raltegravir-potassium and Acquired-Immunodeficiency-Syndrome

Global antiretroviral therapy has entered a new era. Integrase strand transfer inhibitor (INSTI) has become the first choice in acquired immunodeficiency syndrome (AIDS) treatment. Because INSTI has high antiviral efficacy, rapid virus inhibition, and good tolerance. However, INSTIs may increase the risk of obesity. Each INSTI has its unique impact on weight gain in patients with human immunodeficiency virus (HIV)/AIDS. This study systematically assessed different INSTIs in causing significant weight gain in HIV/AIDS patients by integrating data from relevant literature.. PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), China Science and Technology Journal Database (VIP), and Wanfang databases were searched to find studies on the influence of different INSTIs in weight gain. Data on weight change were extracted, and a network meta-analysis was performed.. Eight studies reported weight changes in HIV/AIDS patients were included. Results of the network meta-analysis showed that the weight gain of HIV/AIDS patients treated with Dolutegravir (DTG) was significantly higher than that of Elvitegravir (EVG) [MD = 1.13, (0.18-2.07)]. The consistency test results showed no overall and local inconsistency, and no significant difference in the results of the direct and indirect comparison was detected (p > 0.05). The rank order of probability was DTG (79.2%) > Bictegravir (BIC) (77.9%) > Raltegravir (RAL) (33.2%) > EVG (9.7%), suggesting that DTG may be the INSTI drug that causes the most significant weight gain in HIV/AIDS patients.. According to the data analysis, among the existing INSTIs, DTG may be the drug that causes the most significant weight gain in HIV/AIDS patients, followed by BIC.

Topics: Acquired Immunodeficiency Syndrome; Body Weight; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Network Meta-Analysis; Raltegravir Potassium

Selection of optimal second-line antiretroviral therapy (ART) has important clinical and programmatic implications. To inform the 2016 revision of the WHO ART guidelines, we assessed the comparative effectiveness and safety of available second-line ART regimens for adults and adolescents in whom first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens have failed.. In this systematic review and network meta-analysis, we searched for randomised controlled trials and prospective and retrospective cohort studies that evaluated outcomes in treatment-experienced adults living with HIV who switched ART regimen after failure of a WHO-recommended first-line NNRTI-based regimen. We searched Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials for reports published from Jan 1, 1996, to Aug 8, 2016, and searched conference abstracts published from Jan 1, 2014, to Aug 8, 2016. Outcomes of interest were viral suppression, mortality, AIDS-defining illnesses or WHO stage 3-4 disease, discontinuations, discontinuations due to adverse events, and serious adverse events. We assessed comparative efficacy and safety in a network meta-analysis, using Bayesian hierarchical models.. We identified 12 papers pertaining to eight studies, including 4778 participants. The network was centred on ritonavir-boosted lopinavir plus two nucleoside or nucleotide reverse transcriptase inhibitors. Ritonavir-boosted lopinavir monotherapy was the only regimen inferior to others. With the lower estimate of the 95% credible interval (CrI) not exceeding the predefined threshold of 15%, evidence at 48 weeks supported the non-inferiority of ritonavir-boosted lopinavir plus raltegravir to regimens including ritonavir-boosted protease inhibitor plus two NRTIs with respect to viral suppression (odds ratio 1·09, 95% CrI 0·88-1·35). Estimated efficacy of ritonavir-boosted darunavir (800 mg once daily) was too imprecise to determine non-inferiority. Overall, regimens did not differ significantly with respect to continuations, AIDS-defining illnesses or WHO stage 3-4 disease, or mortality.. With the exception of ritonavir-boosted lopinavir plus raltegravir, the evidence base is unable to provide strong support to alternative second-line options to ritonavir-boosted protease inhibitor plus two NRTIs, and thus more trials are warranted.. WHO.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Anti-HIV Agents; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Network Meta-Analysis; Prospective Studies; Raltegravir Potassium; Retrospective Studies; Reverse Transcriptase Inhibitors; Ritonavir

