Prevalence, beliefs and impact of drug-drug interactions between antiretroviral therapy and illicit drugs among people living with HIV in Spain.

Drug use implies important challenges related to HIV management, particularly due to an increased risk of potential interactions between antiretroviral therapy (ART) and illicit drugs (pDDIs). This study analyses the prevalence and severity of pDDIs among people living with HIV (PLHIV). It also explores their awareness of pDDIs and their beliefs about the toxicity that they may cause, as well as the impact of pDDIs on selected health variables. We conducted an on-line cross-sectional survey across 33 Spanish hospitals and NGOs to collect demographics and clinical data. pDDIs were checked against the Interaction Checker developed by Liverpool University. The sample of the present study was composed of 694 PLHIV who used illicit drugs. They represented 49.5% of the 1,401 PLHIV that participated in the survey. After excluding 38 participants due to lack of information on their ART or illicit drug use, 335 (51.1%) participants consuming drugs presented with some potentially significant pDDIs between their ART and illicit drugs, with a mean of 2.1±1.7 (1-10) pDDIs per patient. The drugs most frequently involved in pDDIs were cocaine, cannabis, MDMA and nitrates ("poppers"). The prevalence of pDDIs across ART regimens was: protease inhibitors (41.7%); integrase inhibitor-boosted regimens (32.1%), and non-nucleoside reverse transcriptase inhibitors (26.3%). An awareness of pDDIs and beliefs about their potential toxicity correlated positively with intentional non-adherence (p<0.0001). Participants with pDDIs exhibited a higher prevalence of intentional non-adherence (2.19±1.04 vs. 1.93±0.94; p = 0.001). The presence of pDDIs was not associated with poorer results in the clinical variables analysed. A significant proportion of PLHIV who use drugs experience pDDIs, thereby requiring close monitoring. pDDIs should be considered in the clinical management of HIV patients. Adequate information about pDDIs and indicators about how to manage ART when PLHIV use drugs could improve ART non-adherence.

Dolutegravir and pregnancy outcomes in women on antiretroviral therapy in Brazil: a retrospective national cohort study.

BACKGROUND: Dolutegravir has been widely available in Brazil since 2017. Following the signal that infants born to women with dolutegravir exposure at conception in Botswana had a higher risk of neural tube defects (NTDs), public health leaders initiated a national investigation to evaluate periconception dolutegravir exposure among all pregnant Brazilian women with HIV and its potential association with risk of NTDs, stillbirth, or miscarriage before 22 weeks (also called spontaneous abortion). METHODS: In this retrospective, observational, national, cohort study, we identified all women with pregnancies and possible dolutegravir exposure within 8 weeks of estimated date of conception between Jan 1, 2017, and May 31, 2018, and approximately 3:1 matched pregnant women exposed to efavirenz between Jan 1, 2015, and May 31, 2018, using the Brazilian antiretroviral therapy database. We did detailed chart reviews for identified women. The primary outcomes were NTD and a composite measure of NTD, stillbirth, or miscarriage. NTD incidences were calculated with 95% CI. The composite outcome was examined with logistic regression using propensity score matching weights to balance confounders. FINDINGS: Of 1427 included women, 382 were exposed to dolutegravir within 8 weeks of estimated date of conception. During pregnancy, 183 (48%) of 382 dolutegravir-exposed and 465 (44%) of 1045 efavirenz-exposed women received folic acid supplementation. There were 1452 birth outcomes. There were no NTDs in either dolutegravir-exposed (0, 95% CI 0-0·0010) or efavirenz-exposed groups (0, 95% CI 0-0·0036). There were 23 (6%) stillbirths or miscarriages in 384 dolutegravir-exposed fetuses and 28 (3%) in the 1068 efavirenz-exposed fetuses (p=0·0037). Logistic regression models did not consistently indicate an association between dolutegravir exposure and risk of stillbirths or miscarriages. After study closure, two confirmed NTD outcomes in fetuses with periconception dolutegravir exposure were reported to public health officials. An updated estimate of NTD incidence incorporating these cases and the estimated number of additional dolutegravir-exposed pregnancies between Jan 1, 2015 and Feb 28, 2019, is 0·0018 (95% CI 0·0005-0·0067). INTERPRETATION: Neither dolutegravir nor efavirenz exposure was associated with NTDs in our national cohort; incidence of NTDs is probably well under 1% in dolutegravir-exposed HIV-positive women but still slightly above HIV-uninfected women (0·06%) in Brazil. FUNDING: The Brazilian Ministry of Health and the United States' National Institutes of Health.

A two-week regimen of high-dose integrase inhibitors does not cause nephrotoxicity in mice.

