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Background The aim of this work is to investigate the intestinal permeability of lamivudine and explore its absorption mechanism. Method Caco-2 cells monolayer and single-pass intestinal perfusion (SPIP) were selected for the investigation of lamivudine under different conditions, such as different concentration, absorption time, bidirectional transportation, and transportation with efflux transporters inhibitor. The concentration of lamivudine both in Caco-2 cells monolayer samples and SPIP samples was detected by HPLC-UV. Then the permeability parameters were calculated. Results The established HPLC-UV method reach the requirements for detection. There is no statistically difference between absorption parameters of lamivudine both in Caco-2 cells monolayer and SPIP (P > 0.05) under different dose groups. After transportation with efflux transporters inhibitor, the efflux rate of lamivudine in three dose groups was significantly decreased from 2.67, 2.59 and 2.59 to 1.78, 1.61, and 1.81 respectively. Lamivudine exhibits an absorption mechanism of passive diffusion. Conclusion The absorption of lamivudine may be related to efflux transporters. In addition, lamivudine is a moderate-permeability drug in Biopharmaceutics Classification System.

BACKGROUND The World Health Organization (WHO) 2019 antiretroviral treatment guidelines recommend use of optimal treatment regimens in all populations. Dolutegravir-based regimens are the preferred first-line and second-line treatment in infants and children with HIV 4 weeks of age and above. There is an urgent need for optimal pediatric formulations of dolutegravir as single-entity (SE) and fixed-dose combination (FDC) to ensure correct dosing and adherence for swallowing and palatability. This article outlines the chronology of dolutegravir pediatric formulation development as granules and conventional and dispersible tablets in a total of 5 pharmacokinetic studies evaluating the relative bioavailability of dolutegravir SE and FDC formulations in healthy adults. METHODS The relative bioavailability studies were 2-part, Phase I, open-label, randomized studies in healthy adults. Dolutegravir SE study compared conventional dolutegravir 50 and 25 mg with equivalent conventional 10-mg and dispersible 5-mg tablets, respectively. Subsequently, dolutegravir FDC study compared adult FDC of abacavir/dolutegravir/lamivudine and adult FDC of dolutegravir/lamivudine with their respective pediatric FDC formulations, taken as dispersion immediately or swallowed whole. RESULTS As observed in previous studies, dolutegravir administered as dispersion (granules/dispersible tablets) showed relatively higher bioavailability compared with conventional tablets. The bioavailability of dolutegravir dispersible tablets (both SE and FDC) was approximately 1.6-fold higher when compared with conventional tablets. In addition, the bioavailability of abacavir/lamivudine was not impacted by dispersible formulation. CONCLUSIONS These studies demonstrate the successful development of pediatric dolutegravir-containing formulations as SE and FDC that permit pediatric dosing in line with WHO recommendations.

BACKGROUND Long-term impact of drug resistance in perinatally-infected children and adolescents living with HIV (CALWH) is poorly understood. We determined drug resistance and examined its long-term impact on failure and mortality in Kenyan CALWH failing 1st-line NNRTI-based ART. SETTING Academic Model Providing Access to Healthcare; western Kenya. METHODS Participants were enrolled in 2010-13 (timepoint-1) and a subsample re-enrolled after 4-7 years (timepoint-2). Viral load was performed on timepoint-1 samples, with genotyping of those with detectable viral load. Primary endpoints were treatment failure (viral load>1,000 copies/mL) at and death before timepoint-2. Multinomial regression analysis was used to characterize resistance effect on death, failure and loss-to-follow-up, adjusting for key variables. RESULTS The initial cohort (n=480) was 52% (n=251) female, median age eight years, median CD4% 31, 79% (n=379) on zidovudine/abacavir+lamivudine+efavirenz/nevirapine for median two years. Of these, 31% (n=149) failed at timepoint-1. Genotypes at timepoint-1, available on n=128, demonstrated 93% (n=119) extensive resistance, impacting 2nd-line. Of 128, 22 failed at timepoint-2, 17 died and 32 were lost-to-follow-up before timepoint-2. Having ≥5 resistance mutations at timepoint-1 was associated with higher mortality (relative risk ratio=8.7, confidence interval 2.1-36.3) and loss-to-follow-up (relative risk ratio=3.2, confidence interval 1.1-9.2). Switching to 2nd-line was associated with lower mortality (relative risk ratio

The presence of pharmaceutical contaminants in nature is an environmental problem generating increasing concerns. Due to this, it is necessary to evaluate treatments capable of degrading these contaminants, such as the advanced oxidation processes (AOPs). In this work, the photoperoxidation and photo-Fenton AOP were applied to degrade a mixture of lamivudine and zidovudine in an aqueous medium and synthetic effluent (SE). To this end, a bench reactor (UV-C; UV-A and sunlight irradiations) was built. The AOP treatments efficiency was evaluated by ultraviolet/visible spectrophotometry. The tests involved the application of the irradiations individually and combined. The best operational conditions were [H2O2] of 600 mg L-1 and [Fe] of 0.5 mg L-1, for both matrices, with degradations of 90.53% and 89.32% for the photoperoxidation and photo-Fenton processes in aqueous media and 88.69% and 85.79% in SE. Kinetic studies showed a good fit for two pseudo-first-order models with R2 > 0.93. Toxicity tests involving the application of lettuce, carrot, and tomato seeds showed an inhibition for the three seeds when submitted to solutions after treatment, for both matrices, this fact is corroborated by the HPLC analysis, in which the formation of small peaks was verified, suggestive of the formation of by-products. Thus, it can be affirmed that both photo-Fenton and photoperoxidation processes efficiently degrade the drug mixture when applying UV-C radiation.

Introduction: The integrase strand transfer inhibitor dolutegravir (DTG) has a high genetic barrier to resistance. Only rare cases of resistance to DTG have been reported when it is used as a component of antiretroviral therapy regimens in treatment-experienced patients unless there was prior use of a first-generation integrase inhibitor. Patient presentation: A 38-year-old woman diagnosed with tuberculosis was switched to a second-line antiretroviral regimen of zidovudine, lamivudine and dolutegravir 50 mg 12-hourly together with rifampicin-based TB treatment. Based on treatment history and a previous resistance test there was resistance to lamivudine but full susceptibility to zidovudine. The patient did not suppress her viral load on this regimen and later admitted to only taking dolutegravir 50 mg in the morning because of insomnia. Management and outcome: A second resistance test was performed which showed intermediate level of resistance to dolutegravir. Her regimen was changed to tenofovir, emtricitabine and ritonavir-boosted atazanavir with rifabutin replacing rifampicin for the remainder of her TB treatment. She achieved viral suppression on this regimen. Conclusion: To our knowledge this is the first case report from South Africa of emergent dolutegravir resistance in a treatment-experienced, integrase inhibitor-naive patient. Factors that may have contributed to resistance emergence in this patient were that there was only one fully active nucleoside reverse transcriptase inhibitor in the regimen and lower exposure to dolutegravir because of the reduced dosing frequency while on rifampicin.

Introduction: Toxic side effects from antiretroviral overdose in children have not been widely reported. Antiretroviral drugs are widely used as oral medications throughout sub-Saharan Africa. Patient presentation: We describe the clinical presentation and management of a 3-year-old male in rural Kenya, who accidentally overdosed on abacavir/lamivudine combination pills. The number of pills taken was approximately 250 tablets, that is 15 g of abacavir and 7.5 g of lamivudine. He presented 24 hours later to Homabay County Referral Hospital, with unresponsiveness, inability to feed and absence of playfulness. Physical examination revealed a sick-looking, ‘unconscious’ child, responding only to voice, with tachycardia, hypertension and moderate dehydration. Management and outcome: He was managed conservatively with rehydration, namely intravenous 1125 mL of 5% dextrose in 0.9% saline, and the monitoring of his neurologic status, urine output and all vital signs. He regained normal neurological function after 24 hours, and recovered uneventfully, but was lost to follow-up. Conclusion: In an area endemic for HIV and where antiretroviral drug use is commonplace, there is a need for health education to ensure that parents keep drugs out of the reach of children. In the case of a suspected overdose, parents need to be reminded to seek medical attention immediately. Physician awareness of the clinical presentation, management and challenges with an antiretroviral drug overdose is also important.

Antiretroviral options for neonates (younger than 28 days) should be expanded. We evaluated the pharmacokinetics, safety, and acceptability of the "4-in-1" fixed-dose pediatric granule formulation of abacavir/lamivudine/lopinavir/ritonavir (30/15/40/10 mg) in neonates.The PETITE study is an ongoing phase I/II, open-label, single-arm, 2-stage trial conducted in South Africa. In stage 1, term neonates exposed to HIV on standard antiretroviral prophylaxis (nevirapine ± zidovudine) received single dose(s) of the 4-in-1 formulation, followed by intensive pharmacokinetic sampling and safety assessments. At each PK visit, blood was drawn after an observed dose at 1, 2, 4, 8, and 12 hours postdose. In this study, we have reported the planned interim pharmacokinetic and safety analysis after completion of the single-dose administration.Sixteen neonates, with a median (range) birth weight of 3130 g (2790-3590 g), completed 24 pharmacokinetic visits. The 4-in-1 formulation imposed relatively high doses of abacavir [8.6 mg/kg (6.6-11.4)] and lamivudine [4.3 mg/kg (3.3-5.7)] but lower doses of lopinavir [11.5 mg/kg (8.8-15.2)]. The geometric means (GM, 90% CI) AUC0-12 of abacavir, lamivudine, and lopinavir were 29.87 (26.29-33.93), 12.61 (10.72-14.83), and 3.49 (2.13-5.72) µg.h/mL, respectively. Lopinavir GM AUC0-12 was below the predefined target (20-100 µg.h/mL), and ritonavir concentrations were only detectable in 4 of the 120 (3%) samples. No adverse events were related to study drugs. No neonate had difficulty swallowing the 4-in-1 formulation.The high doses of abacavir and lamivudine (in mg/kg) and AUCs were safe, and the formulation was well tolerated; however, lopinavir/ritonavir exposures were extremely low, preventing its use in neonates use in neonates. Alternative pediatric solid antiretroviral formulations must be studied in neonates.

