Marco Floridia

Antiretroviral treatment in pregnancy: a six-year perspective on recent trends in prescription patterns, viral load suppression, and pregnancy outcomes.

The aim of the study was to describe the recent trends in antiretroviral treatment in late pregnancy and the sociodemographic changes among pregnant women with HIV over the last 6 years. Data from the National Program on Surveillance on Antiretroviral Treatment in Pregnancy in Italy were grouped per calendar year, and changes in antiretroviral treatment, population characteristics, maternal immunovirologic status and newborn clinical parameters were analyzed. A total of 981 HIV-infected mothers who delivered between 2002 and 2008 were evaluated. The proportion of women receiving at least three antiretroviral drugs at delivery increased significantly from 63.0% in 2002 to 95.5% in 2007-2008, paralleled by a similar upward trend in the proportion of women who achieved complete viral suppression at third trimester (from 37.3 in 2002 to 80.9 in 2007-2008; p < 0.001). The co-formulation of zidovudine plus lamivudine remained the most common nucleoside backbone in pregnancy, even if a significant increase in the use of tenofovir plus emtricitabine was observed in more recent years. Starting from 2003, nevirapine prescription declined, paralleled by a significant rise in the use of protease inhibitors (PI), which were present in more than 60% of regimens administered in 2007-2008. Nelfinavir was progressively replaced by ritonavir-boosted PIs, mainly lopinavir. No significant changes in preterm delivery, Apgar score, birth weight, and birth defects were observed during the study period, and the rate of HIV transmission remained below 2%. These data demonstrate a significant evolution in the treatment of HIV in pregnancy. Constant improvements in the rates of HIV suppression were observed, probably driven by the adoption of stronger and more effective regimens and by the increasing options available for combination treatment.

Effect of sex, age, and transmission category on the progression to AIDS and survival of zidovudine-treated symptomatic patients

ObjectiveTo evaluate the effect of transmission category and demographic, clinical and immunological characteristics on the progression to AIDS and survival of zidovudine-treated patients. DesignProspective multicentre cohort study of symptomatic non-AIDS patients. SettingEighty-three clinical centres reporting data to the National Zidovudine Registry. PatientsA total of 1468 patients enrolled between July 1987 and January 1991 were analysed. Main outcome measuresThree-year AIDS-free survival probability estimates since therapy start. Cox proportional hazards regression analysis was used to identify independent predictors of progression to AIDS and survival. ResultsFaster progression was associated with increasing age (8% risk increase for a 5-year increase), low baseline CD4+ count (39% risk increase for 100 × 106/l cells decrease), and zidovudine > 1000 mg/day (20% risk increase compared with ≤ 1000 mg/day). Homosexual men had a 33% risk increase compared with other risk groups. The presence of fever and oral candidiasis at enrolment were also independently associated with a higher risk of progression. Differences in the risk of progression were not significant between men and women. Older age, baseline CD4+ count, homosexual behaviour, fever and oral candidiasis were independently associated with a shorter survival. ConclusionsOur results confirm that age and baseline CD4+ count are independent predictors of progression, but do not provide evidence for differences in clinical outcome between the sexes. The higher risk of progression to AIDS and shorter survival for homosexual men appears to be correlated with the higher risk of developing Kaposis sarcoma.

