Ana González-Cordón

Dual therapy with etravirine plus raltegravir for virologically suppressed HIV-infected patients: a pilot study

BACKGROUND Clinical use of protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) may be hampered by toxicity, interactions or resistance issues. Simple and effective antiretroviral regimens avoiding both drug classes may be needed for selected patients. METHODS This was a prospective cohort study. Virologically suppressed patients on PI or NRTI regimens, with problems of tolerability, safety concerns due to comorbidities or risk of drug interactions for both PIs and NRTIs, were given the opportunity to switch their regimen to etravirine plus raltegravir. Patients were required not to have prior virological failure to raltegravir and if there was prior non-nucleoside reverse transcriptase inhibitor (NNRTI) virological failure, only patients in whom efficacy of etravirine could be anticipated through the Stanford Drug Resistance Database were included. Follow-up was scheduled for at least 48 weeks, unless the patient was lost to follow-up or discontinued therapy. RESULTS Twenty-five patients were included. Their median age was 54 years; they had a median of 16 years on antiretroviral therapy and a median of nine previous regimens; 21 (84%) patients had previous virological failure; and 15 (60%) patients had a genotypic test that showed three or more NRTI mutations in 9 (36%), four or more PI mutations in 11 (44%) and at least one NNRTI mutation in 8 (32%) patients. At 48 weeks efficacy was 84% (95% CI 65.3%-93.6%) by intent-to-treat analysis and 91.3% (95% CI 73.2%-97.6%) by per-protocol analysis. One (4%) patient died, two (8%) discontinued due to intolerance and one (4%) experienced virological failure. The CD4/CD8 ratio and plasma lipids improved. CONCLUSIONS Dual therapy with etravirine plus raltegravir was well tolerated and maintained durable viral suppression in selected virologically suppressed patients for whom both PI and NRTI therapy was challenging.

Early lipid changes with atazanavir/ritonavir or darunavir/ritonavir.

Ritonavir‐boosted atazanavir and darunavir are protease inhibitors that are recommended for initial treatment of HIV infection because each has shown better lipid effects and overall tolerability than ritonavir‐boosted lopinavir. The extent to which lipid effects and overall tolerability differ between treatments with atazanavir and darunavir and whether atazanavir‐induced hyperbilirubinaemia may result in more favourable metabolic effects are issues that remain to be resolved.

Dolutegravir monotherapy in HIV-infected patients with sustained viral suppression

OBJECTIVES We reviewed the 24 week outcomes of HIV-infected patients from our hospital who had their ART switched to dolutegravir monotherapy on an individual clinical basis. METHODS Retrospective hospital database assessment of virally suppressed patients in whom the treating physician had switched to 50 mg of dolutegravir once daily due to one or more of the following reasons: antiretroviral-related adverse effects; comorbidities; risk of interactions; or archived resistance. Patients had ≥24 weeks of follow-up. Population, virological and immunological responses and safety and tolerability are described. RESULTS Thirty-three (22 on PIs, of whom 18 had ritonavir-boosted PI monotherapy) patients were identified: median (IQR) age of 56 (50-62) years, 55% women, median (IQR) of 19 (17-23) years of known HIV infection, 39% prior AIDS events, median (IQR) of 8 (4-13) years with undetectable plasma HIV-1 RNA and median (IQR) CD4 cell count of 596 (420-843) cells/mm(3). Twenty-five (76%) patients had antiretroviral-related adverse effects, 32 (97%) patients had comorbidities, 28 (85%) patients had risk of interactions and 16 (48%) patients had archived resistance. One patient with suboptimal adherence had low-level virological failure through weeks 4-24. HIV RNA genotypic resistance tests detected no integrase mutations at weeks 4 and 24, but 118R was detected in 7% of the integrated HIV DNA at 24 weeks. Patients had significant median decreases in triglycerides (-117 mg/dL), total cholesterol (-36 mg/dL), the total cholesterol/HDL cholesterol ratio (-0.7) and high-sensitivity C-reactive protein (-0.05 mg/dL) (P ≤ 0.007), although the Chronic Kidney Disease Epidemiology Collaboration equation also decreased (-7.1 mL/min) (P < 0.0001). CONCLUSIONS These data suggest the efficacy of dolutegravir monotherapy as a maintenance strategy to be further confirmed in randomized clinical trials.

