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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.

We describe the main issues encountered in pregnancy care in two perinatally infected adolescents with HIV. Despite the young maternal age, both mothers complied well with visits and treatment during pregnancy and delivered at week 38 through elective caesarean section. Both, however, missed the regular gynaecological and the routine HIV visits scheduled after pregnancy. Both infants following HIV exposure were confirmed HIV-negative at the end of tests performed in the first year of life. A growing number of similar cases is expected as perinatally infected children enter adolescence and become sexually active. These two cases indicate the feasibility of an adequate pregnancy care in very young HIV-positive women, but suggest that potential difficulties may be encountered in this population in maintaining optimal care after delivery. Such objectives might be better obtained with a timely transition of adolescents with HIV from paediatric clinics to a multiservice care setting which includes infectious diseases clinics, obstetric and gynaecologic departments and, particularly, counselling and educational services.

Limited information is currently available on the metabolic profile of nevirapine in pregnancy. We used data from a national observational study to evaluate plasma lipid profile in pregnant women receiving nevirapine. Lipid values were collected during routine clinical visits. Midpregnancy (second trimester) lipid values were analyzed according to use of nevirapine, calculating differences and 95% confidence intervals (CI) between women taking and not taking this drug. In order to adjust for possible confounders, multivariable models were constructed using as dependent variables levels of total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), triglyceride (TG) levels and TC/HDL-C ratio, and as independent variables age, body weight, previous treatment history, CD4 count, and presence of any antiretroviral therapy, use or nonuse of protease inhibitors, stavudine, and nevirapine at the time of blood sampling. Overall, 375 women had available data for analysis. Pregnant women on nevirapine, compared to women not taking this drug, had in univariate analyses higher levels of HDL-C (difference: +13.0mg/dL [95%CI 7.4-18.6], p < 0.001), lower values of TC/HDL-C ratio (difference: -0.51 [0.23-0.80], p < 0.001) and a trend for lower levels of triglycerides (difference: -17.6mg/dL [0.7-35.9], p = 0.06). Higher HDL-C levels were also associated with use of protease inhibitors and with no previous antiretroviral experience before pregnancy. The associations with higher HDL-C levels were confirmed in multivariable analyses. Our study indicates in pregnant women an association between nevirapine use and higher HDL-C levels. Further studies should assess whether this effect is due to an intrinsic activity of nevirapine and define the potential mechanisms involved.

The objective of this study was to evaluate the plasma drug concentrations in human immunodeficiency virus (HIV)-infected pregnant women receiving highly active antiretroviral therapy (HAART) and to define the rate of occurrence of subtherapeutic concentrations for some commonly used antiretroviral drugs during pregnancy. We evaluated HIV-infected women (n = 68) in the third trimester of pregnancy in steady-state treatment with an HAART regimen administrated on a twice a day basis, which included 2 nucleoside reverse transcriptase inhibitors plus nelfinavir (NFV), lopinavir/ritonavir (LPV/r), or nevirapine (NVP). Blood samples were collected at predose (C(trough)). The following thresholds were used to define therapeutic drug concentrations-NFV: 0.8 microg/mL; LPV: 4.0 microg/mL/1.0 microg/mL (experienced/naive); and NVP: 3.1 microg/mL. At predose sampling, adequate drug concentrations were found in a higher proportion of women receiving NFV (70.8%) and LPV (75.0%) than NVP (55.6%). Median C(trough) plasma concentrations were 1.2 microg/mL for NFV, 5.5 microg/mL for LPV, and 3.1 microg/mL for NVP. Women receiving lopinavir/ritonavir had the lowest rates of detectable (>50 copies/mL) HIV RNA (15.4%) compared with rates of 22.2% and 41.7% among women receiving NVP and NFV, respectively. Genotypic resistance was detected in 50% of women with detectable HIV RNA for whom samples were available for testing. Subtherapeutic predose concentrations among HIV-infected pregnant women were more commonly found with NVP than with protease inhibitors. LPV administration was associated with the best viral load suppression.

