Family Health Days program contributions in vaccination of unreached and under-immunized children during routine vaccinations in Uganda.

BACKGROUND: We explored the contributions of the Family Health Days (FHDs) concept, which was developed by the Uganda Ministry of Health (MOH) and UNICEF as a supplementary quarterly outreach program in addition to strengthening the routine expanded program for immunization (EPI), with the aim to increase coverage, through improved access to the unimmunized or unreached and under-immunized children under 5 years. METHOD: A cross-sectional descriptive study of the Uganda MOH, Health Management Information Systems (HMIS) and UNICEF in house FHDs data was conducted covering six quarterly implementations of the program between April 2012 and December 2013. The FHDs program was implemented in 31 priority districts with low routine vaccination coverage from seven sub-regions in Uganda in a phased manner using places of worship for service delivery. RESULTS: During the six rounds of FHDs in the 31 districts, a total of 178,709 and 191,223 children received measles and Diphtheria-Pertussis-Tetanus (DPT3) vaccinations, respectively. The FHDs' contributions were 126% and 144% for measles and 103% and 122% for DPT3 in 2012 and 2013, respectively of the estimated unreached annual target populations. All implementing sub-regions after two rounds in 2012 attained over and above the desired target for DPT3 (85%) and measles (90%). The same was true in 2013 after four rounds, except for Karamoja and West Nile sub-regions, where in some districts a substantial proportion of children remained unimmunized. The administrative data for both DPT3 and measles immunization showed prominent and noticeable increase in coverage trend in FHDS regions for the months when the program was implemented. CONCLUSION: The FHDs program improved vaccination equity by reaching the unreached and hard-to-reach children and bridging the gap in immunization coverage, and fast tracking the achievement of targets recommended by the Global Vaccine Action Plan (GVAP) for measles and DPT3 (85% and 90% respectively) in implementing sub-regions and districts. The FHDs is an innovative program to supplement routine immunizations designed to reach the unreached and under immunized children.

Lopinavir/ritonavir significantly influences pharmacokinetic exposure of artemether/lumefantrine in HIV-infected Ugandan adults.

BACKGROUND: Treatment of HIV/malaria-coinfected patients with antiretroviral therapy (ART) and artemisinin-based combination therapy has potential for drug interactions. We investigated the pharmacokinetics of artemether, dihydroartemisinin and lumefantrine after administration of a single dose of 80/480 mg of artemether/lumefantrine to HIV-infected adults, taken with and without lopinavir/ritonavir. METHODS: A two-arm parallel study of 13 HIV-infected ART-naive adults and 16 HIV-infected adults stable on 400/100 mg of lopinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors (ClinicalTrials.gov, NCT 00619944). Each participant received a single dose of 80/480 mg of artemether/lumefantrine under continuous cardiac function monitoring. Plasma concentrations of artemether, dihydroartemisinin and lumefantrine were measured. RESULTS: Co-administration of artemether/lumefantrine with lopinavir/ritonavir significantly reduced artemether maximum concentration (C(max)) and area under the concentration-time curve (AUC) [median (range): 112 (20-362) versus 56 (17-236) ng/mL, P = 0.03; and 264 (92-1129) versus 151 (38-606) ng · h/mL, P < 0.01]. Dihydroartemisinin C(max) and AUC were not affected [66 (10-111) versus 73 (31-224) ng/mL, P = 0.55; and 213 (68-343) versus 175 (118-262) ng · h/mL P = 0.27]. Lumefantrine C(max) and AUC increased during co-administration [2532 (1071-5957) versus 7097 (2396-9462) ng/mL, P < 0.01; and 41,119 (12,850-125,200) versus 199,678 (71,205-251,015) ng · h/mL, P < 0.01]. CONCLUSIONS: Co-administration of artemether/lumefantrine with lopinavir/ritonavir significantly increases lumefantrine exposure, but decreases artemether exposure. Population pharmacokinetic and pharmacodynamic trials will be highly valuable in evaluating the clinical significance of this interaction and determining whether dosage modifications are indicated.

Nevirapine pharmacokinetics when initiated at 200 mg or 400 mg daily in HIV-1 and tuberculosis co-infected Ugandan adults on rifampicin.