Objective: To document antiretroviral use in Latin America during the last decade. Methods: We collected indicators from 79 HIV health care centres in 14 Latin American Spanish-speaking countries for 2013–2017. Indicators were analysed by age, sex and other characteristics and weighted by the estimated people under care (PUC) population in each country. Results: We gathered information on 116 299 PUC. One-third belonged to centres reporting a shortage of at least one antiretroviral therapy (ART) drug for >30 days during 2017. At end 2017, 95.1% of PUC were receiving ART. During 2013–2017, 45 329 people living with HIV were admitted to 39 centres. ART initiated during the first year after admission increased from 76.7% in 2013 to 83.8% in 2017. In 35 centres across the study period, 71.7% of PUC started ART with tenofovir disoproxil fumarate and lamivudine, and zidovudine use decreased. The third most common ART drug, EFV, reached 64.8%. Raltegravir and other alternatives increased annually to almost 10% of total use in 2017. Conclusions: Initial ART in Latin America is not based on the most recent scientific evidence and recommendations; use of drugs with higher efficacy and safety profiles and guarantee of ART availability continues to be a public health challenge.

We prospectively investigated the neurological development in infants born from mothers treated with telbivudine (LdT) in the third trimester for prevention of hepatitis B virus (HBV) mother-to-infant transmission. Mothers with high HBV load were assigned to either the LdT group (n = 81, 600 mg of LdT each day from gestational week 28 to delivery) or the Control group (n = 39, untreated). Their infants were followed for 36 months to assess physical and neurological developments with Gesell Developmental Schedule tools. At 12 months after birth, the mean scores in the LdT group for gross motor, fine motor, adaptive, linguistic, and personal social domains were similar to those in the Control group. At 36 months, infants in the LdT group had higher mean scores for gross motor than the Control group (98.42 ± 9.69 vs. 94.54 ± 7.48, P = 0.03). In the LdT group, the rates of normal development were higher for gross motor (96.30% vs. 82.05% P = 0.01) and lower for adaptive (74.07% vs. 92.31% P = 0.02). Multivariate regression analyses showed that exposure to LdT during pregnancy was independently associated with infant’s development in gross motor (OR 6.49, 95% CI 1.37–30.20, P = 0.02) and adaptive (OR 0.18, 95% CI 0.05–0.71, P = 0.01) at 36 months. These results suggest that prenatal LdT exposure might affect neurological development in long-term observation. Abbreviations: LdT: telbivudine; HBV: hepatitis B virus; HBsAg: hepatitis B surface antigen; HBeAg: hepatitis Be antigen; HbsAb: hepatitis B surface antibody; ALT: alanine aminotransferase; NA: nucleoside/nucleotide analog; LAM: lamivudine; MTCT: mother-to-child transmission; GDS: Gesell Developmental Schedule; OR: odds ratio; CI: confidence interval; DQ: developmental quotient; RMB: renminbi; BMI: body mass Index; HBIG: hepatitis B immunoglobulin.

BACKGROUND: The determination of antiretroviral drugs in hair is receiving considerable research interest to assess long-term adherence to antiretroviral therapy (ART). Currently in China, lamivudine, zidovudine, nevirapine, efavirenz, ritonavir, and lopinavir are combined as first- and second-line free therapy regimens and are recommended for people living with human immunodeficiency virus (HIV) (PLWH). Simultaneous determination of the six antiretroviral drugs in human hair is important for accurately and widely assessing long-term adherence in Chinese PLWH receiving different ART regimens. METHODS: Six drugs were extracted from 10-mg hair samples incubated in methanol for 16 h at 37 °C and then analyzed by liquid chromatography with tandem mass spectrometry (LC-MS/MS) using a mobile phase of 95% methanol, with an electrospray ionization (ESI) source in multiple reaction monitoring and positive mode. RESULTS: The LC-ESI(+)-MS/MS method exhibited a linear range (R(2) > 0.99) within 6–5000, 10–5000, 6–50000, 12–50000, 8–5000, and 8–12500 pg/mg for lamivudine, zidovudine, nevirapine, efavirenz, ritonavir, and lopinavir. For all six drugs, the limits of quantification ranged between 6 and 12 pg/mg. The intra-day and inter-day coefficients of variation were within 15%, and the recoveries ranged from 91.1% to 113.7%. Furthermore, the other validation parameters (i.e., selectivity, matrix effect, stability, and carryover) met the acceptance criteria stipulated by guidelines of the United States Food and Drug Administration and European Medicines Agency. Significant intergroup differences were observed between high- and low-adherence groups, with high inter-correlations in the hair content of the six drugs. CONCLUSIONS: The developed method demonstrated good reliability, to comprehensively and accurately assess adherence in PLWH receiving different ART regimens.

PURPOSE Despite effective antiretroviral therapy, rates of end-stage liver disease (ESLD) remain high. It is not clear whether contemporary antiretrovirals contribute to the risk of ESLD. METHODS We included patients from cohorts with validated ESLD data in the North American AIDS Cohort Collaboration on Research and Design. Patients had to initiate antiretroviral therapy after 1 January 2004 with a nucleos(t)ide backbone of either abacavir/lamivudine or tenofovir/emtricitabine and a contemporary third (anchor) drug. Patients were followed until a first ESLD event, death, end of a cohort's ESLD validation period, loss to follow-up or 31 December 2015. We estimated associations between cumulative exposure to each drug and ESLD using a hierarchical Bayesian survival model with weakly informative prior distributions. RESULTS Among 10 564 patients included from 12 cohorts, 62 had an ESLD event. Of the nine anchor drugs, boosted protease inhibitors atazanavir and darunavir had the strongest signals for ESLD, with increasing hazard ratios (HR) and narrowing credible intervals (CrI), from a prior HR of 1.5 (95% CrI 0.32-7.1) per 5 year's exposure to posterior HRs respectively of 1.8 (95% CrI 0.82-3.9) and 2.0 (95% CrI 0.86-4.7). Both backbones and efavirenz showed no signal. Hepatitis C coinfection was the most important covariate risk factor (HR 4.4, 95% CrI 2.6-7.0). CONCLUSIONS While contemporary antiretrovirals pose less risk for ESLD than hepatitis coinfection, atazanavir and darunavir had a toxicity signal. We show how hierarchical Bayesian modelling can be used to detect toxicity signals in cohort event monitoring data even with complex treatments and few events.

Background The efficacy and tolerability of an antiretroviral regimen are important considerations for selection of HIV-1 infection maintenance therapy. Abacavir/lamivudine plus rilpivirine (ABC/3TC + RPV) has been shown in international studies to be effective and well-tolerated in virologically suppressed individuals. This study evaluated the effectiveness and safety of switching to ABC/3TC + RPV as maintenance therapy in virologically suppressed HIV-1 infected individuals in Singapore. Methods In this retrospective, single-centre study, we included individuals who were prescribed ABC/3TC + RPV, had HIV-1 viral load (VL) Results A total of 222 individuals were included in the study. The primary outcome was achieved in 197 individuals [88.8%, 95% confidence interval: 83.7–92.4%]. There were 21 individuals (9.5%) who discontinued treatment for non-virologic reasons. The remaining 4 individuals experienced virologic failure, of whom, 3 of these individuals had developed emergent antiretroviral resistance and had HIV-1 VL > 500 copies/ml at the end of the 48 ± 12 weeks follow-up period. The remaining individual experienced sustained low level viremia and subsequently achieved viral suppression without undergoing resistance testing. A total of 49 adverse events were observed in 31 out of 222 individuals (14.0%), which led to 13 individuals discontinuing therapy. Neuropsychiatric adverse events were most commonly observed (53.1%). A statistically significant increase in CD4 was observed (p Conclusion ABC/3TC + RPV is a safe and effective switch option for maintenance therapy in virologically suppressed HIV-1 individuals with in Singapore.

Background Treatment failure continues to be an impediment to the efficacy of highly active antiretroviral therapy (HART) in the treatment of human immunodeficiency virus type 1 infection (HIV-1). The World Health Organization (WHO) recommends third-line antiretroviral therapy (ART) for patients who have failed second-line ART. Darunavir (DRV) boosted with ritonavir (DRV/r) has a higher genetic barrier to resistance, is active against multidrug-resistant HIV isolates, retaining virological activity even when multiple protease mutations are present, and has been shown to be cost-effective when compared to other boosted protease inhibitors (PIs). Case Summary This is a case of a 40-year-old female known HIV/AIDS patient who has been on ART for the last 14 years with good adherence and regular follow-up, and who is now on 3rd line ART medication with TLD (tenofovir/lamivudine/dolutegravir)+DRV/r (in her 11th month) after being diagnosed with second-line treatment failure. After 6 months and 1 week of therapy, the viral load (VL) was sent, and the result was undetectable. The patient's clinical conditions had greatly improved. Conclusion Third-line ART therapy, which was once thought to be a salvageable treatment, is now the primary option for second-line ART failure. TLD in combination with ritonavir-boosted darunavir is found to be effective at lowering viral loads in the blood below detectable limits. Despite a lack of data on the use of third-line ART in Ethiopia, access to third-line ART containing ritonavir-boosted darunavir is recommended because it has been shown to be an effective alternative for patients who have failed second-line ART. We recommend that more research be done with a larger sample size, and that the findings in this paper be used with caution.

