Adverse Drug Reactions to Antiretroviral Therapy: Frequency, Type, and Risk Factors in Children in Mali.

OBJECTIVE: The aim of our study was to evaluate the frequency, type, and risk factors associated with adverse drug reactions (ADRs) in HIV-positive children with adherence to antiretroviral therapy (ART) at the Unit of Care and Accompaniment for People Living With HIV (USAC) of Bamako. METHODS: A cross-sectional study was conducted at USAC of Bamako from May 1, 2014, to July 31, 2015. We included children aged 1 to 14 years with at least 6 months of ARV treatment initiated at USAC, with or without ADRs. Data collection was based on information collected from parents and clinical/biological assessments. RESULTS: Median age of participants was 36 months and female sex was predominant (54.8%). Poor adherence during the study was observed in 15% of cases. Of patients in the study, 52% had a CD4 count less than 350 cells/mm3 at the time of adverse events. In bivariate analysis, we found that participants with adherence to ART tended to be younger than those with non-adherence to ART (36 vs 72 months, p = 0.093). In multivariable analysis, prophylactic treatment was the only factor marginally associated with ART adherence in HIV patients (p = 0.09). No other adverse biological effects or clinical conditions were associated with ART adherence in this study. CONCLUSIONS: In this study we found that ADRs were frequent in HIV-positive patients but less frequent in ART-adherent HIV-positive children. Therefore, it is essential to regularly monitor children receiving ARVs to detect and treat the complications associated with these therapies according to ART adherence.

Diagnostic Laboratories' Capacities and Preparedness for Emerging Viral Diseases in Guinea and Mali.

The 2014-2016 Ebola epidemic in Guinea highlighted the need for more extensive evaluation of laboratories diagnostic capacities and preparedness in anticipation of future emerging viral disease outbreaks. We developed a questionnaire to assess the diagnostic capacities and preparedness of the four major medical laboratories in Guinea and Mali that are responsible for the provision of Ebola, Lassa, and Dengue diagnostics. The questionnaire inquired about the current state and need for equipment and reagents and adequacy of equipment and training received. In Guinea, all three diagnostic laboratories have the capacity and are well-prepared to perform Ebola diagnostics, however, only two have the capacity and trained staff to diagnose Lassa and none are currently prepared to diagnose Dengue infection. In Mali, the University Clinical Research Center (UCRC) laboratory, which was in charge of Ebola diagnostics during the last epidemic, currently has the capacity and is prepared to diagnose Ebola, Lassa, and Dengue infections. Combined, Guinea and Mali appear to have complementary capacity and preparedness to diagnose these Category A Priority Pathogens. While, the equipment, reagents and training efforts should be maintained, the gap in Dengue diagnostic capability in Guinea should be addressed with further equipping and training of additional district laboratories to strengthen the public health response for all viral diseases in these high-risk, yet, low-resource settings.

Antiretroviral-induced adverse drug reactions in HIV-infected patients in Mali: a resource-limited setting experience.

BACKGROUND: There are few reports in the literature from sub-Saharan Africa (SSA) regarding antiretroviral-induced adverse drug reactions (ADRs). Antiretroviral therapy (ART) is now widely available in SSA, and ADRs during HIV infection are also frequent. In this study, we reported the frequency and risk factors of ART-induced ADRs in a Malian population. METHODS: This prospective cohort study was performed in the HIV Care and Counseling Centre (CESAC) of Mali from 2011 to 2012. Adult patients infected with HIV and who had recently started ART were included and followed-up clinically Were included in this study, adult patients living with HIV and had recently started ART who were followed up for at least 6 months to determine the incidence of ADRs using Naranjo's classification scale. RESULTS: During this study, 357 (42.3%) patients presented ADRs (40.1% of our patients (n=338) experienced at least one ADR, and 2.2% (n=19) experienced at least two ADRs). The prevalence of ADRs by organ system was: 45.9% neurological (n=164); 29.4% metabolic (blood chemistry) (n=105); 15.4% hematological (n=55). High probable rate of ADR was observed as indicated by the Naranjo score in 83.7% of the cases. Zidovudine (AZT) and stavudine (d4T) use was identified as a risk factor for either anaemia or peripheral neuropathy whereas nevirapine (NVP) and female gender were risk factors for skin reactions. Patients with advance disease had the highest rate of ADRs compared to the others. CONCLUSIONS: Based on the Naranjo probability scale, our data show that ADRs such as peripheral neuropathy and anemia are very frequent. These ADR was linked to AZT and D4T. Our findings highlight the need for active monitoring, continuous pharmacovigilance of ART and change of some ART drug in this population.

Efavirenz and Lopinavir Levels in HIV-Infected Women and Their Nursing Infants, in Mali.

