Antiretroviral Combination Research Articles

Efficacy and safety of abacavir/lamivudine plus rilpivirine as a first-line regimen in treatment-na\xefve HIV-1 infected adults

BackgroundThe anti-retroviral combination of abacavir/lamivudine plus rilpivirine (ABC/3TC/RPV) is not recommended by international guidelines as the first-line regimen. However, it is potent, well-tolerated, and affordable, especially in resource-limited settings. This study evaluates the efficacy and safety of ABC/3TC/RPV as an initial regimen for treatment-naïve HIV-1 infected patients.MethodsA retrospective study was conducted in the largest HIV care centre in Singapore, with data collected June 2011 to September 2017. All treatment-naïve HIV-1 infected adults prescribed ABC/3TC as part of their initial anti-retroviral therapy regimen were included. The third drug was a non-nucleoside reverse-transcriptase inhibitor (NNRTI) such as RPV or efavirenz (EFV), or boosted protease-inhibitor (PI). Patients were followed up for 48 weeks. The primary end-point was the percentage of patients achieving virologic suppression, analysed using on-treatment analysis. Secondary outcomes included CD4-count change, treatment discontinuation and treatment-related adverse events.Results170 patients were included in the study, 66 patients in the RPV group, 104 patients in the comparator group (EFV or boosted PI). 96% (n = 24) in the RPV group and 87% (n = 26) in the comparator group achieved viral suppression at 48 weeks (p = 0.28). Median (interquartile range) time to viral suppression was similar: 17 (14–24) weeks in the RPV group, and 21 (13–26) weeks in the comparator group. There were no statistically significant differences in the CD4 count between the two groups. 14% (n = 9) of patients on RPV discontinued treatment before 48 weeks, compared to 30% (n = 31) from the comparator group (p = 0.053). Of these, 23 discontinuations were due to drug adverse effects, and only 1 attributed to RPV (p < 0.01). One patient in each group had virologic failure.ConclusionRPV is effective, safe and considerably more tolerable than compared to NNRTI or boosted PI in ABC/3TC-containing regimens for treatment-naïve patients. It offers an affordable and attractive option, especially in resource-limited settings.

Structure-Activity-Relationship and Mechanistic Insights for Anti-HIV Natural Products.

Acquired Immunodeficiency Syndrome (AIDS), which chiefly originatesfroma retrovirus named Human Immunodeficiency Virus (HIV), has impacted about 70 million people worldwide. Even though several advances have been made in the field of antiretroviral combination therapy, HIV is still responsible for a considerable number of deaths in Africa. The current antiretroviral therapies have achieved success in providing instant HIV suppression but with countless undesirable adverse effects. Presently, the biodiversity of the plant kingdom is being explored by several researchers for the discovery of potent anti-HIV drugs with different mechanisms of action. The primary challenge is to afford a treatment that is free from any sort of risk of drug resistance and serious side effects. Hence, there is a strong demand to evaluate drugs derived from plants as well as their derivatives. Several plants, such as Andrographis paniculata, Dioscorea bulbifera, Aegle marmelos, Wistaria floribunda, Lindera chunii, Xanthoceras sorbifolia and others have displayed significant anti-HIV activity. Here, weattempt to summarize the main results, which focus on the structures of most potent plant-based natural products having anti-HIV activity along with their mechanisms of action and IC50 values, structure-activity-relationships and important key findings.

