Combination Of Lamivudine Research Articles

Systematic development of a gastroretentive fixed dose combination of lamivudine and zidovudine for increased patient compliance

The present study describes systematic development of a gastroretentive bilayer tablet formulation containing fixed dose combination of lamivudine and zidovudine exhibiting controlled drug release and floating-bioadhesive characteristics. Effervescent floating-bioadhesive bilayer tablets containing rational blend of polymers were formulated by non-aqueous granulation employing isopropyl alcohol. A face centred cubic design was employed for optimizing various critical material attributes of the bilayer tablets, which were evaluated for bioadhesive strength (BS), buoyancy time (Tb) and drug release characteristics as the critical quality attributes for each layer. The optimum composition for each layer was selected by “trading off” the magnitude of various quality attributes by maximization of BS, Tb and drug release characteristics, and demarcated in the design space. Gamma scintigraphic studies in healthy volunteers indicated gastroretentive behaviour of the optimized formulation upto 6 h, while the marketed immediate release formulation taken as control showed maximum gastroretentivity only upto 1 h. In a nutshell, these studies corroborated development of an optimal and stable once-a-day controlled release gastroretentive system of lamivudine and zidovudine.

Controlled Porosity Osmotic Pump Tablets of Zidovudine and Lamivudine Combination: Optimization and Characterization

Controlled Porosity Osmotic Pump Tablets of Zidovudine and Lamivudine Combination: Optimization and Characterization

Development and Evaluation of Controlled Porosity Osmotic Pump Tablets for Zidovudine and Lamivudine Combination

The present work was aimed to develop and evaluate controlled porosity osmotic pump (CPOP) tablets of zidovudine-lamivudine combination for the treatment of AIDS. The tablets were prepared by wet granulation method incorporating drug, various excipients, controlled release polymer hydroxyl propyl methyl cellulose (HPMCE5M LV) and osmogen (Mannitol) in the core. The CPOP tablets consist of an osmotic core coated with a micro porous membrane made up of cellulose acetate (CA) which is incorporated with sorbitol as porogen. Prior to compression the prepared granules were evaluated for pre compression parameters such as angle of repose, bulk density, tapped density, Carr’s index and Hausner’s ratio. After compression the prepared granules were evaluated for thickness, coat thickness, hardness, weight variation, friability, drug content, diameter, in vitro drug release study and scanning electron microscopy (SEM) study. The release kinetics for different formulations were analyzed using zero order model equation, first order model equation, Higuchi model equation, Korsmeyer Peppas model equation and Hixson-Crowell equation. The optimized formulation of drug release was independent of pH, agitation intensity, but dependent on the osmotic pressure of the release media. FTIR and DSC study revealed that there was no interaction between drug and excipients. Formulations subjected to stability testing (at 40±2oC/75±5% RH) as per ICH guidelines for three months indicated stability with no significant changes in thickness, hardness, weight variation, friability, drug content and dissolution profiles.

Abacavir/lamivudina + atazanavir no potenciado en la práctica clínica diaria: doce años de experiencia

ObjectiveTo describe the experience using the combination abacavir, lamivudine plus non-boosted atazanavir (ABC/3TC+ATV) in a group of pretreated patients. Patients and methodsWe performed a retrospective observational study to describe baseline characteristics and the evolution of patients who had received or were treating with ABC/3TC+ATV, from November 2004 and June 15th 2015, in the clinical setting. ResultsOverall, 236 patients were included in the study. Median age (IQR) was 45 (42-50) years and 69% were male. The main reasons for using this combination were previous toxicity in 130 patients (56%), simplification in 60 (20%) and virologic failure in 29 (14%). Previous treatment was based in boosted protease inhibitor in 115 patients (48.7%), 3 analogs in 56 (28%) and non-analogous based in 19 (8.1%). Median treatment length was 2.2 years (IQR0.8-5.3). A total of 66 (28%) patients continue receiving ABC/3TC+ATV (median time 5.7, IQR2.2-8.3), treatment was changed in 170 patients (72%) (median time 1.6 years, IQR0.7-3.6), and 22 (9.3%) patients were lost. Virological failure was assessed in 30 patients. ConclusionIn selected patients, ABC/3TC+ATV is a durable and attractive therapeutic alternative.

