Possible Herb-Drug Interaction Risk of Some Nutritional and Beauty Supplements on Antiretroviral Therapy in HIV Patients.

This study was carried out to assess the drug interaction potential of a variety of beauty and sports/nutritional supplements when co-administered with antiviral drug therapy, especially anti-HIV drugs. Ethanolic extracts of seven dietary supplements (two beauty products, three nutritional protein supplement products and two weight loss/body building products) were examined in human liver cells (HepG2 cells and primary hepatocytes) for their influence on the hepatic metabolism of five antiviral drugs (elvitegravir, rilpivirine, tenofovir, dolutegravir, and cobicistat), all of which are substrates for a key drug metabolizing enzyme CYP3A4. Our results showed that six of the seven supplements caused a 1.5 - 2 fold induction in PXR transcriptional activity in HepG2 cells. PXR regulates the expression of key drug metabolizing enzymes including CYP3A4. Follow up studies indicated a 1.5 - 3 fold induction in CYP3A4 enzyme activity in HepG2 cells treated with these supplements. We further investigated the effects of the supplement on the metabolism of above mentioned anti-viral drugs in HepG2 cells and primary hepatocytes. Of the five drugs, rilpivirine and dolutegravir metabolism was increased by up to 2-folds over the no supplement control by some of the supplements. Our findings indicate that concomitant consumption of these products with anti-HIV drugs may compromise the efficacy of antivirals therapy due to supplement-induced metabolism via induction of CYP3A4 activity.

Physiologically Relevant Concentrations of Dolutegravir, Emtricitabine, and Efavirenz Induce Distinct Metabolic Alterations in HeLa Epithelial and BV2 Microglial Cells.

Microglia, the resident brain phagocytes, likely play a key role in human immunodeficiency virus (HIV) infection of the central nervous system (CNS) and subsequent neuropathogenesis; however, the nature of the infection-induced changes that yield damaging CNS effects and the stimuli that provoke microglial activation remains elusive, especially in the current era of using antiretroviral (ARV) drugs for ARV therapy (ART). Altered microglial metabolism can modulate cellular functionality and pathogenicity in neurological disease. While HIV infection itself alters brain energy metabolism, the effect of ARV drugs, particularly those currently used in treatment, on metabolism is understudied. Dolutegravir (DTG) and emtricitabine (FTC) combination, together with tenofovir (TAF or TDF), is one of the recommended first line treatments for HIV. Despite the relatively good tolerability and safety profile of FTC, a nucleoside reverse transcriptase inhibitor, and DTG, an integrase inhibitor, adverse side effects have been reported and highlight a need to understand off-target effects of these medications. We hypothesized that similar to previous ART regimen drugs, DTG and FTC side effects involve mitochondrial dysfunction. To increase detection of ARV-induced mitochondrial effects, highly glycolytic HeLa epithelial cells were forced to rely on oxidative phosphorylation by substituting galactose for glucose in the growth media. We assessed ATP levels, resazurin oxidation-reduction (REDOX), and mitochondrial membrane potential following 24-hour exposure (to approximate effects of one dose equivalent) to DTG, FTC, and efavirenz (EFV, a known mitotoxic ARV drug). Further, since microglia support productive HIV infection, act as latent HIV cellular reservoirs, and when dysfunctional likely contribute to HIV-associated neurocognitive disorders, the experiments were repeated using BV2 microglial cells. In HeLa cells, FTC decreased mitochondrial REDOX activity, while DTG, similar to EFV, impaired both mitochondrial ATP generation and REDOX activity. In contrast to HeLa cells, DTG increased cellular ATP generation and mitochondrial REDOX activity in BV2 cells. Bioenergetic analysis revealed that DTG, FTC, and EFV elevated BV2 cell mitochondrial respiration. DTG and FTC exposure induced distinct mitochondrial functional changes in HeLa and BV2 cells. These findings suggest cell type-specific metabolic changes may contribute to the toxic side effects of these ARV drugs.

Bone Safety of Dolutegravir-Containing Regimens in People Living with HIV: Results from a Real-World Cohort.

