Efficacy and safety of therapies for COVID-19 in pregnancy: a systematic review and meta-analysis.

BACKGROUND: Clinical evidence suggests that pregnant women are more vulnerable to COVID-19, since they are at increased risk for disease progression and for obstetric complications, such as premature labor, miscarriage, preeclampsia, cesarean delivery, fetal growth restriction and perinatal death. Despite this evidence, pregnant women are often excluded from clinical trials, resulting in limited knowledge on COVID-19 management. The aim of this systematic review and meta-analysis is to provide better evidence on the efficacy and safety of available COVID-19 treatment in pregnant women. METHODS: Four authors searched major electronic databases from inception until 1 st November-2022 for controlled trials/observational studies, investigating outcomes after the administration of anti-SARS-CoV-2 treatments in pregnant women affected by COVID-19. The analyses investigated the cumulative incidence of delivery and maternal outcomes in pregnant women, comparing those taking active medication vs standard care. Risk ratios (RRs) with 95% confidence intervals were calculated. Statistical significance was assessed using the random effects model and inverse-variance method. This systematic review and meta-analysis was conducted in accordance with the updated 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol has been registered in Prospero (number registration: CRD42023397445). RESULTS: From initially 937 non duplicate records, we assessed the full texts of 40 articles, finally including ten studies. In six studies, including 1627 patients, the use of casirivimab/imdevimab (CAS/IMD), remdesivir, and IFN-alpha 2b significantly decreased the need of cesarean section ((RR = 0.665; 95%CI: 0.491-0.899; p = 0.008; I 2 = 19.5%;) (Table 1, (Fig. 1). Treatments did not decrease the risk of preterm delivery, admission to neonatal ICU, or stillbirth/perinatal loss (p-values > 0.50 for all these outcomes) and did not prevent the progression of disease towards severe degrees (k = 8; 2,374 pregnant women; RR = 0.778; 95%CI: 0.550-1.099; p = 0.15; I 2 = 0%). Moreover, the use of medications during pregnancy did not modify the incidence of maternal death in two studies (Table 2). CONCLUSIONS: To our analysis, CAS/IMD, remdesivir, and IFN alpha 2b reduced the number of cesarean sections but demonstrated no effect on disease progression and other obstetric and COVID-19 related outcomes. The inability to evaluate the influence of viral load on illness development in pregnant women was attributed to lack of data. In our systematic review, no major side effects were reported. Though, it is essential for the medical community to focus more on clinical trials and less on episodic case reports and case series, with standardization of fetal and maternal outcomes.

CD4/CD8 ratio in pregnant women with HIV and its association with pregnancy outcome: data from a national study in Italy.

PURPOSE: To evaluate associations between CD4/CD8 ratio and pregnancy outcomes in women with HIV. METHODS: We evaluated, in a national study of pregnant women with HIV receiving antiretroviral treatment (ART), values of CD4/CD8 ratio at entry in pregnancy, changes between first and third trimester, and possible associations with preterm delivery, low birthweight, and HIV-RNA < 50 copies/ml at third trimester in univariate and multivariate analyses. RESULTS: Among 934 women, 536 (57.4%) were already on ART at conception. CD4/CD8 ratio (baseline value 0.570) increased significantly between the first and third trimesters, particularly in women who started ART in pregnancy (+ 0.163, vs. + 0.036 in women already on treatment). The rate of CD4/CD8 ratio normalization, defined by achieving a ratio ≥ 1 at the third trimester, was 13.2%. In multivariable analyses, women who entered pregnancy with a CD4/CD8 ratio < 0.3, compared to women with ratio ≥ 1, were almost four-times less likely to have third-trimester HIV-RNA < 50 copies/ml (AOR 0.258, 95%CI 0.111-0.601), and more than twice as likely to have preterm delivery (AOR 2.379, 95%CI 1.082-5.232). For preterm delivery, also a baseline CD4/CD8 ratio between 0.3 and 0.45 was significantly associated with an increased risk (AOR: 3.415, 95%CI 1.690-6.900). CONCLUSION: We described for the first time independent associations of low CD4/CD8 ratio with preterm delivery and HIV-RNA suppression.