HAART THERAPY IN GHANA: COMPARATIVE ASSESSMENT OF THE EFFECTIVENESS OF DIFFERENT HAART COMBINATIONS AT KOMFO ANOKYE TEACHING HOSPITAL

Objective: Although all marketed antiretrovirals (ARVs) have proven efficacy, genetic differences can result in varied effectiveness. This study was conducted to determine the effectiveness of different Highly Active Antiretroviral Therapy (HAART) combinations among patients attending HIV clinic at a Major Teaching Hospital in Ghana.&#x0D; Methods: The study was a retrospective study involving 500 patients at an HIV clinic in the Ashanti Region of Ghana.&#x0D; Results: Twelve major antiretroviral combinations for HAART were prescribed at the study center. The most prescribed drug combinations were AZT+3TC+EFV and AZT+3TC+NVP. The study identified that HAART, irrespective of the kind of drug combination used, was effective at increasing CD4 count within the first 6 mo of therapy initiation in the study population. However, the magnitude of the increases differed from combination to combination. All HAART combinations with zidovudine as one of the drugs resulted in higher CD4 counts compared with combinations containing stavudine. HAART with nevirapine also resulted in a higher CD4 count than those with efavirenz. However, efavirenz-based combinations appeared to be more effective in critically ill patients and patients with mean CD4+T helper cells count below 100 cell/mm3. More importantly, efavirenz was common among all HAART combinations that resulted in treatment failure.&#x0D; Conclusion: There was significant variation in response to different HAART combination among Ghanaian HIV patients. However, there was no statistically significant difference in mean CD4 count between the two most predominately used HAART i. e AZT+3TC+EFV and AZT+3TC+NVP.

A Computational Approach for the Prediction of Treatment History and the Effectiveness or Failure of Antiretroviral Therapy.

Human Immunodeficiency Virus Type 1 (HIV-1) infection is associated with high mortality if no therapy is provided. Currently, the treatment of an HIV-1 positive patient requires that several drugs should be taken simultaneously. The resistance of the virus to an antiretroviral drug may lead to treatment failure. Our approach focuses on predicting the exposure of a particular viral variant to an antiretroviral drug or drug combination. It also aims at the prediction of drug treatment success or failure. We utilized nucleotide sequences of HIV-1 encoding protease and reverse transcriptase to perform such types of prediction. The PASS (Prediction of Activity Spectra for Substances) algorithm based on the naive Bayesian classifier was used to make a prediction. We calculated the probability of whether a sequence belonged (P1) or did not belong (P0) to the class associated with exposure of the viral sequence to the set of drugs that can be associated with resistance to the set of drugs. The accuracy calculated as the average Area Under the ROC (Receiver Operating Characteristic) Curve (AUC/ROC) for classifying exposure of the sequence to the HIV-1 protease inhibitors was 0.81 (±0.07), and for HIV-1 reverse transcriptase, it was 0.83 (±0.07). To predict cases of treatment effectiveness or failure, we used P1 and P0 values, obtained in PASS, along with the binary vector constructed based on short nucleotide descriptors and the applied random forest classifier. Average AUC/ROC prediction accuracy for the prediction of treatment effectiveness or failure for the combinations of HIV-1 protease inhibitors was 0.82 (±0.06) and of HIV-1 reverse transcriptase was 0.76 (±0.09).

Evaluating emtricitabine + rilpivirine + tenofovir alafenamide in combination for the treatment of HIV-infection

ABSTRACTIntroduction: Antiretroviral therapy (ART) is recommended for all people who are living with HIV to suppress viral load and to stop the progression and transmission of HIV-1. Fixed-dose combinations of antiretrovirals largely reduce pill burden.Areas covered: The authors first provide an overview of the use of non-nucleoside reverse transcriptase inhibitor (NNRTI) based therapy in HIV care. They then summarize the properties of each drug in the fixed-dose combination of tenofovir alafenamide/emtricitabine/rilpivirine/(TAF/FTC/RPV). The efficacy and safety of each component and the combination as a whole are reviewed: FTC is non-inferior to lamivudine (3TC) at assessed dosages; TAF was non-inferior to tenofovir disoproxil fumarate (TDF); the viral efficacy of RPV is non-inferior with EFV at the assessed dosage; TAF/FTC/RPV is non-inferior in efficacy but shows less of a decline in bone mineral density and renal function compared to TDF/FTC/RPV. Finally, adverse effects and drug–drug interaction data with FTC/RPV/TAF are discussed.Expert opinion: TAF/FTC/RPV can be used as an initial regimen for people living with HIV whose HIV RNA <100,000 copies/ml and CD4 cell count > 200 cells/mm3 when INSTI-based regimens are not a treatment option. Future antiretroviral therapy development may focus on dual therapy-based regimens containing RPV, particularly as long-acting formulations.