Background Remdesivir is a novel broad-spectrum antiviral therapeutic with activity against several viruses that cause emerging infectious diseases. The purpose of this study is to explore how commonly utilized antiretroviral therapy (tenofovir disoproxil fumarate/lamivudine [TDF/3TC] and atazanavir/ritonavir [ATV/r]) influence plasma and intracellular concentrations of remdesivir. Methods This is an open-label, randomized, fixed sequence single intravenous dosing study to assess pharmacokinetic interactions between remdesivir and TDF/3TC (Study A, crossover design) or TDF/3TC plus ATV/r (Study B). Healthy volunteers satisfying study entry criteria will be enrolled in the study and randomized to either Study A; N=16 (Sequence 1 or Sequence 2) or Study B; N=8. Participants will receive standard adult doses of antiretroviral therapy for 7 days and a single 200mg remdesivir infusion administered over 60 min. Pharmacokinetic blood sampling will be performed relative to the start of remdesivir infusion; predose (before the start of remdesivir infusion) and 30 min after the start of remdesivir infusion. Additional blood samples will be taken at 2, 4, 6, 12, and 24 h after the end of remdesivir infusion. Discussion This study will characterize the pharmacokinetics of remdesivir from a typical African population in whom clinical use is anticipated. Furthermore, this study will deliver pharmacokinetic datasets for remdesivir drug concentrations and demographic characteristics which could support pharmacometric approaches for simulation of remdesivir treatment regimens in patients concurrently using tenofovir/lamivudine and/or atazanavir/ritonavir. Trial registration ClinicalTrials.gov NCT04385719. Registered 13 May 2020.

Summary Objectives The main aim of the study was to develop an economical, insightful, accurate and simple RP-HPLC-DAD method with high precision and good sensitivity for concurrent determination of Tenofovir disoproxil fumarate, Doravirine and Lamivudine in blended bulk form and their combined tablet form. Material and methods A method with Ascentis C18 (150 × 4.6 mm, 5 μm) column, mobile phase ratio of 0.1% ortho phosphoric acid and Acetonitrile in 70:30 (v/v), 1 mL/min flow rate and detection wavelength of 260 nm was highly proficient in effective separation of all three drugs. The developed method was validated in accordance with ICH specifications. Results The retention times of Doravirine, Lamivudine and Tenofovir disoproxil fumarate observed were 2.4, 2.9, and 3.6 min, respectively. The linear responses were observed for Doravirine, Lamivudine and Tenofovir disoproxil fumarate in the range of 12.5–75 μg/mL, 75–225 μg/mL and 75–225 μg/mL, respectively. The limit of detection and quantification values were calculated to be 0.36 μg/mL and 0.11 μg/mL for Lamivudine, 0.55 μg/mL and 1.66 μg/mL for Tenofovir disoproxil fumarate and 0.03 μg/mL and 0.09 μg/mL for Doravirine. The % RSD values of the intra-day and inter-day precision were calculated in the range of 0.134–1.749. The mean percentage recovery of all three analytes was in the range of 98.85–100.18%. The statistical results of the validation parameters ensured that the method was accurate, specific, and precise with good sensitivity. Investigation of analytes under different stressed conditions ensures the stability of analytes reflecting the stability indication of the method. The developed method has high proficiency in separation of Tenofovir disoproxil fumarate, Doravirine and Lamivudine. The degradation products generated due to stress conditions also separated with good resolution. Conclusion The current method is a stability-indicating assay method consisting of appropriate specificity, accuracy, precision and sensitivity. The developed method has a good potential to be adopted by the pharmaceutical industrial sector.

BACKGROUND Results from clinical trials and observational studies suggest that dolutegravir plus lamivudine could be an effective and well-tolerated option for simplification in HIV-1-positive patients. We aimed to assess long-time efficacy and safety in our multicenter cohort. METHODS This was a retrospective study enrolling HIV-1-infected, virologically suppressed patients switching to dolutegravir + lamivudine. We performed survival analysis to evaluate time to virological failure (VF, defined by a single HIV-RNA ≥1000 copies/mL or by 2 consecutive HIV-RNA ≥ 50 copies/mL) and treatment discontinuation (defined as the interruption of either 3TC or dolutegravir), assessing predictors via Cox regression analyses. RESULTS Seven-hundred eighty-five patients were considered for the analysis: 554 were men (70.6%), with a median age of 52 years (interquartile range 45-58 years). Estimated probabilities of maintaining virological suppression at weeks 96, 144, and 240 were 97.7% (SD ±0.6), 96.9% (SD ±0.8), and 96.4% (SD ±0.9), respectively. A non-B HIV subtype (P = 0.014) and a previous VF (P = 0.037) resulted predictors of VF. We did not observe differences in probability of VF in people living with HIV with an M184V resistance mutation (P = 0.689); however, in a deeper analysis, M184V mutation was a predictor of VF (P = 0.038) in patients with time of virological suppression

Background To establish a simple, sensitive, accurate, precise, efficient, economical RP-UPLC method for simultaneous estimation of Doravirine, Lamivudine and Tenofovir disoproxil fumarate in bulk and their combined pharmaceutical formulations. Optimization of Chromatographic separation was achieved on analytical column HSS C18 (100 × 2.1 mm, 1.8 μ) maintained at temperature 30 °C and mobile phase consisting of 0.01 N Potassium dihydrogen orthophosphate buffer (pH-4.8) and acetonitrile in the ratio 60:40 v/v and at a flow rate 0.3 mL/min in isocratic mode. The injection volume was set as 1 µl detection wavelength is 260 nm. The proposed method validation was done as per International Council on Harmonization Q2 (R1) guidelines. Results Doravirine, Lamivudine and Tenofovir disoproxil fumarate were eluted at retention times of 1.2, 1.5, and 1.8 min respectively. The proposed method was identified an excellent linearity over concentration range of 12.5–75.0 µg/mL for Doravirine and 37.5–225.0 µg/mL for Lamivudine and 37.5–225.0 µg/mL for Tenofovir disoproxil fumarate. The percentage relative standard deviation for intra-day and inter-day precision of the present method was less than 2% for Doravirine, Lamivudine and Tenofovir disoproxil fumarate. Accuracy of the present method was evaluated by recovery studies which were in the range of 99.62–99.88% for Doravirine and 98.78–99.44% for Lamivudine and 99.67–100.52% for Tenofovir disoproxil fumarate. The limit of detection and limit of quantification were found to be 0.249 µg/mL and 0.756 µg/mL for Doravirine and 0.24 µg/mL and 0.727 µg/mL for Lamivudine and 0.797 µg/mL and 2.966 µg/mL for Tenofovir disoproxil fumarate. Forced degradation studies were carried out under various stress conditions like acid, base, peroxide, thermal, photo and neutral conditions. Conclusions The present method makes sure about no degraded impurity peak interference at the retention time of analyte peak hence can be applied for quality control investigation of Doravirine, Lamivudine and Tenofovir disoproxil fumarate in bulk and pharmaceutical formulations.

Background The long interspersed element-1 (LINE-1, L1) participates in memory formation, and DNA methylation patterns of L1 may suggest resilience or vulnerability factors for post-traumatic stress disorder (PTSD), of which the principal manifestation is a pathological exacerbation of fear memory. However, the unique roles of L1 in the reconsolidation of fear memory remain poorly understood. Objective The present study investigated the roles of L1 in the reconsolidation of context-dependent fear memory. Methods The current study used male mice obtained at two months of age. Mice underwent fear conditioning and fear recall in observation chambers. Fear memory was assessed by calculating the percentage of time spent freezing in a total of 5 min. The medial prefrontal cortex (mPFC) and hippocampus of the mice were removed and snap-frozen in nitrogen liquid for further analysis. Open Reading Frame 1 (ORF1) mRNA, and Open Reading Frame 2 (ORF2) mRNA of L1 were analyzed by Real-Time Quantitative Polymerase Chain Reaction. After the reactivation of fear memory, lamivudine was administered to inhibit L1 retrotransposition and its effects on fear memory reconsolidation were observed. Results The expression of ORF1 and ORF2 mRNA in the mPFC and hippocampus after the recent (24 hours) and remote (14 days) fear memory recall exhibited an augmentation via different temporal and spatial patterns. The reconsolidation and spontaneous recovery of fear memory were markedly inhibited in mice administrated with lamivudine, which could block L1. The expression of DNA methyltransferase (Dnmt) mRNA was diminished following lamivudine treatment in the remote fear memory recall. Conclusions The retrotransposition of L1 participated in the reconsolidation of fear memory after the reactivation of fear memory , and with lamivudine treatment, spontaneous recovery was decreased with time after the recent and remote fear memory recall, which might provide more clues for understanding the roles of L1 in fear memory and the possible strategy for treating PTSD.

Chronic hepatitis B (CHB) infection is a worldwide health problem with significant morbidity. Children with CHB require a lifetime of monitoring for infection activation, hepatic disease and its complications, and hepatocellular carcinoma (HCC). Children with CHB which is in the immune active stage are candidates for antiviral treatment. As new medications have been approved for children, the treatment recommendations have changed. This review summarizes the recent data. With the demonstration of safety and efficacy of entecavir and tenofovir in children, previously used medications like lamivudine and adefovir are no longer recommended as the first-line treatments. Health care providers should provide counseling regarding monitoring, natural history, and transmission to children with CHB and their families. Children in the immune active stage are candidates for antiviral treatment. With more approved therapies over the last few years for a wider age range of children, there are safe, effective, and well-tolerated therapeutic options.