Discovery and Development of the Anti-Human Immunodeficiency Virus Drug, Emtricitabine (Emtriva, FTC).

The HIV/AIDS epidemic, which was first reported on in 1981, progressed in just 10 years to a disease afflicting 10 million people worldwide including 1 million in the US. In 1987, AZT was approved for treating HIV/AIDS. Unfortunately, its clinical usefullness was severly limited by associated toxicities and the emergence of resistance. Three other drugs that were approved in the early 1990s suffered from similar liabilities. In 1990, the Liotta group at Emory University developed a highly diastereoselective synthesis of racemic 3'-thia-2',3'-dideoxycytidine and 3'-thia-2',3'-5-fluorodideoxycytidine and demonstrated that these compounds exhibited excellent anti-HIV activity with no apparent cytotoxicity. Subsequently, the enantiomers of these compounds were separated using enzyme-mediated kinetic resolutions and their (-)-enantiomers (3TC and FTC, respectively) were found to have exceptionally attractive preclinical profiles. In addition to their anti-HIV activity, 3TC and FTC potently inhibit the replication of hepatitis B virus. The development of FTC, which was being carried out by Burroughs Wellcome, had many remarkable starts and stops. For example, passage studies indicated that the compound rapidly selected for a single resistant mutant, M184V, and that this strain was 500-1000-fold less sensitive to FTC than was wild-type virus. Fortunately, it was found that combinations of AZT with either 3TC or FTC were synergistic. The effectiveness of AZT-3TC combination therapy was subsequently demonstrated in four independent clinical trials, and in 1997, the FDA approved Combivir, a fixed dose combination of AZT and 3TC. In phase 1 clinical trials, FTC was well tolerated by all subjects with no adverse events observed. However, the development of FTC was halted by the aquistition of Wellcome PLC by Glaxo PLC in January 1995. In 1996, Triangle Pharmaceuticals licensed FTC from Emory and initiated a series of phase I/II clinical studies that demonstrated the safety and efficacy of the drug. In August 1998, FTC was granted "Fast Track" status, based primarily on its potential for once daily dosing. While the outcomes of two subsequent phase III trials were positive, a third phase III clinical trial involving combinations of 3TC or FTC with stavudine and neviripine had to be terminated due to serious liver-related adverse events. Although analysis of the data suggested that the liver toxicity was due to neviripine, the FDA decided that the study could not be used for drug registration. Ultimately, in January 2003, Gilead Sciences acquired Triangle Pharmaceuticals and completed the development of FTC (emtricitabine), which was approved for once a day, oral administration in July 2003. A year later, Truvada, a once a day, oral, fixed dose combination of emtricitabine and tenofovir disoproxyl fumarate received FDA approval and quickly became the accepted first line therapy when used with a third antiretroviral agent. In July 2006, the FDA approved Atripla, a once a day, oral, fixed dose combination of emtricitabine, tenofovir disoproxyl fumarate, and efavirenz, which represented the culmination of two decades of research that had transformed AIDS from a death sentence to a manageable chronic disease.

Efficacy of long-term tenofovir-based rescue therapy in patients with chronic hepatitis B refractory to nucleoside/nucleotide analogs.