Prevalence, Correlates and Outcomes of Smoking in Pregnant Women with HIV: A National Observational Study in Italy.

Background: Few studies have evaluated in pregnant women with HIV the prevalence of smoking and its associations with maternal and neonatal outcomes. Objectives: to assess the prevalence of smoking among women with HIV in early pregnancy and the association between smoking and pregnancy outcomes in this particular population. Methods: We used data from a multicenter observational study to define the prevalence of smoking in women with HIV in early pregnancy, and the role of smoking status and intensity as risk factors for adverse maternal and neonatal outcomes. Main outcome measures were fetal growth restriction [FGR], preterm delivery [PD] and low birthweight [LB], evaluated in univariate and multivariate analyses. Results: The overall (2001-2018) prevalence of reported smoking (at least one cigarette/day) was 25.6% (792/3097), with a significant decrease in recent years (19.0% in 2013-2018). Women who smoked were less commonly African, had lower body mass index, older age, a longer history of HIV infection and higher CD4 counts. In univariate analyses, smokers were significantly more likely to have PD, LB, FGR and detectable HIV viral load at third trimester. Multivariable analyses confirmed for smokers a significantly higher risk of LB (adjusted odds ratio [AOR]: 1.69, 95%CI 1.22-2.34) and FGR (AOR 1.88, 95%CI 1.27-2.80), while the associations with detectable HIV and PD were not maintained. Conclusions: The common prevalence of smoking among pregnant women with HIV and its association with adverse outcomes indicates that smoking cessation programs in this population may have a significant impact on neonatal and maternal health.

Persistence of ZIKV-RNA in the cellular fraction of semen is accompanied by a surrogate-marker of viral replication. Diagnostic implications for sexual transmission.

As asymptomatic infections represent 80% of ZIKV-infected individuals, sexual transmission is a rising concern. Recent studies highlighted a preferential association of ZIKV with the cellular fraction (CF) of different specimen types. Our aim was to evaluate the presence of ZIKV-RNA in different body fluids, focusing on semen specimens to assess the ZIKV-RNA content in either the unfractionated sample, its CF or seminal plasma (SP). In addition, to establish if the presence of ZIKV genome was associated with active virus replication, we measured the levels of negative-strand ZIKV-RNA. ZIKV total-RNA was detected in blood, urine and unfractionated semen, and neg-RNA in semen CF and SP samples longitudinally collected from two ZIKV-positive men followed at the National Institute for Infectious Diseases "L. Spallanzani", Italy. In both patients, ZIKV total-RNA was detected in CF with ct values always lower than in the corresponding unfractionated samples, and was observed even in the CF from negative unfractionated semen samples. In Patient 2, neg-RNA was also detected in CF, suggesting ongoing viral replication. Our results demonstrate higher clinical sensitivity of CF as compared to whole semen testing, emphasizing the need to extend ZIKV-RNA testing to CF, to rule out virus presence and the possible risk of sexual transmission.

Early antiretroviral treatment (eART) limits viral diversity over time in a long-term HIV viral suppressed perinatally infected child.

BACKGROUND: HIV genetic diversity implicates major challenges for the control of viral infection by the immune system and for the identification of an effective immunotherapeutic strategy. With the present case report we underline as HIV evolution could be effectively halted by early antiretroviral treatment (eART). Few cases supported this evidence due to the difficulty of performing amplification and sequencing analysis in long-term viral suppressed patients. Here, we reported the case of limited HIV-1 viral evolution over time in a successful early treated child. CASE PRESENTATION: A perinatally HIV-1 infected infant was treated within 7 weeks of age with zidovudine, lamivudine, nevirapine and lopinavir/ritonavir. At antiretroviral treatment (ART) initiation HIV-1 viral load (VL) and CD4 percentage were >500,000 copies/ml and 35%, respectively. Plasma genotypic resistance test showed a wild-type virus. The child reached VL undetectability after 33 weeks of combination antiretroviral therapy (cART) since he maintained a stable VL <40copies/ml. After 116 weeks on ART we were able to perform amplification and sequencing assay on the plasma virus. At this time VL was <40 copies/ml and CD4 percentage was 40%. Again the genotypic resistance test revealed a wild-type virus. The phylogenetic analysis performed on the HIV-1 pol sequences of the mother and the child revealed that sequences clustered with C subtype reference strains and formed a monophyletic cluster distinct from the other C sequences included in the analysis (bootstrap value >90%). Any major evolutionary divergence was detected. CONCLUSIONS: eART limits the viral evolution avoiding the emergence of new viral variants. This result may have important implications in host immune control and may sustain the challenge search of new personalized immunotherapeutic approaches to achieve a prolonged viral remission.