BACKGROUND As a consequence of the improved availability of combined antiretroviral therapy (cART) in resource-limited countries, an emergence of HIV drug resistance (HIVDR) has been observed. We assessed the prevalence and spectrum of HIVDR in patients with failure of second-line cART at two HIV clinics in central Ethiopia. METHODS HIV drug resistance was analysed in HIV-1-infected patients with virological failure of second-line cART using the geno2pheno application. RESULTS Among 714 patients receiving second-line cART, 44 (6.2%) fulfilled the criteria for treatment failure and 37 were eligible for study inclusion. Median age was 42 years [interquartile range (IQR): 20-45] and 62.2% were male. At initiation of first-line cART, 23 (62.2%) were WHO stage III, mean CD4 cell count was 170.6 (range: 16-496) cells/µL and median (IQR) HIV-1 viral load was 30 220 (7963-82 598) copies/mL. Most common second-line cART regimens at the time of failure were tenofovir disoproxil fumarate (TDF)-lamivudine (3TC)-ritonavir-boosted atazanavir (ATV/r) (19/37, 51.4%) and zidovudine (ZDV)-3TC-ATV/r (9/37, 24.3%). Genotypic HIV-1 resistance testing was successful in 35 (94.6%) participants. We found at least one resistance mutation in 80% of patients and 40% carried a protease inhibitor (PI)-associated mutation. Most common mutations were M184V (57.1%), Y188C (25.7%), M46I/L (25.7%) and V82A/M (25.7%). High-level resistance against the PI ATV (10/35, 28.6%) and lopinavir (LPV) (5/35, 14.3%) was reported. As expected, no resistance mutations conferring integrase inhibitor resistance were detected. CONCLUSIONS We found a high prevalence of resistance mutations, also against PIs (40%), as the national standard second-line cART components. Resistance testing before switching to second- or third-line cART is warranted.

Background: In the current study, asimple and specific stability indicating RP-HPLC method was developed and validated for the determination of Lamivudine and Raltegravir in bulk drug and it tablet dosage form using an UV-detector. Good separation was achieved by isocratic ally on a Zorbax SB-Phenyl (150 × 4.6 mm, 3.5 μ, 80 A°) column, using a mobile phase composition of buffer (0.1% v/v Phosporic acid in water): Acetonitrile (40:60 v/v) at a flow rate of 1.0 mL/min. The eluted analytes detected at 260 nm wavelength. Results: Lamivudine and Raltegravir were eluted at 3.1 and 5.4 min respectively with run time 7 min. Linearity in the method was measured in the concentration range of 30 – 70 μg/mL and 60 – 140 μg/mL for Lamivudine and Raltegravirrespectively. The percentage recoveries of Lamivudine and Raltegravirwere determined to be 100.30% and 100.53%, respectively. The validation of the developed method is carried as per USFDA and ICH guidelines, and the degradants were well resolved from Raltegravir and Lamivudine peaks. The developed RP-HPLC method was highly precise, specific, sensitive, and stability indicating. Conclusion: The results of the analysis prove that thedeveloped RP-HPLC method is simple, economical and widely acceptable, which can be used in routine quality control tests in the industry.

We aim to characterize the drug resistance mutations in reverse transcriptase gene of HIV-1 subtype C-infected North Indian population in those who are failing first-line antiretroviral therapy (ART) and if these mutations are associated with mortality. We also attempted the assessment of switch over to second-line antiretroviral therapy in these patients. Based on the immunological marker CD4 count (

Background Introduction of tenofovir (TDF) plus lamivudine (3TC) and dolutegravir (DTG) in first- and second-line HIV treatment regimens in South Africa warrants characterization of acquired HIV-1 drug resistance (ADR) mutations that could impact DTG-based antiretroviral therapy (ART). In this study, we sought to determine prevalence of ADR mutations and their potential impact on susceptibility to drugs used in combination with DTG among HIV-positive adults (≥ 18 years) accessing routine care at a selected ART facility in KwaZulu-Natal, South Africa. Methods We enrolled adult participants in a cross-sectional study between May and September 2019. Eligible participants had a most recent documented viral load (VL) ≥ 1000 copies/mL after at least 6 months on ART. We genotyped HIV-1 reverse transcriptase and protease genes by Sanger sequencing and assessed ADR. We characterized the effect of ADR mutations on the predicted susceptibility to drugs used in combination with DTG. Results From 143 participants enrolled, we obtained sequence data for 115 (80%), and 92.2% (95% CI 85.7–96.4) had ADR. The proportion with ADR was similar for participants on first-line ART (65/70, 92.9%, 95% CI 84.1–97.6) and those on second-line ART (40/44, 90.9%, 95% CI 78.3–97.5), and was present for the single participant on third-line ART. Approximately 89% (62/70) of those on first-line ART had dual class NRTI and NNRTI resistance and only six (13.6%) of those on second-line ART had major PI mutations. Most participants (82%) with first-line viraemia maintained susceptibility to Zidovudine (AZT), and the majority of them had lost susceptibility to TDF (71%) and 3TC (84%). Approximately two in every five TDF-treated individuals had thymidine analogue mutations (TAMs). Conclusions Susceptibility to AZT among most participants with first-line viraemia suggests that a new second-line regimen of AZT + 3TC + DTG could be effective. However, atypical occurrence of TAMs in TDF-treated individuals suggests a less effective AZT + 3TC + DTG regimen in a subpopulation of patients. As most patients with first-line viraemia had at least low-level resistance to TDF and 3TC, identifying viraemia before switch to TDF + 3TC + DTG is important to avoid DTG functional monotherapy. These findings highlight a need for close monitoring of outcomes on new standardized treatment regimens.

Antiretroviral therapy [ART] has been developed remarkably within last three decades, since the first NRTI (nucleoside reverse transcriptase inhibitor) developed. For the mostly patients the challenge of complete and sustain suppression of viral has been clarify, since the triple therapy arrived. Convenient pill burden and tolerability are the main limiting factor for enhancing the long term benefit of ART. ABACAVIR (ABA) and LAMIVUDINE (LAM) are synthetic nucleotide analog (SNA) that showing a synergistic and potent inhibitory effect on human immunodeficiency virus-I (HIV-I), causative agent of AIDS. ABA and LAM belongs to nucleoside reverse transcriptase inhibitor (NRTI) class. As per new therapeutic strategy these two antiretroviral (ARV) drugs are required for the treatment of AIDS. When ARV regimens changed due to lack to virologic response ABA should be avoided. ABA is getting converted in to the active metabolite (carbovir triphosphate) which is an deoxyguanosine-5’ triphosphate analog by intracellular enzymes. LAM gets converted in its active 5’-triphosphate metabolite through phosphorylation. Chemically, ABA is (1S, cis)-4-[2-amino-6-(cyclopropyl amino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulphate and LAM is (2R, cis)-4-amino-1-(2-hydroxymethyl-1, 3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Fig. 1 and 2 show ABA and LAM’s structure respectively.

Hepatitis B virus (HBV) infection is one of the main causes of morbidity and mortality worldwide. Most children acquire the infection perinatally or during early childhood and develop a chronic hepatitis characterized by a high viral replication and a low-inflammation phase of infection, with normal or only slightly raised aminotransferases. Although a conservative approach in children is usually recommended, different therapies exist and different therapeutic approaches are possible. The main goals of antiviral treatment for children with chronic HBV infection are to suppress viral replication and to warn the disease progression to cirrhosis and hepatocellular carcinoma, although these complications are rare in children. Both United States Food and Drug Administration (US-FDA) and European Medicines Agency (EMA) have approved interferon alfa-2b for children aged 1 year and older, pegylated interferon alfa-2a and lamivudine for children aged 3 years and older, entecavir for use in children aged 2 years and older, and adefovir for use in those 12 years of age and older. Tenofovir disoproxil fumarate is approved by EMA for children aged 2 years and older and by US-FDA for treatment in children aged 12 years and older. Finally, EMA has approved the use of tenofovir alafenamide for treatment of children aged 12 years and older or for children weighing more than 35 kg independent of age. This narrative review will provide the framework for summarizing indications to antiviral therapy in the management of chronic HBV infection in children and adolescents.

A simple, rapid, and economical method has been developed for the simultaneous estimation of the latest FDA approved antiviral drug combination, Dolutegravir, Lamivudine, and tenofovir disoproxil fumarate in tablet dosage form using Shimadzu LC-20 AT HPLC with a Phenomenex Luna column compartment., the method was developed using HPLC graded methanol with o-phosphoric acid as a mobile phase and successfully validated the developed method as per the ICH guidelines. The method was found to be linear, accurate, precise, robust, and rugged. The limit of detection and the limit of quantification was found to be 2.6μg/ml and 8.18μg/ml for Dolutegravir, 14.63 μg/ml and 44.35 μg/ml for Lamivudine and 16.43 μg/ml and 49.81 μg/ml for tenofovir disoproxil fumarate respectively. The retention time was found to be 3.0, 2.3 and 2.7 min for Dolutegravir, Lamivudine and tenofovir disoproxil fumarate respectively. All of assessed parameters complied with the acceptance criteria hence indicated the usefulness of the RP-HPLC method for the determination of assay and in-vitro dissolution study for tablet dosage form which contains lamivudine, tenofovir disoproxil fumarate, and dolutegravir active substances. Hence the method can be applied for routine quality control of the drugs.