BACKGROUND: The integrase inhibitors, raltegravir and dolutegravir, are nucleoside reverse transcriptase inhibitor-sparing agents which may be used as part of first-line antiretroviral therapy for HIV. These drugs inhibit creatinine secretion through organic cation transporters, thus elevating serum creatinine without affecting glomerular filtration. We sought to determine whether subtle signs of nephrotoxicity could be observed in mice administered a two-week regimen of high-dose integrase inhibitors. METHODS: C57BL/6 mice were fed standard water (CTRL, n = 6), raltegravir-containing water (40 mg/kg/day, n = 6), or dolutegravir-containing water (2.7 mg/kg/day, n = 6) for two weeks and sacrificed. Endpoints were assessed including urine microalbumin, kidney injury molecule-1 renal tissue gene expression, renal histopathology, serum creatinine, and blood urea nitrogen. RESULTS: The results are NOT consistent with a direct nephrotoxic effect of the integrase inhibitors in mice. Serum creatinine was significantly elevated in raltegravir and dolutegravir mice (p < 0.05) compared to control (raltegravir = 0.25 mg/dl, dolutegravir = 0.30 mg/dl versus CTRL = 0.17 mg/dl). Blood urea nitrogen, cystatin C, and urine microalbumin were unchanged. Kidney injury molecule-1 tissue expression in raltegravir and dolutegravir groups was nonsignificantly elevated compared to control (1.2-fold compared to control). Renal histopathology by periodic acid-Schiff staining failed to reveal glomerular or tubular renal injury in any group. CONCLUSION: These studies are consistent with integrase inhibitors competitively inhibiting creatinine secretion. While no evidence of direct nephrotoxicity was observed after two weeks of high-dose drug administration, additional studies may be performed to understand whether these drugs lead to chronic nephropathy.

Elevated liver enzymes resulting from an interaction between Raltegravir and Panax ginseng: a case report and brief review.

BACKGROUND: In the last decade, some evidence has arisen supporting the usefulness of Asian ginseng (Panax ginseng, fam. Araliaceae) as a complementary remedy in patients receiving antiretroviral therapy. However, its role in current therapeutics remains unclear. METHODS: The patient was admitted for an acute elevation of liver enzymes, marked jaundice, and significant weight loss after taking ginseng-based tablets starting approximately 39 days prior. His past medical history (PMH) was also significant for HIV+, long-term hepatitis C, an episode of mitochondrial toxicity, and several comorbidities. His outpatient medications included raltegravir 400 mg plus lopinavir/ritonavir 400/100 mg twice daily, aspirin 100 mg daily, and esomeprazole 40 mg daily as needed. RESULTS: The cessation of the ginseng lozenges led to a progressive improvement in the performance status and laboratory values. Both the Hansten and Horn nomogram and the Roussel Uclaf Causality Assessment Method indicated that the association between the ginseng medicine and the liver injury was probable (six points). CONCLUSIONS: We suggest that ginseng is involved in the episode through an interaction resulting in elevated plasma concentrations of raltegravir. As a consequence, clinicians should be alert when managing patients on other CYP3A4-metabolized drugs or previous liver-damaging conditions. However, larger studies are required to explicitly clarify these statements.

Cost-effectiveness of raltegravir in HIV/AIDS.

Raltegravir is a first-in-class HIV-1 integrase inhibitor with established antiviral efficacy in treatment-naive and treatment-experienced patients with multidrug-resistant HIV-1 infection. In this article, we summarize pharmacoeconomic evaluations of raltegravir-based treatment regimens, compared with alternative therapies, in the treatment of patients with HIV infection and/or AIDS. Cost-effectiveness evaluations of raltegravir in treatment-experienced patients conducted using a continuous-time, state-transition Markov cohort model suggest that raltegravir, combined with optimized background therapy, falls within the range that would generally be considered cost effective compared with optimized therapy alone in Spanish, Swiss and UK health systems. In treatment-naive populations, raltegravir was evaluated using a three-stage continuous-time state-transition cohort model. Raltegravir-based initiation treatment strategies (first-line raltegravir) were compared with protease inhibitor and non-nucleoside reverse-transcriptase inhibitor initiation strategies, in which raltegravir was retained for salvage therapy. First-line raltegravir was cost-effective versus retaining raltegravir for salvage therapy in several European populations. A separate economic model was used to evaluate first-line raltegravir against two alternative initiation regimens representing standard clinical practice in Australia; raltegravir proved to be cost effective in both scenarios. In all studies examined, results were sensitive to factors including treatment duration, mortality rate, analytic time horizon, health utility weights, cost of raltegravir and optimized therapy, incidence of opportunistic infection and discount rates. Nonetheless, raltegravir remained cost effective under most scenarios.