Persistent detection of Zika virus RNA in semen for six months after symptom onset in a traveller returning from Haiti to Italy, February 2016.

A man in his early 30s reported in January 2016 a history of fever, asthenia and erythematous rash during a stay in Haiti. On his return to Italy, ZIKV RNA was detected in his urine and saliva 91 days after symptom onset, and in his semen on day 188, six months after symptom onset. Our findings support the possibility of sexual transmission of ZIKV and highlight the importance of continuing to investigate non-vector-borne ZIKV infection.

Atazanavir and lopinavir profile in pregnant women with HIV: tolerability, activity and pregnancy outcomes in an observational national study.

BACKGROUND: Atazanavir and lopinavir represent the main HIV protease inhibitors recommended in pregnancy, but comparative data in pregnant women are limited. METHODS: Women from a national observational study, exposed in pregnancy to either atazanavir or lopinavir, were compared for glucose and lipid profiles, liver function tests, CD4 count, HIV RNA and main pregnancy outcomes. Statistical methods included univariate and multivariable analyses. RESULTS: The study population included 428 pregnancies (lopinavir, 322; atazanavir, 106). The lopinavir group was characterized by higher rates of HIV diagnosis in pregnancy and treatment indication for maternal health, lower CD4 counts, higher HIV RNA levels, less frequent antiretroviral treatment at conception and shorter duration of drug exposure during pregnancy. No differences in pregnancy outcomes, glucose metabolism and weight gain were observed. The two groups also showed in a multivariable analysis similar odds for detectable HIV RNA in the third trimester (adjusted OR 0.85, 95% CI 0.35-2.10, P = 0.730). Total lipid levels were significantly higher in the lopinavir group (median values in the third trimester 239 versus 221 mg/dL for total cholesterol and 226 versus 181 mg/dL for triglycerides; P < 0.001 for both comparisons) and bilirubin levels were significantly higher in the atazanavir group (1.53 versus 0.46 mg/dL, P < 0.001). CONCLUSIONS: In this observational study atazanavir and lopinavir showed similar safety and activity in pregnancy, with no differences in the main pregnancy outcomes. Atazanavir use was associated with a better lipid profile and with higher bilirubin levels. Overall, the study findings confirm that these two HIV protease inhibitors represent equally valid alternative options.

Pregnancy outcomes in HIV-infected women of advanced maternal age.

BACKGROUND: There is limited information on pregnancy outcomes in women with HIV who are of a more advanced maternal age. METHODS: Data from a national observational study in Italy were used to evaluate the risk of nonelective cesarean section, preterm delivery, low birthweight, major birth defects, and small gestational age-adjusted birthweight according to maternal age (<35 and ≥35 years, respectively). RESULTS: Among 1,375 pregnancies with live births, 82.4% of deliveries were elective cesarean sections, 15.8% were nonelective cesarean sections, and 1.8% were vaginal deliveries. Rates of nonelective cesarean section were similar among mothers ≥35 and <35 years (odds ratio [OR], 1.22; 95% CI, 0.90-1.65;P = .19). Preterm delivery and low birthweight were significantly more common among women ≥35 years in univariate but not in multivariate analyses. Newborns from women ≥35 and <35 years showed no differences inZ scores of birthweight, with a similar occurrence of birthweight <10th percentile (12.1% vs 12.0%; OR, 1.02; 95% CI, 0.71-1.46;P = .93). The overall rate of birth defects was 3.4% (95% CI, 2.4-4.4), with no differences by maternal age (≥35 years, 3.5%; <35 years, 3.3%; OR, 1.05; 95% CI, 0.56-1.98;P = .88). DISCUSSION: In this study of pregnant women with HIV, older women were at higher risk of some adverse pregnancy outcomes, such as preterm delivery and low birthweight. The association, however, did not persist in multivariable analyses, suggesting a role of some predisposing factors associated with older age.

