Persistence of nevirapine exposure during the postpartum period after intrapartum single-dose nevirapine in addition to zidovudine prophylaxis for the prevention of mother-to-child transmission of HIV-1

OBJECTIVE: To determine nevirapine (NVP) plasma levels during the postpartum period after a single intrapartum NVP dose for the prevention of mother-to-child transmission. METHODS: Plasma samples at delivery and during days 8 to 45 postpartum were obtained from HIV-infected Thai women who received an intrapartum NVP dose in the Perinatal HIV Prevention Clinical Trial-2 (PHPT-2) for the prevention of perinatal HIV transmission. These data were combined with NVP concentration data from 2 phase 1 studies of NVP for a population analysis. RESULTS: The median NVP level fell to 68 ng/mL (range: <50-228, n = 43) 8 to 14 days after dosing and to 51 ng/mL (range: <50-166, n = 25) between 15 and 21 days. During the second and third weeks postpartum, NVP levels were below the limit of quantitation in 23% and 44% of samples, respectively. Between 21 and 45 days, no sample had a quantifiable NVP concentration. A simulation derived from the population analysis predicts that NVP concentration falls to less than 10 ng/mL in 5% of women by 11 days, in 50% of women by 17.5 days, and in 95% of women by 28 days. CONCLUSIONS: Significant NVP concentrations remained for up to 20 days in these Thai women. To ensure that coverage is maintained until NVP concentrations fall to nonsuppressive levels, 1 month of additional antiretroviral treatment after delivery should be considered to prevent the emergence of resistant viruses.     

Interactions of human organic anion transporters and human organic cation transporters with nonsteroidal anti-inflammatory drugs

The purpose of this study was to elucidate the interactions of human organic anion transporters (hOATs) and human organic cation transporters (hOCTs) with nonsteroidal anti-inflammatory drugs (NSAIDs) using cells stably expressing hOATs and hOCTs. NSAIDs tested were acetaminophen, acetylsalicylate, salicylate, diclofenac, ibuprofen, indomethacin, ketoprofen, mefenamic acid, naproxen, piroxicam, phenacetin, and sulindac. These NSAIDs inhibited organic anion uptake mediated by hOAT1, hOAT2, hOAT3, and hOAT4. By comparing the IC(50) values of NSAIDs for hOATs, it was found that hOAT1 and hOAT3 exhibited higher affinity interactions with NSAIDs than did hOAT2 and hOAT4. HOAT1, hOAT2, hOAT3, and hOAT4 mediated the uptake of either ibuprofen, indomethacin, ketoprofen, or salicylate, but not acetylsalicylate. Although organic cation uptake mediated by hOCT1 and hOCT2 was also inhibited by some NSAIDs, hOCT1 and hOCT2 did not mediate the uptake of NSAIDs. In conclusion, hOATs and hOCTs interacted with various NSAIDs, whereas hOATs but not hOCTs mediated the transport of some of these NSAIDs. Considering the localization of hOATs, it was suggested that the interactions of hOATs with NSAIDs are associated with the pharmacokinetics and the induction of adverse reactions of NSAIDs.     

Low-doses of indinavir boosted with ritonavir in HIV-infected Thai patients: pharmacokinetics, efficacy and tolerability

OBJECTIVES: To assess the steady-state pharmacokinetics of two reduced doses of indinavir boosted with ritonavir (indinavir/ritonavir) in HIV-infected Thai patients. PATIENTS AND METHODS: Thirteen immunocompromised antiretroviral-naive patients (6 males, 7 females) initiated 600/100 mg indinavir/ritonavir, zidovudine and lamivudine, every 12 h. After 1 month, blood samples were taken at pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 h after drug intake. Indinavir dosing was then reduced to 400 mg (twice daily) and 1 week later an identical series of samples were drawn. Patients then resumed 600 mg of indinavir. HIV-1 RNA viral load was determined at 8, 24 and 48 weeks. Indinavir plasma levels were determined by HPLC and pharmacokinetic parameters by non-compartmental analysis. RESULTS: Median (range) weight was 58 kg (51-73) for men and 53 kg (46-59) for women. On 600 mg of indinavir, median indinavir AUC, C(max), and C(min) were 39.3 mg.h/L (20.6-50.5), 6.2 mg/L (3.7-9.0) and 0.41 mg/L (0.12-0.77), respectively, and on indinavir 400 mg, 18.3 mg.h/L (11.1-33.0), 3.8 mg/L (2.2-7.8) and 0.17 mg/L (0.10-0.39), respectively. No renal complications were observed. At 48 weeks, 6/13 (46%) patients had stopped 600 mg of indinavir due to intolerability (gastrointestinal and cutaneous), and 5/7 (71%) patients had a HIV-1 viral load <50 copies/mL. CONCLUSIONS: Reduced doses of indinavir/ritonavir maintained adequate indinavir plasma levels compared to current guidelines suggesting that these doses are efficacious in this setting. Considering the poor tolerability of 600 mg of indinavir, the 400 mg of indinavir may be preferred due to its lower exposure indices but long-term efficacy data are needed.     