To assess efficacy and safety of dolutegravir (DTG) + lamivudine (3TC) vs. DTG + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in treatment-naive adults with HIV-1 in the prespecified 144-week secondary analyses of GEMINI-1 and GEMINI-2.Design:Identical, multicenter, phase III, randomized, non-inferiority studies (double-blind through 96 weeks).Methods:Participants with HIV-1 RNA ≤500 000 copies/ml and no major viral resistance mutations to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, or protease inhibitors were randomized 1:1 to once-daily DTG + 3TC or DTG + TDF/FTC.Results:At week 144, DTG + 3TC (N = 716) was noninferior to DTG + TDF/FTC (N = 717) in proportion of participants achieving HIV-1 RNA, This study was funded by ViiV Healthcare

Background We report a case of sudden, lethal metabolic acidosis in a 70-year-old man on long-term nucleoside reverse transcriptase inhibitor (NRTI) -based antiretroviral therapy (ART) who had developed atypical necrotizing fasciitis 1 month after kidney transplantation. Case presentation The HIV infection of the patient was treated for the last four months with an integrase strand inhibitor (dolutegravir 50 mg/d) plus a NRTI backbone including lamivudine (150 mg/d) and abacavir (600 mg/d). In this renal transplant patient we hypothesize that the co-existence of sepsis, renal failure and an accumulation of lamivudine led to the development of fatal metabolic acidosis and hyperlactatemia. Although lamivudine is only rarely associated with hyperlactatemia, there is evidence that overdose may be a risk factor for developing it. In our patient the lamivudine concentration two days after stopping and during hemodiafiltration was more than 50 times higher than therapeutic target trough concentrations. Likely reasons for this were renal impairment and concurrent treatment with trimethoprim, known to inhibit the renal elimination of lamivudine. Conclusions NRTIs could trigger the development of hyperlactatemia in septic patients. The use of NRTI sparing regimens might be considered in the presence of this critical condition.

Background and Aims: Nephrotoxicity is an adverse effect, which may occur with the use of tenofovir/lamivudine/efavirenz (TLE) in the treatment of human immune deficiency virus (HIV) infection. Curcumin (CUM), an isolate of Curcuma longa L. is used in folk medicine for the treatment of ailments. This study attempts to establish whether CUM supplementation can protect against a rat model of TLE-induced nephrotoxicity. Materials and Methods: Adult male Wistar rats (n=40) were randomly grouped and supplemented orally with CUM (50, 100 and 200 mg/kg/day) prior to the oral administration of TLE (300/300/600 mg/kg/day) for 30 days. After the treatment, the rats were fasted overnight, weighed and anesthetized. Blood samples were collected, and sera were extracted for biochemical analyses. Kidney samples were excised, weighed and processed for oxidative stress markers and histology. Results: Body weight was decreased (p

Background Previously selected lamivudine resistance-associated mutations (RAMs) may remain archived within the proviral HIV-DNA. Objectives To evaluate the ability of proviral DNA genotyping to detect lamivudine RAMs in HIV-1 virologically suppressed participants; the correlation between Sanger and next generation sequencing (NGS); and predictive factors for detection of lamivudine RAMs in proviral DNA. Methods Cross-sectional study of participants on stable antiretroviral therapy and suppressed for ≥1 year. Analysis of proviral DNA was performed by Sanger sequencing in whole blood and by NGS in PBMCs. Results We analysed samples from 102 subjects (52 with and 50 without lamivudine RAMs in historical plasma RNA-genotypes). Among participants with previous lamivudine resistance, Sanger sequencing detected RAMs in 26.9%. Detection rates significantly increased using NGS: 47.9%, 64.6%, 75% and 87.5% with the 20%, 10%, 5% and 1% thresholds, respectively. As for participants without historical lamivudine resistance, Sanger detected the RAMs in 1/49 (2%), and NGS (5% threshold) in 8/45 (17.8%). Multivariate models fitted to the whole population revealed that having a history of lamivudine resistance was a risk factor for detection of lamivudine RAMs by NGS. Among participants with historical lamivudine resistance, multivariate analysis showed that a longer time since HIV diagnosis was associated with persistence of archived mutations by NGS at thresholds of >10% [OR 1.10 (95% CI: 1.00–1.24)] and >5% [OR 1.16 (95% CI: 1.02–1.32)]. Conclusions Proviral DNA Sanger sequencing does not detect the majority of historical lamivudine RAMs. NGS increases the sensitivity of detection at lower thresholds, although the relevance of these minority populations with lamivudine RAMs needs further evaluation.

The present research aimed to develop & Evaluation of Lamivudine Nanosuspension. Lamivudine is a potent in vitro inhibitor of human immune deficiency virus belongs to the category of anti-retroviral drugs. The formulated Nanosuspension was subjected to various evaluation parameters like particle size, polydispersity index, zeta potential, drug content, viscosity, saturation solubility studies, In vitro release, treatment of kinetic data, and stability studies. The polydispersity ranged from 0.218 PDI to 0.331 PDI and zeta potential ranged from -1.60 mV to -4.79 mV are the important evaluation parameters are responsible for the stability of nanosuspensions. The Polydispersity index presents the quantity of particle size distribution ranges from 452.4 nm to 532.2 nm. In this result, LNSF4 shows spectacular drug content range of 86±1.8% to 97±2.5% it is the maximum drug content. The Brook field viscometer to determine the viscosity of Lamivudine Nano suspension of different formulations was found to be 44.4±2.1 cps to 87.7±1.4 cps. The general Nanosuspension formulations LNSF4 shows 98.64 % better controlled released in comparison with abundant formulation. In all the cases the best-fit model encounter uoto be peppas with ‘n’ value between 0.768 to 0.917. The ‘n’ value of formulation LNSF4 was 0.876 and suggesting so the drug was released by Zero-order kinetics. Acceleration stability studies intermediate storage condition has been changed from 30°C ± 2°C and 60% RH ± 5% Relative Humidity. After a 90 days study it revolves that there’s no change in Drug content, In vitro drug release, and particle size. Keywords: Lamivudine, Nanosuspension, Saturation solubility, Scanning Electron Microscopy, Stability study.

Nucleoside analogue (NA) therapy for chronic hepatitis B (CHB) is associated with improved clinical outcomes, but usually requires long‐term use. Whether treatment can be safely withdrawn and the factors associated with post‐withdrawal outcome are not well defined. To assess long‐term outcomes after stopping antiviral therapy, patients with hepatitis B e antigen (HBeAg)–negative CHB who had received antiviral therapy for 4 or more years with hepatitis B virus (HBV) DNA (≤100 IU/mL) were prospectively withdrawn from antiviral therapy and monitored monthly for the initial 6 months and every 3 months thereafter. Those with clinical relapse were retreated according to severity of relapse. Fifteen patients were withdrawn from lamivudine (4), adefovir (5), or a combination of the two (6) after a mean treatment duration of 8.4 years. The mean age was 45 years, 13 were male, and 8 were initially HBeAg‐positive before treatment. After a mean follow‐up of 6.6 years, outcomes differed by pretreatment HBeAg status. All patients who were HBeAg+ before treatment experienced virological relapse (8 of 8); 6 of 8 experienced clinical relapse; 4 of 8 had ALT flares; 5 of 8 required re‐initiation of treatment, one of whom cleared hepatitis B surface antigen (HBsAg); and 3 of 8 remained off treatment, one of whom cleared HBsAg. In contrast, 4 of 7 patients who were HBeAg‐negative before treatment experienced virological relapse, 3 of 7 experienced clinical relapse, and 1 of 7 had an alanine aminotransferase (ALT) flare. None restarted treatment, and 4 of 7 cleared HBsAg. Low pre‐withdrawal HBsAg level was predictive of HBsAg loss. Conclusion: NA therapy can be safely withdrawn with long‐term remission and high rates of HBsAg loss in most HBeAg‐negative patients without cirrhosis. Patients who were initially HBeAg+ should not be withdrawn from treatment, because clinical relapse was frequent and often severe.

Alem Endeshaw Woldeyohanins,1 Asmamaw Emagn Kasahun,1 Chilot Abiyu Demeke,1 Zemene Demelash Kifle2 1Department of Pharmaceutics and Social Pharmacy, School of Pharmacy Gondar, University of Gondar-College of Medicine and Health Sciences, Gondar, Ethiopia; 2Department of Pharmacology, School of Pharmacy Gondar, University of Gondar-College of Medicine and Health Sciences, Gondar, EthiopiaCorrespondence: Alem Endeshaw WoldeyohaninsDepartment of Pharmaceutics and Social Pharmacy, School of Pharmacy Gondar, University of Gondar-College of Medicine and Health Sciences, P.O. Box 196, Gondar, EthiopiaTel +251 920292874Fax +251-58-1141240Email aleend2008@gmail.com; Alem.Endashaw@uog.edu.etBackground: Globally, more than eight million under-five children die every year because of diseases that could be treated or prevented with drug therapy. Thus, this study aimed to evaluate the utilization and availability of the World Health Organization (WHO) suggested priority life-saving medicines for under-five-year-old children in Gondar town.Methods: Institutional-based cross-sectional survey was conducted from March 2020 to May 2020 in public health centers of Gondar town. Data entry and validation were performed in EpiData 3.1 and exported to SPSS version 20 for descriptive analysis like frequency, percentage, mean, standard deviation, and median.Results: The availability of zinc phosphate and oral rehydration salt for the diarrheal cases was 57.14% and 85.71%, respectively. The availabilities of amoxicillin dispersible tablet and gentamicin injection for the treatments of pneumonia cases were 71.43% and 42.85%, respectively, and the availability of paracetamol tablet was high (85.71%). The availabilities of artemether/lumefantrine tablet and artesunate rectal were ranged between fairly high (57.1%) to very low (28.5%), respectively, and the availabilities of zidovudine/lamivudine/nevirapine-based antiretroviral regimen was 100%, a utilization for this regimen was high (96.29%). Two (3.70%) of the surveyed cases were utilized lopinavir/ritonavir-based regimen. The utilization of priority medicines was low for pain management and pneumonia which was 18.5% and 48.18%, respectively.Conclusion: The study concluded that medicine was not consistently available throughout public health centers in Gondar town. Thus, this finding suggests the integration of WHO-recommended life-saving priority medicines into the essential drug management systems and health unit logistics to raise their utilization and availability.Keywords: availability, utilization, priority medicines, Gondar, Ethiopia