HIV, a major cause of morbidity and mortality worldwide has been transformed by antiretroviral (ARV) therapy into a manageable condition. Drug resistance, tolerability and drug interactions remain major concerns when choosing ARV therapy. Raltegravir , the first integrase inhibitor in the armamentarium against HIV, has been shown to be efficacious in both treatment-naïve and treatment-experienced patients when used in combination as part of nucleoside-reverse transcriptase inhibitor-containing regimens. Its key advantages include safety, tolerability and fewer drug interactions but it has some important limitations such as a lower barrier to resistance and a twice-daily dosing schedule. Its role in nucleoside-sparing regimens is under investigation.. PubMed was searched for publications in English from 2004 to September 2013 using the terms 'raltegravir', 'integrase inhibitor' and 'MK-0518'. Relevant publications were reviewed and reference lists were examined for further publications. Conference abstracts from the Conference on Retroviruses and Opportunistic Infections, Interscience Conference on Antimicrobial Agents and Chemotherapy, and International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention for 2013 were also reviewed.. Raltegravir is an important agent for both naïve and experienced HIV patients. Its key features include its tolerability, efficacy and lack of significant drug interactions.

Topics: Acquired Immunodeficiency Syndrome; Clinical Trials as Topic; Drug Interactions; Drug Resistance, Viral; HIV Infections; HIV Integrase Inhibitors; Humans; Pyrrolidinones; Raltegravir Potassium

The adipokines leptin and adiponectin, produced primarily by adipose tissue, have diverse endocrine and immunologic effects, and circulating levels reflect adipocyte lipid content, local inflammation, and tissue composition. We assessed relationships between changes in regional fat depots, leptin and adiponectin levels, and metabolic and inflammatory markers over 96 weeks in the AIDS Clinical Trials Group (ACTG) A5260s metabolic substudy of the A5257 randomized trial of tenofovir disoproxil fumarate/emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir, or raltegravir among treatment-naive persons with human immunodeficiency virus (PWH).. Fat depots were measured using dual-energy absorptiometry and abdominal computed tomographic imaging at treatment initiation and 96 weeks later. Serum leptin and adiponectin, homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hsCRP) were measured at the same timepoints. Multivariable regression models assessed relationships between fat depots, adipokines, HOMA-IR, and hsCRP at week 96.. Two hundred thirty-four participants maintained viral suppression through 96 weeks (90% male, 29% black, median age 36 years). Serum leptin increased over 96 weeks (mean change 22%) while adiponectin did not (mean change 1%), which did not differ by study arm. Greater trunk, limb, and abdominal subcutaneous and visceral fat were associated with higher HOMA-IR and hsCRP at 96 weeks, but serum leptin level was a stronger determinant of these endpoints using a mediation model approach. A similar mediating effect was not observed for adiponectin.. Higher circulating leptin is associated with greater HOMA-IR and hsCRP independent of fat depot size, suggesting that greater adipocyte lipid content may contribute to impaired glucose tolerance and systemic inflammation among PWH starting antiretroviral therapy.

Topics: Acquired Immunodeficiency Syndrome; Adipokines; Adult; Female; HIV Infections; Humans; Insulin Resistance; Male; Raltegravir Potassium; Weight Gain

AIDS Clinical Trials Group study A5334s evaluated the pharmacokinetics of raltegravir before and during combined administration of ombitasvir, paritaprevir/ritonavir, plus dasabuvir (OBV/PTV/r + DSV) and weight-based ribavirin in human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfected adults. The pharmacokinetics of OBV/PTV/r + DSV during raltegravir coadministration were also characterized.. Adults living with HIV/HCV coinfection receiving steady-state raltegravir (400 mg twice daily) with 2 nucleos(t)ide analogues were enrolled. Pharmacokinetics of raltegravir were assessed prior to HCV therapy, and 4 weeks later following initiation of OBV/PTV/r (25/150/100 mg) once daily + DSV (250 mg) twice daily. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were used to compare the following: raltegravir pharmacokinetics with HCV therapy (week 4) vs before HCV therapy (week 0); OBV/PTV/r and DSV pharmacokinetics vs historical healthy controls; raltegravir pharmacokinetics at week 0 vs historical control adults living with HIV.. Eight of 11 participants had decreased raltegravir exposures after initiation of HCV therapy. The GMRs (90% CI) for maximum concentration and area under the concentration-time curve of raltegravir with vs without HCV therapy were 0.68 (0.38-1.19) and 0.82 (0.58-1.17), respectively. Comparing OBV/PTV/r pharmacokinetics in healthy controls, A5334s study participants demonstrated generally lower maximum concentration and area under the concentration-time curve values by 41-82% and 4-73%, respectively. Raltegravir exposures tended to be higher in A5334s study participants compared to adults living with HIV.. The majority of participants' plasma raltegravir exposures were lower after initiation of HCV therapy in coinfected adults; however, confidence intervals were wide.

