Integrase inhibitors have shown better tolerability than other drugs in clinical trials, but some post-marketing data have suggested potential differences among them.
We compared rates and reasons ...for discontinuation of raltegravir-, elvitegravir- and dolutegravir-based regimens in a large cohort of HIV-infected patients.
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.
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.
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.
OBJECTIVE:To evaluate the cardiac structure and function of the fetuses of pregnant women with HIV infection on combined antiretroviral treatment (cART) and the HIV-related and nonrelated ...determinants of abnormal findings.
DESIGN:A prospective cohort study including 42-noninfected fetuses from HIV pregnant women on cART and 84 fetuses from non-HIV-infected women.
METHODS:Fetal echocardiography was performed at 26–32 weeks of pregnancy to assess cardiac structure and function. The impact of maternal and perinatal factors on fetal cardiac remodelling was evaluated by multivariate regression analysis.
RESULTS:Fetuses from HIV pregnant women on cART presented larger hearts and pericardial effusion together with thicker myocardial septal walls (mean 3.56 mm (SD 0.88) vs non-HIV mean 2.75 mm (SD 0.77); P = 0.002) and smaller left ventricular cavities (10.81 mm (SD 2.28) vs 12.3 mm (SD 2.54); P = 0.033). Fetuses from HIV women also presented signs of systolic (mitral systolic annular peak velocity 5.85 cm/s (SD 0.77) vs non-HIV 6.25 cm/s (SD 0.97); P = 0.007) and diastolic (isovolumic relaxation time 52 ms (SD 8.91) vs non-HIV 45 ms (SD 7.98); P < 0.001) dysfunction. In the multivariate analysis, maternal treatment with zidovudine was the only factor significantly associated with fetal cardiac changes (P = 0.014).
CONCLUSION:Fetuses from HIV-infected mothers on cART have cardiac remodelling and dysfunction, which might explain the cardiovascular changes described in childhood. Fetal cardiac remodelling was essentially associated with maternal treatment with zidovudine which challenges its use during pregnancy.
Current therapies for chronic hepatitis C virus (HCV) in HIV co-infected patients have a low success rate and are poorly tolerated. We have evaluated the efficacy and safety of interferon alfa-2b ...(IFN) + ribavirin (RBV) versus pegylated interferon alfa-2b (PEG-INF) + RBV.
Randomized, single-centre, open-label clinical trial including patients with: detectable HCV-RNA, alanine aminotransferase > 1.5-fold upper limit of normal, abnormal liver histology, CD4 cell count > 250 x 10/l and HIV RNA < 10 000 copies/ml. Patients were assigned to INF (3 x 10 units three times/week) or PEG-IFN (100-150 microg/week) plus RBV (800-1200 mg/day). Duration of treatment was 48 weeks (only 24 weeks for HCV genotypes 2 or 3 and baseline HCV RNA < 800 000 IU/ml). The primary endpoint was a sustained virological response (SVR).
Ninety-five patients were randomized (43 INF + RBV, 52 PEG-INF + RBV), 68% males, 82% injecting drug users; 63% genotypes 1 or 4 and 36% genotypes 2 or 3; 62% fibrosis index grade >/=2 and 30% bridging fibrosis/cirrhosis. SVR was significantly higher in the PEG-INF + RBV arm, 44% versus 21% (intent to treat; P = 0.017). Among patients with genotypes 1 or 4, SVR were 38% versus 7% (P = 0.007) and 53% versus 47% (P = 0.730) for genotypes 2 or 3. CD4 cell count but not its percentage dropped in both arms and HIV RNA viral load did not change from baseline. Side effects were very frequent in both arms leading to treatment discontinuation in 14 patients without statistical differences between arms (P = 0.565).
PEG-INF + RBV was significantly more effective than INF + RBV for the treatment of chronic hepatitis C in HIV co-infected patients, mainly of genotype 1 or 4.
Few randomized clinical trials have investigated antiretroviral regimens in very advanced HIV-1-infected patients. The objective was to study the immune reconstitution in very immunosuppressed ...antiretroviral-naive, HIV-1-infected individuals by comparing an efavirenz-based regimen with 2 ritonavir-boosted protease inhibitor regimens.
Randomized, controlled, open-label, multicenter clinical trial. Eighty-nine HIV-1-infected antiretroviral-naive patients with <100 CD4 cells per cubic millimeter were randomly assigned in a 1:1:1 ratio to efavirenz (n = 29), atazanavir/ritonavir (n = 30), or lopinavir/ritonavir (n = 30) combined with tenofovir plus emtricitabine. The primary outcome was median increase in CD4 cell count at week 48. Secondary end points were the proportion of patients with HIV-1 RNA <50 copies per milliliter, adverse events, disease progression, and death.