Saquinavir: Clinical pharmacology and efficacy

Saquinavir is an HIV protease inhibitor with no, or limited, effect on the activity of other structurally related human aspartic proteinases. As with other HIV protease inhibitors, saquinavir inhibits the cleavage of the gag-pol protein substrate leading to the release of structurally defective and functionally inactive viral particles. It is active on both HIV-1 and HIV-2, and also has activity on chronically infected cells and HIV strains resistant to reverse transcriptase inhibitors. Synergy of action has been observed with other antiretroviral drugs. Saquinavir is characterised by a low bioavailability which is further reduced in the fasting state. Metabolism is mainly hepatic through cytochrome P450 (CYP) 3A4, but intestinal metabolism through the same system has also been reported. To achieve higher drug plasma concentrations and increase the antiviral effect, a new formulation of saquinavir with a higher bioavailability has recently been introduced. Higher plasma drug concentrations may also be obtained by combining the drug with CYP blockers, such as ritonavir or ketoconazole. Because of its metabolic interference with the CYP system, saquinavir cannot be coadministered with astemizole, terfenadine or cisapride. Rifampicin (rifampin) is also contraindicated because coadministration can lead to decreases in saquinavir concentrations. Interactions have also been reported with other drugs metabolised through the same system, including non-nucleoside reverse transcriptase inhibitors and HIV protease inhibitors. Resistance has been observed after both in vitro and in vivo drug exposure, with a relatively specific mutation profile compared with other protease inhibitors. Saquinavir is generally well tolerated, with mild gastrointestinal symptoms representing the most commonly observed adverse effects. Although characterized by low bioavailability, in phase III trials saquinavir has been shown to have clinical efficacy in terms of survival and progression rate. As with the other protease inhibitors, saquinavir should be used in combination with other antiretroviral drugs. Current therapeutic guidelines, however, recommend the selection of an initial treatment regimen with other protease inhibitors with higher in vivo activity in terms of RNA and CD4 response. The results of ongoing studies will clarify to what extent a new saquinavir formulation, recently introduced, is superior to the previous one in terms of antiviral activity and to provide comparisons with other protease inhibitors. Further studies are also needed to define the best place of saquinavir within treatment strategies based on protease inhibitors, particularly in respect to the optimal sequence for its use with other protease inhibitors, and the dynamics of cross-resistance and its role within regimens based on the combination of protease inhibitors.

Diagnosis of HIV infection in pregnancy: data from a national cohort of pregnant women with HIV in Italy

We analysed the characteristics of the pregnancies with a previously undetected HIV infection in a national observational study of pregnant women with HIV in Italy. In a total of 443 pregnancies with available date of HIV diagnosis, 118 were characterized by a previously undetected HIV infection (26.6%, 95% CI 22.5-30.8). The following factors were independently associated with this occurrence in a multivariate analysis (adjusted odds ratios; 95% CIs): foreign nationality (5.1, 2.8-9.3); no pre-conception counselling (35.9, 4.8-266.1); first pregnancy (2.1, 1.2-4.0); asymptomatic status (6.8, 1.5-30.6). Women with previously undetected infection started antiretroviral treatment significantly later during pregnancy (P < 0.001). Missed diagnosis was responsible for one case of transmission. A high rate of previously undetected HIV infection was observed. This suggests a good HIV detection during pregnancy, but also the need to reinforce HIV testing strategies among women of childbearing age. We identified some determinants which may be considered for intervention measures.

Rapid HIV-RNA decline following addition of raltegravir and tenofovir to ongoing highly active antiretroviral therapy in a woman presenting with high-level HIV viraemia at week 38 of pregnancy

patients are seen by a doctor at least once every week. All doses ,800 mg are diluted to 20 mL with normal saline. Larger doses are given as the neat 40 mg/mL solution supplied in the manufacturers’ vials. In the period between November 1995 and October 2009, we documented the administration of 5593 doses (3652 of tobramycin and 1941 of gentamicin). The drugs were administered in 361 courses (244 of tobramycin and 117 of gentamicin) to 132 patients. Sixty-seven of these patients had cystic fibrosis and received multiple courses. Twelve of the remaining 65 had bronchiectasis and also received more than one course. The other remaining patients were treated for a variety of diagnoses, typically requiring only one course. One hundred and forty-five courses were administered to children and 216 to adults. The ages of the patients ranged from 3 to 84 years. The median dose was 360 mg of tobramycin and 320 mg of gentamicin in cystic fibrosis, and 240 mg of tobramycin and 170 mg of gentamicin in those without cystic fibrosis. The median course duration was between 15 and 18 days across the same groups. One patient, a middle-aged female with complex medical problems, developed vestibular toxicity and some hearing loss 16 h after her last dose of 320 mg of tobramycin. There has never been the suggestion of neuromuscular toxicity or hearing loss at the time of injection. Current recommendations are that tobramycin and gentamicin be given by infusion over ≥30 min. We have shown that tobramycin and gentamicin can be safely administered by slow push over 3–5 min. We recommend that consideration be given to the use of this simple method as the standard of care.