Topics: 2-Naphthylamine; Acquired Immunodeficiency Syndrome; Adult; Anilides; Antiviral Agents; Coinfection; Cyclopropanes; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; HIV-1; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Raltegravir Potassium; Ritonavir; Sulfonamides; Uracil; Valine

Topics: Acquired Immunodeficiency Syndrome; Atazanavir Sulfate; Darunavir; Drug Administration Schedule; Drug Therapy, Combination; Guideline Adherence; HIV Infections; HIV Protease Inhibitors; Humans; Oligopeptides; Pyridines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides

To compare 48-week changes in body fat distribution and bone mineral density (BMD) between patients switching from a ritonavir-boosted protease inhibitor (PI/r) to raltegravir (RAL) and patients continuing with PI/r.. Substudy of the prospective, randomized, open-label, multicenter SPIRAL study.. Patients were randomized (1 : 1) to continue with the PI/r-based regimen or switch to RAL, maintaining the rest of the treatment unchanged. Dual-energy X-ray absorptiometry and computed tomography scans were performed at baseline and after 48 weeks to measure body fat and bone composition, analyzing intragroup and intergroup differences.. Eighty-six patients were included and 74 patients (39 RAL, 35 PI/r) completed the substudy. Significant increases in median [interquartile range (IQR)] visceral adipose tissue (VAT) [20.7 (-2.4 to 45.6) cm(2), P = 0.002] and total adipose tissue (TAT) [21.4 (-1.3 to 55.4) cm(2), P = 0.013] were seen within the PI/r group. No significant changes in body fat were seen with RAL or between treatment groups. Regarding bone composition, total BMD [0.01 (0 to 0.02) g/cm(2), P = 0.002], total hip BMD [0.01 (0 to 0.03) g/cm(2), P = 0.015] and total hip T score [0.12 (-0.05 to 0.21) SD, P = 0.004] significantly increased with RAL, with no significant changes within the PI/r group. Differences between treatment groups were significant in femoral neck BMD [0.01 (-0.02 to 0.02) g/cm(2), P = 0.032] and T score [0.01 (-0.18 to 0.18) SD, P = 0.016].. Although there were no significant changes in body fat between groups, maintaining a PI/r-based regimen was associated with a significant increase in VAT and TAT. Switching to RAL led to a significant increase in femoral neck BMD when comparing between groups.

Topics: Absorptiometry, Photon; Acquired Immunodeficiency Syndrome; Adipose Tissue; Adult; Anti-HIV Agents; Body Composition; Body Fat Distribution; Bone Density; Female; Femur Neck; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Tomography, X-Ray Computed; Treatment Outcome

