Dose Of Nevirapine Research Articles

The role of corticosterone in nevirapine-induced idiosyncratic drug-induced liver injury.

Nevirapine, an antiretroviral used in the treatment of HIV, is associated with idiosyncratic drug-induced liver injury (IDILI), a potentially life-threatening adverse drug reaction. Its usage has decreased due to this concern, but it is still widely used in lower-resource settings. In general, the mechanisms underlying idiosyncratic drug reactions (IDRs) are poorly understood, but evidence indicates that most are immune-mediated. There is very limited understanding of the early immune response following administration of drugs associated with IDRs, which likely occurs due to reactive metabolite formation. In this work, we aimed to characterize the links between covalent binding of nevirapine, the development of an early immune response, and the subsequent liver injury using a mouse model. We describe initial attempts to characterize an early immune response to nevirapine followed by the discovery that nevirapine induced the release of corticosterone. Corticosterone release was partially associated with the degree of drug covalent binding in the liver but was also likely mediated by additional mechanisms at higher drug doses. Transcriptomic analysis confirmed metabolic activation, glucocorticoid signaling, and decreased immune activation; GDF-15 also warrants further investigation as part of the immune response to nevirapine. Finally, glucocorticoid blockade preceding the first dose of nevirapine attenuated nevirapine-induced liver injury at 3 weeks, suggesting that acute glucocorticoid signaling is harmful in the context of nevirapine-induced liver injury. This work demonstrates that nevirapine induces acute corticosterone release, which contributes to delayed-onset liver injury. It also has implications for screening drug candidates for IDILI risk and preventing nevirapine-induced IDILI.

Effects of the Pratt pouch model of dispensing nevirapine prophylaxis on HIV exposed infant completion of 6 weeks of prophylaxis in Uganda.

IntroductionThe innovative Pratt pouch could optimize dispensing nevirapine prophylaxis to HIV-exposed infants in pre-measured single dose pouches to increase completion of the full 6 week infant nevirapine regimen.Materials and methodsNineteen health facilities with highest HIV positivity rates among pregnant women across 9 districts in southwest and central Uganda were assigned to control and intervention groups. HIV-positive women enrolled at intervention facilities received pouches filled with premeasured single doses of nevirapine using Uganda national guidelines, which were integrated into the existing drug distribution system. During antenatal care (ANC) women received 14 pouches to cover time until the 6 day postpartum visit, with an additional 8 pouches if women were delayed in returning to the facility, and 28 pouches after delivery. Women enrolled at control facilities received standard nevirapine syrup following delivery for postnatal infant prophylaxis. In a select number of intervention facilities, during ANC, women received all 42 pouches needed to complete the 6 weeks regimen. Medical record data from enrolled women were extracted; interviews with HIV-positive women during postnatal care visits were conducted. Data were collected January to August 2018 (control sites) and October 2019 to February 2020 (intervention sites). Unadjusted and adjusted logistic regression models were used to identify factors associated with facility delivery, postnatal care follow-up visit, and completion of the full 6 weeks infant nevirapine regimen.ResultsSignificantly more women in the intervention (n = 320) versus control (n = 340) group had facility delivery (292/316, 92.4% versus 169/340, 49.7%, p<0.0001), postnatal visits within 2 weeks postpartum (295/297, 99.3% versus 133/340, 39.1%, p<0.0001) and reported their infants completing the full 6 weeks infant prophylaxis regimen (299/313, 95.5% versus 210/242, 86.8%, p = 0.0002). Dispensing 42 versus 14 pouches during ANC did not have negative effects on these outcomes. Among out-of-facility deliveries, a higher proportion of infants received nevirapine within 72 hours of birth in the intervention versus control group, 95.8% versus 77.9%. In multivariate models, the intervention group was the only significant factor associated with facility delivery or completion of the full 6 weeks infant prophylaxis.ConclusionsUse of the Pratt pouch resulted in an increase in HIV-exposed infants completing the full 6weeks prophylaxis regimen and associated benefits including increasing facility delivery and women’s adherence to postnatal care services.

Nevirapine Pharmacokinetics in Neonates Between 25 and 32 Weeks Gestational Age for the Prevention of Mother-to-Child Transmission of HIV.