Limited data are currently available on antiretroviral pharmacokinetics in breast milk (BM) and in breastfed infants' blood. To explore these parameters in patients in Mali, we measured plasma antiretroviral levels in human immunodeficiency virus (HIV)-infected mothers and their breastfed infants over 6 months. We specifically analyzed the concentrations of efavirenz (EFV) and lopinavir (LPV) in the plasma of mothers living with HIV and their breastfed infants. Blood samples were collected at delivery and at month 1, 3, and 6 postpartum. EFV and LPV concentrations were measured by liquid chromatography-tandem mass spectrometry. HIV-1 RNA load was measured by Abbott M2000RT RealTime System at delivery and 6 months postpartum for mothers, and at 3 and 6 months postbirth for infants. The median duration of antiretroviral therapy at study inclusion was 57 months [interquartile range (IQR), 0-168 months]. The median EFV ratios of infant plasma/maternal plasma (MP) were 0.057 at month 1, 0.072 at month 3, and 0.048 at month 6. During the study period, the median BM/MP ratio of EFV was 1.16 (IQR, 0.96-20.62), which corresponds to a relative infant dose of 2.46% of the recommended weight-adjusted pediatric EFV dose at month 6. The apparent infant clearance of EFV was 0.146 l/h per kilogram at month 6. The LPV concentrations in the plasma of all infants were undetectable. No drug-related adverse reaction or toxicity was observed in any of the infants. The two women who presented a viral load of >50 copies/ml at month 6 had undetectable plasma drug concentrations at the same period. This study showed that breastfed infants received a low level of EFV but not LPV from their treated mothers.

Comparing Treatment Outcomes of Antiretroviral Therapy in HIV-1 and HIV-2 Infected Patients, in Bamako, Mali.

BACKGROUND: HIV-2 leads to a less-severe disease than HIV-1 but is known to be resistant to Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). We goaled to evaluate the clinical and biological outcomes of HIV-1 and HIV-2 infected-patients under Antiretroviral Therapy (ART) that do not include NNRTIs. METHODS: This is a case-control study of 100 participants (half in each group) to measure the frequency of clinical and biological adverse effects, and disease outcome at 6 and 12 months of treatment (M6 and M12) We included. RESULTS: Opportunistic infections were more frequent in HIV-1 infected patients with 82% when compared to HIV-2, 68%. However, the prevalence of treatment adverse events was slightly higher in HIV-2 infected patients. The average increase of CD4 cell count at M6 of treatment was 139.93 and 159.41 cells/mm3, for HIV-2 and HIV-1 groups respectively, and at 153 and 217 cells/mm3, at M12 for HIV-2 and HIV-1 respectively. A total of nine HIV-2 and six HIV-1 deaths were reported during the study. CONCLUSION: This study has shown that ART regimens that do not include NNRTIs are effective equally in the treatment of HIV-1 and HIV-2 infections. Nevertheless, we recommend regular and continuous laboratory monitoring for all HIV treated patients.

Transmitted antiretroviral drug resistance in newly HIV-infected and untreated patients in Ségou and Bamako, Mali.

The WHO recommends regular surveillance for transmitted antiretroviral drug-resistant viruses in HIV antiretroviral treatment (ART)-naive patients in resource-limited settings. This study aimed to assess the prevalence of mutations associated with resistance in ART-naive patients newly diagnosed with HIV in Bamako and Ségou in Mali. HIV-positive patients who never received ART were recruited in Bamako and Ségou, Mali. The reverse transcriptase (RT) and protease (PR) genes of these patients were sequenced by the "ViroSeq" method. Analysis and interpretation of the resistance were made according to the WHO 2009 list of drug resistance mutations. In all, 51/54 (94.4%) sample patients were sequenced. The median age (IQR) of our patients was 24 (22-27) years and the median CD4 count was 380 (340-456) cells/mm(3). The predominant subtype was recombinant HIV-1 CRF02_AG (66.7%) followed by CRF06_cpx (12%) and CRF09_cpx (4%). Four patients had mutations associated with resistance, giving an overall prevalence of resistance estimated at 7.9%. There were two (4%) patients with nucleoside reverse transcriptase inhibitor (NRTI) mutations (one M184V and one T215Y), two (4%) with non-NRTI mutations (two K103N), and one (2%) with a protease inhibitor mutation (one I54V). The prevalence of primary resistance in newly infected patients in Mali is moderate (7.9%). This indicates that the standard NNRTI-based first-line regimen used in Mali is suboptimal for some patients. This study should be done regularly to inform clinical practice.

Polymorphisms of HIV-2 integrase and selection of resistance to raltegravir.