In the on-treatment analysis, the median (interquartile range) increase in the CD4 count after 48 weeks was +193 (129-349) cells per microliter in the efavirenz arm, +197 (146-238) cells per microliter in the ritonavir-boosted atazanavir arm, and +205 (178-327) cells per microliter in the ritonavir-boosted lopinavir arm (P = 0.73). The percentage of patients achieving viral suppression was similar in all 3 treatment arms at 48 weeks {efavirenz, 85.71% 95% confidence interval (CI): 68.5 to 94.3; atazanavir, 80% 95% CI: 62.7 to 90.5; and lopinavir, 82.8% 95% CI: 65.5 to 92.4; P = 0.88}. Bacterial translocation, inflammation, immune activation, and apoptotic markers, but not D-dimer, declined significantly and similarly in the 3 treatment arms. Adverse events had a similar incidence in all 3 antiretroviral regimens. No patients died.
The immune reconstitution induced by an efavirenz-based regimen in very advanced HIV-1-infected patients was similar to that induced by a ritonavir-boosted protease inhibitor-based regimen (ClinicalTrials.gov registration number: NCT00532168).
To assess the effects of initiating abacavir-containing therapy on plasma lipids and cardiovascular biomarkers.
Sub-study of the BICOMBO study in which participants were randomized to switch their ...nucleoside backbone to either abacavir/lamivudine or tenofovir/emtricitabine.
We assessed 48-week changes in fasting lipids and several biomarkers including serum high-sensitivity C-reactive protein (hsCRP), monocyte chemoattractant protein-1 (MCP-1), osteoprotegerin, interleukin (IL)-6, IL-10, tumor necrosis factor alpha (TNF-alpha), intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), selectin E and P, adiponectin, insulin, and D-dimer in otherwise healthy, virologically suppressed HIV-infected patients randomly switched to abacavir/lamivudine or tenofovir/emtricitabine with no history of cardiovascular disease, no prior abacavir or tenofovir use, and no virological failure or AIDS during follow-up.
Eighty (46 abacavir/lamivudine and 34 tenofovir/emtricitabine) patients were included. Baseline characteristics were similar between groups and between patients in the sub-study vs. those not. There were no significant differences in baseline lipids and markers between groups. Although total (6.5 vs. -6.7%, P < 0.0001) and low-density lipoprotein (LDL) (8.6 vs. -9.1%, P = 0.004) cholesterol increased significantly in the abacavir/lamivudine group relative to the tenofovir/emtricitabine group, we found no significant changes in the biomarkers: CRP (-3.9 vs. 0.0%), MCP-1 (5.9 vs. 4.0%), osteoprotegerin (5.1 vs. -2.8%), IL-6 (0.0 vs. 0.0%), IL-10 (0.0 vs. 0.0%), TNF-alpha (0.0 vs. 0.0%), ICAM-1 (6.6 vs. 5.2%), VCAM-1 (0.02 vs. -0.01%), selectin E (-0.4 vs. 7.8%), selectin P (4.6 vs. 12.6%), insulin (-2.5 vs. 8.8%), adiponectin (-2.2 vs. 15.4%), and D-dimer (0.0 vs. 0.0%) (P > or = 0.12 for all comparisons).
Abacavir/lamivudine increased total and LDL cholesterol compared with tenofovir/emtricitabine, but it did not cause inflammation, endothelial dysfunction, insulin resistance, or hypercoagulability in virologically suppressed HIV-infected patients.
BACKGROUND:Data comparing abacavir/lamivudine versus tenofovir/emtricitabine in antiretroviral-naive patients are controversial. We compared 48-week efficacy and safety of these combinations as ...substitutes of nucleosides in patients with virological suppression.
METHODS:We randomly assigned 333 HIV-1-infected patients on lamivudine-containing triple regimens with <200 copies per milliliter for at least 6 months to switch their nucleosides to either abacavir/lamivudine (n = 167) or tenofovir/emtricitabine (n = 166). The primary outcome was treatment failure “switching = failure” intention to treat (ITT) analysis, noninferiority margin 12.5%. Secondary outcomes were time to treatment failure, virological failure, adverse events, and changes in CD4 count, fasting plasma lipids, lipodystrophy, body fat, bone mineral density, and renal function.
RESULTS:Treatment failure occurred in 32 patients (19%) on abacavir/lamivudine and 22 patients (13%) on tenofovir/emtricitabine difference 5.9%; (95% confidence interval −2.1% to 14.0%), P = 0.06. Four patients in the abacavir/lamivudine group versus none in the tenofovir/emtricitabine group developed virological failure difference 2.4; (95% confidence interval 0.05 to 6.0), P = 0.04. Twenty-three patients (14%) assigned to abacavir/lamivudine and 10 (6%) to tenofovir/lamivudine experienced grade 3 or 4 adverse effects (P = 0.03). CD4 counts and plasma lipids showed higher increments in the abacavir/lamivudine group than in the tenofovir/emtricitabine group.
CONCLUSIONS:In HIV-1-infected patients with virological suppression, abacavir/lamivudine did not meet the noninferiority outcome for treatment efficacy compared with tenofovir/emtricitabine.
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.
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.
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.
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.
Combinations of new classes of antiretroviral drugs are attractive options to avoid toxicity associated with nucleoside reverse transcriptase inhibitors (NRTIs) and to provide a full active regimen ...in patients with some degree of resistance to NRTIs. However, data on the pharmacokinetic (PK) profiles of these regimens are limited. We explore the plasma PK profile of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients.
