A Reduction Grade of Lipodystrophy and Limited Side Effects after HAART Regimen with Raltegravir, Lamivudine, Darunavir and Ritonavir in an HIV-1 Infected Patient after Six Years of Antiretroviral Therapy.

HIV-associated lipodystrophy commonly presents with fat loss in the face, buttocks, arms and legs, hypocomplementaemia, glomerulonephritis, and autoimmune disorders. The exact mechanism of HIV-associated lipodystrophy is not fully elucidated. There is evidence indicating that it can be caused by both antiretroviral medications and HIV infection in the absence of antiretroviral medication. Lipodystrophy seems to be mainly due to HIV-1 protease inhibitors. Interference with lipid metabolism is postulated as pathophysiology. Also, the development of lipodystrophy is associated with specific nucleoside reverse transcriptase inhibitors (NRTI). Mitochondrial toxicity is postulated to be involved in the pathogenesis associated with NRTI. Here, we analyse the side effects and examine the impact of the highly active antiretroviral therapy (HAART) regimen including raltegravir, lamivudine, darunavir and ritonavir in an HIV-1 infected patient with severe lipodystrophy after six years of antiretroviral therapy.

A Simplified HAART Regimen with Raltegravir and Lamivudine, and Pharmacokinetic Interactions with a Combined Immunosuppressive Therapy with Tacrolimus and Everolimus in an HIV/HCV/HBV/HDV Patient after Liver Transplantation.

In this case report, we examine the impact of a simplified two-drug highly active antiretroviral therapy (HAART) regimen of raltegravir and lamivudine in a patient co-infected with human immunodeficiency virus (HIV) and hepatitis C, D and B viruses (HCV/HDV/HBV) under immunosuppressive therapy after liver transplantation. Pharmacokinetic interactions between integrase inhibitors and immunosuppressant drugs are described. Raltegravir, the first integrase inhibitor, associated with lamivudine, was introduced because its metabolism does not interfere with immunosuppressant therapy. During post-orthotopic liver transplantation follow-up, the patient's transaminases level increased and his antiretroviral therapy (HAART) of tenofovir/emtricitabine and fosamprenavir was changed, due to suspected drug toxicity. After seven months of follow-up, the patient showed good tolerance, good viro-immunological control with undetectable HIV viraemia and stable concentrations of immunosuppressive drugs. This case indicates that the combination of raltegravir and lamivudine is an optimal and effective strategy because it resulted in an important reduction of hepatic transaminases in a patient with very critical clinical conditions.

HIV-1 coreceptor switch during 2 years of structured treatment interruptions.

The purpose of this investigation was to determine the impact on human immunodeficiency virus (HIV) tropism of uncontrolled virus exposure during 2 years of intermittent highly active antiretroviral therapy (HAART). The Istituto Superiore di Sanità-Pulsed Antiretroviral Therapy (ISS-PART) randomized study compared the outcome of 2 years of structured treatment interruptions (STIs) versus standard continuous treatment in first-line HAART responder subjects. The STI schedule consisted of five STIs of 1, 1, 2, 2, and 3 months, respectively, separated by four periods of 3-month therapy. In the present study, coreceptor tropism was assessed in 12 patients of the STI arm at different time points over a period of 2 years. Tropism was determined on DNA and RNA by V3 loop region sequencing. The Geno2pheno algorithm (false-positive rate, FPR: 20%) was used for data interpretation. At baseline, 9/12 subjects (75.0%) had CCR5-tropic viruses in their HIV. Three had a CXCR4-tropic virus. Ten patients maintained the same coreceptor in DNA after 2 years, whereas in two patients, a shift occurred (one R5-X4, one X4-R5). In a patient with an R5 virus at baseline, a transient change to X4 tropism was seen in the rebounding virus during STI. Changes in tropism were not associated with the amplitude and duration of virus exposure during STIs, residual viremia at baseline, or the development of resistance mutations in the RT region. Our preliminary results suggest that viral replication, observed after short periods of treatment interruption, is not enough to drive the evolution of HIV tropism.

Sustained increase of serum creatine phosphokinase levels and progressive muscle abnormalities associated with raltegravir use during 32-week follow-up in an HIV-1 experienced patient on simplified HAART regimen, intolerant to protease inhibitors and abacavir: a case report.

