmodium falciparum malaria. The role of pharmacogenetic variation on anti-malarial drug disposition and efficacy during pregnancy is not well investigated. The study aimed to examine the effect of pharmacogenetics on lumefantrine (LF) pharmacokinetics and treatment outcome in pregnant women. Methods Pregnant women with uncomplicated falciparum malaria were enrolled and treated with artemether-lumefantrine (ALu) at Mkuranga and Kisarawe district hospitals in Coast Region of Tanzania. Day-7 LF plasma concentration and genotyping forCYP2B6 (c.516G>T, c.983T>C), CYP3A4*1B, CYP3A5 (*3, *6, *7) and ABCB1 c.4036A4G were determined. Blood smear for parasite quantification by microscopy, and dried blood spot for parasite screening and genotyping using qPCR and nested PCR were collected at enrolment up to day 28 to differentiate between reinfection from recrudescence. Treatment response was recorded following the WHO protocol. Results In total, 92 pregnant women in their second and third trimester were included in the study and 424 samples were screened for presence of P. falciparum. Parasites were detected during the follow up period in 11 (12%) women between day 7 and 28 after treatment and PCR genotyping confirmed recrudescent infection in 7 (63.3%) women. The remaining four (36.4%) pregnant women had reinfection: one on day 14 and three on day 28. The overall PCR-corrected treatment failure rate was 9.0% (95% CI 4.4–17.4). Day 7 LF concentration was not significantly influenced by CYP2B6, CYP3A4*1B and ABCB1 c.4036A>G genotypes. Significant associations between CYP3A5 genotype and day 7 plasma LF concentrations was found, being higher in carriers of CYP3A5 defective variant alleles than CYP3A5*1/*1 genotype. No significant influence of CYP2B6, CYP3A5 and ABCB1 c.4036A>Genotypes on malaria treatment outcome were observed. However, CYP3A4*1B did affect malaria treatment outcome in pregnant women followed up for 28 days (P = 0.018). Conclusions Genetic variations in CYP3A4 and CYP3A5may influence LF pharmacokinetics and treatment outcome in pregnant women