Differential Body Composition Effects of Protease Inhibitors Recommended for Initial Treatment of HIV Infection: A Randomized Clinical Trial

BACKGROUND It is unclear whether metabolic or body composition effects differ between protease inhibitor-based regimens recommended for initial treatment of human immunodeficiency virus (HIV) infection. METHODS ATADAR is a phase 4, open-label, multicenter, randomized clinical trial. Stable antiretroviral-naive HIV-infected adults were randomly assigned to atazanavir/ritonavir 300/100 mg or darunavir/ritonavir 800/100 mg in combination with tenofovir/emtricitabine daily. Predefined endpoints were treatment or virological failure, drug discontinuation due to adverse effects, and laboratory and body composition changes at 96 weeks. RESULTS At 96 weeks, 56 (62%) atazanavir/ritonavir and 62 (71%) darunavir/ritonavir patients remained free of treatment failure (estimated difference 8.2%; 95% confidence interval [CI], -.6 to 21.6) and 71 (79%) atazanavir/ritonavir and 75 (85%) darunavir/ritonavir patients remained free of virological failure (estimated difference 6.3%; 95% CI, -.5 to 17.6). Seven patients discontinued atazanavir/ritonavir and 5 discontinued darunavir/ritonavir due to adverse effects. Total and high-density lipoprotein cholesterol similarly increased in both arms, but there was a greater increase in triglycerides in the atazanavir/ritonavir arm. At 96 weeks, body fat (estimated difference 2862.2 gr; 95% CI, 726.7 to 4997.7; P = .0090), limb fat (estimated difference 1403.3 gr; 95% CI, 388.4 to 2418.2; P = .0071), and subcutaneous abdominal adipose tissue (estimated difference 28.4 cm(2); 95% CI, 1.9 to 55.0; P = .0362) increased more in the atazanavir/ritonavir arm than in darunavir/ritonavir arm. Body fat changes in the atazanavir/ritonavir arm were associated with higher insulin resistance. CONCLUSIONS We found no major differences between atazanavir/ritonavir and darunavir/ritonavir in efficacy, clinically relevant side effects, or plasma cholesterol fractions. However, atazanavir/ritonavir led to higher triglycerides and more total and subcutaneous fat than darunavir/ritonavir. Also, fat gains with atazanavir/ritonavir were associated with insulin resistance. Clinical Trials Registration. NCT01274780.

Brote epidémico de hepatitis aguda C en pacientes infectados por el virus de la inmunodeficiencia humana

BACKGROUND Recent studies suggest an increased incidence of acute infection with hepatitisC virus (AHC) in men who have sex with men (MSM) co-infected with HIV. Early treatment with interferon-alpha, alone or in combination with ribavirin, significantly reduces the risk of chronic evolution. METHODS This retrospective study includes all HIV patients with AHC in our centre from 2003 to March 2013. AHC was defined by seroconversion of HCV antibodies and detection of serum HCV RNA. RESULTS 93 episodes of AHC were diagnosed in 89 patients. All but three were MSM with a history of unprotected sex. Thirty-seven (40%) patients had other associated sexually transmitted disease. The 29% (27) had any symptoms suggestive of AHC. HCV genotype 4 was the most common (41%), followed by genotype1. Seventy patients started treatment with interferon-alfa and weight-adjusted ribavirin. Currently 46 have completed treatment and follow-up, reaching 26 of them (56.5%) sustained viral response. CONCLUSIONS The incidence of AHC in HIV MSM patients from our centre has increased exponentially in recent years; sexual transmission remains the main route of infection. Early treatment with interferon-alpha and ribavirin achieved a moderate response in these patients.