Background: Few studies have assessed the determinants of birthweight in newborns from HIV-positive mothers in analyses that adjusted for different gestational age at delivery., Method: We calculated gestational age-adjusted birthweight Z-score values in a national series of 600 newborns from women with HIV and in 600 newborns from HIV-negative women matched for gender and gestational age. The determinants of Z-score values in newborns from HIV-positive mothers were assessed in univariate and multivariate regression analyses., Results: Compared to newborns from HIV-negative women, newborns from HIV-positive women had significantly lower absolute birthweight (2799 vs. 2887 g; p = .007) and birthweight Z score (-0.430 vs. -0.222; p < .001). Among newborns from mothers with HIV, the maternal characteristics associated with significantly lower Z-score values in univariate analyses were recent substance use (Z-score difference [ZSD] 0.612, 95% CI 0.359-0.864, p < .001), smoking >10 cigarettes/day (ZSD 0.323, 95% CI 0.129-0.518, p = .001), absence of pregnancies in the past (ZSD 0.200, 95% CI 0.050-0.349, p = .009), no antiretroviral treatment in the past (ZSD 0.186, 95% CI 0.044-0.327, p = .010), and Caucasian ethnicity compared to Hispanic (ZSD 0.248, 95% CI 0.022-0.475, p = .032). Body mass index (BMI) at conception and maternal glycemia levels during pregnancy were also significantly related to birthweight Z scores. Glycemia, BMI, and recent substance use maintained a significant association with Z-score values in multivariate analyses. In the multivariate analysis, the only factors significantly associated with Z-score values below the 10th percentile were recent substance use (adjusted odds ratio [AOR] 3.17, 95% CI 1.15-8.74) and smoking (AOR 2.26, 95% CI 1.13-4.49)., Discussion: We identified several factors associated with gestational age-adjusted birthweight in newborns from women with HIV. Smoking and substance use have a significant negative impact on intrauterine growth, which adds to an independent HIV-related effect on birthweight. Prevention and information on this issue should be reinforced in women with HIV of childbearing age to reduce the risk of negative outcomes in their offspring.

Purpose: To analyze the changes over two decades in HIV-infected pregnant women followed at a highly specialized regional center for antenatal care in southern Italy., Method: Since 1985, all HIV-infected pregnant women attending our center have been monitored using progressively updated protocols., Results: By December 2006, 230 deliveries in 159 women had been monitored. Deliveries in HIV-infected women increased from 0.16% (4/2,499) of all deliveries in 1985 to 0.73% (15/2,042) in 2006. The sociodemographic profile of the women changed greatly over the study period, and there was a shift from injecting drug use to heterosexual contact as the main transmission route and an increased proportion of foreign women. Subsequent to improvements in clinical care, the proportion of infected pregnant women receiving antiretroviral treatment increased from 27% (17/63) before 1996 to 81% (63/78) in 2006, with a corresponding decrease in the mother-to-child transmission rate from 36% (16/44) to 0.6% (1/157)., Conclusion: The increasing number of HIV-infected pregnant women can be attributed to nonselective antenatal HIV screening, the spread of HIV infection through heterosexual contacts, and the desire of HIV-infected women to have children. In this context, highly specialized reference centers can play an important role in providing HIV-infected pregnant women with optimal care and in reducing mother-to-child transmission rates to very low levels.