Few studies have investigated the efficacy of long-term tenofovir disoproxil fumarate (TDF)-based rescue therapy in patients with chronic hepatitis B refractory to nucleoside/nucleotide analogs. We retrospectively analyzed 40 Japanese patients with chronic hepatitis B refractory to nucleoside/nucleotide analogs who received TDF-based rescue therapy [TDF monotherapy, TDF plus lamivudine (LAM) combination therapy, or TDF plus entecavir (ETV) combination therapy] followed up for a median of 45 months (range 14-99months). Viral response, changes in hepatitis B surface antigen levels from the baseline, and viral breakthrough during therapy were analyzed. The proportion of patients with undetectable serum hepatitis B virus (HBV) DNA levels (less than 2.1 log copies per milliliter) (viral response) during TDF-based rescue therapy was 68, 78, 85, 88, 83, 81, 88, and 100% at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, and 4years respectively. There were no differences in the viral response rate between the TDF plus LAM group and the TDF plus ETV group. The mean reduction from the baseline in hepatitis B surface antigen levels in patients with LAM-resistant HBV was greater than the reductions in patients with adefovir dipivoxil (ADV)-resistant or ETV-resistant HBV at 2 and 3years (P=0.024, and P=0.025 respectively). However, two patients with ADV- or ETV-resistant HBV at the baseline developed viral breakthrough during TDF-based rescue therapy. Long-term therapy with a TDF-based rescue regimen demonstrated high viral suppression in patients in whom LAM plus ADV combination therapy, ETV plus ADV combination therapy, or ETV monotherapy had failed. However, patients with ADV- or ETV-resistant HBV at the baseline may develop viral breakthrough and resistance, and careful follow-up is advised.

Management of Clevudine-Resistant Chronic Hepatitis B: A Multicenter Cohort Study.

Background/AimsData are lacking regarding the management of chronic hepatitis B (CHB) with resistance to clevudine (CLV). This study evaluated the efficacy of different rescue therapies for CLV-resistant CHB.MethodsPatients with CLV-resistant CHB were enrolled in the cohort, and all patients developed virologic breakthrough during CLV therapy and had confirmed-genotypic resistance to CLV (rtM204I mutation) before enrollment.ResultsOf the 107 patients, 12 received adefovir (ADV), 21 received a CLV plus ADV combination (CLV+ADV), 34 received a lamivudine plus ADV combination (LAM+ADV), and 40 received entecavir (ETV) therapy for 48 weeks. The CLV+ADV group had the lowest hepatitis B virus (HBV) DNA level (p<0.0001) and showed the greatest reduction of HBV DNA levels from baseline compared to all other groups (p=0.004) at week 48. HBV DNA was undetectable (<70 IU/mL) in 0%, 57.1%, 21.2%, and 27.5% (p=0.003) of the patients in each group, respectively, at week 48. At the end of the study, the mean alanine transaminase (ALT) level, rate of ALT normalization, and rate of hepatitis B envelope antigen loss or seroconversion did not differ between groups.ConclusionsCLV+ADV combination therapy in patients with CLV-resistant CHB more effectively suppresses HBV replication than ETV, ADV, or LAM+ADV therapy.

Durability of the virological response after lamivudine discontinuation in lamivudine-resistant patients with a complete virological response after lamivudine and adefovir combination therapy.

We investigated the durability of virological response after lamivudine (LAM) discontinuation in LAM-resistant chronic hepatitis B (CHB) patients with complete virological response after LAM-adefovir (ADV) combination therapy. We enrolled 58 patients switched to ADV monotherapy with undetectable viral loads (<12 IU/ml) and normal alanine aminotransferase levels after ADV add-on combination treatment for at least 6 months in LAM-resistant CHB patients. Virologic relapse was defined as HBV DNA detection at more than 20 IU/ml by quantitative polymerase chain reaction determined on two consecutive measurements. During median 40.9 months of follow-up (range 11.5-79.0 months), seven (12.1%) patients experienced virological relapse. The cumulative rate of virological relapse at 3 and 5 years was 5.5% and 22.4%, respectively. Two patients had elevated alanine aminotransferase during virological relapse. These seven patients with virological relapse had undetectable HBV DNA after switching to tenofovir therapy. In our study, switching to ADV monotherapy resulted in sustained HBV DNA suppression in 87.9% of the patients during median 40.9 months follow-up. This adapting step-down strategy, switching from combination therapy to monotherapy in virologically suppressed CHB patients with stable liver disease, may reduce the cost burden and the risk of potentially harmful effects of combination therapy. J. Med. Virol. 89:85-90, 2017. © 2016 Wiley Periodicals, Inc.

Is the tenofovir based therapy almighty for previous treatment failure in chronic hepatitis B?

