Carlo Biagetti

Metabolic bone disease in HIV infection.

HIV mainly replicates in CD4þ T lymphocytes andmonocyte/macrophages causing severe immunologicalimpairment. In addition to the immune system, HIVinfection affects tissues and organs such as kidney, liver,the central nervous system, heart and bone showing acomplex pathogenesis [1].The advent and widespread use of highly activeantiretroviral therapy (HAART) in the last two decadeshasled toa markedimprovementinthe treatmentofHIVdisease even though viral infection cannot be eradicatedbecause HAART does not completely eliminate the viralreservoirs [2]. HAART has dramatically changed thecourseofHIVinfection froma fatalinfectiontoachronicand relatively manageable disease. The increased lifeexpectancyofHIVpatientsandtheeffectsofHAARThavechanged the management of HIV infection. Nowadaysmedical treatment is no longer focused solely on HIVinfection, opportunistic diseases and monitoring immunederangement, but also includes the control of metabolic,cardiovascular, liver, bone and kidney complications. Inparticular, bone alterations have been observed in thecourse of HIV disease representing a pivotal clinicalprobleminthemanagementofHIVpatientsespeciallyforapossible development of bone fractures [3]. The majorbonelesionsdetectableinHIVpatientsarerelatedtobonedemineralization (osteopenia/osteoporosis and osteoma-lacia) and osteonecrosis ([4] for a review).This report will discuss the pathogenesis, diagnosis andtreatment of major bone complications represented bybone demineralization diseases during HIV infection andHAART treatment.

HIV‐1 DNA proviral load in treated and untreated HIV‐1 seropositive patients

As proviral human immunodeficiency virus type 1 (HIV-1) DNA can replenish and revive viral infection upon activation, its detection might offer significant therapeutic information, complementing the input provided by plasma RNA determination in the follow-up of infected individuals. A selected group of acutely infected subjects was studied to verify both total and 2-long terminal repeat (2-LTR) DNA proviral load during the acute phase of infection and thereafter. Patients were divided in two sex- and age-matched groups: 19 naive individuals who did not receive antiretroviral therapy during the observation period and 20 subjects treated according to current guidelines. Total and 2-LTR HIV-1 DNA proviral load, in addition to RNA viral load and CD4 cell count, were determined in peripheral blood mononuclear cells (PBMC) at baseline, 6 and 12 months after the first sampling. Total and 2-LTR HIV-1 DNA proviral load exhibited no significant variation at any time in the naive patients (total HIV-1 DNA ranging from 896 + or - 731 to 715 + or - 673 copies/10(5) PBMC and 2-LTR HIV-1 DNA ranging from 94 + or - 105 to 65 + or - 44 copies/10(5) PBMC), whereas a significant reduction in both total HIV-1 DNA (ranging from 997 + or - 676 to 262 + or - 174 copies/10(5) PBMC) and 2-LTR HIV-1 DNA proviral load (ranging from 116 + or - 55 to 26 + or - 35 copies/10(5) PBMC) was detected in highly active antiretroviral therapy (HAART) patients, together with a CD4(+) T cell count increase and RNA load decrease. HAART negatively affects both the labile HIV burden and the integrated proviral DNA, at least in the initial period of successful treatment, suggesting that quantification of HIV-1 DNA proviral load may be an important parameter in monitoring HIV infection.

Antiretroviral Therapy in the Real World : Population-Based Pharmacoeconomic Analysis of Administration of Anti-HIV Regimens to 990 Patients.