A nucleoside reverse transcriptase inhibitor (NRTI) backbone is a recommended component of standard highly active antiretroviral therapy (sHAART). However, long-term NRTI exposure can be limited by toxicities. NRTI class-sparing alternatives are warranted in select patient populations. This is a 48-week single-center, open-label pilot study in which 60 HIV-infected adults with plasma HIV-1 RNA (<50 copies/ml) on sHAART were randomized (2:1) to lopinavir/ritonavir (LPV/r) 400/100 mg BID+raltegravir (RAL) 400 mg BID switch (LPV-r/RAL arm) or to continue on sHAART. The primary endpoint was the proportion of subjects with HIV-RNA<50 copies/ml at week 48. Secondary efficacy and immunologic and safety endpoints were evaluated. Demographics and baseline lipid profile were similar across arms. Mean entry CD4 T cell count was 493 cells/mm(3). At week 48, 92% [95% confidence interval (CI): 83-100%] of the LPV-r/RAL arm and 88% (95% CI: 75-100%) of the sHAART arm had HIV-RNA<50 copies/ml (p=0.70). Lipid profile (mean ± SEM, mg/dl, LPV-r/RAL vs. sHAART) at week 24 was total-cholesterol 194 ± 5 vs. 176 ± 9 (p=0.07), triglycerides 234 ± 30 vs. 133 ± 27 (p=0.003), and LDL-cholesterol 121 ± 6 vs. 110 ± 8 (p=0.27). There were no serious adverse events (AEs) in either arm. Regimen change occurred in three LPV-r/RAL subjects (n=1, due to LPV-r/RAL-related AEs) vs. 0 in sHAART. There were no differences between arms in bone mineral density, total body fat composition, creatinine clearance, or CD4 T cell counts at week 48. In virologically suppressed patients on HAART, switching therapy to the NRTI-sparing LPV-r/RAL combination produced similar sustained virologic suppression and immunologic profile as sHAART. AEs were comparable between arms, but the LPV-r/RAL arm experienced higher triglyceridemia.

Topics: Acquired Immunodeficiency Syndrome; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Protease Inhibitors; HIV-1; Humans; Lipids; Lopinavir; Male; Middle Aged; Pilot Projects; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load

To examine immune restoration in duodenal tissue and correlates of reduction of immune activation in chronic HIV-infected patients randomized to different treatment regimens.. Randomized clinical trial (RCT) comparing raltegravir to a non-nucleoside reverse transcriptase inhibitor-based regimen, both with fixed-dose tenofovir difumerate/emtricitabine.. Antiretroviral therapy (ART)-naive volunteers underwent upper endoscopy for duodenal biopsies before and after 9 months of therapy. Tissue was paraffin-embedded for immunohistochemistry or digested into single-cell suspensions for flow cytometry of lymphocyte subsets and activation phenotype. Plasma-soluble CD14 levels were measured as a surrogate for bacterial translocation.. Sixteen HIV-positive and seven control individuals completed study procedures. Small increases in duodenal lamina propria CD4 T-cell numbers were observed, especially when viewed relative to populations in control volunteers, with no differences between treatment arms. The increase in CD4 T-cell percentage was due largely to declines in CD8 T-cell numbers, which were disproportionately increased compared to peripheral blood and controls. Patients randomized to the raltegravir arm had consistent declines in both sCD14 levels and CD8 T-cell numbers in the duodenal tissue lamina propria.. This first RCT of lymphocyte population restoration in duodenal tissue demonstrates more modest increases in CD4 T-cell numbers during the first 9 months of therapy than when considering CD3/CD4 percentages only. Although reduced after 9 months of ART, disproportional increased CD8 populations persist in duodenal gastrointestinal-associated lymphoid tissue (GALT). Local rather than systemic antigenic stimulation appears to be driving expanded CD8 T lymphocytes in GALT. Factors other than viral-induced CD8 expansion may be contributing to this local immunologic response.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Drug Therapy, Combination; Endoscopy; Female; Gastrointestinal Tract; Humans; Immune Reconstitution Inflammatory Syndrome; Immunohistochemistry; Lymphocyte Activation; Lymphoid Tissue; Male; Nevirapine; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load