Eleven newborns from 25 to 32 weeks of gestational age, weighting from 0.66 to 1.60 kg received 2 mg/kg doses of nevirapine syrup. In 15 samples, collected 8.75-89 hours after drug intake, concentrations ranged from 0.65 to 16.68 mg/L. Three nevirapine dose of 2 mg/kg at day 0, 2 and 6 days of life achieved nevirapine concentrations above the proposed nevirapine target for HIV prophylaxis for at least 11 days.

Pharmacokinetics and safety of early nevirapine-based antiretroviral therapy for neonates at high risk for perinatal HIV infection: a phase 1/2 proof of concept study

With increasing intention to treat HIV as early as possible, evidence to confirm the safety and therapeutic drug concentrations of a nevirapine-based antiretroviral regimen in the early neonatal period is needed. This study aims to establish dosing of nevirapine for very early treatment of HIV-exposed neonates at high risk of HIV acquisition. IMPAACT P1115 is a multinational phase 1/2 proof-of-concept study in which presumptive treatment for in-utero HIV infection is initiated within 48 h of birth in HIV-exposed neonates at high risk of HIV acquisition. Participants were neonates who were at least 34 weeks gestational age at birth and enrolled within 48 h of birth, born to women with presumed or confirmed HIV infection who had not received antiretrovirals during this pregnancy. The regimen consisted of two nucleoside reverse transcriptase inhibitors plus nevirapine dosed at 6 mg/kg twice daily for term neonates (≥37 weeks gestational age) or 4 mg/kg twice daily for 1 week and 6 mg/kg twice daily thereafter for preterm neonates (34 to <37 weeks gestational age). Here, we report the secondary outcomes of the study: nevirapine exposures in study weeks 1 and 2 and treatment-associated grade 3 or 4 adverse events at least possibly related to study treatment up to study week 4. A population pharmacokinetic model to assess nevirapine exposure was developed from dried blood spot and plasma nevirapine concentrations at study weeks 1 and 2. Nevirapine exposure was assessed in all patients with available blood samples and safety was assessed in all participants. This trial is registered at ClinicalTrials.gov (NCT02140255). Between Jan 23, 2015, and Sept 4, 2017, 438 neonates were enrolled and included in analyses; 36 had in-utero HIV infection and 389 (89%) were born at term. Neonates without confirmed in-utero HIV infection received nevirapine for a median of 13 days (IQR 7-14). Measured dried blood spot nevirapine concentrations were higher than the minimum HIV treatment target (3 μg/mL) in 314 (90%, 95% CI 86-93) of 349 neonates at week 1 and 174 (87%, 81-91) of 201 at week 2. In Monte-Carlo simulations, week 1 nevirapine concentrations exceeded 3 μg/mL in 80% of term neonates and 82% of preterm neonates. DAIDS grade 3 or 4 adverse events at least possibly related to antiretrovirals occurred in 30 (7%, 95% CI 5-10) of 438 infants but did not lead to nevirapine cessation in any neonates; neutropenia (25 [6%] neonates) and anaemia (six [1%]) were most common. Nevirapine at the dose studied was confirmed to be safe and provides therapeutic exposure concentrations. These data support nevirapine as a component of presumptive HIV treatment in high-risk neonates. National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.

Investigating time dependent brain distribution of nevirapine via mass spectrometric imaging.

Central nervous system (CNS) HIV infection causes brain tissue inflammation and tissue deficit that contributes to neuroAIDS. This complication is escalated by the blood-brain barrier (BBB), which prevents easy access to antiretroviral drugs entering the CNS. In this study the aims were to investigate the BBB membrane penetration and brain localization patterns of Nevirapine (NVP) using Imaging Mass Spectrometry (MSI). Sprague-Dawley rats received an intraperitoneal dose of NVP (50mgkg-1). Plasma and brain samples were harvested, and mass spectrometric methods were then applied to determine the pharmacokinetic properties and localization patterns of NVP in the brain. The pharmacokinetic parameters demonstrated a rapid bio-distribution of NVP in plasma and brain. The plasma Cmax was 6320ngmL-1 and the brain Cmax was 1923ngmL-1, both at a Tmax of 0.25h. MSI of coronal brain sections showed that NVP penetrated and localized in the brain regions implicated with the development of HIV associated neurodegeneration. NVP has great potential to combat neuroAIDS.