Is the tenofovir based therapy almighty for previous treatment failure in chronic hepatitis B?

Virological Response and Drug Resistance 1 and 2 Years Post-Partum in HIV-Infected Women Initiated on Life-Long Antiretroviral Therapy in Malawi.

The objective of this study was to determine the virological response and the possible emergence of drug resistance at 1 and 2 years postpartum in HIV-positive pregnant women enrolled under the Option B approach and meeting the criteria for treatment. In the study, women with baseline CD4(+) <350/mm(3) received a combination of stavudine, lamivudine, and nevirapine during pregnancy (from week 25 of gestation) and continued it indefinitely after delivery. HIV-RNA was measured at 12 and 24 months postpartum. Drug resistance mutations were assessed in those with HIV-RNA >50 copies/ml. Baseline resistance mutations were assessed in the entire cohort. A total of 107 women were studied. At baseline, resistance mutations were seen in 6.6% of the women. At 12 months, 26.7% of the women had >50 copies/ml and among them 12.9% had virological failure (HIV-RNA >1,000 copies/ml). At 24 months, detectable HIV-RNA was seen in 28.3% of the women and virological failure in 10.1% of the women. Resistance mutations (mainly non-nucleoside reverse transcriptase inhibitors mutations) were seen in 40% of the women with detectable HIV-RNA. Baseline mutations did not correlate with virological failure or the emergence of resistance at later time points. Virological failure 2 years postpartum and emergence of resistance were rare in this cohort of HIV-infected women. These findings are reassuring in the light of the new strategies for the prevention of mother-to-child HIV transmission, recommending life-long antiretroviral therapy administration.

Long-term efficacy of Peg-Interferon/Ribavirin with and without Lamivudine therapy for HBeAg-positive hepatitis B and C dual infection.

The optimal therapeutic strategy for hepatitis B virus (HBV) e antigen (HBeAg)-seropositive and hepatitis C virus (HCV) dually infected patients remains unknown. We aimed to elucidate the effectiveness of peginterferon (Peg-IFN)/ribavirin (RBV) with and without lamivudine (LAM) combination therapy in the clinical settings. Nine patients seropositive for HBV surface antigen, HBeAg, antibodies to HCV and HCV RNA for >6 months were treated with Peg-IFN/RBV with (n = 5) and without (n = 4) a 12-month LAM add-on therapy at treatment week 12. The treatment duration of Peg-IFN/RBV was 24 weeks (HCV genotype 1 [HCV-1] with rapid virological response [RVR] or HCV-2) or 48 weeks (HCV-1 without RVR). Primary endpoints included HBeAg loss and HCV-sustained virological response (SVR). All of the nine patients had undetectable HCV RNA at treatment weeks 4 and 12 and end-of-Peg-IFN/RBV therapy. However, SVR was achieved in 100% of patients treated with triple therapy, compared with only 50% in those with Peg-IFN/RBV therapy (P = 0.167). The 3-year durability of HCV SVR was 100%. HBeAg loss and HBV DNA <2000 IU/mL at 6 months post-LAM treatment were found in 100% and 40% of patients treated with triple therapy, compared with none of the four patients with Peg-IFN/RBV therapy achieved any HBV responses. Of the five patients with triple therapy, four had persistent HBeAg loss during 3-year follow-up period; one developed HBeAg seroreversion 15 months after treatment. For HBeAg-positive HBV/HCV dually infected patients, Peg-IFN/RBV was effective for HCV eradication. Add-on LAM might promote HBeAg loss in the clinical setting.

Efficacy and Safety of Tenofovir and Lamivudine in Combination with Efavirenz in Patients Co-infected with Human Immunodeficiency Virus and Hepatitis B Virus in China.