AbstractObjective and methods: The aim of our study was to analyse retrospectively the nature and frequency of antiretroviral prescriptions for 990 HIV-infected patients followed at our outpatient centre in Bologna, Italy, from January 2003 to March 2004. The main focus of the study was to identify the most commonly prescribed combinations and their related expenses, in order to identify the most competitive treatment regimens with regard to costs. Prescriptions were given directly to patients at monthly intervals, and drug treatment adherence data was stored in an electronic database. Antiretroviral regimens administered for the longest period to each patient during the 15 months of the study were selected for the study. All patients treated for <9 consecutive months and/or with treatment adherence levels <90% were excluded. Physicians assessed antiretroviral therapy at least quarterly according to efficacy and safety criteria, but not in terms of pharmacoeconomic considerations. Direct pharmacy expenses were obtained for the 24 most commonly used therapeutic regimens, covering 80.1% of patients. Results: The zidovudine-lamivudine-efavirenz combination proved to be the most prescribed combination (7.3%), followed by zidovudine-lamivudine-nevirapine (7.1%), lamivudine-stavudine (6.2%), zidovudine-lamivudine-lopinavir-ritonavir (5.2%), didanosine-stavudine-lopinavir-ritonavir (4.8%), and lamivudine-stavudine-nevirapine (4.7%). Anti-HIV combinations varied from a minimum yearly cost of €3895.6 for lamivudine-stavudine to €9422.8 for the zidovudine-lamivudine-lopinavir-ritonavir combination (+241.9%) [year of costing 2003]. There was a significant difference between the two first-line regimens for antiretroviral-naive subjects, with lopinavir-ritonavir-based combinations costing more than €9000 per patient/year compared with efavirenz-containing combinations, which were 28% less expensive. Mean daily costs varied substantially, from a minimum of €10.7 per day for lamivudine-stavudine to a maximum of €25.8 per day (+241.1 %) for zidovudine-lamivudine-lopinavir-ritonavir. Regimens based on non-nucleoside reverse transcriptase inhibitors (NNRTIs) were less costly than most of those including protease inhibitors (PIs). The increased expense of each combination was compared with the cheapest therapeutic selection (lamivudine-stavudine), and costs of all triple combinations were also compared. Regimens based on NNRTIs accounted for 29.3% of our cohort (nevirapine-containing therapies 15.1%, and efavirenz-based ones 14.2%), while PIs were used in the majority of cases (37.3%), with lopinavir-ritonavir as the leading combination (13.6% of patients), followed by nelfinavir (9.9%) and indinavir (9.2%). When drug-related costs were examined, dual nucleoside analogues showed the lowest expense (€10.7–€11.6 per day), while triple nucleoside/nucleotide analogue combinations cost nearly twice as much (€18.5–€20.4 per day). Among the NNRTIs, there were comparable costs for nevirapine-based combinations (€18.3–€18.7 per day), while efavirenz-including regimens were 10% more costly (€19.2–€20.1 per day). A very broad range of combinations and related costs were found with PIs, but apart from indinavir and saquinavir combinations (€15.7–€21.7 per day), all other regimens had a higher daily cost (from €22.0 per day for ritonavir-based regimens to €23.4–€24.3 per day for nelfinavir combinations, and up to €24.9–€25.8 per day with lopinavir-ritonavir). When considering nelfinavir- and lopinavir-containing combinations, the difference compared with NNRTI-based regimens varied from 41% when nevirapine- and lopinavir-ritonavir were compared, to 11.6% when efavirenz and nelfinavir were compared. Conclusions: Investigations that link prescribing patterns and related costs in the setting of HIV disease therapy are needed to improve patient management and help with the planning of healthcare resource allocation.

HIV-1 subtype C transmission network: The phylogenetic reconstruction strongly supports the epidemiological data

The sequence and times of the transmission events was reported after a hospital accident by a phylodynamic reconstruction of transmission network among four subjects. The dated tree allowed to date the transmission events with good approximation, the time point and direction of each transmission, estimated on the basis of the phylogeny, and agreed with the presumptive time of infection on the basis of clinical history-taking.