A Review and Clinical Understanding of Tenofovir: Tenofovir Disoproxil Fumarate versus Tenofovir Alafenamide.

HIV is a serious chronic medical condition. Significant improvements in antiretroviral therapy have led to a transformation in its management. No curative treatment is available for HIV, and lifelong therapy is required with a combination of agents to control viral replication and prevent complications. Some of the older agents are notorious for many side effects, making patient compliance difficult, which is critical to preventing HIV resistance. Tenofovir is one of the newer, more tolerable, nucleotide reverse transcriptase inhibitors on the market; is a mainstay of many antiretroviral therapy combinations; and is now available in 2 different formulations, tenofovir disoproxil fumarate (TDF) and, the more recent, tenofovir alafenamide (TAF). These 2 formulations have very different pharmacokinetics, which seem to affect their efficacy and safety. This manuscript provides insight into the history of TDF and TAF development, their unique pharmacokinetics and pharmacology, clinically important adverse effects, monitoring, interactions, resistance, review of clinical studies, and guideline recommendations and clinical applications for tenofovir’s various indications.

The Adherence to Fixed-Dose Combination Antiretroviral Therapy and Viral Load in HIV Patients

Antiretroviral fixed-dose combination (FDC ARV) has been used in HIV patient therapy. The therapy is recommended to be monitored using a viral load (VL), reflecting the amount of HIV in the blood. Since 2015, the VL testing has been carried out at Pengayoman Cipinang Hospital. However, the evaluation of adherence to the FDC antiretroviral therapy on VL has never been conducted. This study aims to determine the relationship between the adherence level to the FDC ARVs and VL at Pengayoman Cipinang Hospital in 2015-2018. The study used a cross-sectional design and a random sampling technique. The sample size was 70, and data generated from the medical record. Kruskal Wallis test showed no differences in the level of adherence in the group based on gender, education level, marital status, employment status, and the risk factor for HIV. However, there was a significant difference in the age group. Cross-tab data showed virological failure (VL> 400 copies/ml) was found in 1.8% of patients with good adherence, 75% of patients with moderate adherence, and 100% of patients with poor adherence. The Chi-square test showed a significant relationship between adherence to FDC ARV and VL (p=0.000). It can be concluded that there was a significant relationship between the level of adherence in taking ARV FDC and viral load.

Assessments of the level of adherence to antiretroviral therapy and the health status of people living with HIV in Calabar, Nigeria

Background: Medication adherence describes a patient's behavior of accurately following drug regimens; nonadherence describes a patient's inability to accurately follow drug regimens. Several factors such as psychosocial, educational, health-related, and environmental-related factors could contribute in determining the level of adherence to antiretroviral drug. This was a study to assess the level of adherence antiretroviral combination therapy and the health status of people living with HIV in Calabar, Nigeria. Materials and Methods: Questionnaires were administered to 350 HIV persons who attended antiretroviral treatment (ART) clinic to obtain their sociodemographic data, knowledge of ART, service received, and drug history. Stool samples were collected and examined using direct microscopy, formol–ether concentration technique, and modified Ziehl–Neelsen technique for enteric parasites, whereas blood samples were collected for HIV status examination using serial HIV testing algorithm, hemoglobin levels using cyanmethemoglobin method, and counting of CD4 using Partec CyFlow counter. Results: The results showed that 79.43% (278/350) of the participants adhered to antiretroviral drugs, with most of them (47.84%, 133/278) having CD4 counts between 201 and 400 cell/μl. Stigma was the major reason for nonadherence to treatment. Those who adhered to therapy had a lower infection rate and an elevated mean hemoglobin level than those who did not adhere. Conclusion: There was also an elevated hemoglobin level, lower enteric parasite infections, and an improved CD4 count among the adherents than those who did not adhere.