HIV-1 drug resistance in recently HIV-infected pregnant mother's naïve to antiretroviral therapy in Dodoma urban, Tanzania.

BACKGROUND: HIV resistance affects virological response to therapy and efficacy of prophylaxis in mother-to-child-transmission. The study aims to assess the prevalence of HIV primary resistance in pregnant women naïve to antiretrovirals. METHODS: Cross sectional baseline analysis of a cohort of HIV + pregnant women (HPW) enrolled in the study entitled Antiretroviral Management of Antenatal and Natal HIV Infection (AMANI, peace in Kiswahili language). The AMANI study began in May 2010 in Dodoma, Tanzania. In this observational cohort, antiretroviral treatment was provided to all women from the 28th week of gestation until the end of the breastfeeding period. Baseline CD4 cell count, viral load and HIV drug-resistance genotype were collected. RESULTS: Drug-resistance analysis was performed on 97 naïve infected-mothers. The prevalence of all primary drug resistance and primary non-nucleoside reverse-transcriptase inhibitors resistance was 11.9% and 7.5%, respectively. K103S was found in two women with no M184V detection. HIV-1 subtype A was the most commonly identified, with a high prevalence of subtype A1, followed by C, D, C/D recombinant, A/C recombinant and A/D recombinant. HIV drug- resistance mutations were detected in A1 and C subtypes. CONCLUSION: Our study reports an 11.9% prevalence rate of primary drug resistance in naïve HIV-infected pregnant women from a remote area of Tanzania. Considering that the non-nucleoside reverse-transcriptase inhibitors are part of the first-line antiretroviral regimen in Tanzania and all of Africa, resistance surveys should be prioritized in settings where antiretroviral therapy programs are scaled up.

The role of Lung Ultrasound in the diagnosis of SARS-COV-2 disease in pregnant women.

AIM: To evaluate the role of lung ultrasound (LUS) in recognizing lung abnormalities in pregnant women affected by COVID-19 pneumonia. MATERIALS AND METHODS: An observational study analyzing LUS patterns in 60 consecutively enrolled pregnant women affected by COVID-19 infection was performed. LUS was performed by using a standardized protocol by Soldati et al. The scoring system of LUS findings ranged from 0 to 3 in increasing alteration severity. The highest score obtained from each landmark was reported and the sum of the 12 zones examined was calculated. RESULTS: Patients were divided into two groups: 26 (43.3%) patients with respiratory symptoms and 32 (53.3%) patients without respiratory symptoms; 2 patients were asymptomatic (3.3%). Among the patients with respiratory symptoms 3 (12.5%) had dyspnea that required a mild Oxygen therapy. A significant correlation was found between respiratory symptoms and LUS score (p < 0.001) and between gestational weeks and respiratory symptoms (p = 0.023). Regression analysis showed that age and respiratory symptoms were risk factors for highest LUS score (p < 0.005). DISCUSSION: LUS can affect the clinical decision course and can help in stratifying patients according to its findings. The lack of ionizing radiation and its repeatability makes it a reliable diagnostic tool in the management of pregnant women.

Treatment with valacyclovir during pregnancy for prevention of congenital cytomegalovirus infection: a real-life multicenter Italian observational study.