The stability of the reservoir of latently infected memory CD4 T-cells may be associated with continuous replenishment from residual HIV-1, not completely eliminated by otherwise successful antiretroviral therapy (ART). Treatment intensification could help to control residual virus and to modify the latent reservoir. The objective of this work is to assess the effect of intensifying therapy with raltegravir on the HIV-1 cell reservoir.. A pilot open-label phase-II clinical trial was performed to analyze ART intensification with raltegravir after 48 weeks in chronically HIV-1-infected patients on stable ART.. We measured the number of latently infected memory CD4 T cells, residual viremia, 2-long terminal repeat circles, CD4/CD8 T-cell activation, lymphocyte subpopulations, gut homing receptor, and bacterial translocation.. A significant decay of HIV-1 latent reservoir was observed after intensification in the nine patients included (P = 0.021). No variation was found in either residual viremia or 2-long terminal repeat circles, whereas CD8 T-cell activation decreased at week 36 (P = 0.028). No differences were found in naive T-cell or effector memory cell counts, and the frequencies of gut homing receptor on activated or effector memory CD8 T cells. Bacterial translocation was stable, with the exception of a late decrease in lipopolysaccharide levels.. In this pilot noncomparative trial, treatment intensification with raltegravir significantly decreased the latent cellular HIV-1 reservoir and CD8 T-cell activation. Despite the limitations inherent to trial design, our results suggest that ART intensification should be considered as an adjuvant strategy to eradicate HIV-1 infection.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Drug Administration Schedule; Female; HIV-1; Humans; Immunocompromised Host; Immunologic Memory; Lymphocyte Activation; Male; Middle Aged; Pilot Projects; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Viral Load; Viremia; Virus Latency

To determine the safety and efficacy of changing enfuvirtide to raltegravir in HIV-1-infected patients with HIV-1 RNA below the level of quantification for at least 6 months on an enfuvirtide-containing antiretroviral regimen.. Prospective, nonrandomized, historical control study.. Patients were recruited from 11 Kaiser Permanente HIV clinics in California. Those patients eligible for inclusion (>or=18 years old, well controlled on antiretroviral medications) had enfuvirtide changed to raltegravir 400 mg, given twice daily orally; all other background antiretrovirals remained unchanged. The primary end point was percentage of patients with HIV-1 RNA below the limit of quantification after 24 weeks of raltegravir therapy. Analyses were by intention to treat.. Fifty-two patients were enrolled in the trial. After 24 weeks of therapy with raltegravir, 49 (94.2%, confidence interval: 1.2% to 15.9%) patients had HIV-1 RNA levels below the limit of quantification. Patients had a median CD4 cell increase of 32 cells per cubic millimeter after 24 weeks of raltegravir therapy. Treatment satisfaction as measured by patient questionnaires improved with the raltegravir-containing regimen. Adverse events were infrequent and generally mild in nature.. In treatment-experienced patients on a stable virologically suppressive enfuvirtide-containing regimen, raltegravir can safely be substituted for enfuvirtide.

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome

The long-term effectiveness of human immunodeficiency virus (HIV) treatments containing integrase inhibitors is unknown.. We use observational data from the Centers for AIDS Research Network of Integrated Clinical Systems and the Centers for Disease Control and Prevention to estimate 4-year risk of AIDS and all-cause mortality among 415 patients starting a raltegravir regimen compared to 2646 starting an efavirenz regimen (both regimens include emtricitabine and tenofovir disoproxil fumarate). We account for confounding and selection bias as well as generalizability by standardization for measured variables, and present both observational intent-to-treat and per-protocol estimates.. At treatment initiation, 12% of patients were female, 36% black, 13% Hispanic; median age was 37 years, CD4 count 321 cells/µL, and viral load 4.5 log10 copies/mL. Two hundred thirty-five patients incurred an AIDS-defining illness or died, and 741 patients left follow-up. After accounting for measured differences, the 4-year risk was similar among those starting both regimens (ie, intent-to treat hazard ratio [HR], 0.96 [95% confidence interval {CI}, .63-1.45]; risk difference, -0.9 [95% CI, -4.5 to 2.7]), as well as among those remaining on regimens (ie, per-protocol HR, 0.95 [95% CI, .59-1.54]; risk difference, -0.5 [95% CI, -3.8 to 2.9]).. Raltegravir and efavirenz-based initial antiretroviral therapy have similar 4-year clinical effects. Vigilance regarding longer-term comparative effectiveness of HIV regimens using observational data is needed because large-scale experimental data are not forthcoming.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cohort Studies; Cyclopropanes; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Raltegravir Potassium; Reverse Transcriptase Inhibitors; RNA, Viral; Tenofovir; United States; Viral Load; Young Adult