Sustained increase of serum creatine phosphokinase (CPK) concentrations and muscle abnormalities have been reported in patients taking raltegravir (RAL). In this report, we describe a case of sustained and asymptomatic increase of serum CPK concentrations associated with raltegravir, zidovudine, and lamivudine in an HIV-1 experienced patient with intolerance to protease inhibitor, abacavir and penicillin during 32 weeks of continuous drug monitoring.

Virological failure at one year in triple-class experienced patients switching to raltegravir-based regimens is not predicted by baseline factors.

We evaluated rates and determinants of virological failure in triple-class experienced patients receiving raltegravir-based regimens from a national observational study over 48 weeks, defined by any one of the following: (1) no HIV-RNA suppression to undetectable levels (<50 copies/mL) during follow-up; (2) detectable viral load after obtaining undetectable levels; and (3) leaving the study before 48 weeks. Among 101 eligible patients, 26 (25.7%; 95% CI 17.2-34.2) had virological failure. No significant differences between patients with and without virological failure were observed for gender, age, route of transmission, baseline CD4/HIV-RNA, CDC group, hepatitis B or C co-infections, resistance (based on the last genotype available), type and number of concomitant drug classes, concomitant use of darunavir, atazanavir, etravirine, enfuvirtide or maraviroc, and health-related quality-of-life measures. A high rate of treatment response was observed. The analyses did not identify any baseline factor associated with failure, including resistance status. Even if we cannot exclude the presence of pre-existing minority resistant variants not captured by genotypic tests, the lack of baseline predictors of failure suggests the need to monitor patients closely during follow up for other factors, such as potential drug interactions and reduced levels of adherence, which may favour virological failure.

A reduced grade of liver fibro-steatosis after raltegravir, maraviroc and fosamprenavir in an HIV/HCV co-infected patient with chronic hepatitis, cardiomyopathy, intolerance to nelfinavir and a marked increase of serum creatine phosphokinase levels probably related to integrase inhibitor use.

The use of new antiretroviral drugs in HIV infection is particularly important in patients with intolerance or resistance to other antiretroviral agents. Raltegravir and maraviroc represent new, important resources in salvage regimens. A reduced grade of liver fibro-steatosis after a combination of raltegravir and maraviroc (second-line) has not been studied and the mechanism by which these new drug classes induced a marked reduction of grade of liver diseases is currently unknown. In the present case report, nested in an ongoing multicentre observational study on the use of new antiretroviral inhibitors in heavy treatment-experienced HIV patients, we evaluated the correlation between a "short therapeutic regimen" raltegravir maraviroc and fosamprenavir and liver diseases. The aim of this report is to describe the use of a three-drug regimen based on two novel-class antiretroviral agents (raltegravir and maraviroc) plus the protease inhibitor fosamprenavir, in an experienced HIV-infected patient with chronic progressive hepatitis C complicated by liver fibrosis; an overwhelming increased serum creatine kinase level occurred during treatment, and is probably related to integrase inhibitor administration. At present no information is available regarding this correlation.

Raltegravir, tenofovir, and emtricitabine in an HIV-infected patient with HCV chronic hepatitis, NNRTI intolerance and protease inhibitors-induced severe liver toxicity.

BACKGROUND: In HIV-infected patients with HCV-related chronic hepatitis, liver impairment and drug toxicity may substantially reduce the number of possible therapeutic options. CASE DESCRIPTION: we here describe the case of an HCV-HIV coinfected woman who had repeated severe episodes of drug-related liver toxicity with indinavir, saquinavir, fosamprenavir, and darunavir, with minimal further therapeutic options left in this class. Previous treatment-limiting side effects with efavirenz and nevirapine also precluded use of non-nucleoside reverse transcriptase inhibitors. Introduction of an integrase-inhibitor regimen based on raltegravir, tenofovir, and emtricitabine allowed a prompt achievement of undetectable viral load and a substantial rise of CD4 count to high levels, with no subsequent episodes of hepatic toxicity, and no other side effects. CONCLUSIONS: given the relatively common prevalence of HCV-related chronic hepatitis among people with HIV, raltegravir might represent an important alternative option for a substantial number of patients who cannot be treated with protease inhibitors or NNRTI because of drug-related hepatic toxicity.

The mutational archive in proviral DNA does not change during 24 months of continuous or intermittent highly active antiretroviral therapy.