Background: In pregnant women taking antiretroviral treatment at conception treatment may be transiently stopped for safety concerns. Limited data are available on the consequences of such discontinuations., Methods: We used data from a national study to compare different treatment pathways during pregnancy. Overall, 321 women were evaluated and classified into three groups: women not on treatment at conception and who started treatment during pregnancy (starters; n=91); women on treatment at conception who temporarily discontinued treatment during first trimester (discontinuers; n=114); and women on treatment at conception who maintained treatment (continuers; n=116)., Results: At conception, the three groups had similar CD4+ T-cell counts (499, 495 and 470 cells/mm3, respectively; P>0.10); starters had significantly higher median HIV RNA levels at conception (5,690 copies/ml) compared with both continuers (58 copies/ml, P<0.001) and discontinuers (49 copies/ml, P<0.001). Continuers maintained undetectable HIV RNA at all pregnancy trimesters, while discontinuers showed at first and second trimester transient negative effects on HIV (4,776 and 386 copies/ml, respectively) and CD4+ T-cell levels (376 and 392 cells/mm3, respectively), which were reversed at last trimester (52 copies/ml and 432 cells/mm3, respectively). No significant differences were observed among the groups in HIV RNA and CD4+ T-cell counts at third trimester, preterm delivery, low birth weight or mode of delivery. The number of cases of HIV transmission and birth defects were too limited to allow comparisons., Conclusions: Early discontinuation of antiretroviral treatment in pregnancy produces transient virological and immunological effects without precluding the achievement of a good viral suppression at the end of pregnancy; no clinical consequences were observed.

The health-related quality of life (HRQoL) outcomes in HIV-infected, treatment-naive patients starting different HAART regimens in a 3-year, randomized, multinational trial were compared. HRQoL was measured in a subgroup of patients enrolled in the INITIO study (153/911), using a modified version of the MOS-HIV questionnaire. The regimens compared in the INITIO trial were composed by two NRTIs (didanosine + stavudine) plus either an NNRTI (efavirenz) or a PI (nelfinavir), or both (efavirenz + nelfinavir). Primary HRQoL outcomes were Physical and Mental Health Summary scores (PHS and MHS, respectively). During follow-up, an increase of PHS score was observed in all treatment arms. The MHS score remained substantially unchanged with the four-drug combination and showed with both NNRTI- and PI-based three-drug regimens a marked trend toward improvement, which became statistically significant when a multiple imputation method was used to adjust for missing data. Overall, starting all the combination regimens compared in the INITIO study was associated with a maintained or slightly improved HRQOL status, consistently with the positive immunological and virological changes observed in the main study. The observed differences in the MHS indicate a possible HRQoL benefit associated to the use of three-drug, two-class regimens and no additional benefit for the use of four-drug, three-class regimens, confirming that three-drug, two-class regimens that include two NRTIs plus either an NNRTI or a PI should be preferred as initial treatment of HIV infection.

We used data from the main surveillance study of HIV and pregnancy in Italy to evaluate possible differences in pregnancy care and outcomes according to nationality. Among 960 women followed in 2001-06, 33.5% were of foreign nationality, mostly from African countries. Foreign women had lower rates of preconception counselling and planning of pregnancy. They had more frequently HIV diagnosed during pregnancy, with a later start of antiretroviral treatment and lower treatment rates at all trimesters but not when the entire pregnancy, including delivery, was considered. No differences were observed between the two groups in ultrasonography assessments, hospitalisations, AIDS events, intrauterine or neonatal deaths, and mode and complications of delivery. Foreign women had a slightly lower occurrence of preterm delivery and infants with low birthweight. The results indicate good standards of care and low rates of adverse outcomes in pregnant women with HIV in Italy, irrespective of nationality. Specific interventions, however, are needed to increase the rates of counselling and HIV testing before pregnancy in foreign women.

Lipid values were measured during pregnancy in HIV-infected, treatment-experienced women. A previous history of lipodystrophy was associated with significantly higher triglyceride values at all pregnancy trimesters. In multivariate analyses lipodystrophy independently increased the risk of hypertriglyceridemia by threefold at the first trimester, and by eightfold at the second and third trimesters. Protease inhibitor treatment was also independently associated with hypertriglyceridemia.