OBJECTIVE: Few data exist about the effect of dolutegravir (DTG) on bone mineral density (BMD) in real life. The aim of this study was to determine rates of change in BMD over time in people living with HIV (PLWH) treated with DTG. DESIGN: The SCOLTA project is a multicenter observational study enrolling HIV-infected people who start newly commercialized drugs prospectively, with the aim of identifying toxicities and adverse events (AE) in a real-life setting. METHODS: Dual-energy X-ray absorptiometry at the femoral neck (FN) and lumbar spine (LS) was performed at study entry (baseline, BL) and after 96 weeks. Percentage BMD change from BL was evaluated using a general linear model, including factors potentially associated with bone loss. RESULTS: One hundred and sixty PLWH were enrolled (26.3% female, mean age 49.9 ± 11.2 years) from April 2015 to April 2017. Overall, we could calculate BMD change from baseline, for at least one site, in 133 subjects (83.1%). After a median of 102 weeks (IQR: 90-110), mean FN BMD increased, but not significantly, whereas LS BMD showed a significant mean increase of 13.1 (95% confidence interval, CI: 1.7-24.6) mg/cm3 (+1.6%, 95% CI: 0.3%, 2.8%) after a median time of 102 weeks (IQR: 84-110). As regards LS BMD, patients with osteopenia/osteoporosis at study entry experienced a high increase from baseline (20.6, 95% CI: 3.1, 38.1 mg/cm3), as well as experienced subjects (16.9, 95% CI: 4.7, 29.2 mg/cm3) and those on vitamin D supplementation (26.8, 95% CI: 7.7, 45.9 mg/cm3). CONCLUSION: Dolutegravir-containing regimens could reduce the negative impact of antiretroviral therapy on bone, especially in patients with low BMD.

Successful use of once-daily high-dose darunavir and dolutegravir in multidrug-resistant HIV.

WHAT IS KNOWN AND OBJECTIVE?: Antiretroviral (ARV) resistance may result during periods of consistently poor adherence. We report the successful use of a novel once-daily (QD) ARV regimen in a patient with multidrug-resistant (MDR) HIV. CASE SUMMARY: Once-daily darunavir 1200 mg/ritonavir 100 mg, dolutegravir and emtricitabine/tenofovir alafenamide was initiated with directly observed therapy. With the assistance of therapeutic drug monitoring, dolutegravir dosing was increased to 150 mg daily. The patient maintained virologic suppression for 18 months. WHAT IS NEW AND CONCLUSIONS?: In this case, QD darunavir/ritonavir achieved similar trough concentrations to twice daily dosing with dolutegravir dose titration necessitated and resulted in HIV virologic control.

Clinical benefit of dolutegravir in HIV-1 management related to the high genetic barrier to drug resistance.

This manuscript reviews the reasons why Integrase inhibitors should now routinely constitute a part of first line antiretroviral therapy for the treatment of HIV disease. The use of these drugs that are generally well tolerated has resulted in far less drug resistance than was the case with most other categories of antiviral compounds. In addition, the integrase inhibitor family of drugs has been less prone to the problem of transmitted drug resistance which is due to a wide variety of substitutions in the HIV genome that can be sexually transmitted from one person to another. However, the use of integrase inhibitors in first line therapy may unfortunately not soon happen in developing country settings where non-nucleoside reverse transcriptase inhibitors continue to be a mainstay of initial therapy, primarily for reasons of cost. As long as this situation continues, problems of drug resistance and transmitted drug resistance will be common in such settings. Current evidence also suggests that the use of dolutegravir as a first line integrase inhibitor may limit development of drug resistance to an extent that exceeds the use of other members of this family of drugs. This may be due to particular patterns of resistance involving dolutegravir, whereby the mutations that are associated with resistance against this compound may actually diminish both HIV replication capacity as well as integrase enzymatic activity in a far-reaching and unique manner. This gives potential hope that the use of dolutegravir in first line therapy could actually form part of the long-sought goal of attainment of a functional cure for HIV disease.