Residual HIV viremia, defined by low levels of plasma HIV RNA with enhanced-sensitivity assays, may persist even in the presence of successful antiretroviral therapy, but little is known about its determinants. Our objective was to evaluate the rate and determinants of residual viremia in patients who show stable undetectable plasma HIV-1 RNA with conventional assays. Forty-four multidrug-experienced patients with undetectable levels of HIV RNA for at least 2 years under raltegravir-based regimens were evaluated. An ultrasensitive (2.5 copies/ml) real-time PCR method was used to quantify plasma HIV RNA. After 12 months of salvage treatment, 48.3% of the patients had residual viremia between 2.5 and 37 copies/ml. The proportion of patients with plasma HIV RNA below 2.5 copies/ml decreased from 51.7% at 12 months to 30.8% at 24 months. The presence of residual viremia was not associated with levels of viremia before starting raltegravir. Considering CD4 counts, hepatitis B or C virus (HBV or HCV) coinfection, or other demographic characteristics, for the time interval between HIV diagnosis and initiation of antiretroviral therapy, patients with a longer interval (>1 year) were significant less likely to have RNA levels below 2.5 copies/ml at 12 months compared to patients who started therapy within 1 year of HIV diagnosis (28.6% vs. 73.3%, p=0.027). Half of the patients showing undetectable HIV viremia with conventional assays had low-level viremia with ultrasensitive assays, with no predictive role of viroimmunological status at the start of the regimen. The potential influence of the interval between HIV diagnosis and initiation of treatment should be confirmed in subjects with a known date of seroconversion.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Coinfection; DNA, Viral; Female; HIV Seropositivity; HIV-1; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Viral Load; Viremia

Raltegravir (RAL) is the first licensed antiretroviral integrase inhibitor that may be used both for treatment-naïve human immunodeficiency virus type 1 (HIV-1) patients and for salvage therapy. The Brazilian public free access programme limits its use for salvage therapy, with scarce information regarding RAL resistance from patients failing a RAL-containing salvage regimen. This study evaluated RAL resistance mutations detected by population sequencing in 69 HIV-infected patients with advanced disease failing a RAL-containing regimen in a real-world setting. RAL resistance mutations were identified in 47/69 patients (68%). The most common salvage regimen, used by 56/69 patients (81%), included lamivudine, tenofovir, darunavir/ritonavir and RAL. At failure, major RAL resistance mutations included Q148H/R/K (21/47; 45%), N155H (14/47; 30%), Y143R/H/C (3/47; 6%) and E92Q (1/47; 2%). Most samples with Q148H/R/K also showed G140S/A/C (21/47; 45%). RAL resistance was significantly associated with less than two active drugs in the optimised background therapy regimen at failure [39/39 (100%) vs. 9/17 (53%); P<0.001] and with a longer cumulative duration with detectable viraemia (viral load >50 copies/mL) (86 weeks vs. 32 weeks; P=0.001). A high frequency of RAL mutations was observed in this study. In addition, these results reinforce the importance of close monitoring of RAL-containing regimens to reduce the time of failure and consequent resistance accumulation.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Brazil; Drug Resistance, Viral; Female; HIV; Humans; Male; Middle Aged; Mutation, Missense; Prevalence; Pyrrolidinones; Raltegravir Potassium; Salvage Therapy; Sequence Analysis, DNA; Treatment Failure; Young Adult

Topics: Abdominal Pain; Acquired Immunodeficiency Syndrome; Adenine; AIDS-Related Opportunistic Infections; CD4 Lymphocyte Count; Cholangitis; Deoxycytidine; Emtricitabine; Humans; Jaundice; Male; Organophosphonates; Plasmapheresis; Pyrrolidinones; Raltegravir Potassium; Tenofovir; Treatment Outcome; Viral Load; Young Adult