Background:The prevalence of hepatitis B virus (HBV) infection is high among individuals infected with human immunodeficiency virus (HIV) in China. Both HIV and HBV can be treated with tenofovir disoproxil fumarate (TDF) and lamivudine (3TC), so we evaluated the safety and efficacy of combination antiretroviral therapy (ART) that included TDF, 3TC, and efavirenz (EFV) among ART-naive individuals who were co-infected with HIV and HBV.Methods:One hundred HIV/HBV co-infected ARV-naive individuals were started on the regimen of TDF, 3TC, and EFV, and the levels of plasma HBV DNA, HIV RNA, and biochemical evaluation related to the function of liver and kidney were analyzed.Results:Concerning efficacy, this study found that by week 48, the vast majority co-infected participants receiving this ART regimen had undetectable HBV DNA levels (71%) and/or HIV RNA levels (90%). Concerning safety, this study found that the median estimated glomerular filtration rate of participants decreased from baseline (109 ml·min−1·1.73 m−2) to week 12 (104 ml·min−1·1.73 m−2) but was almost back to baseline at week 48 (111 ml·min−1·1.73 m−2).Conclusion:This combination ART regimen is safe and effective for patients with HIV/HBV co-infection.Trial Registration:ClinicalTrials.gov, NCT01751555; https://clinicaltrials.gov/ct2/show/NCT01751555.

A simultaneous determination of related substances by high performance liquid chromatography in a drug product using quality by design approach

The combination of Abacavir, Lamivudine and Dolutegravir is an anti-retroviral formulation that displays high efficacy and superiority in comparison to other anti-retroviral combinations. Analysis of related substances in this combination drug product was very challenging due to the presence of nearly thirty peaks including the three active pharmaceutical ingredients (APIs), eleven known impurities and other pharmaceutical excipients. Objective of this study was to develop a single, selective, and robust high performance liquid chromatography method for the efficient separation of all peaks. Initially, one-factor-at-a-time (OFAT) approach was adopted to develop the method. But, it could not resolve all the critical peaks in such complex matrix. This led to the advent of two different HPLC methods for the determination of related substances, one for Abacavir and Lamivudine and the other for Dolutegravir. But, since analysis of a single sample using two methods instead of one is time and resource consuming and thus expensive, an attempt was made to develop a single and robust method by adopting quality by design (QbD) principles. Design of Experiments (DoE) was applied as a tool to achieve the optimum conditions through Response surface methodology with three method variables, pH, temperature, and mobile phase composition. As the study progressed, it was discovered that establishment of the design space was not viable due to the completely distant pH requirements of the two responses, i.e. (i) retention time for Lamivudine carboxylic acid and (ii) resolution between Abacavir impurity B and unknown impurity. Eventually, neglecting one of these two responses each time, two distinguished design spaces have been established and verified. Edge of failures at both design spaces indicate high probability of failure. It therefore, becomes very important to identify the most robust zone or normal operating range (NOR) within the design space with low risk of failure and high quality assurance. For NOR establishment, Monte Carlo simulation was performed on the basis of which process capability index (Cpk) was derived. Finally, the selectivity issue problem faced due to the pH dependency and the dissimilar pH needs of the two critical responses was resolved by introducing pH gradient into the program. This new ternary gradient program has provided a single robust method. Thus, two HPLC methods for the analysis of the combination drug product have been replaced with a selective, robust, and cost effective single method.

Combination antiretroviral studies for patients with primary biliary cirrhosis.