Integrase Strand Transfer Inhibitors (INSTIs) Resistance Mutations in HIV-1 Infected Turkish Patients.

OBJECTIVES: Integrase strand transfer inhibitor (INSTI) is a new class of antiretroviral (ARV) drugs designed to block the action of the integrase viral enzyme, which is responsible for insertation of the HIV-1 genome into the host DNA. The aim of this study was to evaluate for the first time INSTI resistance mutations in Turkish patients. METHODS: This study was conducted in Turkey, between April 2013 and April 2015 using 169 HIV-1-infected patients (78 ARV naive patients and 91 ARV-experienced patients). Laboratory and clinical characteristics of ARV naive and ARV-experienced patients were as follows: gender (M/F): 71/7 and 80/11, median age: 38 and 38.4; median CD4(+) T-cell: 236 and 216 cells/mm(3), median HIV-1 RNA: 4.95+E5 and 1.08E+6 copies/ml. Population-based seqeunces of the reverse transcriptase, protease, and integrase domains of the HIV-1 pol gene were used to detect HIV-1 drug resistance mutations. RESULT: INSTI resistance mutations were not found in recently diagnosed HIV-1-infected patients. However, ARV-experienced patients had major resistance mutations associated with raltegravir and elvitegravir; the following results were generated:F121Y, Y143R, Q148R and E157Q (6/91 - 6.6%). CONCLUSIONS: The prevalence of INSTI resistant mutations in ART-experienced patients suggested that resistance testing must be incorporated as an integral part of HIV management with INSTI therapies.

Evaluation of the impact of multivalent metal ions on the permeation behavior of Dolutegravir sodium.

Interactions between active pharmaceutical ingredients (APIs) and polyvalent cations are an important factor within drug absorption in the gastrointestinal tract. Dolutegravir sodium, as a second-generation integrase stand transfer inhibitor for the treatment of HIV was investigated regarding chelation with Al(3+), Ca(2+), Fe(3+), Mg(2+ )and Zn(2+) ions at three different molar ratios. Furthermore, the influence of drug-ion chelates on the permeability of the drug across two intestinal membrane models was analyzed. For this purpose, Caco-2 monolayer model and Ussing chamber technique utilizing freshly excited rat intestinal mucosa were chosen and a buffer system without additional Mg(2+) and Ca(2+) ions was tested regarding cell detachment. The addition of polyvalent cations in an equal molar ratio to the drug solution decreased the dissolved drug by at least 11%. An increased multivalent cation concentration in a ratio of 1:10 afforded an API drop in the solution of at least 88% with the exception of Mg(2+). In particular, Dolutegravir sodium was chelated with iron ions to nearly 100%. Overall, the higher the amount of metal ions in the solution, the lower was the detected amount of the drug. The permeation experiments across the Caco-2 monolayer and the rat intestinal mucosa pointed out that the addition of AlCl3, CaCl2 and ZnCl2 in a molar ratio of 10:1 to the drug led to significantly decreased drug permeation. According to these results the co-administration of Al(3+), Ca(2+ )or Zn(2+ )as well as of supplementary medications containing these polyvalent ions is in case of oral Dolutegravir delivery not recommended.

Discordant predictions of residual activity could impact dolutegravir prescription upon raltegravir failure.