Emergence and clearance of gametocytes in uncomplicated Plasmodium falciparum malaria

We reviewed the records of 1,175 patients with uncomplicated Plasmodium falciparum malaria to determine the prevalence of gametocytemia. All patients were admitted and received artemisinin combination therapy. Blood films were checked daily until discharge. Circulating gametocytes were observed in 240 (20.2%) of patients and in most cases (222 of 240, 92.5%) gametocytemia was detected during the first 24 hours after admission. Gametocytes were first seen in 174 cases on admission, in 24 cases at 12 hours, and in 24 cases at 24 hours. The longest interval between admission and first appearance of gametocytes was 192 hours. The median gametocyte clearance time was 163 hours (range = 12-806) in the 219 patients in whom gametocytemia resolved. However, 21 patients (9.8%) still had gametocytemia on discharge. Gametocytemia generally is present within the first 24 hours after admission, and emerges in only 1.9% of patients later on during treatment with artemisinin.     

Critical interactions between Global Fund-supported programmes and health systems: a case study in Papua New Guinea

In Papua New Guinea, investment by the Global Fund to Fight AIDS, Tuberculosis and Malaria (the Global Fund) has played an important role in scaling up the response to HIV and tuberculosis (TB). As part of a series of case studies on how Global Fund-supported programmes interact with national health systems, we assessed the nature and extent of integration of the Global Fund portfolios within the national HIV and TB programmes, the integration of the HIV and TB programmes within the general health system, and system-wide effects of Global Fund support in Papua New Guinea. The study relied on a literature review and 30 interviews with key stakeholders using the Systemic Rapid Assessment Toolkit and thematic analysis. Global Fund-supported activities were found to be largely integrated, or at least coordinated, with the national HIV and TB programmes. However, this has reinforced the vertical nature of these programmes with respect to the general health system, with parallel systems established to meet the demands of programme scale-up and the performance-based nature of Global Fund investment in the weak health system context of Papua New Guinea. The more parallel functions include monitoring and evaluation, and procurement and supply chain systems, while human resources and infrastructure for service delivery are increasingly integrated at more local levels. Positive synergies of Global Fund support include engagement of civil-society partners, and a reliable supply of high-quality drugs which may have increased patient confidence in the health system. However, the severely limited and overburdened pool of human resources has been skewed towards the three diseases, both at management and service delivery levels. There is also concern surrounding the sustainability of the disease programmes, given their dependence on donors. Increasing Global Fund attention towards health system strengthening was viewed positively, but should acknowledge that system changes are slow, difficult to measure and require long-term support.     

Maternal Antibodies to Pneumolysin but Not to Pneumococcal Surface Protein A Delay Early Pneumococcal Carriage in High-Risk Papua New Guinean Infants