Following the characterization of a human betaretrovirus in patients with primary biliary cirrhosis (PBC), pilot studies using antiretroviral therapy have been conducted as proof of principal to establish a link of virus with disease and with the eventual aim to find better adjunct therapies for patients unresponsive to ursodeoxycholic acid. In the first open label pilot study, the reverse transcriptase inhibitor lamivudine had little demonstrable biochemical or histological effect after 1 year. Whereas, lamivudine in combination with zidovudine was associated with a significant reduction in alkaline phosphatase as well as improvement in necroinflammatory score, cholangitis and ductopenia over a 12 mo period. A double blind, multi-center randomized controlled trial using lamivudine with zidovudine for 6 mo confirmed a significant reduction in alkaline phosphatase, ALT and AST in patients on antiviral therapy. However, none of the patients achieved the stringent endpoint criteria for normalization of alkaline phosphatase. Furthermore, some patients developed biochemical rebound consistent with drug resistance. A major fault of these studies has been the inability to measure the viral load in peripheral blood and therefore, provide a direct correlation between improvement of hepatic biochemistry and reduction in viral load. Nevertheless, viral mutants to lamivudine with zidovudine were later characterized in the NOD.c3c4 mouse model of PBC that has been used to test other antiretroviral regimens to betaretrovirus. The combination of tenofovir and emtricitabine reverse transcriptase inhibitors and the HIV protease inhibitor, lopinavir were found to abrogate cholangitis in the NOD.c3c4 mouse model and the same regimen normalized the liver tests in a PBC patient with HIV and human betaretrovirus infection. This combination antiretroviral therapy has now been used in a double blind randomized controlled crossover study for patients with PBC followed by an open label extension study. Only a third of the PBC patients were able to tolerate the lopinavir but those maintained on tenofovir, emtricitabine and lopinavir experienced sustained and clinically meaningful reduction in hepatic biochemistry. While we await the histological and virological evaluation, it is clear that better tolerated regimens of antiretroviral treatment will be required in future clinical trials.

Stability indicating validated UPLC technique for the simultaneous analysis of raltegravir and lamivudine in pharmaceutical dosage forms

BackgroundWHO study reveals that approximately 2.1 million people became recently infected with HIV, including 240,000 children below 15 years of age in the year of 2013. Latest FDA approved drug combination of raltegravir and lamivudine, which could be used for the treatment of HIV patients (AIDS). This combination therapy can delay the progress of HIV infection and damage to immune system of the HIV patient. A cost-effective and fast analytical method is required to develop for the research establishment to evaluate quality and storage parameters of the each molecule. Material and methodA simple and quick approach of stability indicating UPLC technique was established for the simultaneous determination of newly invented anti-HIV drug combo of raltegravir and lamivudine in bulk and pharmaceutical combo within a 4min of chromatographic run. UPLC separation of the two drugs was attained with a BEH Shield RP18 (2.1mm×100mm, 1.7μm), analytical column using buffer potassium dihydrogen orthophosphate pH 3 adjusted with orthophosphoric acid:methanol (30:70, %v/v) in isocratic mode at a flow rate of 0.230ml/min. The column was maintained at an ambient temperature, and detection of two drugs was examined at 254nm using a PDA detector. ConclusionsThus demonstrated technique was exposed for forced degradation studies in five different stress conditions. This projected method was found to be selective and stability indicating, as no obstructing peaks of degradation compounds were detected. The assay of the dosage form and robustness study was obtained within the limit of ICH guidelines.

Treatment outcomes of first-line antiretroviral therapy in HIV-1-positive patients in Serbia

IntroductionAccess to combination antiretroviral treatment (cART) and toxicity profiles of antiretroviral medications have significantly improved during the last three decades. In order to optimise treatment outcomes, achieve favourable virological suppression and immunological status, balanced with potential adverse effects of cART, it is considered beneficial to maintain first-line antiretroviral treatment for as long as possible. However, the Republic of Serbia, as a resource-limited setting, often experiences interruptions to drug supplies. Data are very limited in Serbia concerning the initial antiretroviral regimens prescribed and the reasons for treatment changes. AimsThe aim of this study was to determine the most frequently prescribed antiretroviral drugs within first-line cART regimens in drug-naïve patients in Serbia and the reasons for switching drugs. MethodsAll HIV-infected individuals who started cART at the HIV/AIDS Center of Infectious and Tropical Diseases, Clinical Centre of Serbia, from 1 January 2004 until 1 July 2014 were included. A cohort of 339 patients were retrospectively analysed to review their initial treatment regimens. All analyses were performed using the SPSS statistical package version 11.0. Descriptive measurements and Kaplan–Meier survival curves were used. ResultsThe most frequently prescribed nucleoside reverse transcriptase inhibitor (NRTI) backbones in the cART regiment were fixed combinations of abacavir and lamivudine (n=181, 53.3%) and of zidovudine and lamivudine (n=103, 30.5%). Efavirenz was the most commonly prescribed ‘third’ drug (n=254, 75%). Where given, reasons for switching initial cART were shortage of antiretroviral drugs (e.g. out of stock, n=53, 37.6%), toxicity (n=49, 34.3%), physician choice (n=21, 14.6%), resistance (n=15, 10.6%), and patient choice (n=4, 2.9%). Mean duration of first-line cART was 20±17 months. ConclusionThe most frequently prescribed initial cART regimen in Serbia is not the preferred first choice, but an alternative option according to the international antiretroviral treatment guidelines. Duration of first-line cART is short and a switch to second-line cART is often made due to a shortage of antiretroviral medications and the more severe side effects resulting from the use of older drugs.