BACKGROUND: Dolutegravir is approved for the treatment of HIV-1 patients exposed to other integrase inhibitors, but the decision to use dolutegravir in this setting should be informed by drug resistance testing. OBJECTIVES: This study determined the extent of disagreement in predicted residual dolutegravir activity after raltegravir use, and identified individual mutational patterns for which uncertainty exists among HIV-1 expert systems. STUDY DESIGN: Mutation patterns were classified in raltegravir signature pathways including positions 143, 148 and 155, and interpreted into clinically informative resistance levels using genotypic drug resistance interpretation systems ANRS v24, HIVdb v7.0 and Rega v9.1.0, and instructions of dolutegravir use as approved by the Food and Drug Administration and the European Medicines Agency. RESULTS: In 216HIV-1 patients failing raltegravir-therapy, 87% patients displayed mutations associated with resistance towards integrase inhibitors. A total of 141 unique mutational patterns were observed, with N155H (25.4%), Q148H (16.2%) and Y143R (8.3%) the most prevalent signature mutations. The Q148 pathway occurred almost exclusively in HIV-1 subtype B viruses. Concordances in predicted dolutegravir susceptibility scores among 5 systems were obtained in 57.8% of patients, and concordant intermediate resistant and concordant resistant scores were only observed in 6.5% and 0.9% of patients, respectively. However, systems individually scored higher levels of dolutegravir intermediate resistance and resistance, ranging from 4.2% to 10.2% and from 14.8% to 22.7% of patients, respectively. A consensus on interpreting the extent of residual activity was lacking in 34.7% of patients and was highly resistance pathway-specific. CONCLUSIONS: Dolutegravir may potentially be effective in the majority of HIV-1 patients failing raltegravir, but concern over the uncertainty in predicted residual activity could withhold clinicians from prescribing dolutegravir during its clinical assessment.

Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects.

All commercially available integrase inhibitors are 2-metal binders and may be affected by co-administration with metal cations. The purpose of this study was to evaluate the effect of calcium and iron supplements on dolutegravir pharmacokinetics and strategies (dose separation and food) to attenuate the effects if significant reductions in dolutegravir exposure were observed. This was an open-label, crossover study that randomized 24 healthy subjects into 1 of 2 cohorts to receive 4 treatments: (1) dolutegravir alone, fasting; (2) dolutegravir with calcium carbonate or ferrous fumarate, fasting; (3) dolutegravir with calcium carbonate or ferrous fumarate with a moderate-fat meal; (4) dolutegravir administered 2 hours before calcium carbonate or ferrous fumarate, fasting. Plasma dolutegravir AUC(0-∞), Cmax , and C24 were reduced by 39%, 37%, and 39%, respectively, when co-administered with calcium carbonate while fasting and were reduced by 54%, 57%, and 56%, respectively, when co-administered with ferrous fumarate while fasting. Dolutegravir administration 2 hours before calcium or iron supplement administration (fasted), as well as administration with a meal, counteracted the effect. Dolutegravir and calcium or iron supplements can be co-administered if taken with a meal. Under fasted conditions, dolutegravir should be administered 2 hours before or 6 hours after calcium or iron supplements.

Highly multidrug-resistant HIV: clonal analysis and therapeutic strategies.

OBJECTIVES: There are today HIV-infected patients in therapeutic impasses because of highly multidrug-resistant (HMDR) viruses. We studied the distribution of resistance mutations at clonal level, and we analysed the therapeutic strategies used in such cases to achieve undetectable viraemia. METHODS: The HMDR profile was defined as a genotypic sensitivity score (GSS) ≤ 1.5 for etravirine and raltegravir with full resistance to darunavir. About 30 clones per gene and per patient were sequenced. Virtual phenotypes were determined. Efficacy of therapeutic strategies was evaluated by follow-up of viral loads, CD4 cell counts and trough concentrations of drugs. RESULTS: Among 1310 patients on treatment and with genotypic resistance testing, 25 (2%) were resistant to darunavir and 11 (0.8%) had an HMDR profile. Five-hundred clones could be analysed for four of them. HMDR profiles were harboured by the great majority of clones and all resistance mutations were located on the same strains for all genes. Despite this and a regimen with a GSS <2.0 in three patients, they achieved a viraemia <20 copies/mL. These results were obtained using different strategies: high doses of drugs; combination of antiretrovirals with full or intermediate susceptibility, such as tipranavir, etravirine or maraviroc; and use of alternative compounds, such as foscarnet or interferon. CONCLUSION: Patients with HMDR HIV were uncommon, but, in such cases, all resistance mutations were borne on the same majority strains. In this study, tipranavir was the only protease inhibitor with full or intermediate susceptibility. Despite very limited therapeutic options, an undetectable viraemia can be achieved by combining different strategies.