Supplemental Digital Content is Available in the Text., Background: Pregnant women using antiretrovirals (ARVs) may have persistent vaginal viral shedding, which could be associated with sexual and perinatal HIV transmission. However, there are scant data on vaginal viral load (VVL) in pregnant women with undetectable plasma viral load (PVL). Methods: This study was a post hoc analysis of an open-label randomized trial to evaluate the virologic response of 2 ART regimens. The participants were ART-naive women living with HIV initiating ART regimens between 20 and 36 weeks of pregnancy recruited at 19 clinical sites in 6 countries. Participants were randomized to receive 400 mg of raltegravir 2 times a day or 600 mg of efavirenz 4 times a day in addition to 150 mg of lamivudine and 300 mg of zidovudine 2 times a day. VVL and PVL tests were performed at every study visit. The primary outcome measures were HIV-1 PVL and VVL at maternal study week 4 and rates of perinatal HIV transmission. Results: A total of 408 were enrolled, of whom 323 had VVL samples 4 weeks after enrollment and were included in this analysis. Among women with undetectable/nonquantifiable PVL during ART, the overall rate of quantifiable VVL at week 4 was 2.54% (7/275). Of the 275 with nonquantifiable PVL, 99.1% (115/116) and 96.2% (153/159) had nonquantifiable VVL in the efavirenz and raltegravir arms, respectively. None of the 7 women with quantifiable VVL at the week 4 study visit transmitted HIV to their infants. Conclusions: Detectable VVL in pregnant women with undetectable/nonquantifiable PVL while receiving ART was rare and not associated with perinatal HIV transmission.

The aim of the present study was to compare the efficacy and durability of treatment switch to two-drug (2DR) vs. three-drug (3DR) integrase inhibitor (InSTI)-based regimens in a real-life setting.Within the ODOACRE cohort, we selected adult patients with HIV RNA 50 copies/mL switching to an InSTI-based 2DR or 3DR. Survival analyses were performed to estimate the probability of virological failure (VF, defined as one HIV RNA 1000 copies/mL or two consecutive HIV RNA 50 copies/mL) and treatment discontinuation (TD, defined as any modification, intensification or interruption of the regimen), and to evaluate their predictors.Overall, 1666 patients were included, of whom 1334 (80%) were treated with a 3DR (19.9%, 25.0% and 55.1% elvitegravir-, raltegravir- and dolutegravir-based, respectively) and 332 (20%) with a 2DR (79.2% dolutegravir + lamivudine and 20.8% dolutegravir + rilpivirine). Over a median (interquartile range) follow-up of 100 (52-150) weeks, 52 (3.1%) patients experienced VF with an incidence of 1.5/100 person-year of follow-up (PYFU). The estimated 96-week probability of VF was similar for the 2DR and 3DR groups (2.3% vs. 2.8%, P = 0.53), but it was higher for elvitegravir (4.9%) and raltegravir (5.0%) than for dolutegravir (1.5%) (P = 0.04). Four hundred (24%) patients discontinued their InSTI-based regimen, with an incidence of 11.3/100 PYFU. At 96 weeks, 3DRs showed a higher probability of TD for any reason (20.6% vs. 11.2%, P 0.001) and TD for toxicity (9.0% vs. 6.6%, P = 0.02) when compared with 2DRs. A higher risk of TD for central nervous system toxicity was observed for dolutegravir than for elvitegravir and raltegravir (4.0% vs. 2.5% vs. 0.6%, P = 0.005).In virologically suppressed HIV-infected patients, 2DRs showed an efficacy similar to 3DRs but with better tolerability.

Background: Dolutegravir (DTG) plus lamivudine (2-DR) is suggested as an initial and switch option in HIV-1 treatment. Objective: To analyze the effectiveness, durability, and safety of 2-DR compared with DTG plus abacavir/lamivudine (3-DR). Methods: This was an observational, ambispective study that included all treatment-naïve (TN) and treatment-experienced (TE) patients who started 2-DR or 3-DR between July 1, 2018, and November 30, 2020. The primary end point was noninferiority, at 24 and 48 weeks, of 2-DR versus 3-DR regarding the percentage of patients with viral load (VL)≥50 and 200 copies/mL in TN (4% margin) and VLResults: 242 patients were included (53 TN and 189 TE). Two TN patients on 2-DR had VL≥50 copies/mL and 1 had VL≥200 copies/mL at week 24. In TE patients on 2-DR, 90.2% achieved VLConclusion and Relevance: Our results did not show noninferiority in terms of virological effectiveness. Nevertheless, all effectiveness measures support the use of 2-DR in a real-life cohort of TN and TE. Additionally, durability and safety of 2-DR were confirmed to be similar to that of 3-DR.

Introduction Dolutegravir (DTG), a novel HIV-integrase strand transfer inhibitor (INSTI), is usually used with multiple antiretrovirals (ARVs) for treatment of HIV. DTG is now approved as Tivicay tablets in over 120 countries and Triumeq combination tablets (DTG/abacavir [ABC]/lamivudine [3TC]) in over 90 countries. In Japan, these formulations have been marketed since 2014 and 2015. The post-marketing prospective surveillance has been conducted as part of the HIV-Related Drug (HRD) cooperative survey aimed to collect actual drug use information in all of these DTG-treated patients in accordance with conditions for initial approvals. Methods The survey has been conducted to evaluate long-term safety and effectiveness of DTG since 2014, for approximately 6 years. The safety was evaluated by incidence of adverse drug reactions (ADRs) and change in body weight. The effectiveness was evaluated by plasma HIV RNA copies/mL and peripheral CD4+ cell counts. Results Of 2292 patients in 30 Japanese sites, 565 (24.65%) reported ADRs. The most common ADR was blood creatinine increased (4.28%). Incidence of ADRs was statistically significantly higher in patients with severe symptoms (Centers for Disease Control and Prevention [CDC] categories B and C) than those with category A, and in patients with comorbidities than those without comorbidities. Whereas incidence of ADRs was statistically significantly lower in antiretroviral therapy (ART)-experienced patients than that in ART-naïve patients. Incidence of ADRs related to suicide or self-injurious behavior was statistically significantly higher in patients with comorbidities of psychiatric disorders than those without comorbidities. The body weight tended to increase over time and those changes and percentage changes from baseline were greater in ART-naïve patients compared with ART-experienced patients. HIV RNA copies/mL and CD4+ cell counts showed favorable shifts from baseline in both ART-naïve and ART-experienced patients. Conclusion The results of the survey identified no new safety and effectiveness risks in Japanese patients with HIV/AIDS treated with DTG. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01842-3.

Pharmacokinetics, safety, and tolerability of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg were assessed in this phase 1, single‐arm, open‐label, single‐dose study in fasted healthy male (n = 4) and female (n = 8) participants of Japanese heritage. Participants received a single dose of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg after an 8‐hour fast, with safety assessments and blood samples for pharmacokinetic parameters collected through 72 hours after dosing. Geometric mean maximum plasma concentrations were 5.22 μg/mL (time to maximum concentration [tmax], 1.01 hours) for abacavir, 4.13 μg/mL (tmax, 3.50 hours) for dolutegravir, and 3.35 μg/mL (tmax, 2.98 hours) for lamivudine. Geometric mean area under the concentration‐time curve values were 18.20, 71.60, and 16.60 μg • h/mL for abacavir, dolutegravir, and lamivudine, respectively. No adverse events were reported, and no clinically significant findings were observed in laboratory values, physical examinations, or 12‐lead electrocardiographic parameters. Single‐tablet administration of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg was well tolerated in Japanese participants. Exposure to abacavir and lamivudine was comparable with that seen in previous studies. A modest increase in exposure to dolutegravir vs previous clinical studies was observed but is not expected to impact the clinical management of HIV‐1 or increase the risk for adverse events.

Introduction: Mother-to-child transmission of HIV can occur during pregnancy, labour, or breastfeeding. The first-line regimen for prophylaxis in HIV infected pregnant women is combination of Tenofovir, Lamivudine and Efavirenz (TLE). Aim: To evaluate the safety and efficacy of the TLE regimen in the Prevention of Mother-To-Child Transmission (PMTCT) of HIV. Materials and Methods: The present hospital-based, retrospective cohort study was conducted at ART centre, Prevention of Parent to Child Transmission (PPTCT) centre, and Department of Medicine, SP Medical College, Bikaner from July 2016 to June 2019. HIV positive gravidas, on triple-drug regimen TLE (Tenofovir 300 mg, Lamivudine 300 mg, Efavirenz 600 mg) before conception and, those detected HIV reactive antenatally during study period were included in this study and started on TLE regimen. After delivery, these newborns were given syrup Nevirapine as per the PPTCT guidelines. Infants were tested with Rapid test and PCR for HIV, at six weeks, six months, 12 months, and 18 months of life. Results: Out of 87 pregnant women, enrolled and delivered at the study institute, 85 were live births and two were stillbirths. Out of 85 live-born babies, four have died during infancy and two were lost to follow-up despite repeated counselling. Five babies were referred to nearby Anti-Retroviral Therapy (ART) centers. So, the study followed 74 babies out of which one girl child was found to be positive for HIV-1 at 18 months of age (transmission rate of HIV was 1.35 and efficacy of TLE 98.65%). No major adverse effects of TLE were noted and all women continued TLE. Conclusion: The use of a triple-drug regimen (TLE) declined the risk of transmission of HIV from mother-to-child at negligible level, without drug resistance and with safety and tolerability as compared to single drug.