Evaluating the Concordance of Clinician Antiretroviral Prescribing Practices and HIV-ASSIST, an Online Clinical Decision Support Tool.

Individualized selection of antiretroviral (ARV) therapy is complex, considering drug resistance, comorbidities, drug-drug interactions, and other factors. HIV-ASSIST (www.hivassist.com) is a free, online tool that provides ARV decision support. HIV-ASSIST synthesizes patient and virus-specific attributes to rank ARV combinations based upon a composite objective of achieving viral suppression and maximizing tolerability. To evaluate concordance of HIV-ASSIST recommendations with ARV selections of experienced HIV clinicians. Retrospective cohort study. New and established patients at the Johns Hopkins Bartlett HIV Clinic and San Francisco Veterans Affairs HIV Clinic completing clinic visits were included. Chart reviews were conducted of the most recent clinic visit to generate HIV-ASSIST recommendations, which were compared to prescribed regimens. For each provider-prescribed regimen, we assessed its corresponding HIV-ASSIST "weighted score" (scale of 0 to 10 +, scores of < 2.0 are preferred), rank within HIV-ASSIST's ordered listing of ARV regimens, and concordance with the top five HIV-ASSIST ranked outputs. Among 106 patients (16% female), 23 (22%) were ARV-naïve. HIV-ASSIST outputs for ARV-naïve patients were 100% concordant with prescribed regimens (median rank 1 [IQR 1-3], median weighted score 1.1 [IQR 1-1.2]). For 18 (17%) ARV-experienced patients with ongoing viremia, HIV-ASSIST outputs were 89% concordant with prescribed regimens (median rank 2 [IQR 1-3], median weighted score 1 [IQR 1-1.2]). For 65 (61.3%) patients that were suppressed on a current ARV regimen, HIV-ASSIST recommendations were concordant 88% of the time (median rank 1 [IQR 1-1], median weighted score 1.1 [IQR 1-1.6]). In 18% of cases, HIV-ASSIST weighted score suggested that the prescribed regimen would be considered "less preferred" (score > 2.0) than other available alternatives. HIV-ASSIST is an educational decision support tool that provides ARV recommendations concordant with experienced HIV providers from two major academic centers for a diverse set of patient scenarios.

Cohort profile: The Observational cohort for the study of DOlutegravir in Antiretroviral Combination REgimens (ODOACRE)

PurposeThe Observational cohort for the study of DOlutegravir in Antiretroviral Combination REgimens (ODOACRE) cohort was established in Italy in 2016 to evaluate the overall efficacy and tolerability of dolutegravir (DTG)-based...

PIN150 ANALYSIS OF TREATMENT SEQUENCES FROM THE FRENCH NATIONAL SNIIRAM DATABASE: CASE STUDY OF INCIDENT PEOPLE LIVING WITH HIV IN 2013

The study purpose was to describe the changes and discontinuations of antiretroviral combination therapy (cART) (number of treatments, occurrence, duration) over the cohort of incident people living with HIV (PLWHIV) in 2013, included in the French national Health Insurance database (SNIIRAM). It also aims at experimenting data mining methods to study treatment sequences. From the SNIIRAM, we extracted PLWHIV affiliated to the general insurance scheme (N=96,423) through specific chronic diseases status and/or reimbursement of HIV laboratory tests and/or HIV-related hospitalizations and/or reimbursements of antiretroviral drugs in 2013. Incident patients (N=3,373) were followed for 2 years to identify their cART, categorized as single, double, triple or quadruple+ combination therapies. The treatment sequences were arranged according to a similarity criterion. It was performed by an Agglomerative Clustering algorithm configured with the Hamming distance and the Ward linkage method. The result is a graph containing one discretized timeline per patient. The lines were put in order one above the other and follow the 2-year follow-up. Finally, a smoothing was applied to the image to homogenize and highlight distinctive patterns. The combination of Agglomerative Clustering and of image processing forms an innovative methodology called TAK: Time-sequence Analysis through K-clustering. Over the 3,373 incident patients, 363 (11%) received no antivirals drugs during the follow-up, 385 (11%) were only treated after 6 months and 255 (8%) stopped cART at least one period during follow-up. 1,675 (50%) patients solely received a triple therapy over the follow-up, 484 (14%) changed at least once from a triple therapy to a single/double. In 2013, a triple therapy was the reference treatment and 30% of the patients had a 6-month period without any cART. This study validates the relevance of combining clustering methods with image processing to visualize the treatment sequences of a cohort in a clear and synthetic way.