The relationship between zidovudine, lamivudine and nevirapine plasma drug levels and antiretroviral treatment outcomes in Nigeria children living with HIV

Plasma concentrations of antiretrovirals are significant and important determinants of treatment failure and toxicity. The relationship between antiretroviral pharmacokinetic exposures and immunovirological outcomes has not been extensively studied in our setting. The aim of this study was to investigate the relationship between antiretroviral plasma concentrations and virological and immunological treatment outcomes in children living with human immunodeficiency virus (HIV) A retrospective collection of demographic, clinical , laboratory data and a prospective determination of plasma drug concentrations in 120 children aged 2-14 years after two years of receiving fixed dose zidovudine, lamivudine and nevirapine tablets using a simple, rapid, sensitive and validated method of high performance liquid chromatography with UV detection for simultaneous quantification of zidovudine, lamivudine and nevirapine in human plasma. All analyses were performed using graph pad prism version 5.0. A perfect agreement (p 100 cells/mm3). At 2 years zidovudine, lamivudine and nevirapine therapeutic levels, zidovudine supra therapeutic levels ,and nevirapine subtherapeutic levels were respectively significantly associated with immunologic success (CD4%>15 %). Low nevirapine levels can be used to identify those that require adherence counseling. Despite good virological and immunological outcomes, plasma concentrations of zidovudine, lamivudine and nevirapine were not significantly associated with virological and immunological outcomes (Absolute CD4 counts) but was significantly associated with immunological outcomes (CD4%). Plasma drug levels may be good surrogates of adherence but not of treatment outcomes. Monitoring CD4% remains important to optimize paediatric HIV treatment.Keywords: Antiretroviral treatment, children, therapeutic drug monitoring, treatment outcomes, immune-virological outcomes, plasma concentrations, zidovudine, lamivudine and nevirapine

Factors Influencing Maternal Adherence to Infant’s Nevirapine Prophylaxis in a Cross-Sectional Study Conducted at Mulago Hospital, Kampala, Uganda

To eliminate mother to child transmission of HIV, existing interventions might need to be scaled-up and rigorously implemented. One of the strategies to reduce vertical transmission of HIVis the 4-6weeks daily single oral dose ofNevirapine (NVP) or Zidovidinerecommended for newbornsto HIV positive mothers. Maternal optimal adherence to these anti-retroviral prophylaxis regimens is imperative to prevention of vertical transmission of HIV. Limited studies investigated maternal adherence to infant’s NVP prophylaxis regimen and associated factors. This study examined the level and factors influencing maternal adherence to infant’s NVPprophylaxis regimenat six weeks of age. Maternal adherence to infant’s NVP regimen was defined as dispensation of 95% of the total daily single dose of NVPsuspension to infants at 6 weeks of age. Maternal adherence, socio-demographic and psychosocial factors were measured using a pre-tested questionnaire. Bivariate analysis and binary logistic regression model were used to determine the level and factors influencing maternal adherence to infant’s NVP regimen respectively. Results showed that 77% of the mothers had optimal adherence. Maternal age ≥ 20 years and believe in the effectiveness of NVP in prevention of vertical transmission of HIV were associated with increased likelihood of adherence to infants NVP regimen (OR 6.18; 95% CI: 1.64-23.24) and (OR 12.69; 95% CI 3.07-52.44) respectively.In conclusion maternal maturity and perceived benefits of NVP seems to be important positive drivers of optimal adherence. This suggests the importance of considering psychosocial and demographic characteristics of mothers in policy and intervention designing.