Incomplete IgG response to HIV-1 proteins and low avidity levels in recently converted HIV patients treated with early antiretroviral therapy

OBJECTIVES To evaluate the evolution of antibody avidity and Western blot reactivity in recently infected HIV-1 subjects and to study the impact of highly active antiretroviral therapy (HAART) on avidity maturation of HIV-1-specific immunoglobulin G (IgG) in patients with recent HIV-1 infection. METHODS Thirty-six HIV-1 seroconverters were enrolled in this study and followed longitudinally over 24 months to evaluate if the administration of antiretroviral therapy during primary infection affects Western blot reactivity and the evolution of antibody avidity. The patients were divided into two groups; group A consisted of 19 HIV-1-untreated patients who did not receive any drug treatment during our follow-up period; group B consisted of 17 subjects who were treated early with an association of two nucleoside reverse transcriptase inhibitors (NRTI) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) within 3 months after seroconversion. RESULTS At diagnosis, Western blot analysis and avidity index (mean value) were exactly matched in untreated and treated patients; subsequently, however, a significantly lower reactivity to HIV-1 pol and gag proteins and a lower avidity index (mean values) were observed in HAART-treated patients up until the end of the follow-up period. CONCLUSIONS The impaired production and maturation of the humoral immunological response in antiretroviral-treated patients might be related to a rapid suppression of HIV replication, driven by HAART. These results could have important implications in understanding the complex mechanism of the immune response during HIV infection.

HIV-1 infection of a nurse from a newborn with an unknown HIV infection: A case report

BACKGROUND HIV infection of healthcare workers by injury is an important issue in the management and prophylaxis of HIV-related disease. OBJECTIVES To describe a case where a nurse has been HIV-1 infected by needle-stick whilst taking blood from a newborn with an unknown HIV infection. STUDY DESIGN Virological, immunological and clinical analysis of a peculiar case of HIV transmission from newborn to nurse has been reported. RESULTS The nurse has been infected by needle-stick injury whilst taking blood from a newborn with an unknown HIV infection. The delayed declaration of accident by nurse and the inaccurate medical management of pregnant woman determined the subsequent absence of correct prophylaxis measures and then the impossibility to tackle the HIV transmission. CONCLUSION This case indicates that HIV serological screening of pregnant women and prompt accident notification by health-care workers represent basic preventive measures that should effectively tackle the spread of HIV infection.

Bone Mass Loss in Patients With Human Immunodeficiency Virus Type 1 Infection: Association With Male Sex and Protease Inhibitor Therapy

The aim of our study was to evaluate the prevalence of osteopenia/osteoporosis in patients with human immunodeficiency virus (HIV) type 1 infection and to assess their possible correlation with antiretroviral therapy. Patients were enrolled among adult subjects with HIV type 1 infection referring to our tertiary care outpatient center. Bone mineral density was measured in the lumbar spine and femoral proximal head by dual-energy x-ray absorptiometry. A total of 95 HIV-infected patients (45 men) were enrolled: 12 subjects were naive to antiretroviral therapy, 18 received 3 nucleoside reverse-transcriptase inhibitors (NRTIs), 28 were treated with 2 NRTIs plus 1 non-NRTI, and 37 received 2 NRTIs plus 1 protease inhibitor (PI). Prevalence of osteopenia and osteoporosis according to lumbar T score was 37.9% and 9.5%, respectively, and osteoporosis was significantly more frequent in men than in women (20% vs. 0%; P < 0.001). The mean value of lumbar T score was significantly lower in PI-treated patients (−1.32 ± 0.48) than in naive subjects (−0.62 ± 0.24) or in those receiving 3 NRTIs (−0.68 ± 0.34) or 1 non-NRTI (−0.86 ± 0.44) (P < 0.05). Bone metabolism alterations associated with HIV infection probably have a multifactorial pathogenesis, but in our study, bone mass loss seems prompted by the male sex and a PI-based therapy.

PI and OPG/RANKL levels in human osteoblast cells

Purpose of the study The association between loss of bone mineral density (BMD) and PI use is evidenced on several in vitro models and seems to have different etiology depending on specific molecule. Although an HAART regimen always contains one or more transcriptase inhibitors, there are no specific data available regarding specific PI action on BMD. However, some in vitro experiments showed that these compounds might induce the differentiation of osteoclast cells. In order to analyse the specific effect of each PI on human osteoblast we analysed OPG and RANKL levels after exposing the cells to each PI.