Integration of HIV DNA into host chromosome requires a 3'-processing (3'-P) and a strand transfer (ST) reactions catalyzed by virus integrase (IN). Raltegravir (RAL), commonly used in AIDS therapy, belongs to the family of IN ST inhibitors (INSTIs) acting on IN-viral DNA complexes (intasomes). However, studies show that RAL fails to bind IN alone, but nothing has been reported on the behaviour of RAL toward free viral DNA. Here, we assessed whether free viral DNA could be a primary target for RAL, assuming that the DNA molecule is a receptor for a huge number of pharmacological agents. Optical spectroscopy, molecular dynamics and free energy calculations, showed that RAL is a tight binder of both processed and unprocessed LTR (long terminal repeat) ends. Complex formation involved mainly van der Waals forces and was enthalpy driven. Dissociation constants (Kds) revealed that RAL affinity for unbound LTRs was stronger than for bound LTRs. Moreover, Kd value for binding of RAL to LTRs and IC50 value (half concentration for inhibition) were in same range, suggesting that RAL binding to DNA and ST inhibition are correlated events. Accommodation of RAL into terminal base-pairs of unprocessed LTR is facilitated by an extensive end fraying that lowers the RAL binding energy barrier. The RAL binding entails a weak damping of fraying and correlatively of 3'-P inhibition. Noteworthy, present calculated RAL structures bound to free viral DNA resemble those found in RAL-intasome crystals, especially concerning the contacts between the fluorobenzyl group and the conserved 5'C(4)pA(3)3' step. We propose that RAL inhibits IN, in binding first unprocessed DNA. Similarly to anticancer drug poisons acting on topoisomerases, its interaction with DNA does not alter the cut, but blocks the subsequent joining reaction. We also speculate that INSTIs having viral DNA rather IN as main target could induce less resistance.

Topics: Acquired Immunodeficiency Syndrome; DNA, Viral; HIV Integrase; HIV Integrase Inhibitors; HIV Long Terminal Repeat; HIV-1; Humans; Pyrrolidinones; Raltegravir Potassium

The antiretroviral agent tenofovir can cause hypophosphatemic osteomalacia due to renal phosphate wasting. The potential role for Fibroblast Growth Factor 23 (FGF23), a phosphaturic hormone is unknown. We evaluated FGF23 plasma concentrations in an HIV-positive patient with neurofibromatosis in whom hypophosphatemia developed during tenofovir therapy. This patient presented with diffuse pain, hypophosphatemia and tubular dysfunction with inadequate phosphate reabsorption. The full recovery after tenofovir discontinuation indicates that the hypophosphatemia was related to tenofovir and not to von Recklinghausen disease. Our data argue against a role for FGF23 in tenofovir-induced hypophosphatemia nor in the regulation of hypophosphatemia in this situation.

Topics: Acquired Immunodeficiency Syndrome; Adenine; Adult; Anti-HIV Agents; Drug Substitution; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hypophosphatemia; Male; Neurofibromatosis 1; Organophosphonates; Osteomalacia; Phosphates; Pyrrolidinones; Raltegravir Potassium; Tenofovir; Treatment Outcome

We studied the penetration of raltegravir and HIV shedding in the genital tract among 14 HIV-1-infected women receiving a raltegravir-containing regimen who had <40 copies/ml blood plasma (BP) HIV RNA. None of the cervicovaginal fluid (CVF) samples showed detectable HIV RNA. Median raltegravir concentrations were 235 ng/ml in BP and 93 ng/ml in CVF, with a CVF/BP ratio of approximately 2.3. This good penetration of raltegravir may contribute to the control of viral replication in the female genital tract.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Cervix Uteri; Female; HIV-1; Humans; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Vagina

Topics: Acquired Immunodeficiency Syndrome; Adult; Antineoplastic Agents; Antiretroviral Therapy, Highly Active; Brain; Central Nervous System Neoplasms; Humans; Lamivudine; Lymphoma, T-Cell; Magnetic Resonance Imaging; Male; Methotrexate; Pyrrolidinones; Raltegravir Potassium; Stavudine; Treatment Outcome