OBJECTIVES: The aim of the study was to determine the modifications of the mutational archive in proviral HIV-1 DNA occurring during 24 months of intermittent or continuous highly active antiretroviral therapy (HAART). METHODS: The study population included subjects enrolled in the Istituto Superiore di Sanità Pulsed Antiretroviral Therapy (ISS PART) clinical trial. All of these patients were on first-line HAART and had plasma HIV-1 RNA below 50 HIV-1 RNA copies/mL. A genotypic resistance test was performed on HIV-1 DNA extracted from peripheral blood mononuclear cells (PBMC) at baseline and after 24 months of follow-up. Resistance-associated mutations (RAMs) were defined according to the International AIDS Society (IAS) USA classification. RESULTS: Sixty-nine subjects were included in the study [36 enrolled in arm A of the ISS PART (continuous HAART) and 33 enrolled in arm B (intermittent HAART)]. No major modifications of the mutational archive were found in either group after 24 months of follow-up, in terms of both the proportion of subjects with mutations and the total number of mutations. CONCLUSIONS: In this patient population, the mutational archive in HIV-1 DNA extracted from PBMC was stable for 24 months, irrespective of HAART modality, whether continuous or intermittent.

Rabies infection: epidemiology and prophylaxis.

Authors of this paper underline the importance of worldwide epidemiological rabies infection and the prevention. Specifically, a program of health education first aid md's, family doctors, veteriners, animal's traders, and to students of ground schools (primary and secondary) in a large medical regional area of Rome was developed. This article is informative to whom can concern rabies infection risks in Italy in order to reduce the abuse of vaccination influencing on behaviors and on the relation humans-animals.

Plasma HIV-1 copy number and in vitro infectivity of plasma prior to and during combination antiretroviral treatment.

Some studies on untreated patients have shown a general correlation between plasma HIV copy number and plasma infectivity in in vitro models. Recent observations also indicate that HIV-RNA level is an important predictor of perinatal transmission and may also have a role in heterosexual transmission. To further analyse the correlation between HIV viral load and plasma infectivity, we studied the relationship between HIV-1 plasma copy number and plasma infectivity prior to and during treatment with antiretroviral combination regimens in HIV-1 infected adults. Plasma infectivity was assessed in vitro by coculture of plasma from HIV-positive patients with PHA-stimulated fresh PBMC from uninfected donors. A positive plasma isolation, in almost all cases (43/45) and irrespective of treatment status, was associated with an HIV viral load higher than 100000 copies per ml, with higher plasma HIV-1 RNA values in isolation-positive samples compared with isolation-negative samples (median values, 710000 vs. 37500 copies per ml, respectively). SI and NSI strains had similarly high viral load values (470000 vs. 790000 copies per ml), but CD4 counts were lower in the SI phenotype group. Our data indicate that low levels of viral load are only exceptionally associated with isolation from plasma in the in vitro model we used. This observation confirms indirectly the presence of an association between viral load and infectivity. The requisite of a high plasma viral load in order to obtain infectivity (i.e. positivity of HIV isolation from plasma) also seems maintained under antiretroviral treatment, adding confidence in the conclusion that reductions in viral load translate into reduction of plasma infectivity. Due to the extreme complexity of factors determining transmission, a very prudent interpretation of the results is essential when information from experimental studies has to be transferred to clinical situations requiring assessment of risks or clinical decisions.

Quality of life outcomes of combination zidovudine- didanosine-nevirapine and zidovudine-didanosine for antiretroviral-naive advanced HIV-infected patients.

OBJECTIVES: To evaluate the quality of life outcomes in antiretroviral-naive patients randomized to zidovudine plus didanosine versus zidovudine plus didanosine plus nevirapine for treatment of advanced HIV disease (the Istituto Superiore di Sanità 047 trial). DESIGN: A 48-week randomized, double-blind trial. METHODS: Sixty patients were enrolled and evaluated over 24 weeks. Quality of life was assessed using a modified version of the Medical Outcomes Study-HIV Health Survey. For analysis, we calculated two summary scores reflecting the physical (PHS) and the mental (MHS) components of health. RESULTS: Although the three-drug combination was superior at inducing immunologic and virologic responses, the two-drug regimen was superior for both PHS and MHS, especially at week 8 where differences were both statistically and clinically significant (5.8 and 9.2 points, respectively, P< 0.02 for both). Quality of life changes paralleled trends in body weight and Karnofsky performance status score. CONCLUSION: Although a three-drug antiretroviral therapy regimen was superior in terms of short term virologic/immunologic response, the two-drug regimen was better in terms of quality of life. In general, triple therapy remains the most effective treatment option. However, quality of life assessments can yield results that may be discordant with and complementary to those obtained using conventional endpoints. Comparative trials should collect a comprehensive range of outcome measures, including patient-reported quality of life, in order to provide clinicians and patients with additional information that may influence treatment decisions.