HBsAg seroclearance or seroconversion induced by peg-interferon alpha and lamivudine or adefovir combination therapy in chronic hepatitis B treatment: a meta-analysis and systematic review.

Seroclearance or seroconversion of hepatitis B surface antigen (HBsAg) is generally considered as the clinical endpoint. The purpose of the present meta-analysis was to evaluate pegylated interferon alpha (PEG-IFNα) with or without lamivudine (LAM) or adefovir (ADV) combination treatment in HBsAg seroclearance or seroconversion with CHB. Randomized controlled trials of adults with CHB prior to May 30th 2015, with 48-52 weeks of PEG-IFNα and LAM or ADV combination therapy or monotherapy, were included. Review Manager Software 5.2.0 was used for meta-analysis. No statistical difference was noticed in HBsAg seroclearance (9.9% vs 7.1%, OR = 1.47, 95% CI 0.75, 2.90; p = 0.26) or observed in HBsAg seroconversion (4.2% vs 3.7%, OR = 1.17, 95% CI 0.57, 2.37; p = 0.67) between PEG-IFNα + LAM and PEG-IFNα + placebo for 24-26 weeks follow-up after treatment on hepatitis B e antigen (HBeAg)-positive CHB. Statistical difference was not showed in HBsAg disappearance (10.5% vs 6.4%, OR = 1.68, 95% CI 0.75, 3.76; p = 0.21) but was demonstrated in HBsAg seroconversion (6.3% vs 0%, OR = 7.22, 95% CI 1.23, 42.40; p = 0.03) between PEG-IFNα + ADV and PEG-IFNα for 48-52 weeks treatment on HBeAg-positive CHB By systematical evaluation, there were no differences in HBsAg disappearance and seroconversion between PEG-IFNα + placebo and PEG-IFNα + LAM for 48-52 weeks treatment on HBeAg-positive CHB. There were no differences in HBsAg disappearance and seroconversion between PEG-IFNα + placebo and PEG-IFNα + LAM during 24 weeks to 3 years follow-up after treatment on HBeAg-negative CHB by systematical evaluation. The combination between PEG-IFNα and LAM or ADV was not superior to monotherapy of PEG-IFNα in terms of HBsAg seroclearance or seroconversion.

Concentrations of tenofovir, lamivudine and efavirenz in mothers and children enrolled under the Option B-Plus approach in Malawi.

To evaluate antiretroviral drug concentrations in mothers and infants enrolled under the Option B-Plus approach for the prevention of HIV mother-to-child transmission in Malawi and to assess the maternal virological response after 1 year of treatment. Forty-seven women and 25 children were studied. Mothers were administered during pregnancy a combination of tenofovir, lamivudine and efavirenz and continued it during breastfeeding (up to 2 years) and thereafter. Drug concentrations were evaluated in mothers (plasma and breast milk) at 1 and 12 months post-partum and in infants (plasma) at 6 and 12 months of age. Drug concentrations were determined using an LC-MS/MS validated methodology. In breast milk, tenofovir concentrations were very low (breast milk/maternal plasma ratio = 0.08), while lamivudine was concentrated (breast milk/plasma ratio = 3) and efavirenz levels were 80% of those found in plasma. In infants, median levels at 6 months were 24 ng/mL tenofovir, 2.5 ng/mL lamivudine and 86.4 ng/mL efavirenz. At month 12, median levels were below the limit of quantification for the three drugs. No correlation was found between drug concentrations and laboratory parameters or indices of growth. HIV-RNA >1000 copies/mL was seen at month 1 in 15% of the women and at month 12 in 8.5%. Resistance was found in half of the women with detectable viral load. Breastfeeding infants under Option B-Plus are exposed to low concentrations of antiretroviral drugs. With this strategy, mothers had a good virological response 1 year after delivery.