In vitro–in vivo correlation of the drug–drug interaction potential of antiretroviral HIV treatment regimens on CYP1A1 substrate riociguat

ABSTRACTObjectives: Riociguat is a soluble guanylate cyclase stimulator licensed for the treatment of pulmonary arterial hypertension (PAH), a potentially fatal complication of human immunodeficiency virus infection. This study investigated the inhibitory potency of selected antiretroviral regimens on the metabolic clearance of riociguat.Methods: The inhibitory potential of the components of six antiretroviral combinations (ATRIPLA® (efavirenz/emtricitabine/tenofovir disoproxil), COMPLERA® (rilpivirine/emtricitabine/tenofovir disoproxil), STRIBILD® (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil), TRIUMEQ® (abacavir/dolutegravir/lamivudine), and two ritonavir-boosted regimens) on riociguat metabolism were evaluated in recombinant human CYP1A1 and CYP3A4 as well as in human hepatocytes exhibiting both CYP1A1 and CYP3A4 activity. In vitro-in vivo correlation was performed between calculated and observed increases in riociguat exposure in vivo.Results: Using both in vitro systems, the predicted increase in exposure of riociguat was highest with components of TRIUMEQ® followed by COMPLERA®, ATRIPLA®, STRIBILD®, and the ritonavir-boosted regimens. Further experiments in human hepatocytes confirmed CYP1A1 to be the predominant enzyme in the metabolic clearance of riociguat.Conclusion: Antiretroviral treatment containing the potent CYP1A1 inhibitor abacavir had the greatest impact on riociguat metabolic clearance. The impact of comedications containing only strong CYP3A4 inhibitors e.g. ritonavir was less pronounced, suggesting a benefit of riociguat over PAH-targeting medications with contraindications for use with strong CYP3A4 inhibitors.

2511. Characterization of Patient Pill Preferences from a Prospective Placebo vs. Placebo Ease of Swallowability Study

BackgroundHIV therapy has been moving toward smaller size, once a day regimens in hopes of improved adherence. Surprisingly, few publications characterize HIV patient’s pill preferences. To evaluate HIV-negative or treatment-naïve pill preference, we conducted a prospective randomized study at the Infectious Diseases Clinic at Henry Ford Hospital in Detroit, MI.MethodsFifty patients were recruited, receiving questionnaires regarding factors influencing the ease of swallowability, medication habits, pill preferences and adherence while being randomized to receive placebo pills representing currently FDA approved combination antiretrovirals DTG/ABC/3TC and BIC/FTC/TAF. Statistical analyses presented are descriptive.ResultsPatients preferred pills or tablets (84%) as their preferred form of medication. Patient’s ideal pill length size was reported between 4–9 millimeters (96%), with no responses > 13 mm. The most important factors for ease of swallowability were stated as size (40%) and smoothness (38%). Interestingly, 80% of participants then reported that size and shape of the pills was only “some or less” important to them for their pills; however, 32% of participants stated that size, and shape (16%), could make them not want to take a pill daily. When offered the choice of regimens, patients preferred taking more, smaller pills (42%) vs. fewer larger pills (36%) or liquids (14%). Three most common factors indicated as making medication adherence difficult included taking multiple doses daily (38%), large pills (16%), and multiple pills per dose (14%). When given free response, pills having a smooth coating was reinforced by 10 of the 25 (40%) participants who commented.ConclusionPatient preferences for medications are varied and nuanced, but carry implications on patients self-reported likelihood to remain adherent to a regimen. Care should be taken in a clinical setting, such as HIV, to take pill characteristics into account when selecting antiretroviral regimens for patients.Disclosures All authors: No reported disclosures.