A randomized, double-blind trial on the use of a triple combination including nevirapine, a nonnucleoside reverse transcriptase HIV inhibitor, in antiretroviral-naive patients with advanced disease.

The immunologic and virologic activity of nevirapine in combination with two nucleosides (zidovudine [ZDV] and didanosine [ddI]) was evaluated in antiretroviral-naive patients with a CD4 count <200/mm3 or clinical AIDS. In all, 68 patients were enrolled in a 48-week double-blind, placebo-controlled trial. A group of 32 patients received ZDV + ddI + nevirapine, and 36 patients received ZDV + ddI. Primary efficacy parameters were the activity on HIV-1 RNA and on peripheral blood CD4+ cells, with differences between groups analyzed by the Wilcoxon's nonparametric two-sample test. Baseline RNA was high in both treatment groups (median values, 5.8 and 5.7 log10). RNA and CD4 responses were significantly higher with the triple combination (median RNA reductions, 2.69 versus 1.05 log10 at 24 weeks and 1.97 versus 1.20 log10 at 48 weeks; median CD4 increases, 81 versus 64 cells/mm3 at 24 weeks and 101 versus 27 cells/mm3 at 48 weeks). This study demonstrates that a triple combination of ZDV + ddI + nevirapine used as first-line regimen in antiretroviral-naive patients can induce sustained virologic and immunologic response in patients with low CD4 count or a previous diagnosis of AIDS.

A randomized trial (ISS 902) of didanosine versus zidovudine in previously untreated patients with mildly symptomatic human immunodeficiency virus infection.

In this multicenter study (ISS 902), 554 previously untreated patients with <500 CD4 cells/mm3 and mildly symptomatic human immunodeficiency virus disease were randomized to receive zidovudine or didanosine (ddI). After a mean follow-up of 20 months, 80 patients (40 zidovudine, 40 ddI) had died and 146 had at least one AIDS-defining event (73 zidovudine, 73 ddI). Overall, no difference was found between treatments with respect to progression to AIDS or death. The analysis of relative risk (RR) of progression over time, however, showed an initially minor risk for zidovudine patients and an inversion in the zidovudine-ddI RR in the second and third years of follow-up. Didanosine showed a greater effect on CD4 cell count response. The two drugs confirmed the toxicity patterns already reported in other trials, with a low occurrence of pancreatitis (ddI 1.3%, zidovudine 0.4%). The overall results suggest that, in this population, zidovudine and ddI monotherapies have comparable long-term clinical efficacy and that more powerful regimens should be preferred.

A randomized trial (ISS 901) of switching to didanosine versus continued zidovudine after the diagnosis of AIDS.

Although the efficacy of switching from zidovudine (AZT) to didanosine (ddI) has already been evaluated in controlled studies, prior investigations were not specifically designed to evaluate this issue in patients with acquired immune deficiency syndrome (AIDS). This open, randomized, multicenter study (ISS 901) was designed to evaluate the clinical benefit in patients with AIDS of switching to ddI after 6-18 months of AZT and no major intolerance. Patients were randomized to continue AZT, maintaining the current dosage at randomization (n = 79), or to receive ddI (n = 80) at the dosage of 375 mg and 250 mg b.i.d. for body weight > 60 and < or = 60 kg, respectively. Primary efficacy measures were survival and time to new AIDS-defining events, analyzed by the intent-to-treat approach. The two groups were comparable for baseline characteristics, follow-up (15 months), and time spent on allocated treatment. At the end of the study, 104 patients (48 AZT, 56 ddI) had died and 90 had at least one new AIDS-defining event (44 AZT, 46 ddI). Kaplan-Meier estimates of survival and of time to first new AIDS-defining event showed no differences between the treatment groups. No differences were detected in other efficacy measurements (p24 antigenemia, CD4+ count, Karnofsky score, and body weight), occurrence of severe toxicities, and treatment modifications. Pancreatitis occurred only in ddI-treated patients (6%). In our population of patients with advanced disease, switching from AZT to ddI did not produce apparent benefits, suggesting that application of this strategy earlier in the course of human immunodeficiency virus disease should be considered.