AIDS dementia complex in the Italian National AIDS Registry: temporal trends (1987–93) and differential incidence according to mode of transmission of HIV-1 infection

OBJECTIVES To investigate the occurrence of AIDS dementia complex (ADC) in Italy and its incidence over time, examining possible correlations between this condition and some demographic and immunological variables. DESIGN Inception cohort. Data collected from the case notification forms of the Italian National AIDS Registry. SUBJECTS 16813 consecutive AIDS cases reported to the National AIDS Registry from August 1, 1987 through October 31, 1993 were included. STATISTICAL METHODS All data refer to the time of AIDS diagnosis as reported on the case notification forms. Main analyses of the monthly proportion of ADC cases were by multiple logistic regression. RESULTS 1364 subjects (8.1%) were reported with a diagnosis of ADC as the first AIDS defining disease, either as the only manifestation or associated with other AIDS defining conditions. At the time of AIDS diagnosis, the observed ADC/AIDS proportion was significantly higher among intravenous drug users (IVDU), 9.1%, compared to heterosexuals, 6.3%, and homo-bisexual men, 5.2%. Simple logistic regression analysis showed a significant (p < 0.0001) quadratic trend in the monthly ADC/AIDS proportion, peaking in March 1990 and decreasing thereafter. Multiple logistic regression, adjusting for month of diagnosis, showed that IVDUs have consistently the highest risk and homo-bisexual men the lowest, although differences tended to decrease with increasing age. Older age, in fact, was highly associated with an increased risk, especially within the homo-bisexual and heterosexual transmission categories. CD4 + cells counts proved to have no significant effect on the risk of progressing to AIDS with ADC rather than with any other AIDS indicative disease. CONCLUSIONS ADC is a relatively frequent manifestation at diagnosis of AIDS among Italian patients, and particularly in IVDUs. Differences in its occurrence were found according to time of diagnosis, transmission category and age.

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

ObjectivesTo 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). DesignA 48-week randomized, double-blind trial. MethodsSixty 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. ResultsAlthough 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. ConclusionAlthough 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.

Risk factors and occurrence of rash in HIV-positive patients not receiving nonnucleoside reverse transcriptase inhibitor: data from a randomized study evaluating use of protease inhibitors in nucleoside-experienced patients with very low CD4 levels (<50 cells/microL).

Most of the studies evaluating rash in HIV‐positive patients have focused on nonnucleoside reverse transcriptase inhibitors (NNRTI), particularly nevirapine, and little is known about the occurrence of rash and the risk factors for its development in patients receiving regimens not based on NNRTI.

Survival of zidovudine-treated patients with AIDS compared with that of contemporary untreated patients. Italian Zidovudine Evaluation Group

OBJECTIVE To assess the long-term effectiveness of zidovudine (AZT) in patients with acquired immunodeficiency syndrome (AIDS). This assessment has never been adequately done because controlled clinical trials were stopped early and survival comparisons were made with historical controls. DESIGN Nonrandomized contemporary observational study of patients treated and not treated with zidovudine. SETTING Twenty-three AIDS treatment centers throughout Italy that reported cases to the National Registry of AIDS Cases between July 1987 and March 1988. PATIENTS One hundred fifty-nine zidovudine-treated and 112 untreated patients with AIDS, the majority of whom had acquired human immunodeficiency virus (HIV) infection through intravenous drug use. OUTCOME MEASURES Median survival and 1- and 2-year survival for treated and untreated groups, as estimated using the Kaplan-Meier method. Cox proportional hazards regression analysis was also used to identify independent predictors of survival among the variables studied. RESULTS Patients were similar with respect to CD4/CD8 ratio, age, sex, clinical and immunological status at diagnosis, and source of HIV infection. After 24 months, survival was 45.9% (95% confidence interval [CI], 36.1% to 55.7%) in the treated group and 20.5% (95% CI, 12.6% to 28.3%) in the untreated group, with median survival of 21.2 and 9.6 months, respectively. CONCLUSIONS Possible biases of this study include imperfect matching for clinical status and better overall medical care of treated patients. Nevertheless, we believe that the observed differences in survival were primarily due to zidovudine treatment.

Birth defects in a national cohort of pregnant women with HIV infection in Italy, 2001-2011

We used data from a national study of pregnant women with HIV to evaluate the prevalence of congenital abnormalities in newborns from women with HIV infection.