To describe the antiretroviral management of a patient diagnosed simultaneously with HIV/AIDS and diffuse large B-cell lymphoma, focusing on the drug-drug interactions between highly active antiretroviral therapy (HAART) and concomitant cancer chemotherapy.. A 55-year-old white man was recently diagnosed with HIV/AIDS and presented 1 month later with complaints of nausea, vomiting, abdominal pain, double vision, right eye discomfort/swelling, and a 3.6-kg weight loss. An excisional biopsy of a right inguinal lymph node confirmed a new diagnosis of diffuse large B-cell lymphoma. HAART and a chemotherapeutic regimen, including cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) with intrathecal methotrexate, was to be initiated. As the potential for multiple drug-drug interactions existed, raltegravir, abacavir, and lamivudine were chosen for the initial HAART regimen. The patient achieved and maintained an undetectable viral load throughout 6 CHOP cycles.. HAART improves the chemotherapeutic response in patients with HIV and lymphoma. Multiple drug-drug interactions are possible in patients who are to receive CHOP and HAART. Cyclophosphamide and vincristine are metabolized via the CYP3A4 isoenzyme. Protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors both inhibit and induce CYP3A4, with the potential for altered chemotherapeutic and cytotoxic effects. When PIs are combined with CHOP, mortality is reduced, but increased adverse effects are demonstrated. Raltegravir, an integrase inhibitor, is eliminated via glucuronidation and results in minimal drug-drug interactions. Raltegravir improves virologic and immunologic responses in HAART-naïve patients and thus would be a suitable alternative for preventing chemotherapeutic-HAART interactions.. There is limited information published regarding the potential for interactions between HAART and cancer chemotherapy. While further research is necessary, it is important for clinicians to consider the potential for drug-drug interactions when designing a HAART regimen concurrently with chemotherapy.

Topics: Acquired Immunodeficiency Syndrome; Antineoplastic Combined Chemotherapy Protocols; Antiretroviral Therapy, Highly Active; Cyclophosphamide; Doxorubicin; Drug Interactions; HIV Integrase Inhibitors; Humans; Lymphoma, AIDS-Related; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Middle Aged; Prednisone; Pyrrolidinones; Raltegravir Potassium; Vincristine

Four catechins with the galloyl moiety, including catechin gallate (CG), epigallocatechin gallate (EGCG), gallocatechin gallate (GCG), and epicatechin gallate (ECG), were found to inhibit HIV-1 integrase effectively as determined by our ELISA method. In our docking study, it is proposed that when the HIV-1 integrase does not combine with virus DNA, the four catechins may bind to Tyr143 and Gln148, thus altering the flexibility of the loop (Gly140-Gly149), which could lead to an inhibition of HIV-1 integrase activity. In addition, after combining HIV-1 integrase with virus DNA, the four catechins may bind between the integrase and virus DNA, consequently, disrupt this interaction. Thus, the four catechins may reduce the activity of HIV-1 integrase by disrupting its interaction with virus DNA. The four catechins have a highly cooperative inhibitory effect (IC₅₀=0.1 μmol/L). Our study suggests that catechins with the galloyl moiety could be a novel and effective class of HIV-1 integrase inhibitors.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Catechin; DNA, Viral; Enzyme-Linked Immunosorbent Assay; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Pyrrolidinones; Raltegravir Potassium

Topics: Acquired Immunodeficiency Syndrome; Drug Resistance, Multiple; HIV Integrase Inhibitors; HIV-1; Humans; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Salvage Therapy

Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; Anti-HIV Agents; Clinical Trials as Topic; Cyclohexanes; Humans; Maraviroc; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; Triazoles

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Anti-Infective Agents; CCR5 Receptor Antagonists; CD4 Antigens; Clinical Trials as Topic; Humans; Nitriles; Organic Chemicals; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium

Topics: Acquired Immunodeficiency Syndrome; CCR5 Receptor Antagonists; Clinical Trials as Topic; Darunavir; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Organic Chemicals; Pyrimidinones; Pyrrolidinones; Raltegravir Potassium; Receptors, CCR5; Ritonavir; Salvage Therapy; Sulfonamides