Efficacy and safety of raltegravir in treatment-experienced HIV-1-infected patients switching from enfuvirtide-based regimens: 48 week results of the randomized EASIER ANRS 138 trial.

OBJECTIVES: To assess the sustainable efficacy and safety of a switch from enfuvirtide to raltegravir in patients with multidrug-resistant HIV infection. METHODS: One hundred and seventy patients with multidrug-resistant HIV infection and suppressed plasma HIV RNA levels < 400 copies/mL under an enfuvirtide-based regimen were randomized to maintain their regimen or to switch to a raltegravir-based regimen (immediate group) in a 48 week prospective, randomized, open-label trial. At week 24, patients in the maintenance arm also switched to raltegravir (deferred group). Baseline genotypic susceptibility scores (GSSs) were calculated using available historical resistance tests. Efficacy was assessed by the cumulative proportion of patients with virological failure, defined as a confirmed plasma HIV RNA ≥ 400 copies/mL up to week 48. The EASIER ANRS 138 trial is registered at ClinicalTrials.gov (NCT00454337). RESULTS: At baseline, 86% of patients had plasma HIV RNA levels <50 copies/mL and 86% had a GSS ≥ 1. Through to week 48, in the on-treatment analysis, only one patient in the immediate group, with a GSS of 0, developed virological failure. At week 48, 90% of patients in both the immediate and deferred groups had plasma HIV-1 RNA levels <50 copies/mL. Median CD4 cell counts remained stable during follow-up. Of note, 12 of 66 (18.2%) patients receiving a regimen combining raltegravir and ritonavir-boosted tipranavir experienced alanine aminotransferase elevations, which led to a switch from tipranavir to darunavir in 8 cases, without discontinuation of raltegravir. CONCLUSIONS: In well-suppressed patients with multidrug-resistant HIV infection, a switch from enfuvirtide to raltegravir is generally well tolerated and has sustained antiviral efficacy when combined with a potent background regimen.

Raltegravir: in treatment-naive patients with HIV-1 infection.

Raltegravir, a first-in-class, oral HIV type-1 (HIV-1) integrase inhibitor, blocks the covalent integration of HIV-1 complementary DNA into the host genome. In a large, randomized, double-blind, multinational, ongoing trial in treatment-naive patients with HIV-1 infection, raltegravir 400 mg twice daily was noninferior to efavirenz 600 mg once daily in achieving plasma HIV-1 RNA viral levels of <50 copies/mL after 48 weeks' treatment (primary endpoint), when used as part of an antiretroviral therapy (ART) combination regimen. The time to achieve a virological response was significantly shorter in the raltegravir group than in the efavirenz group. Furthermore, significantly more raltegravir than efavirenz recipients achieved HIV-1 RNA viral levels of <50 copies/mL at weeks 2-16. The efficacy of raltegravir in achieving HIV-1 RNA levels of <50 copies/mL was also demonstrated in subgroups of patients separated according to baseline viral levels, CD4+ cell counts and viral subtypes. Preliminary evidence suggests that both virological and CD4+ cell count improvements were maintained at 96 weeks for treatment-naive recipients of raltegravir 400 mg twice daily. As part of an ART combination regimen, raltegravir treatment was generally well tolerated and was associated with significantly fewer drug-related adverse events than efavirenz treatment. Moreover, after 96 weeks, raltegravir treatment was associated with a significantly lower impact on serum lipid levels than efavirenz treatment.

Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir.

Raltegravir is a recently, Food and Drug Administration-approved, small-molecule drug that inhibits retroviral integrase, thereby preventing HIV DNA from inserting itself into the human genome. We report here that the activity profile of raltegravir on the replication of murine leukemia virus is similar to that for HIV, and that the drug specifically affects autoimmune disease in mice, in which endogenous retroelements are suspected to play a role. While NZW and BALB/c mice, which do not succumb to autoimmune disease, are not affected by raltegravir, lupus-prone (NZBxNZW) F(1) mice die of glomerulonephritis more than a month earlier than untreated mice. Raltegravir-treated NZB mice, which share the H-2 haplotype with BALB/c mice, but which are predisposed to autoimmune hemolytic anemia, develop auto-antibodies to their red blood cells >3 months earlier than untreated mice of the same strain. Because nonautoimmune mice are not affected by raltegravir, we consider off-target effects unlikely and attribute the exacerbation of autoimmunity to the inhibition of retroviral integrase.