Effect of long-term administration of antiretroviral drugs (Tenofovir and Nevirapine) on neuroinflammation and neuroplasticity in mouse hippocampi

The use of combination antiretroviral therapy (cART) has been successful in suppressing HIV-1 replication and restoring peripheral immune functioning in HIV-infected individuals. Despite these advances in the management of HIV, neurocognitive impairments continue to be diagnosed in HIV-infected patients on treatment, even when the viral load is low. Of interest is the observation that deficiencies in brain function in these individuals are marked by a persistent presence of neuroinflammation. Therefore, in this study we investigated whether long-term exposure to ART could contribute to neuroinflammation. Mice were subsequently administered a daily single dose of either Tenofovir disoproxil fumarate or Nevirapine orally for 8 weeks. After treatment, hippocampal tissue was collected from the brains of drug-treated and control mice and the levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and brain-derived neurotrophic factor (BDNF) determined. Our results showed that administration of Tenofovir disoproxil fumarate and Nevirapine induced astrogliosis and up-regulated IL-1β and TNF-α. In addition, we found that Nevirapine reduced the expression of BDNF. Together these results suggest that Nevirapine promotes inflammatory and reduces neuroprotective processes in the hippocampus of mice. Our findings therefore highlight the potential of ART to be harmful to the brain and as such these drugs may contribute to the development of HIV-associated neurocognitive disorder (HAND).

Factors associated with delivering premature and/or low birth weight infants among pregnant HIV-positive women on antiretroviral treatment at Dr George Mukhari Hospital, South Africa

Background: Prematurity and low birthweight (LBW) deliveries amongst pregnant women infected with the human immunodeficiency virus (HIV) remain a challenge worldwide. The association between prematurity, LBW and antiretroviral therapy (ART) or prophylactic antiretroviral drug (ARV) exposure in pregnancy is unclear. This study evaluates the risk of delivering a premature and/or LBW infant among HIV-positive pregnant women on ART or prophylactic ARV.Methods: A cross-sectional study was conducted (April to October 2012). HIV-positive women on prophylactic ARV (dual therapy) or lifelong ART (triple therapy or HAART) were enrolled in the study. Women who did not have a documented HIV result during pregnancy, those tested before delivery and those found to be HIV-positive were considered as not exposed to ARV drugs during pregnancy. This group received a standard dose of nevirapine during labour. The control group was made up of HIV-negative women.Results: Of the 496 mothers enrolled in the study, 59% (288/496) were HIV-positive, of whom 72% (206/288) were on ART or prophylactic ARV. The mean age was 27.6 ± 6.5 years (15 to 47 years). The mean gestational age (GA) was 35.9 ± 3.6 weeks (24– 42 weeks). Infants’ birthweights ranged from 550 to 4 900 g (2.5 ± 0.9 kg). HIV-positive mothers not on ART or ARV prophylaxis were likely to deliver an infant at GA 28 weeks (p 0.05) or birthweight 1 000 g (p 0.05) compared with their counterparts. Conclusion: HIV-positive pregnant women not on ART or ARV prophylaxis were at a risk of delivering babies at GA 28 weeks or birthweight 1 000 g. There is a need to encourage early and regular attendance for antenatal care so that HIV-positive pregnant women can be identified and have access to treatment during pregnancy.

Successful prevention of perinatal HIV transmission utilizing direct observation therapy in the setting of Acquired Immunodeficiency Syndrome (AIDS) and progressive multifocal leukoencephalopathy.

We report a case of a 22-year-old G1P0010 African-American female with poorly controlled perinatally acquired HIV/AIDS and recent diagnosis of progressive multifocal leukoencephalopathy (PML) by magnetic resonance imaging (MRI). She presented to a tertiary care facility for prenatal care and direct observation therapy after poor medication adherence during pregnancy. After multiple attempts at outpatient ART management, the patient was admitted at 35 weeks' gestation for direct observation therapy for both antiretroviral therapy and anti-seizure medication. Viral load at that time was 22,487 copies/mL and she was admitted and started on a salvage regimen which included: dolutegravir, tenofovir disoproxil fumarate/emtricitabine, darunavir, ritonavir, and trimethoprim/sulfamethoxazole for Pneumocystis jirovecii prophylaxis. The patient remained on direct observation therapy throughout her two-week hospital stay with final viral load of 1211 copies/mL, CD4 284/uL at time of delivery at 37 weeks' gestation, with minimal seizure activity. The infant received postnatal antiretroviral therapy including three doses of zidovudine and nevirapine with negative HIV PCR at birth, 2, 4, and 6 months postpartum and is currently HIV negative.