Methods: Data from a large national surveillance study was used to describe antiretroviral regimens in pregnant women with HIV, with particular reference to the presence at conception of antiretroviral treatments contraindicated in pregnancy. Therapeutic changes during pregnancy were also analysed., Results: Among 334 women on antiretroviral treatment at conception, less than half (42.4%) reported current pregnancy as planned. A large number of different regimens (80) was observed. All the regimens included at least one nucleoside or nucleotide reverse transcriptase inhibitor. Non-nucleoside reverse transcriptase inhibitors and protease inhibitors were present in similar proportions (39.2% and 40.7%, respectively). The most commonly used drugs were lamivudine (83.2% of regimens), zidovudine (50.0%), stavudine (d4T; 38.0%), nevirapine (25.7%), didanosine (ddl; 17.7%) and nelfinavir (17.7%). Treament with efavirenz (13.5% of regimens) and ddl+d4T (9.6%) was markedly frequent. Use of efavirenz at conception was associated with a subsequent treatment change during pregnancy (odds ratio [OR]: 13.2.; 95% confidence interval [CI]: 3.2-53.8, P < 0.001). A similar but less strong association was found for ddl (OR: 1.8; 95% CI: 1.03-3.25, P = 0.033), whereas being on nevirapine was associated with a lower risk (OR: 0.58; 95% CI: 0.38-0.81, P = 0.013)., Conclusions: Our data show that treatment at conception frequently represents the regimen previously selected for the treatment of the non-pregnant woman. The observed rates of exposure to contraindicated treatment should lead prescribing physicians to consider in HIV-positive women therapeutic choices that take into account the likelihood of an unplanned pregnancy. Such an approach is likely to reduce not only unintended exposures to contraindicated drugs, but also therapeutic changes during pregnancy.

Purpose: To describe the cost of hospitalization and treatment in patients with very advanced disease who tart different regimens based on a protease inhibitor (PI)., Method: An observational retrospective analysis was performed on data from a 48-week randomized, multicenter study. Analysis was based on a subgroup of centers that were geographically defined. Costs of ordinary hospital admissions and of antiretroviral treatment were considered. Incidence of hospitalization and number of days free from hospitalization during the period of observation were calculated. Cost and hospitalization measures were compared among patients receiving three different therapeutic regimens: only PI, PI plus one nucleoside, or PI plus two nucleosides. A multivariate analysis was used to assess cost differences, controlling for variables potentially able to influence outcome., Results: Overall, among 166 patients starting PI (PI plus two nucleosides, 71;PI plus one nucleoside, 65; only PI, 30), 162 ordinary hospital admissions were observed during about 1 year of follow-up. Monthly rates of admission per person and incidence of first hospitalization on 100 person-months showed a clear inverse relationship with the number of drugs comprising the baseline treatment regimen, with the lower rates for the triple therapy group (0.06 and 3.9, respectively), intermediate values for the dual therapy group (0.10 and 8.1, respectively), and higher rates for the PI monotherapy group (0.15 and 13.7, respectively). The average number of days free from hospitalization per month was 29.5 in the triple therapy group, 28.6 in the dual therapy group, and 27.9 in the monotherapy group. The results of cost analysis showed, despite higher cost of antiretroviral treatment, that global costs were progressively lower using regimens of increasing potency: Compared to PI monotherapy, global cost (costs of antiretroviral treatment and of hospitalizations combined) per month per patient was 31.9% lower for the triple therapy group and 19.3% lower for the dual therapy. Global cost for the triple therapy was 15.7% lower compared to global cost for dual therapy. After adjustment for CD4 count, AIDS status, and Karnofsky score, both hospitalization costs and global costs were significantly lower for triple therapy compared to monotherapy (p =.002 and.039, respectively)., Conclusion: In advanced and nucleoside-experienced patients, PI-containing regimens have a differential impact according to the overall strength of the regimen, with the best effects on both hospitalizations and treatment costs obtained using PI within potent combination regimens.