Background and Objective: Hair whitening is among important cosmetic problems in both genders but more annoying between women which necessitates more research about hair repigmenting methods or probable therapeutic drugs. The objective of this research was to review the mechanisms of hair pigmentation as well as the drug-related hair repigmentation. Methods: In this review article, we searched PubMed, Medline and Google scholar databases and reviewed all related articles in this area (hair repigmentation) since the reversal of canities has been an important cosmetic concern many years ago. Results: No reports of changes of hair color have been identified with lamivudine in the present research. Herein can be reported as the first case of hair repigmentation following the use of lamivudine. Conclusion: We reported a case of hair pigmentation with lamivudine for the first time that could be a desirable drug-induced side effect, also review all related articles about hair repigmention or reversal of canities. By research on probable mechanisms of drug-induced hair repigmentation, we may achieve a therapeutic strategy of hair graying as an important and highly prevalent cosmetic concern. Keywords: Lamivudine; hair repigmentation; reversal canities; drug-induced, review

Objectives Dolutegravir/lamivudine (DTG/3TC) is indicated for treatment-naive and experienced people with HIV; however, questions remain about its utility in a test-and-treat setting because of potential transmitted resistance and baseline hepatitis B virus (HBV) co-infection. We present feasibility and efficacy of DTG/3TC in newly diagnosed individuals in a test-and-treat setting. Design The single-arm STAT study evaluated DTG/3TC in a US test-and-treat setting. Methods Eligible adults initiated DTG/3TC 14 days or less after HIV-1 diagnosis without availability of baseline laboratory results. If baseline testing indicated DTG or 3TC resistance, HBV co-infection, or creatinine clearance less than 30 ml/min per 1.73 m2, participants remained on study with treatment modification. Efficacy endpoints included proportions of participants with HIV-1 RNA less than 50 copies/ml at Week 24, regardless of antiretroviral regimen, among all participants (intention-to-treat exposed) and those with available HIV-1 RNA data (observed). Results Of 131 participants enrolled, 8% were female and 50% were non-white. Through Week 24, treatment was modified in eight participants [five with HBV co-infection, one with baseline M184V, one for adverse event (rash), one participant decision]. At Week 24, 78% (102/131) of all participants and 92% (102/111) of those with available data achieved HIV-1 RNA less than 50 copies/ml. Incidence of drug-related adverse events was low (7%); no drug-related serious adverse events occurred. Conclusion These data demonstrate the feasibility, efficacy, and safety of using DTG/3TC as a first-line regimen in a test-and-treat setting, with therapy adjustments for baseline resistance or HBV co-infection occurring safely via routine clinical care as needed [ClinicalTrials.gov, NCT03945981; see Supplemental Digital Content 1, video abstract (Video abstract summarizing the STAT study design and results), http://links.lww.com/QAD/C189].

Virologic failure may occur because of poor treatment adherence and/or viral drug resistance mutations (DRM). In Brazil, the northern region exhibits the worst epidemiological scenarios for the human immunodeficiency virus (HIV). Thus, this study is aimed at investigating the genetic diversity of HIV-1 and DRM in Manaus. The cross-sectional study included people living with HIV on combined antiretroviral therapy and who had experienced virological failure during 2018-2019. Sequencing of the protease/reverse transcriptase (PR/RT) and C2V3 of the viral envelope gp120 (Env) regions was analyzed to determine subtypes/variants of HIV-1, DRMs, and tropism. Ninety-two individuals were analyzed in the study. Approximately 72% of them were male and 74% self-declared as heterosexual. Phylogenetic inference (PR/RT-Env) showed that most sequences were B subtype, followed by BF1 or B C mosaic genomes and few F1 and C sequences. Among the variants of subtype B at PR/RT, 84.3% were pandemic ( B PAN ), and 15.7% were Caribbean ( B CAR ). The DRMs most frequent were M184I/V (82.9%) for nucleoside reverse transcriptase inhibitors (NRTI), K103N/S (63.4%) for nonnucleoside reverse transcriptase inhibitor (NNRTI), and V82A/L/M (7.3%) for protease inhibitors (PI). DRM analysis depicted high levels of resistance for lamivudine and efavirenz in over 82.9% of individuals; although, low (7.7%) cross-resistance to etravirine was observed. A low level of resistance to protease inhibitors was found and included patients that take atazanavir/ritonavir (16.6%) and lopinavir (11.1%), which confirms that these antiretrovirals can be used—for most individuals. The thymidine analog mutations-2 (TAM-2) resistance pathway was higher in B CAR than in B PAN . Similar results from other Brazilian studies regarding HIV drug resistance were observed; however, we underscore a need for additional studies regarding subtype B CAR variants. Molecular epidemiology studies are an important tool for monitoring the prevalence of HIV drug resistance and can influence the public health policies.

We present a challenging case of HIV-related lymphangioma-like Kaposi sarcoma (LLKS) affecting the oral cavity. A 54-year-old Brazilian male patient was referred to our center complaining of bleeding lesions affecting the oral cavity for 2 months. Interestingly, these oral lesions were the first clinical manifestation of HIV infection. Clinically, multiple erythematous nodular and patch lesions were observed. An incisional biopsy was performed, revealing numerous microscopic angled and irregular vascular channels lined with flattened endothelial cells. More cellularized and solid areas consisting of more fusiform cells with little pleomorphism and with slit-like vascular channels were noted. Based on immunoreactivity for CD31, CD34, D2-40, and HHV-8, the final diagnosis was oral LLKS. Highly active antiretroviral therapy (HAART) was initiated with dolutegravir, tenofovir, and lamivudine. During follow-up, the patient showed KS metastases to other sites and a chemotherapeutic protocol was initiated. Regression of the oral lesion was clearly noted by the clinicians 1 year after the KS diagnosis. Dentists should be able to recognize systemic diseases that affect the oral cavity such as KS in order to make an early diagnosis of its oral manifestations and to implement effective therapeutic measures to ensure a better prognosis.

Introduction Human immunodeficiency virus (HIV) infection is a state of profound immunodeficiency. Disorders of hematopoietic system are a common but often overlooked complication of HIV infection. This can manifest at any stage of the disease but more commonly in the advanced stage with low CD4 count. Anemia is the most common hematological abnormality in HIV patients and prevalence ranges from 1.3 to 95%. As HIV disease progresses, the prevalence and severity of anemia also increase. Hence, this study was undertaken to assess the hematological parameters of HIV-infected patients on highly active antiretroviral therapy (HAART) at different treatment durations with the hope to improve the HAART outcome in HIV patients and its correlation with CD4 count. Methods This prospective longitudinal study enrolled 134 HIV-infected patients admitted to or attending the OPD in the Department of Medicine or Antiretroviral Therapy (ART) Center (Center of Excellence), Regional Institute of Medical Sciences (RIMS), Imphal, Manipur, from 2018 to 2020. Complete hemogram, CD4 count, and other related-blood investigations were studied. Results The mean age of the study population was 39.9 ± 11.04 years. Of the 134 patients, 75 (56%) were males and 59 (44%) were females. Twelve (9%) patients had a history of injecting drug use (IDU). TLE (tenofovir, lamivudine, efavirenz) regimen was started on 112 (83.6%) patients and the majority of them (69/134 [51.5%]) had a CD4 count of 200 to 499 cells/mm3, which increased significantly 6 months after HAART to 99 to 1,149 cells/mm3, with a mean of 445 ± 217 cells/mm3. There were significant improvements in hemoglobin (Hb) levels, total leukocyte count (TLC), absolute neutrophil count (ANC), and absolute lymphocyte count (ALC) after HAART indicating a positive correlation with CD4 count (p < 0.05). Thrombocytopenia was observed higher after HAART when compared to baseline. There was a positive correlation between platelet count and CD4 count. However, the mean corpuscular volume (MCV) and erythrocyte sedimentation rate (ESR) had a negative correlation with CD4 count. Conclusion The study inferred a strong positive correlation between CD4 and Hb levels, TLC, ANC, ALC, and platelet count after HAART with improvement in these values as CD4 count increases. Specific treatment intervention based on the changes in the immunohematological profile trends can help prevent most of the adverse effects on HIV patients in our community.