Acute and chronic resistance training downregulates select LINE-1 retrotransposon activity markers in human skeletal muscle.

Herein, we examined if acute or chronic resistance exercise affected markers of skeletal muscle long interspersed nuclear element-1 (LINE-1) retrotransposon activity. In study 1, 10 resistance-trained college-aged men performed three consecutive daily back squat sessions, and vastus lateralis biopsies were taken before (Pre), 2 h following session 1 (Post1), and 3 days following session 3 (Post2). In study 2, 13 untrained college-aged men performed a full-body resistance training program (3 days/wk), and vastus lateralis biopsies were taken before ( week 0) and ~72 h following training cessation ( week 12). In study 1, LINE-1 mRNA decreased 42-48% at Post1 and 2 ( P < 0.05), and reverse transcriptase (RT) activity trended downward at Post2 (-37%, P = 0.067). In study 2, LINE-1 mRNA trended downward at week 12 (-17%, P = 0.056) while LINE-1 promoter methylation increased (+142%, P = 0.041). Open reading frame (ORF)2p protein expression (-24%, P = 0.059) and RT activity (-26%, P = 0.063) also trended downward by week 12. Additionally, changes in RT activity versus satellite cell number were inversely associated ( r = -0.725, P = 0.008). Follow-up in vitro experiments demonstrated that 48-h treatments with lower doses (1 μM and 10 μM) of efavirenz and nevirapine (non-nucleoside RT inhibitors) increased myoblast proliferation ( P < 0.05). However, we observed a paradoxical decrease in myoblast proliferation with higher doses (50 μM) of efavirenz and delavirdine. This is the first report suggesting that resistance exercise downregulates markers of skeletal muscle LINE-1 activity. Given our discordant in vitro findings, future research is needed to thoroughly assess whether LINE-1-mediated RT activity enhances or blunts myoblast, or primary satellite cell, proliferative capacity.

Factors associated with delivering premature and/or low birth weight infants among pregnant HIV-positive women on antiretroviral treatment at Dr George Mukhari Hospital, South Africa

AbstractBackground: Prematurity and low birthweight (LBW) deliveries amongst pregnant women infected with the human immunodeficiency virus (HIV) remain a challenge worldwide. The association between prematurity, LBW and antiretroviral therapy (ART) or prophylactic antiretroviral drug (ARV) exposure in pregnancy is unclear. This study evaluates the risk of delivering a premature and/or LBW infant among HIV-positive pregnant women on ART or prophylactic ARV.Methods: A cross-sectional study was conducted (April to October 2012). HIV-positive women on prophylactic ARV (dual therapy) or lifelong ART (triple therapy or HAART) were enrolled in the study. Women who did not have a documented HIV result during pregnancy, those tested before delivery and those found to be HIV-positive were considered as not exposed to ARV drugs during pregnancy. This group received a standard dose of nevirapine during labour. The control group was made up of HIV-negative women.Results: Of the 496 mothers enrolled in the study, 59% (...

Prevention of TB using rifampicin plus isoniazid reduces nevirapine concentrations in HIV-exposed infants.

Newborns of HIV-infected mothers are given daily doses of nevirapine to prevent HIV-1 acquisition. Infants born to mothers with TB should also receive TB preventive therapy. TB preventive regimens include isoniazid for 6 months or rifampicin plus isoniazid for 3 months (RH preventive therapy). The effect of concomitant RH preventive therapy on nevirapine concentrations in infants is unknown. Tshepiso was a prospective case-control cohort study of pregnant HIV-infected women with and without TB whose newborn infants received standard doses of nevirapine for HIV prophylaxis. Infants born to mothers with TB also received RH preventive therapy. Infant plasma nevirapine concentrations were measured at 1 and 6 weeks. The effects of RH preventive therapy on nevirapine disposition were investigated in a population pharmacokinetic model. Of 164 infants undergoing pharmacokinetic sampling, 46 received RH preventive therapy. After adjusting for weight using allometric scaling, the model estimated a 33% reduction in nevirapine trough concentrations with RH preventive therapy compared with TB-unexposed infants not receiving concomitant rifampicin and a 30% decline in trough concentrations in a typical infant between day 7 and 35 post-partum. Rifampicin-based TB preventative treatment reduces nevirapine concentrations significantly in HIV-exposed infants. Although the nevirapine exposures required to prevent HIV acquisition in breastfeeding infants are undefined, given the potential risks associated with underdosing nevirapine in this setting, it is prudent to avoid rifampicin-based preventive therapy in HIV-exposed children receiving prophylactic nevirapine.