The prevalence and the genotypic and phenotypic characteristics of multinucleoside-resistant (MNR) human immunodeficiency virus type 1 (HIV-1) variants in Europe were investigated in a multicenter study that involved centers in nine European countries. Study samples (n = 363) collected between 1991 and 1997 from patients exposed to two or more nucleoside analogue reverse transcriptase inhibitors (NRTIs) and 274 control samples from patients exposed to no or one NRTI were screened for two marker mutations of multinucleoside resistance (the Q151M mutation and a mutation with a 2-amino-acid insertion at codon 69, T69S-XX). Q151M was identified in six of the study samples (1. 6%), and T69S-XX was identified in two of the study samples (0.5%; both of them T69S-SS), but both patterns were absent among control samples. Non-NRTI (NNRTI)-related changes were observed in viral strains from two patients, which displayed the Q151M resistance pattern, although the patients were NNRTI naive. The patients whose isolates displayed multinucleoside resistance had received treatment with zidovudine and either didanosine, zalcitabine, or stavudine. Both resistance patterns conferred broad cross-resistance to NRTIs in vitro and a poor response to treatment in vivo. MNR HIV-1 is found only among multinucleoside-experienced patients. Its prevalence is low in Europe, but it should be closely monitored since it seriously limits treatment options.

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.

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.

This study assessed the activity and tolerability of an HIV-protease inhibitor, saquinavir, alone or in combination with zidovudine. A total of 92 previously untreated HIV-infected patients with CD4 cell counts < 300 cells/mm3 participated in a parallel, randomized double-blind study. Patients were randomized to receive one of five treatments, each three times a day: 600 mg of saquinavir; 200 mg of zidovudine; 75, 200 or 600 mg of saquinavir in combination with 200 mg of zidovudine. The primary treatment period was 16 weeks, with monthly extensions in patients who did not show major disease progression or toxicity. The main measures of the efficacy of therapy used were changes in CD4 cell counts and in the concentration of HIV-1 RNA in the plasma (as determined by quantitative polymerase chain reaction). The 600 mg dose of saquinavir in combination with zidovudine induced a 1.6 log (after 4 weeks) and a 0.7 log (after 16 weeks) median reduction in plasma RNA concentration; this reduction was greater than those seen in the other four treatment groups. The combination of 600 mg of saquinavir with zidovudine also resulted in a larger and more sustained improvement in the CD4 cell count than either saquinavir or zidovudine monotherapy or the other combination therapies. In the group receiving 200 mg of saquinavir in combination with zidovudine, the maximal median change in CD4 cell count occurred at week 2 (85 cells/mm3), and by week 16 had fallen to 15 cells/mm3. In the group receiving 600 mg of saquinavir plus zidovudine, the median change in CD4 cell count remained high for the 16-week period (median change of 48 cells/mm3 at week 2 and 61 cells/mm3 at week 16). Saquinavir was safe and very well tolerated, either alone or in combination with zidovudine. The incidence of adverse events was greater in the four groups receiving zidovudine therapy, and all the most commonly reported adverse events have previously been associated with zidovudine therapy. Few changes in laboratory values occurred during the study, except for known zidovudine-associated toxicities. The most frequent abnormalities were raised aspartate aminotransferase and alanine aminotransferase levels, depressed calcium levels, and abnormally high or low phosphate levels. Despite the low oral bioavailability of saquinavir, combined virological and immunological data show definite antiviral activity in vivo for the combination of saquinavir at 600 mg plus zidovudine at 200 mg (each three times daily). The combination of drugs with different mechanisms of action represents an advance in the treatment of HIV infection.

Objective: To evaluate the effect of transmission category and demographic, clinical and immunological characteristics on the progression to AIDS and survival of zidovudine-treated patients., Design: Prospective multicentre cohort study of symptomatic non-AIDS patients., Setting: Eighty-three clinical centres reporting data to the National Zidovudine Registry., Patients: A total of 1468 patients enrolled between July 1987 and January 1991 were analysed., Main Outcome Measures: Three-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., Results: Faster progression was associated with increasing age (8% risk increase for a 5-year increase), low baseline CD4+ count (39% risk increase for 100 x 10(6)/l cells decrease), and zidovudine > 1000 mg/day (20% risk increase compared with < or = 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., Conclusions: Our 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 Kaposi's sarcoma.