Simultaneous And Extended Delivery Of Stavudine, Lamivudine And Nevirapine In Fixed Dose Combination Using Sandwiched Osmotic Tablets For Hiv Therapy.

Current HIV-therapy recommends combination of stavudine, lamivudine and nevirapine. Stavudine and lamivudine are administered as fixed combination while nevirapine as separate dosage form which often results in poor compliance and adherence to therapy by patients and therefore, there is a need to develop dosage forms that can overcome the problems of currently available dosage forms for treatment of HIV infection. The present study developed a single unit osmotic system for simultaneous and extended delivery of stavudine, lamivudine and nevirapine that can ensure patients compliance and adherence to HIV-therapy. Sandwich osmotic pump tablets (SOPTs) of stavudine, lamivudine and nevirapine in fixed dose combination were designed and evaluated for the effect of variables such as PEO (polymer), KCl (osmogen), and orifice diameter on the physicochemical characteristics and the release behavior of the drugs. A 24 h zero order release of stavudine, lamivudine and nevirapine from the formulations was observed and the release rate of the drugs was found to be affected by PEO, KCl, and orifice diameter. The in vitro release data of SOPT correlated with in vivo predictions by super - position method. The results of the study propose that a single unit osmotic system (SOPT) of stavudine, lamivudine and nevirapine is beneficial to overcome the disadvantages of currently available dosage forms for effective control of HIV infection.

HAART, DOTS and renal disease of patients co-infected with HIV/AIDS and TB in the South West Region of Cameroon.

BackgroundTuberculosis is the commonest infection among HIV/AIDS patients. This co-infection constitutes a major death threat in the world. There is paucity of data about renal disease amongst patients on HAART and DOTS therapy in Cameroon.MethodsThis was a hospital-based cross-sectional study in the Buea, Limbe and Kumba government Hospitals. Spectrophotometric method was used for the quantitative determination of serum creatinine, urea, albumin and total protein levels. Glomerular filtration rate was estimated using the MDRD method. The student’s t test, ANOVA and logistic regression were used to analyse the data.ResultsOut of 200 participants, 101 (50.5 %) were males. The ages ranged from 21 to 65 years with a mean age of 38.04 ± 10.52 years. Compared to adults on DOTS alone, adults on HAART alone had a significantly higher prevalence of eGFR <60 ml/min/1.73 m2 (10/70 (14.3 %) vs. 1/70 (1.4 %), OR = 11.5 [1.4–92.5], p = 0.02) while more participants on HAART/DOTS had significantly higher serum creatinine (18/60 (30 %) vs 10/70 (14.3) OR = 2.57 [1.08–6.12], p = 0.033). Though participants on HAART/DOTS combined therapy had low eGFR, the association was not statistically significant (OR = 6.27, 95 % CI;0.71–55.27, p = 0.098). Participants on the Zidovudine, Lamivudine, Nevirapine regimen showed a statistically significant difference in the mean serum creatinine and albumin levels between the HAART/DOTS combined therapy and HAART group (p = 0.0219 and 0.0001 respectively).ConclusionCompared to adults on DOTS, adults on HAART were more likely to have renal dysfunction (eGFR <60 ml/min per 1.73 m2). Adult on a combination of HAART and DOTS had a similar prevalence of renal dysfunction as those on HAART alone. This study showed that the use of the HAART regimen (Tenofovir, Lamivudine and Efavirenz combination) among the HAART treated adults was nephrotoxic. However, other combined HAART and DOTS regimens had no nephrotoxic effect. Abnormal kidney function can be associated with HAART use.