Nevirapine Pharmacokinetics and Safety in Neonates Receiving Combination Antiretroviral Therapy for Prevention of Vertical HIV Transmission.

Nevirapine (NVP)-based combination antiretroviral therapy is routinely prescribed to infants deemed at high risk of vertical HIV infection in our centers. We evaluated NVP pharmacokinetics and safety of this regimen. Neonates were recruited prospectively between September 2012 and April 2015 or enrolled retrospectively if treated similarly before prospective study initiation. NVP was dosed at 150 mg/m daily for 14 days, then twice daily for 14 days. NVP levels were drawn at weeks 1, 2, and 4 [target trough (NVP-T): 3-8 mg/L]. Thirty-three neonates were included (23 prospectively). Median gestational age (GA) and birth weight were 38 weeks (32-41 weeks) and 2.9 kg (1.5-4.2 kg), respectively. Median NVP-Ts were 8.2 mg/L (1.6-25.1 mg/L), 3.5 mg/L (1.6-6.8 mg/L), and 4.3 mg/L (0.1-19.9 mg/L) at weeks 1, 2, and 4, respectively. The proportions with therapeutic NVP-T were 42%, 61%, and 73% at these same timepoints. Median apparent oral clearance (CL/F) increased from 0.05 L·kg·h (0.01-0.50 L·kg·h) at week 2 to 0.18 L·kg·h (0.01-0.78 L·kg·h) at week 4. Increased drug exposure [area under the curve (AUCτ)] correlated with younger GA (r = 0.459, P = 0.032) and lower birth weight (r = 0.542, P = 0.009). The most common adverse events potentially attributable to combination antiretroviral therapy were transient asymptomatic hyperlactatemia (26%), anemia (24.7%), and neutropenia (22.1%). Treatment dose NVP was generally well-tolerated and associated with normalization of trough levels over time in most cases without dose adjustment. Lower empiric dosing is recommended for infants <34 weeks of GA. Routine therapeutic drug monitoring may not be required for infants ≥34 weeks of GA.

Once a Daily Dose of Nevirapine (400 mg) Versus Twice-Daily Dose (200 mg) of Nevirapine-Based Highly Active Antiretroviral Therapy Regimens in Antiretroviral Naïve Patients with HIV and Tuberculosis Infection in India

Nevirapine-based antiretroviral therapy against human immunodeficiency virus (HIV) among Tuberculosis (TB) co-infected individual is complicated as administration of rifampicin along with Nevirapine reduces the plasma concentration of Nevirapine. The objective of the present study is to compare efficacy and safety of Nevirapine 400 mg once daily (OD) based antiretroviral therapy (ART) with efavirenz based ART and twice daily dose (200 mg) of Nevirapine-based ART regimens in HIV-TB co-infected individuals. ART-naive HIV-TB patients were randomly assigned to receive either Nevirapine 400 mg OD with zidovudine and lamivudine (Group 1; n=30), Nevirapine 200 mg BD (Group 2; n=30), efavirenz 600 mg (Group 3, n=31); Nevirapine 400 mg OD with tenofovir (Group 4; n=30) and Nevirapine 400 mg OD without concomitant antitubercular therapy (ATT) (Group 5; n=30). The end points were virological (viral load), immunological (CD4 count) and clinical responses and progression of HIV disease marked by the failure of ART. Our results suggest that Nevirapine 400 mg OD based therapy is as effective as efavirenz-based ART in terms of clinical, immunological and virological response. Our data suggests that Nevirapine 400 mg OD group had favorable treatment outcome as compared to Nevirapine 200 mg 1 BD group. We conclude that Nevirapine 400 mg OD based ART combined with tenofovir and lamivudine could be an effective alternative to improve compliance in the resource-limited settings in patients with HIV-TB co-infection. Further large multicentric study with bigger sample size will be required to confirm these findings.