Tolerability of integrase inhibitors in a real-life setting

Background Integrase inhibitors have shown better tolerability than other drugs in clinical trials, but some post-marketing data have suggested potential differences among them. Aims We compared rates and reasons for discontinuation of raltegravir-, elvitegravir- and dolutegravir-based regimens in a large cohort of HIV-infected patients. Methods Retrospective analysis of a prospectively followed cohort including all antiretroviral-naive and all virologically suppressed antiretroviral-experienced patients prescribed a first regimen containing raltegravir, elvitegravir or dolutegravir with at least one follow-up visit. Major outcomes were early discontinuation (≤1 year) due to any reason and more specifically due to toxicity. Incidence was calculated as number of episodes per 1000 person-years. Risk factors for discontinuation were assessed by multivariate Cox models. Results Early discontinuations due to any reason were 271 (raltegravir), 168 (elvitegravir) and 264 (dolutegravir) per 1000 patient-years ( P  =   0.0821). Early discontinuations due to toxicity were 76 (raltegravir), 103 (elvitegravir) and 81 (dolutegravir) per 1000 patient-years ( P  =   0.6792). Overall, the most common toxicities leading to discontinuation were neuropsychiatric, osteomuscular or digestive. Most frequent neuropsychiatric manifestations reported at discontinuation were insomnia, dizziness, headache and anxiety irrespective of the integrase inhibitor. Among discontinuations due to toxicity, neuropsychiatric effects were more common with dolutegravir than with raltegravir or elvitegravir ( P  =   0.0046). Age (HR 1.04, 95% CI 1.02-1.07, P  =   0.0007) was the only independent risk factor for early discontinuation due to toxicity. Conclusions Discontinuations due to any reason tended to be less common with elvitegravir, but discontinuations due to toxicity did not differ among integrase inhibitors. Neuropsychiatric toxicity leading to drug discontinuation was more frequent with dolutegravir.

Atherogenic properties of lipoproteins in HIV patients starting atazanavir/ritonavir or darunavir/ritonavir: a substudy of the ATADAR randomized study

OBJECTIVES To assess LDL subfraction phenotype and lipoprotein-associated phospholipase A2 (Lp-PLA2) in naive HIV-infected patients starting atazanavir/ritonavir or darunavir/ritonavir plus tenofovir/emtricitabine. METHODS This was a substudy of a multicentre randomized study. Standard lipid parameters, LDL subfraction phenotype (by gradient gel electrophoresis) and Lp-PLA2 activity (by 2-thio-PAF) were measured at baseline and weeks 24 and 48. Multivariate regression analysis was performed. Results are expressed as the median (IQR). RESULTS Eighty-six (atazanavir/ritonavir, n=45; darunavir/ritonavir, n=41) patients were included: age 36 (31-41) years; 89% men; CD4 319 (183-425) cells/mm(3); and Framingham score 1% (0%-2%). No differences in demographics or lipid measurements were found at baseline. At week 48, a mild but significant increase in total cholesterol and HDL-cholesterol was observed in both arms, whereas LDL cholesterol increased only in the darunavir/ritonavir arm and triglycerides only in the atazanavir/ritonavir arm. The apolipoprotein A-I/apolipoprotein B ratio increased only in the atazanavir/ritonavir arm. At week 48, the LDL subfraction phenotype improved in the darunavir/ritonavir arm (increase in LDL particle size and in large LDL particles), whereas it worsened in the atazanavir/ritonavir arm (increase in small and dense LDL particles, shift to a greater prevalence of phenotype B); the worsening was related to the greater increase in triglycerides in the atazanavir/ritonavir arm. No changes in total Lp-PLA2 activity or relative distribution in LDL or HDL particles were found at week 48 in either arm. CONCLUSIONS In contrast with what occurred in the atazanavir/ritonavir arm, the LDL subfraction phenotype improved with darunavir/ritonavir at week 48. This difference was associated with a lower impact on plasma triglycerides with darunavir/ritonavir.