Recommended First-Line Antiretroviral Therapy Regimens and Risk of Diabetes Mellitus in HIV-Infected Adults in Resource-Limited Settings.

ObjectiveThe use of some antiretroviral drugs has been associated with a higher risk of diabetes mellitus (DM) in HIV-infected patients, but the risk associated with antiretroviral drug combinations remains unclear. We investigated the association between first-line antiretroviral therapy (ART) regimens, recommended by the World Health Organization (WHO) in 2016, and the risk of DM in adults.MethodWe selected all HIV-infected adults within the Thai National AIDS Program who started a first-line ART regimen consisting the following between October 2006 and September 2013: zidovudine+lamivudine+nevirapine; tenofovir disoproxil fumarate (TDF)+lamivudine+nevirapine; zidovudine+lamivudine+efavirenz; TDF+lamivudine/emtricitabine+efavirenz; zidovudine+lamivudine+ritonavir-boosted lopinavir (LPV/r); or TDF+lamivudine+LPV/r. Diagnosis of DM was defined as having at least 2 of the following characteristics: fasting plasma glucose ≥126 mg/dl, 2010 WHO ICD-10 codes E11-E14, or prescription of antidiabetic drugs. To identify ART regimens associated with DM, we used competing risks regression models that considered mortality without DM as a competing event and adjusted for sex, age, pancreas disease, and stratified by groups defined by a score summarizing the propensity to receive a specific first-line ART regimen.ResultsData from 35 710 adults (49.1% male; median age, 35.0 years; median follow-up, 2.0 years) were included. In the multivariable analysis with zidovudine+lamivudine+nevirapine as the reference group, a higher risk of DM was observed with TDF+lamivudine/emtricitabine+efavirenz (adjusted sub-distribution hazard ratio [aSHR], 1.6; 95% confidence interval [CI], 1.3–1.9), zidovudine+lamivudine+efavirenz (aSHR, 2.0; 95% CI, 1.7–2.3), and TDF+lamivudine+LPV/r (aSHR, 2.7; 95% CI, 1.9–3.9).ConclusionsSeveral of the WHO recommended ART regimens, particularly tenofovir + lamivudine +LPV/r and regimens containing efavirenz, may be associated with an increased risk of DM.

New strategy for identifying potential natural HIV-1 non-nucleoside reverse transcriptase inhibitors against drug-resistance: an in silico study

Non-nucleosides reverse transcriptase inhibitors (NNRTIs), specifically targeting the HIV-1 reverse transcriptase (RT), play a unique role in anti-AIDS agents due to their high antiviral potency, structural diversity, and low toxicity in antiretroviral combination therapies used to treat HIV. However, due to the emergence of new drug-resistant strains, the development of novel NNRTIs with adequate potency, improved resistance profiles and less toxicity is highly required. In this work, a novel virtual screening strategy combined with structure-based drug design was proposed to discover the potential inhibitors against drug-resistant HIV strains. Seven structure-variant RTs, ranging from the wild type to a hypothetical multi-mutant were regarded as target proteins to perform structure-based virtual screening. Totally 23 small molecules with good binding affinity were identified from the Traditional Chinese Medicine database (TCM) as potential NNRTIs candidates. Among these hits, (+)-Hinokinin has confirmed anti-HIV activity, and some hits are structurally identical with anti-HIV compounds. Almost all these hits are consistent with external experimental results. Molecular simulations analysis revealed that top 2 hits (Pallidisetin A and Pallidisetin B) bind stably and in high affinity to HIV-RT, which are ready to be experimental confirmed. These results suggested that the strategy we proposed is feasible, trustworthy and effective. Our finding might be helpful in the identification of novel NNRTIs against drug-resistant, and also provide a new clue for the discovery of HIV drugs in natural products.Communicated by Ramaswamy H. Sarma.