BACKGROUND: rifampicin lowers nevirapine plasma concentrations by inducing cytochrome P450. However, few data are available on this interaction during the lead-in period of nevirapine treatment. METHODS: eighteen HIV-1/tuberculosis co-infected adults receiving rifampicin daily as part of anti-tuberculosis therapy were evenly randomized to nevirapine initiation by dose escalation (NVP200) or nevirapine initiation at 200 mg twice daily (NVP400). Subjects underwent 12 h intensive pharmacokinetic sampling on Days 7, 14 and 21 of nevirapine treatment. A minimum effective concentration (MEC) of 3000 ng/mL was used to interpret nevirapine concentrations 12 h after dosing (C(12)). TRIAL REGISTRATION NUMBER: NCT00617643 (www.clinicaltrials.gov). RESULTS: day 7 geometric mean nevirapine C(12) [90% confidence interval (CI)] was 1504 (1127-2115) ng/mL and 3148 (2451-4687) ng/mL in the NVP200 and NVP400 arms, respectively (P < 0.01). Nevirapine C(12) on Days 14 and 21 was similar. On Day 21, nevirapine concentration in 64% of patients was below the MEC. On Day 7, geometric mean area under the curve (AUC(0-12)) was lower in the NVP200 arm, 25 223 (90% CI, 21 978-29 695) ng·h/mL versus 43 195 (35 607-57 035) ng·h/mL in the NVP400 arm (P  <  0.01). Similarly, on Day 14, nevirapine AUC(0-12) was lower in the NVP200 arm 23 668 (18 253-32 218) ng·h/mL versus the NVP400 arm 44 918 (36 264-62 769) ng·h/mL (P = 0.03). CONCLUSIONS: in co-treated patients, nevirapine concentrations were below the MEC during initiation with dose escalation. Nevirapine initiation at the maintenance dose of 200 mg twice daily is preferred. Sub-therapeutic nevirapine concentrations were common at Day 21 with either regimen. Evaluation of higher nevirapine maintenance doses may be considered.

Cardiac Conduction Safety during Coadministration of Artemether-Lumefantrine and Lopinavir/Ritonavir in HIV-Infected Ugandan Adults.

Background. We aimed to assess cardiac conduction safety of coadministration of the CYP3A4 inhibitor lopinavir/ritonavir (LPV/r) and the CYP3A4 substrate artemether-lumefantrine (AL) in HIV-positive Ugandans. Methods. Open-label safety study of HIV-positive adults administered single-dose AL (80/400 mg) alone or with LPV/r (400/100 mg). Cardiac function was monitored using continuous electrocardiograph (ECG). Results. Thirty-two patients were enrolled; 16 taking LPV/r -based ART and 16 ART naïve. All took single dose AL. No serious adverse events were observed. ECG parameters in milliseconds remained within normal limits. QTc measurements did not change significantly over 72 hours although were higher in LPV/r arm at 24 (424 versus 406; P = .02) and 72 hours (424 versus 408; P = .004) after AL intake. Conclusion. Coadministration of single dose of AL with LPV/r was safe; however, safety of six-dose AL regimen with LPV/r should be investigated.

Suboptimal nevirapine steady-state pharmacokinetics during intrapartum compared with postpartum in HIV-1-seropositive Ugandan women.

BACKGROUND: Conflicting data exist regarding the effect of pregnancy on steady-state nevirapine pharmacokinetics (PK), although steady-state nevirapine concentrations during pregnancy have never been characterized in sub-Saharan Africa. METHODS: This was a longitudinal intensive PK study in Ugandan pregnant women receiving nevirapine-based antiretroviral therapy. Participants underwent intensive 12-hour PK sampling during the second trimester (T2; n = 4), third trimester (T3; n = 15) and 6 weeks postpartum (PP; n = 15). HIV-1 RNA was performed within 2 weeks of each visit. Nevirapine C12 above 3000 ng/mL was classified as optimal based on the suggested value for therapeutic drug monitoring. RESULTS: The pharmacokinetics of nevirapine were influenced by pregnancy, demonstrated by a 20% reduction in the maximum concentration, minimum concentration (C12), and area under the curve between T3 and PP visits (P = 0.001, P = 0.011 and P = 0.005, respectively). Ten subjects (66.7%) had C12 values <3000 ng/mL during T3. Of these participants, 7 partcipant's C12 concentrations increased to >3000 ng/mL during the PP visit. HIV-1 RNA were <1000 copies per milliliter at T3 and <400 copies per milliliter at PP in all patients. CONCLUSIONS: Nevirapine exposure was reduced in Ugandan women during their third trimester compared with the same women PP, however, HIV RNA remained <1000 copies per milliliter. The long-term impact of intermittent suboptimal nevirapine concentrations during pregnancy is unknown.