Protease inhibitor monotherapy is associated with a higher level of monocyte activation, bacterial translocation and inflammation

Monotherapy with protease‐inhibitors (MPI) may be an alternative to cART for HIV treatment. We assessed the impact of this strategy on immune activation, bacterial translocation and inflammation.

A randomized clinical trial comparing ritonavir-boosted lopinavir versus maraviroc each with tenofovir plus emtricitabine for post-exposure prophylaxis for HIV infection

OBJECTIVES The objective of this study was to assess post-exposure prophylaxis (PEP) non-completion at day 28, comparing ritonavir-boosted lopinavir versus maraviroc, both with tenofovir disoproxil/emtricitabine as the backbone. METHODS We conducted a prospective, open, randomized clinical trial. Individuals attending the emergency room because of potential sexual exposure to HIV and who met criteria for receiving PEP were randomized to one of two groups: tenofovir disoproxil/emtricitabine (245/200 mg) once daily plus either ritonavir-boosted lopinavir (400/100 mg) or maraviroc (300 mg) twice daily. Five follow-up visits were scheduled for days 1, 10, 28, 90 and 180. The primary endpoint was PEP non-completion at day 28. Secondary endpoints were adherence, adverse events and rate of seroconversions. This study was registered in ClinicalTrials.gov: NCT01533272. RESULTS One-hundred-and-seventeen individuals were randomized to receive ritonavir-boosted lopinavir and 120 to maraviroc (n = 237). PEP non-completion at day 28 was 38% (n = 89), with significant differences between arms [ritonavir-boosted lopinavir 44% (n = 51) versus maraviroc 32% (n = 38), P = 0.05]. We performed a modified ITT analysis including only those patients who attended on day 1 (n = 182). PEP non-completion in this subgroup was also significantly higher in the ritonavir-boosted lopinavir arm (27% versus 13%, P = 0.004). The proportion of patients with low adherence was similar between arms (52% versus 47%, P = 0.56). Adverse events were reported by 111 patients and were significantly more common in the ritonavir-boosted lopinavir arm (72% versus 51%, P = 0.003). No seroconversions were observed during the study. CONCLUSIONS PEP non-completion and adverse events were both significantly higher in patients allocated to ritonavir-boosted lopinavir. These data suggest that maraviroc is a well-tolerated antiretroviral that can be used in this setting.

Impact of prior virological failure and nucleos(t)ide genotypic resistance mutations on the efficacy of switching from ritonavir-boosted protease inhibitors to raltegravir.

BACKGROUND The virological efficacy of switching from a ritonavir-boosted protease inhibitor (PI/r)- to a raltegravir (RAL)-containing regimen remains controversial according to the results of SWITCHMRK and SPIRAL studies. The aim of this analysis is to assess the impact of prior resistance mutations to nucleos(t)ides and other potential factors on the virological outcome. METHODS This was a substudy of the prospective, open-label, multicentre SPIRAL study. Demographic, virological variables, prior episodes of virological failures (VF) and archived resistance mutations to nucleos(t)ides were identified from databases and its impact measured by genotypic sensitive scores (GSS) according to the genotypic resistance interpretation algorithm from the Stanford HIV Drug Resistance Database on outcome was analysed. RESULTS Of 250 patients (128 RAL and 122 PI/r) included in the main SPIRAL study, 74 (30%) had previous VF with prior genotypic resistance tests (GRT). Median time of virological suppression prior to inclusion in SPIRAL study was 63.5 months. GSS for backbone nucleos(t)ides was <1 in 15/38 (39%) in the RAL arm and in 9/36 (25%) in the PI/r arm (P=0.13). Among those with nucleos(t)ides GSS <1, 0/15 (0%) in the RAL versus 2/9 (22%) in the PI/r arm developed VF (P=0.13). Moreover 0/11 subjects with null or residual (GSS≤0.5) backbone activity developed VF in the RAL arm. CONCLUSIONS The 48-week virological efficacy of switching from a PI/r to RAL in subjects with long-term virological suppression was not compromised by a reduction of the nucleos(t)ide backbone activity.