Kynurenine 3-Monooxygenase Inhibition during Acute Simian Immunodeficiency Virus Infection Lowers PD-1 Expression and Improves Post-Combination Antiretroviral Therapy CD4+ T Cell Counts and Body Weight.

The kynurenine pathway (KP) is a key regulator of many important physiological processes and plays a harmful role in cancer, many neurologic conditions, and chronic viral infections. In HIV infection, KP activity is consistently associated with reduced CD4 T cell counts and elevated levels of T cell activation and viral load; it also independently predicts mortality and morbidity from non-AIDS events. Kynurenine 3-monooxygenase (KMO) is a therapeutically important target in the KP. Using the nonhuman primate model of SIV infection in rhesus macaques, we investigated whether KMO inhibition could slow the course of disease progression. We used a KMO inhibitor, CHDI-340246, to perturb the KP during early acute infection and followed the animals for 1 y to assess clinical outcomes and immune phenotype and function during pre-combination antiretroviral therapy acute infection and combination antiretroviral therapy-treated chronic infection. Inhibition of KMO in acute SIV infection disrupted the KP and prevented SIV-induced increases in downstream metabolites, improving clinical outcome as measured by both increased CD4+ T cell counts and body weight. KMO inhibition increased naive T cell frequency and lowered PD-1 expression in naive and memory T cell subsets. Importantly, early PD-1 expression during acute SIV infection predicted clinical outcomes of body weight and CD4+ T cell counts. Our data indicate that KMO inhibition in early acute SIV infection provides clinical benefit and suggest a rationale for testing KMO inhibition as an adjunctive treatment in SIV/HIV infection to slow the progression of the disease and improve immune reconstitution.

Virological response to integrase strand transfer inhibitor-based antiretroviral combinations in HIV-1 group O-infected patients.

To investigate the virological success rate of an INSTI-based combination of antiretroviral therapy (cART) in a large population of HIV-1/O-infected patients, and to describe resistance-associated mutations (RAM) at virological failure. The virological response of 39 patients receiving INSTI-based cART during their follow-up was analysed i) at the last point of the first INSTI initiation and ii) at their most recent visit. RAM analysis was performed at virological failures. Resistance interpretation was based on the French National Agency of Research on AIDS and viral hepatitis (ANRS) rules. Virological success at both time points of analysis was high, with more than 87% of the patients with undetectable plasma viral load. Among the six patients with virological failure, three selected RAM described for HIV-1/M resistance, and two had already RAM, before INSTI initiation. Our results show that HIV-1/O infected patients receiving INSTI-based cART presented a high rate of virological success whatever their previous lines; we have also shown that resistance rules for HIV-1/M could be considered when failure occurs. These data are of importance especially in the context of WHO recommendations for a wider use of this class.

Use of non-formulary high-cost medicines in an Australian public hospital

Background Clinicians prescribe high-cost medicines for rare diseases and nonapproved indications when conventional therapies have failed. Objective To examine the use of non-formulary high-cost medicines at an Australian public hospital. Methods Retrospective audit of individual patient use applications for nonformulary medicines costing more than $5000 AUD per year at a large tertiary referral hospital in Adelaide, South Australia over a 12-month study period from January 2015 to December 2015. Main outcome measures Total cost of non-formulary high-cost medicines, medication class, indications for use, level of supporting evidence and proposed monitoring outcomes. Results Eighty-seven individual patient use applications were examined. All except one were approved, at a total cost of $1,339,203 AUD. The most common drug classes were anti-CD20 (n = 33, 38%), combined antiretrovirals (n = 10, 11%)and TNF-alpha antagonists (n = 10, 11%). There were 56 indications for these medicines with the majority being inflammatory conditions (n = 52, 60%), followed by infections (n = 14, 16%) and malignancies (n = 14, 16%). Of the first-time individual patient use applications (n = 63), there were 25 applications (40%) that provided a case series as supporting evidence. Approximately half of new individual patient useapplications (n = 32) proposed an objective monitoring outcome, but few (n = 13, 21%) contained sufficient information to allow a third party to determine efficacy of the medication. Conclusions Non-formulary high-cost medicines are being used for a broad range of indications based largely on low levels of evidence. Prospective definition of an adequate response to treatment and reporting of these outcomes is required to improve the evidence-base and to aid decision-making for subsequent treatment courses.