In 1990 the results of a placebo-controlled study conducted within the AIDS Clinical Trials Group (ACTG 019) showed that in the short term, zidovudine was effective in slowing progression to advanced disease in HIV-infected asymptomatic patients with low CD4 cell counts. More recently, the preliminary results of the Concorde Trial suggested that while the data at 1 year agreed with those of ACTG 019, no sustained clinical benefit was detectable at 3 years for early versus deferred therapy. Therefore, the length of the clinical usefulness of zidovudine in this population is still to be determined. We evaluated the 2-year outcome of zidovudine therapy in asymptomatic patients through the prospective follow-up of a cohort of 936 subjects with low CD4+ (< 500/mm3) counts who strictly satisfied, at enrollment, the inclusion and exclusion criteria of the ACTG 019 trial. The clinical end point of the analysis was the development of AIDS. The majority (72.2%) of the individuals in the cohort acquired HIV infection through intravenous drug use; 26.6% were women. The median baseline CD4 cell count was 308/mm3. At 55 weeks of mean follow-up, the progression rate to AIDS (3.2 events per hundred person-years) appears to be comparable to that already reported at the same mean follow-up time for the ACTG 019 zidovudine-treated asymptomatic patients. After 124 weeks of mean follow-up, the overall rate of progression to AIDS was 5.2 per hundred person-years.(ABSTRACT TRUNCATED AT 250 WORDS)

This study reports the effects of the nucleoside analogs dideoxyinosine (DDI) and 3'-azido-3'-deoxythymidine (AZT) on mammalian embryonic development. When administered to pregnant mice (at concentrations ranging from 10 to 300 mg/kg/day), through all or part of gestation, AZT and DDI did not result in any visible effect on mouse embryos nor did they cause any obvious malformation or defect at birth or during postnatal growth. Similarly, when embryonic or fetal mouse or human cells (from brain, limb buds, or different organ rudiments) were exposed to AZT or DDI in vitro, cytotoxicity was observed only in the mM range, with AZT showing slightly higher cytotoxicity and brain cells appearing slightly more sensitive to both nucleosides. However, even in cultures treated with very high concentrations of AZT or DDI, the reduction in the number of terminally differentiated skeletal myotubes, cardiocytes, neurons, and chondrocytes was similar to the reduction in the total number of cells, indicating that AZT and DDI did not selectively inhibit differentiation of any of the above-mentioned cell types. Finally, preimplantation mouse embryos (at the 2-cell or 4-cell stage), treated in vitro with micromolar concentrations of AZT, were arrested at the 4-cell stage. DDI or other nucleoside analogs tested did not have this effect.

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.

We evaluated the incidence of AIDS dementia complex (ADC) in groups of patients who acquired infection through different risk behaviours, and attempted to evaluate the possible role of zidovudine (AZT) treatment in preventing or delaying the onset of ADC. The Italian National AIDS Registry was used to study patients with AIDS for whom ADC was reported as an index disease. Relative risk of presenting ADC between different patient categories has been determined. Logistic regression was used to analyse temporal trends in the proportion of AIDS cases presenting with ADC. Of the 6466 cases reported between August '87 and August '90, ADC was seen in 640 (9.9%). I. V. drug addicts had twice the risk (estimated odds ratio: 1.9; 95% confidence interval: 1.5-2.6, p less than 0.001), compared to homo/bisexuals, of presenting with ADC. There is significant evidence (p less than 0.0001) that after a progressive increase in the period '87-'89, it began a definite decrease in the monthly proportion of ADC cases, starting August '89. AZT was introduced in Italy in July 1987 for patients with AIDS or advanced ARC. The incidence of AIDS dementia complex at the moment of AIDS diagnosis in our population of patients, began to decline 24 months after the introduction of systematic AZT treatment in Italy. This could have been due to inhibition of HIV replication in the Central Nervous System among patients who initiated AZT-treatment before developing full-blown AIDS.