Providing Safe and Effective Preventative Antiretroviral Prophylaxis to HIV-exposed Newborns via a Novel Drug Delivery System in Tanzania.

In developing countries, antiretroviral therapy provides life-saving treatment to HIV-positive women and their children before, during and after birth. However, supply chain challenges such as long distances, medication shortages and nonfacility deliveries often compromise consistent access to prophylactic treatment for at-risk infants. A proposed intervention to address these challenges, often referred to as the "Pratt Pouch," allows for liquid-formulation medications, such as nevirapine (NVP), to be repackaged into single-dose pouches. These pouches are distributed antenatally. HIV-positive women at Kilimanjaro Christian Medical Centre in Moshi, Tanzania received 14 pouches each containing a single dose of NVP for prevention of mother-to-child transmission. Women were trained on how to open the pouch and dispense the medication to their infants after delivery. All participating women were asked to return to Kilimanjaro Christian Medical Centre 7-14 days after delivery, where infant blood spots were collected to assess NVP levels. All enrolled women (21/21) administered NVP to their infants within 24 hours of birth. All enrolled infants (22/22) had NVP blood concentrations over 100 ng/mL and exhibited no health concerns attributable to over or under dosing. The Pratt Pouch intervention provides a clinically appropriate solution for addressing liquid-formulation antiretroviral access challenges in developing countries.

Integrated therapy for HIV and tuberculosis.

Tuberculosis (TB) has been the most common opportunistic infection and cause of mortality among HIV-infected patients, especially in resource-limited countries. Clinical manifestations of TB vary and depend on the degree of immunodeficiency. Sputum microscopy and culture with drug-susceptibility testing are recommended as a standard method for diagnosing active TB. TB-related mortality in HIV-infected patients is high especially during the first few months of treatment. Integrated therapy of both HIV and TB is feasible and efficient to control the diseases and yield better survival. Randomized clinical trials have shown that early initiation of antiretroviral therapy (ART) improves survival of HIV-infected patients with TB. A delay in initiating ART is common among patients referred from TB to HIV separate clinics and this delay may be associated with increased mortality risk. Integration of care for both HIV and TB using a single facility and a single healthcare provider to deliver care for both diseases is a successful model. For TB treatment, HIV-infected patients should receive at least the same regimens and duration of TB treatment as HIV-uninfected patients. Currently, a 2-month initial intensive phase of isoniazid, rifampin, pyrazinamide, and ethambutol, followed by 4 months of continuation phase of isoniazid and rifampin is considered as the standard treatment of drug-susceptible TB. ART should be initiated in all HIV-infected patients with TB, irrespective of CD4 cell count. The optimal timing to initiate ART is within the first 8 weeks of starting antituberculous treatment and within the first 2 weeks for patients who have CD4 cell counts <50 cells/mm3. Non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART remains a first-line regimen for HIV-infected patients with TB in resource-limited settings. Although a standard dose of both efavirenz and nevirapine can be used, efavirenz is preferred because of more favorable treatment outcomes. In the settings where raltegravir is accessible, doubling the dose to 800 mg twice daily is recommended. Adverse reactions to either antituberculous or antiretroviral drugs, as well as immune reconstitution inflammatory syndrome, are common in patients receiving integrated therapy. Early recognition and appropriate management of these consequences can reinforce the successful integrated therapy in HIV-infected patients with TB.

The last and first frontier--emerging challenges for HIV treatment and prevention in the first week of life with emphasis on premature and low birth weight infants.