This was a pilot, open-label, fixed-sequence, prospective, single-center single-arm PK study. The treating physician chose an NRTI-sparing regimen because of toxicity or resistance mutations to NRTIs, which included DRV/RTV 800/100 mg once daily plus RAL 400 mg twice daily. All patients were RAL and DRV naive and had no evidence of protease inhibitor mutations. After at least 15 days on therapy, patients were admitted for a 24-hour PK study. Laboratory tests to assess efficacy and safety were performed at all study visits.
Fifteen patients were included. The geometric mean values for DRV were AUC0-24 68,730 ng·h·mL 95% confidence interval (CI): 58,970-86,480, Ctrough 1330 ng/mL (95% CI: 1110-1760; IC-50 for wild-type and resistant HIV-1 strains was 55 and 550 ng/mL, respectively), Cmax 7630 ng/mL (95% CI: 6740-9000), and t1/2 10.9 hours (95% CI: 9.20-13.99). Geometric mean values for RAL were AUC0-12 3050 ng·h·mL (95% CI: 2530-5180); Ctrough 40 ng/mL (95% CI: 30-80), Cmax 970 ng/mL (95% CI: 840-2270), t1/2 2.68 hours (95% CI: 1.97-4.40). No adverse effects including rash or laboratory test abnormalities were noted. At week 24, the HIV-1 viral load was below 37 copies/mL in all patients.
Our data suggest that dual therapy with RAL 400 mg twice daily plus DRV/RTV 800/100 mg once daily had a favorable PK profile for both drugs and that short-term efficacy and tolerability of this combination were adequate.
High-risk human Papillomavirus infection is a necessary factor for cervical squamous intraepithelial lesions and invasive cervical cancer. In HIV-1-infected women, HPV infection is more prevalent and ...a higher risk of cervical cancer has been identified. We aimed to calculate the prevalence of infection by HR-HPV, determine the factors associated with this infection and abnormal cytology findings and to describe the history of cervical cancer screening in HIV-1-infected women.
We enrolled 479 HIV-1-infected women from the PISCIS cohort. Each patient underwent a gynecological check-up, PAP smear, HPV AND Hybrid capture, HPV genotyping, and colposcopy and biopsy, if necessary. We applied questionnaires to obtain information on sociodemographic, behavioral, clinical, and cervical screening variables. We present a cross-sectional analysis.
Median age was 42 years. The prevalence of HR-HPV infection was 33.2% and that of high-grade squamous intraepithelial lesions (HSIL) was 3.8%. The most common genotypes were 16(23%), 53(20.3%), and 52(16.2%). The factor associated with HR-HPV infection was age <30 years (odds ratioOR,2.5; 95%confidence intervalCI,1.1-5.6). The factors associated with the presence of HSIL or low-grade squamous intraepithelial lesions (LSIL) were CD4T-lymphocyte count <200 cells/mm(3) versus >500 cells/mm(3) (OR,8.4; 95%CI,3.7-19.2), HIV-1 viral load >10,000 copies/mL versus <400 copies/mL (OR,2.1; 95%CI,1.0-4.4), and use of oral contraceptives (OR,2.0; 95%CI,1.0-3.9). Sixty percent of HIV-1-infected women had had one Pap smear within the last 2 years.
The high prevalence of HPV infection and cervical lesions in the HIV-1-infected population in Catalonia, as well as the low coverage and frequency of screening in this group, means that better preventive efforts are necessary and should include vaccination against HPV, better accessibility to screening programs, training of health care professionals, and specific health education for HIV-1-infected women.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
CD4(+) count increase has been reported to be different with lopinavir/r (LPV/r) and efavirenz (EFV)-containing regimens. The different effect of these two regimens on other immune function ...parameters and the relationship with the gain of CD4(+) count have not been assessed in a randomized clinical trial. Fifty antiretroviral treatment (cART) naïve HIV-infected individuals were randomized to receive LPV/r or EFV both with tenofovir/emtricitabine for 48 weeks. A substudy of immunological function restoration was performed in 22 patients (LPV/r n=10 and EFV n=12). Activation, thymic function, apoptosis, senescence, exhaustion, Treg cells, interleukin (IL)-7-receptor/IL-7 system, thymic volume, and lymphoid tissue fibrosis were evaluated at baseline and at week 48. Both groups experienced a CD4(+) count increase that was higher in the EFV group (ΔCD4(+) 88 vs. 315 cells/μl LPV/r vs. EFV, respectively, p<0.001). Despite this difference in CD4(+) gain, the change in other immune function parameters was similar in both treatment groups. Most of parameters evaluated tended to normalize after 48 weeks of cART. A significant decrease in levels of activation, senescence, exhaustion, and apoptosis on CD4(+) and CD8(+) T cells (p<0.001 for all) and a significant increase in markers of thymic function, IL-7 receptor, and in the levels of central memory CD4(+) T cells and naive subsets of CD8(+) T cells (p<0.001 for all) with respect to baseline values were observed without any difference between groups. These data indicate that the differences in CD4(+) gain with different cART regimens are not immunologically meaningful and might explain the similar clinical efficacy of these regimens.
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