Raltegravir: a review of its use in the management of HIV infection in treatment-experienced patients.

Raltegravir (Isentress), an integrase inhibitor, inhibits the insertion of HIV-1 complementary DNA into the host genome. It is indicated in combination with other antiretroviral therapy (ART) agents for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple ART agents. It is the first of a new class of ART agents to be approved that, as a result of a different mechanism of action to other ART agents, has good activity against multidrug-resistant HIV-1 strains. In clinical trials in treatment-experienced patients with HIV-1 infection and evidence of viral replication, the addition of oral raltegravir to an optimized background therapy (OBT) regimen improved virological and immunological responses at 16 and 48 weeks to a greater extent than placebo plus OBT. Raltegravir therapy was generally well tolerated, with a similar incidence of mild to moderate adverse events in the treatment and placebo arms. The introduction of integrase inhibitors extends the options available for managing treatment-experienced patients with multiple-drug-resistant HIV-1 infection. Results to date suggest that the combination of raltegravir and OBT will be a valuable treatment option for this difficult-to-treat patient group.

Raltegravir, an HIV-1 integrase inhibitor for HIV infection.

Merck & Co has developed and launched raltegravir, an HIV-1 integrase inhibitor for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. This drug is the lead from a series of integrase strand transfer inhibitors and, by April 2008, it had been launched in Canada, the US, the UK, France, Germany and Spain, and had been filed for approval in Japan.

[Efficacy of raltegravir: from healthy volunteers to phase III trials]. / Eficacia del raltegravir: desde los voluntarios sanos a la fase III.

Raltegravir is the first in a new class of antiretroviral treatments called integrase inhibitors, which work by preventing HIV from inserting its genetic material into the DNA of the human chromosome. Phase I-III studies have shown this drug to have potent antiretroviral action, which is more rapid than that of protease inhibitors. The dose selected in efficacy studies is 400 mg every 12 h. However, due to the favorable pharmacokinetic profile of raltegravir, the possibility of administration of 600 to 800 mg once daily is under study. Given that this drug is not metabolized by the cytochrome P450 system, the potential for pharmacological interactions is low. Moreover, because humans lack a cellular homologue for HIV integrase, raltegravir has a low potential for toxicity. Raltegravir has an intermediate genetic barrier and consequently there may be cross-resistance across the integrase inhibitor class. For all these reasons, raltegravir is an attractive option in treatment-naive and pretreated patients and in those receiving simplification regimens.

[Secondary effects associated with raltegravir]. / Efectos secundarios asociados al raltegravir.

Integrase inhibitors are a new therapeutic modality against HIV. Raltegravir is the first integrase inhibitor to have been approved by the health authorities for human use. This drug acts by inhibiting the HIV enzyme that catalyzes integration of the virus inside the genome of the host cell. In the host cell, there is no homologue to viral integrase and consequently the potential toxicity of this drug is probably low. The results of safety studies in animal models have shown that the recommended dose in humans is lower than the dose below which no secondary effects are observed. Studies of genotoxicity and carcinogenicity, as well as of fertility and embryo development, have been negative to date. During clinical trials, raltegravir has been shown to have a very good safety profile, with few adverse effects, which were mild-to-moderate and similar to those of the comparator. The most notable were diarrhea, nausea and headache. The lipid profile of raltegravir was better than that of efavirenz. In view of the above, the risk-benefit ratio for raltegravir is positive.

Raltegravir (MK-0518): an integrase inhibitor for the treatment of HIV-1.

In the developed world, access to highly active antiretroviral therapy (HAART) has led to significant reductions in the morbidity and mortality attributed to HIV/AIDS. However, the continual emergence of HIV-1 strains resistant to currently available classes of antiretrovirals highlights the need to develop agents with novel mechanisms of action. Successful completion of the HIV-1 viral life cycle depends in part on the integration of complementary DNA mediated by the enzyme HIV-1 integrase, one of three essential enzymes encoded in the viral genome. The integrase inhibitors have demonstrated the ability to act specifically at the strand transfer step during integration, making HIV-1 integrase a valid and attractive chemotherapeutic target for the treatment of HIV/AIDS. In clinical trials, raltegravir has been shown to be a potent drug with a pharmacokinetic profile that supports a twice-daily dosing schedule. In addition, it has demonstrated a favorable side-effect profile in treatment-naive and -experienced patients and a subset of heavy treatment-experienced patients have been able a achieve virologic suppression with raltegravir as part of combination therapy despite limited treatment options. In October 2007, raltegravir was approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV-1 as part of combination antiretroviral therapy in treatment-experienced patients-providing an additional option for the management of the HIV-1 infected individual.