BACKGROUND: Human Immunodeficiency Virus type 2 is naturally resistant to some antiretroviral drugs, restricting therapeutic options for patients infected with HIV-2. Regimens including integrase inhibitors (INI) seem to be effective, but little data on HIV-2 integrase (IN) polymorphisms and resistance pathways are available. MATERIALS AND METHODS: The integrase coding sequence from 45 HIV-2-infected, INI-naïve, patients was sequenced and aligned against the ROD (group A) or EHO (group B) reference strains and polymorphic or conserved positions were analyzed.To select for raltegravir (RAL)-resistant variants in vitro, the ROD strain was cultured under increasing sub-optimal RAL concentrations for successive rounds. The phenotype of the selected variants was assessed using an MTT assay. RESULTS: We describe integrase gene polymorphisms in HIV-2 clinical isolates from 45 patients. Sixty-seven percent of the integrase residues were conserved. The HHCC Zinc coordination motif, the catalytic triad DDE motif, and AA involved in IN-DNA binding and correct positioning were highly conserved and unchanged with respect to HIV-1 whereas the connecting residues of the N-terminal domain, the dimer interface and C-terminal LEDGF binding domain were highly conserved but differed from HIV-1. The N155 H INI resistance-associated mutation (RAM) was detected in the virus population from one ARV-treated, INI-naïve patient, and the 72I and 201I polymorphisms were detected in samples from 36 and 38 patients respectively. No other known INI RAM was detected.Under RAL selective pressure in vitro, a ROD variant carrying the Q91R+I175M mutations was selected. The Q91R and I175M mutations emerged simultaneously and conferred phenotypic resistance (13-fold increase in IC50). The Q91R+I175M combination was absent from all clinical isolates. Three-dimensional modeling indicated that residue 91 lies on the enzyme surface, at the entry of a pocket containing the DDE catalytic triad and that adding a positive charge (Gln to Arg) might compromise IN-RAL affinity. CONCLUSIONS: HIV-2 polymorphisms from 45 INI-naïve patients are described. Conserved regions as well as frequencies of HIV-2 IN polymorphisms were comparable to HIV-1. Two new mutations (Q91R and I175M) that conferred high resistance to RAL were selected in vitro, which might affect therapeutic outcome.

[Cholera epidemics in Mali between 1995 and 2004]. / Les epidémies de choléra au Mali de 1995 & 2004.

INTRODUCTION: Cholera represents a public health problem in developing countries like Mali. AIM: This work aims to describe the characteristics of the cholera epidemics which occurred in Mali between 1995 and 2004. METHOD: A retrospective survey was conducted within the Division of the fight against the diseases of epidemic potential and the Institute of Public Health and Research of the Ministry of Health of Mali. Individual medical records tracking the follow-up of patients as well as the registers of these structures were used as sources to collect data for the study. RESULTS: There were 12,176 cases of cholera recorded, including 1,406 deaths, from 1995 to 2004. Cholera outbreaks in Mali have been a regular occurrence every year since 2001. The regions of Mopti and Segou seem to be the most impacted by these epidemics. The lethal rates were higher than 1% at the time of each of these epidemics during this period. Vibrio cholerae O: 1, biotype El Tor were responsible for the epidemics, and the serotype Ogawa was prevalent. CONCLUSION: Cholera epidemics have been constant in Mali since the beginning of the 21st century in spite of the efforts which have been made to prevent and control them. A rigorous analysis of the factors which support this persistence and appropriate measures are essential to reverse cholera in this country.

[The movement of wild poliovirus in West Africa: the Malian case]. / Circulation des poliovirus sauvages en Afrique de l'Ouest: l'exemple du Mali.

The objective of this study was to examine the evolution of the movement patterns and trends of the wild poliovirus in Mali through surveillance of acute flaccid paralysis. A retrospective descriptive study was conducted between 1 January 1998 and 31 December 2005 on 1,002 cases of acute flaccid paralysis (AFP) investigated across the country. Reports made to the National Center for Immunization (CNI) of children under 15 years suffering from AFP were included as part of the epidemiological surveillance. The isolation of the poliovirus was done with stool examinations carried out at the Pasteur Institute in Abidjan. Among 1,002 cases of AFP, 156 stool samples were positive for enteroviruses including 59 cases of poliovirus (31 cases of polio vaccine and 28 cases of wild poliovirus), a frequency of 2.3%. Children 0 to 5 years of age were most affected by AFP (59.78%). Paralysis of the legs represented the most frequently affected zone (69.56%). The Mopti region was most heavily affected are with 11 cases of the 28 cases of wild poliovirus, of which boys were most affected (71.43%). Despite the efforts made so far in the fight against polio, wild poliovirus continues to circulate and spread in Mall and the West African sub-region. All countries in West Africa and on the African continent must reach a sufficient level of vaccination coverage in order to eradicate the wild strain like industrialized countries have.