IntroductionThere is new emphasis on identifying and treating HIV in the first days of life and also an appreciation that low birth weight (LBW) and preterm delivery (PTD) frequently accompany HIV-related pregnancy. Even in the absence of HIV, PTD and LBW contribute substantially to neonatal and infant mortality. HIV-exposed and -infected infants with these characteristics have received little attention thus far. As HIV programs expand to meet the 90-90-90 target for ending the HIV pandemic, attention should focus on newborn infants, including those delivered preterm or of LBW.DiscussionIn high prevalence settings, infant diagnosis of HIV is usually undertaken after the neonatal period. However, as in utero infection may be diagnosed at birth, earlier initiation of therapy may limit viral replication and prevent early damage. Globally, there is growing awareness that preterm and LBW infants constitute a substantial proportion of births each year. Preterm infants are at high risk for vertical transmission. Feeding difficulties, apnoea of prematurity and vulnerability to sepsis occur commonly. Feeding intolerance, a frequent occurrence, may compromise oral administration of medications. Although there is growing experience with post-exposure prophylaxis for HIV-exposed term newborn infants, there is less experience with preterm and LBW infants. For treatment, there are even fewer options for preterm infants. Only zidovudine has adequate dosing recommendations for treating term and preterm infants and has an intravenous formulation, essential if feeding intolerance occurs. Nevirapine dosing for prevention, but not treatment, is well established for both term and preterm infants.HIV diagnosis at birth is likely to be extremely stressful for new parents, more so if caring for preterm or LBW infants. Programs need to adapt to support the medical and emotional needs of young infants and their parents, where interventions may be lifesaving.ConclusionsNew focus is required for the newborn baby, including those born preterm, with LBW or small for gestational age to consolidate gains already made in early diagnosis and treatment of young children.

Prevention of mother-to-child HIV transmission: MTCT-PLUS initiative program

Purpose: To evaluate the safety and efficacy of highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV) infected pregnant women to prevent mother-to-child transmission of HIV. Design of the study is observational retrospective evaluation of a prospective cohort. Setting of the study is King Chulalongkorn Memorial Hospital. Participants are HIV-infected Thai women and their offspring. HIV-positive pregnant women who received antenatal care were given antepartum and intrapartum zidovudine (ZDV) plus single dose nevirapine (NVP) or HAART [ZDV + lamivudine (3TC) + NVP] to prevent HIV transmission to the neonate. All newborns received single dose NVP plus 6-weeks of ZDV.HAART was given to their parents if indicated. We followed the infants from February 2003 to June 2006 to determine HIV-status. Calculated HIV maternal-child transmission rate is the main outcome. Among 157 mother-infant pairs, 44 mothers received ZDV plus single dose NVP and 113 mothers received HAART. There was one HIV-infected child in the first group and 3 in the second group, resulting in 2.3% (95% confidence interval, −2.1 to 6.7) transmission rate in the first group versus 2.7% (95% confidence interval, −0.3 to 5.6) in the second group (P = 1.000). All non-infected infants had a normal physical examination at 18 months. Initiation of HAART in HIV-infected pregnant women had comparable efficacy with ZDV plus single dose NVP to prevent mother-to-child transmission of HIV. In addition, the program may have strengthened the role of the family unit and stimulated public awareness reproductive health planning can help in prevention of HIV/AIDS.

Impact of adherence and anthropometric characteristics on nevirapine pharmacokinetics and exposure among HIV-infected Kenyan children.

There are insufficient data on pediatric antiretroviral therapy (ART) pharmacokinetics (PK), particularly for children in low- and middle-income countries. We conducted a prospective nevirapine (NVP) PK study among HIV-infected Kenyan children aged 3-13 years initiating an NVP-based ART regimen. NVP dose timing was measured through medication event monitors. Participants underwent 2 inpatient assessments: 1 at 4-8 weeks after ART initiation and 1 at 3-4 months after ART initiation. Allometric scaling of oral clearance (CL)/bioavailability (F) and volume of distribution (Vd)/F values were computed. Nonlinear mixed-effects modeling using the first-order conditional estimation with interaction method was performed with covariates. The impact of adherence on time below minimum effective concentration was assessed in the final PK model using medication event monitors data and model-estimated individual parameters. Among 21 children enrolled, mean age was 5.4 years and 57% were female. CL/F was 1.67 L/h and Vd/F was 3.8 L for a median child weighing 15 kg. Participants' age had a significant impact on CL/F (P < 0.05), with an estimated decrease in CL of 6.2% for each 1-year increase in age. Total body water percentage was significantly associated with Vd/F (P < 0.001). No children had >10% of time below minimum effective concentration when the PK model assumed perfect adherence compared with 10 children when adherence data were used. Age and body composition were significantly associated with children's NVP PK parameters. ART adherence significantly impacted drug exposure over time, revealing subtherapeutic windows that may lead to viral resistance.