Immunization of pregnant women can be an efficient strategy to induce early protection in infants in developing countries. Pneumococcal protein-based vaccines may have the capacity to induce pneumococcal serotype-independent protection. To understand the potential of maternal pneumococcal protein-specific antibodies in infants in high-risk areas, we studied the placental transfer of naturally acquired antibodies to pneumolysin (Ply) and pneumococcal surface protein A family 1 and 2 (PspA1 and PspA2) in relation to onset of pneumococcal nasopharyngeal carriage in infants in Papua New Guinea (PNG). In this study, 76% of the infants carried Streptococcus pneumoniae in the upper respiratory tract within the first month of life, at a median age of 19 days. Maternal and cord blood antibody titers to Ply (ρ = 0.824, P < 0.001), PspA1 (ρ = 0.746, P < 0.001), and PspA2 (ρ = 0.631, P < 0.001) were strongly correlated. Maternal pneumococcal carriage (hazard ratio [HR], 2.60; 95% confidence interval [CI], 1.25 to 5.39) and younger maternal age (HR, 0.74; 95% CI, 0.54 to 1.00) were independent risk factors for early carriage, while higher cord Ply-specific antibody titers predicted a significantly delayed onset (HR, 0.71; 95% CI, 0.52 to 1.00) and cord PspA1-specific antibodies a significantly younger onset of carriage in PNG infants (HR, 1.57; 95% CI, 1.03 to 2.40). Maternal vaccination with a pneumococcal protein-based vaccine should be considered as a strategy to protect high-risk infants against pneumococcal disease by reducing carriage risks in both mothers and infants.Every year approximately 1 million children under 5 years of age die of pneumococcal pneumonia, meningitis, or sepsis, mostly in developing countries (4). Despite the efficacy of pneumococcal conjugate vaccines, Streptococcus pneumoniae remains an important cause of serious morbidity and mortality in young infants in developing countries (5, 8, 44), where the age of onset of disease is often younger than the recommended vaccination age of 6 weeks old and many of the serotypes causing serious disease are not included in currently available conjugate vaccines. Alternative vaccines and vaccine strategies are therefore needed to induce the earliest protection possible in high-risk infants.Early onset of pneumococcal colonization and prolonged carriage in the upper respiratory tract are believed to play important roles in the high incidence and early onset of pneumococcal diseases in children in developing countries (10, 25). In the highlands of Papua New Guinea (PNG), where this study was performed, all infants carry pneumococci in the upper respiratory tract by the age of 3 months old, and 60% of them are already carriers during the neonatal period at a median age of 17 days old (14). This is in contrast to high-income countries, where less than half of the children experience pneumococcal colonization within the first year of life (3, 10, 43). Besides children, pneumococcal carriage rates remain higher in adulthood in developing countries, including PNG, where approximately half of the adults carry pneumococci in the upper respiratory tract (17, 39), compared to 1 to 13% of adults in low-risk countries (12, 15, 20). Consequently, maternal pneumococcal carriage may be an important risk factor for early colonization in infants in high-risk areas, in particular considering the frequent and close contact between mother and child in the critical early period of life when infants are highly susceptible.In the first few months of life, when the human immune system is still highly immature (27), infants largely depend on passively acquired maternal immunoglobulin G (IgG) antibodies to protect themselves against invading pathogens. Immunization of pregnant women is a strategy that has been proven to reduce infection risks in both mothers and infants (9, 13, 45). This includes the potential to reduce acute lower respiratory illnesses in infants in high-risk areas, as shown with maternal immunization with the 23-valent pneumococcal polysaccharide vaccine (36, 37). However, the efficacy of pneumococcal polysaccharide vaccines on reducing nasopharyngeal colonization is limited, whereas the protective effect of pneumococcal conjugate vaccines is restricted by the number of pneumococcal serotypes that can be included. On the other hand, novel vaccines based on conserved pneumococcal proteins may offer better, serotype-independent protection against pneumococcal carriage and disease. This may include maternal immunization strategies, as supported by findings in mice (21).Pneumolysin (Ply) and pneumococcal surface protein A (PspA) are two conserved proteins that are expressed by virtually all S. pneumoniae isolates and that are being considered as vaccine candidates. Pneumolysin is the thiol-activated cytolysin produced by S. pneumoniae that enables the bacterium to penetrate the host''s physical defenses through its cytotoxic effect on epithelial cells, thus facilitating carriage and disease (28). PspA is a cell wall-associated protein that plays a role in inhibiting complement-mediated opsonization (7, 33) and can prevent lactoferrin-mediated clearance (19). In contrast to Ply, PspA shows structural diversity between pneumococcal strains and has been classified into three families based on the sequence variability of the most C-terminal 100 amino acids of the N-terminal domain of PspA. Although S. pneumoniae strains expressing family 1 or 2 PspA proteins account for 98% of clinical isolates, protective PspA-specific IgG antibodies binding to this highly variable region are family dependent (7).Both Ply and PspA have been shown to be highly immunogenic and to protect mice against disease and colonization following pneumococcal challenge (2, 6, 7, 11, 34). There is evidence that in humans naturally acquired IgA and IgG antibodies to PspA and Ply can mediate protection against subsequent pneumococcal carriage and disease (22, 24, 30, 31, 38, 46). Moreover, naturally acquired antibodies to Ply and PspA have been shown to be transferred from mother to child and to protect against early pneumococcal carriage and infection, at least in populations in low-risk areas (18, 38). It is not known whether these findings hold true for areas of high endemicity, where infants are at a considerably higher risk for early carriage and disease.In order to understand the role of maternal antibodies to Ply and PspA in protecting high-risk infants against early carriage, we studied antibody titers in paired maternal and cord blood samples in relation to the infant''s age of first pneumococcal nasopharyngeal carriage. We hypothesized that, compared to lower-risk settings, maternal Ply- and PspA-specific antibody titers would be higher and would be associated with a delay in the age of first pneumococcal carriage in the offspring.     

The scent of Mycobacterium tuberculosis – Part II breath

Recent figures show that tuberculosis (TB) is advancing and killing more than two million people annually, yet no breakthrough in rapid diagnostics is in sight. Volatile metabolites of Mycobacterium tuberculosis (MTB) may provide just that. It is well established that MTB produces nicotinic acid in vitro. We have converted the free acid into methyl nicotinate and detected statistically significant differences in the breath of smear positive patients compared with healthy (smear negative) subjects.