BACKGROUND: In patients co-infected with HIV and tuberculosis, antiretroviral therapy options are limited due to drug—drug interactions with rifampicin. A previous phase 2 trial indicated that raltegravir 400 mg twice a day or efavirenz 600 mg once a day might have similar virological efficacy in patients given rifampicin. In this phase 3 trial, we assessed the non-inferiority of raltegravir to efavirenz. METHODS: We did a multicentre, open-label, non-inferiority, randomised, phase 3 trial at six sites in Côte d'Ivoire, Brazil, France, Mozambique, and Vietnam. We included antiretroviral therapy (ART)-naive adults (aged ≥18 years) with confirmed HIV-1 infection and bacteriologically confirmed or clinically diagnosed tuberculosis who had initiated rifampicin-containing tuberculosis treatment within the past 8 weeks. Using computerised random numbers, we randomly assigned participants (1:1; stratified by country) to receive raltegravir 400 mg twice daily or efavirenz 600 mg once daily, both in combination with tenofovir and lamivudine. The primary outcome was the proportion of patients with virological suppression at week 48 (defined as plasma HIV RNA concentration

Summary Background Islatravir is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1 infection. We aimed to assess the efficacy and safety of islatravir-based regimens for the treatment of HIV-1. Methods We did a phase 2b, randomised, double-blind, comparator-controlled, dose-ranging trial at 24 clinics or hospitals in four countries (Chile, France, the UK, and the USA). Treatment-naive adults (≥18 years) with plasma HIV-1 RNA concentrations of at least 1000 copies per mL, CD4 T-cell counts of at least 200 cells per mL, and a calculated creatinine clearance of at least 50 mL/min (all within 60 days before study treatment) were eligible for inclusion. Participants were randomly assigned (1:1:1:1) with a block size of four via an interactive voice and web response system to receive oral treatment with one of three doses of islatravir (0·25 mg, 0·75 mg, or 2·25 mg) plus doravirine (100 mg) and lamivudine (300 mg) or to doravirine (100 mg) plus lamivudine (300 mg) plus tenofovir disoproxil fumarate (TDF; 300 mg) once daily with placebo (part 1). Treatment groups were stratified according to screening HIV-1 RNA concentration (≤100 000 copies per mL or >100 000 copies per mL). After at least 24 weeks of treatment, participants taking islatravir who achieved an HIV-1 RNA concentration lower than 50 copies per mL switched to a two-drug regimen of islatravir and doravirine (part 2). All participants and study investigators were masked to treatment in part 1; in part 2, the islatravir dose was masked to all participants and investigators, but the other drugs were given open label. The primary efficacy outcomes were the proportions of participants with an HIV-1 RNA concentration lower than 50 copies per mL at weeks 24 and 48 (US Food and Drug Administration snapshot approach). The primary safety outcomes were the number of participants experiencing adverse events and the number of participants discontinuing study drug owing to adverse events. All participants who received at least one dose of any study drug were included in the analyses. This trial is ongoing, but closed to enrolment of new participants; herein, we report study findings through 48 weeks of treatment. This trial is registered with ClinicalTrials.gov , NCT03272347 . Findings Between Nov 27, 2017, and April 25, 2019, 121 participants (mean age 31 years [SD 10·9], 112 [93%] male, 92 [76%] white, 27 [22%] with HIV-1 RNA concentration >100 000 copies per mL) were randomly assigned: 29 to the 0·25 mg, 30 to the 0·75 mg, and 31 to the 2·25 mg islatravir groups, and 31 to the doravirine, lamivudine, and TDF group. At week 24, 26 (90%) of 29 participants in the 0·25 mg islatravir group, 30 (100%) of 30 in the 0·75 mg islatravir group, and 27 (87%) of 31 in the 2·25 mg islatravir group achieved HIV-1 RNA concentrations lower than 50 copies per mL compared with 27 (87%) of 31 in the doravirine plus lamivudine plus TDF group (difference 2·8%, 95% CI –14·9 to 20·4, for the 0·25 mg islatravir group; 12·9%, –1·6 to 27·5, for the 0·75 mg islatravir group; and 0·3%, –17·9 to 18·5, for the 2·25 mg islatravir group). At week 48, these data were 26 (90%) of 29 in the 0·25 mg islatravir group, 27 (90%) of 30 in the 0·75 mg islatravir group, and 24 (77%) of 31 in the 2·25 mg islatravir group compared with 26 (84%) of 31 in the doravirine plus lamivudine plus TDF group (difference 6·1%, 95% CI –12·4 to 24·4, for the 0·25 mg islatravir group; 6·2%, –12·2 to 24·6, for the 0·75 mg islatravir group; and –6·1%, –27·1 to 14·8, for the 2·75 mg islatravir group). 66 (73%) of participants in the islatravir groups combined and 24 (77%) of those in the doravirine plus lamivudine plus TDF group reported at least one adverse event. Two participants in the 2·25 mg islatravir group and one participant in the doravirine plus lamivudine plus TDF group discontinued owing to an adverse event. No deaths were reported up to week 48. Interpretation Treatment regimens containing islatravir and doravirine showed antiviral efficacy and were well tolerated regardless of dose. Doravirine in combination with islatravir has the potential to be a potent two-drug regimen that warrants further clinical development. Funding Merck, Sharp, & Dohme Corp, a subsidiary of Merck & Co., Inc.

We tried to investigate and compare the safety of a dual therapy (DT) with dolutegravir+lamivudine (DTG +3TC) versus bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). We performed a retrospective analysis in a cohort of virologically suppressed HIV+ pts switching to DT or BIC in our center. Primary endpoint was to evaluate time to treatment discontinuation (TD) for any cause. Survival analysis was employed to determine time to TD and its predictors were analyzed by Cox regression. Moreover, we collected viro-immunological parameters as well as markers of renal function and lipid profile at baseline and after 24 weeks and assessed changes through nonparametric tests. We analyzed 476 patients: 350 starting a DT and 126 starting BIC. Overall, we registered 21 TD: 15 in the DT group during 170 patient-years of follow-up (PYFU) (a rate of 8.8 per 100 PYFU) and 6 in the BIC one during 48 PYFU (12.5 per 100 PYFU). Estimated probabilities of maintaining study regimen after 24 weeks were 95.5% [standard deviation (SD) ±1.1] in the DT group and 94.9% (SD ±2.0) in the BIC group, with no significant differences between them (log-rank

Supplemental Digital Content is Available in the Text., Background: In TANGO, switching to dolutegravir/lamivudine was noninferior at 48 weeks to continuing 3-/4-drug tenofovir alafenamide–based regimens in virologically suppressed individuals with HIV-1. Antiretroviral agents have been associated with weight gain and metabolic complications. Setting: One hundred thirty-four centers; 10 countries. Methods: We assessed weight; fasting lipids, glucose, and insulin; and prevalence of insulin resistance and metabolic syndrome at baseline and week 48 in TANGO participant subgroups by boosting agent use in baseline regimens (boosted and unboosted). Results: In each treatment group, 74% of participants used boosted regimens at baseline. In boosted and unboosted subgroups, weight and fasting glucose changes at week 48 were small and similar between treatment groups. Overall and in the boosted subgroup, greater decreases from baseline were observed with dolutegravir/lamivudine in fasting total cholesterol (P < 0.001), low-density lipoprotein cholesterol (P < 0.001), triglycerides (P < 0.001), total cholesterol/high-density lipoprotein cholesterol ratio (overall, P = 0.017; boosted, P = 0.007), and insulin (boosted, P = 0.005). Prevalence of HOMA-IR ≥2 was significantly lower at week 48 with dolutegravir/lamivudine overall [adjusted odds ratio (aOR), 0.59; 95% confidence interval (CI), 0.40 to 0.87; P = 0.008] and in the boosted subgroup [aOR, 0.56; 95% CI, 0.36 to 0.88; P = 0.012] but not in the unboosted subgroup [aOR, 0.70; 95% CI, 0.31 to 1.58; P = 0.396]. Prevalence of metabolic syndrome at week 48 was low and consistent between treatment groups overall, with differences trending to favor dolutegravir/lamivudine in the unboosted subgroup [aOR, 0.41; 95% CI, 0.15 to 1.09; P = 0.075]. Conclusion: Generally, switching from 3-/4-drug tenofovir alafenamide–based regimens to dolutegravir/lamivudine improved metabolic parameters, particularly when switching from boosted regimens. Because of smaller sample size in the unboosted subgroup, results warrant further investigation.

Infection with human immunodeficiency virus (HIV)‐1 causes immunological disorders and death worldwide which needs to be further assisted by novel anti‐retroviral drug delivery systems. Consequently, finding newer anti‐retroviral pharmaceuticals by using biocompatible, biodegradable nanomaterials comprising a nanoparticle as core and a therapeutic agent is of high global interest. In this experiment, a second generation of a negatively charged nano‐biopolymer linear globular G2 dendrimer was carefully conjugated and loaded with well‐known anti‐HIV drugs lamivudine and efavirenz, respectively. They were characterised by a variety of analytical methods such as Zetasizer, Fourier‐transform infrared spectroscopy, elemental analysis and liquid chromatography‐mass spectroscopy. Additionally, conjugated lamivudine and loaded efazirenz with globular PEGylated G2 dendrimer were tested on an HEK293 T cell infected by single‐cycle replicable HIV‐1 virion and evaluated using XTT test and HIV‐1 P24 protein load. The results showed that lamivudine‐conjugated G2 significantly decreased retroviral activity without any cell toxicity. This effect was more or less observed by efavirenz‐loaded G2. These nano‐constructs are strongly suggested for further in vivo anti‐HIV assays.

OBJECTIVE: Antiretroviral drug (ARV) theranostics facilitates the monitoring of biodistribution and efficacy of therapies designed to target human immunodeficiency virus type-1 (HIV-1) reservoirs. To this end, we have now deployed intrinsic drug chemical exchange saturation transfer (CEST) contrasts to detect ARVs within the central nervous system (CNS). DESIGN AND METHODS: CEST effects for lamivudine (3TC) and emtricitabine (FTC) were measured by asymmetric magnetization transfer ratio analyses. The biodistribution of 3TC in different brain sub-regions of C57BL/6 mice treated with lipopolysaccharides was determined using magnetic resonance imaging (MRI). CEST effects of 3TC protons were quantitated by Lorentzian fitting analysis. 3TC levels in plasma and brain regions were measured using ultraperformance liquid chromatography tandem mass spectrometry to affirm the CEST test results. RESULTS: CEST effects of the hydroxyl and amino protons in 3TC and FTC linearly correlated to drug concentrations. 3TC was successfully detected in vivo in brain sub-regions by MRI. The imaging results were validated by measurements of CNS drug concentrations. CONCLUSION: CEST contrasts can be used to detect ARVs using MRI. Such detection can be used to assess spatial-temporal drug biodistribution. This is most notable within the CNS where drug biodistribution may be more limited with the final goal of better understanding ARV-associated efficacy and potential toxicity.