Computerized quantification of drugs synergism in animal studies or in clinical trials using only ten data points

Abstract The median-effect equation (MEE) derived from the mass-action law (MAL) is the unified theory of dose-effect pharmacodynamics (PD) and biodynamics (BD). MEE enables the linearization of a dose-effect curve into a straight linedefined by two data points. Thus any two data points can represent an entire dose-effect curve. For dose-effect curves using MAL, dose-zero can serve as 3rd point, and the universal reference point, the median-effect dose (Dm) serves as 4th point. This functionality has tremendous significance for in vivo studies. Fewer data points are required for a dose-effect curve, facilitating economical and ethically sustainable PD analyses. The extension of MEE from a single drug to multiple drugs establishes the general combination index equation (CIE), which quantitatively defines synergism (CI 1]. Although the CI method is often (>6000 citations) applied in in vitro studies, it is rarely used in animal studies or clinical trials. In vivo drug combination studies that use only single dose or statistical p value analyses do not allow quantitative synergy claims. This article presents two examples for drug combinations in vivo: (i) in animals (anticancer drug combination against human HCT-116 colon carcinoma xenografts in nude mice, Taxotere + T607) and (ii) in a clinical trial (anti-retroviral drug combinations against HIV/AIDS, AZT + INF). Only 36 patients respectively only 66 nude mice were required. Both examples require only ten data points (D1, D2 and [D1+D2], each with 3 doses plus one control) to quantitatively determine synergism or antagonism with the CompuSyn software.

Absence of Integrase Strand Transfer Inhibitor Associated Resistance in Antiretroviral Therapy Naïve and Experienced Individuals from Western India.

The Indian national AIDS control program heavily relies on low cost nucleoside reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI). With global increase in resistance to these, alternative antiretroviral combinations need to be explored. Owing to higher potency, better efficacy and tolerability, recently WHO recommended integrase strand transfer inhibitor (INSTI) based first-line antiretroviral therapy (ART). There is lack of INSTI resistance surveillance data from India. Thus, there is a need to analyze integrase (IN) gene from primarily HIV-1 subtype C infected Indian population, before widespread introduction of INSTI in first-line ART. Plasma samples were collected from INSTI naïve individuals reporting to ART centre of Pune, India. RNA was extracted and IN gene was amplified by nested polymerase chain reaction (PCR) using prior published primers. PCR product of 867 bp was bi-directionally sequenced and resistance associated mutation were analyzed using Stanford University HIV drug resistance algorithm. A total of 58 HIV-1 sequences from 62 INSTI naïve individuals were successfully genotyped. Of these 58, 40 were ART naïve, newly diagnosed and remaining individuals were on NRTI, NNRTI, or protease inhibitors based failing regimen. The commonest subtype identified in the study was C (93%) followed by A1 (3.5%). A total of 191 (66.31%) fully conserved amino acid (aa) positions were observed in IN gene. Overall there was absence of major INSTI resistance mutation, however, E157Q (13.79%) emerged as common polymorphic mutation. Other accessory mutations were L74IM (34.48%), Q95K (1.72%), and T97A (1.72%). To conclude, this first Indian study on primarily HIV-1 subtype C sequences characterized aa variations in IN gene and indicated absence of major INSTI resistance associated mutations.