BACKGROUND: Valacyclovir is the only treatment demonstrated to be effective for the prevention of vertical transmission of cytomegalovirus within a clinical randomized, placebo-controlled trial and has been reimbursed by the Italian National Health System since December 2020. OBJECTIVE: This study reported the results of a real-life Italian multicenter observational study on cytomegalovirus infection in pregnancy evaluating the effect of the introduction of valacyclovir in the clinical practice for the prevention of vertical transmission of cytomegalovirus. STUDY DESIGN: The outcomes of women who received valacyclovir treatment and their fetuses or newborns were compared with those of a retrospective cohort observed between 2010 and 2020 who did not receive the antiviral treatment. The inclusion criterion was the diagnosis of cytomegalovirus primary infection occurring in the periconceptional period or up to 24 weeks of gestation. The primary outcome was the transmission by the time of amniocentesis. The secondary outcomes were termination of pregnancy, transmission at birth, symptomatic infection at birth, and a composite outcome (termination of pregnancy or transmission at birth). RESULTS: A total of 447 pregnant women from 10 centers were enrolled, 205 women treated with valacyclovir (called the valacyclovir group, including 1 twin pregnancy) and 242 women not treated with valacyclovir (called the no-valacyclovir group, including 2 twin pregnancies). Valacyclovir treatment was significantly associated with a reduction of the diagnosis of congenital cytomegalovirus infection by the time of amniocentesis (weighted odds ratio, 0.39; 90% confidence interval, 0.22-0.68; P=.005; relative reduction of 61%), termination of pregnancy (weighted odds ratio, 0.36; 90% confidence interval, 0.17-0.75; P=.0021; relative reduction of 64%), symptomatic congenital cytomegalovirus infection at birth (weighted odds ratio, 0.17; 90% confidence interval, 0.06-0.49; P=.006; relative reduction of 83%). The treatment had no significant effect on the rate of diagnosis of congenital cytomegalovirus infection at birth (weighted odds ratio, 0.85; 90% confidence interval, 0.57-1.26; P=.500), but the composite outcome (termination of pregnancy or diagnosis of congenital cytomegalovirus infection at birth) occurred more frequently in the no-valacyclovir group (weighted odds ratio, 0.62; 90% confidence interval, 0.44-0.88; P=.024). Of note, the only symptomatic newborns with congenital cytomegalovirus infection in the valacyclovir group (n=3) were among those with positive amniocentesis. Moreover, 19 women (9.3%) reported an adverse reaction to valacyclovir treatment, classified as mild in 17 cases and moderate in 2 cases. Lastly, 4 women (1.9%) presented renal toxicity with a slight increase in creatinine level, which was reversible after treatment suspension. CONCLUSION: Our real-life data confirm that valacyclovir significantly reduces the rate of congenital cytomegalovirus diagnosis at the time of amniocentesis with a good tolerability profile and show that the treatment is associated with a reduction of termination of pregnancy and symptomatic congenital cytomegalovirus infection at birth.

Evidence of Maternal Antibodies Elicited by COVID-19 Vaccination in Amniotic Fluid: Report of Two Cases in Italy.

With SARS-CoV-2 infection, pregnant women may be at a high risk of severe disease and adverse perinatal outcomes. A COVID-19 vaccination campaign represents the key strategy to combat the pandemic; however, public acceptance of maternal immunization has to be improved, which may be achieved by highlighting the promising mechanism of passive immunity as a strategy for protecting newborns against SARS-CoV-2 infection. We tested the anti-SARS-CoV-2 antibody response following COVID-19 full-dose vaccination in the serum and amniotic fluid of two pregnant women who presented between April and June 2021, at the Center for the Treatment and Prevention of Infections in Pregnancy of the National Institute for Infectious Diseases "L. Spallanzani", for antenatal consultancy. Anti-SARS-CoV-2 IgG was found in residual samples of amniotic fluid collected from both women at the 18th week of gestation (63 and 131 days after the second dose's administration). Titers in amniotic fluid mirrored the levels detected in serum and were inversely linked to the time from vaccination. Our results suggest that antibodies elicited by COVID-19 vaccination can cross the placenta and reach the fetus; therefore, they may offer passive immunity at birth. It is critical to fully understand the kinetics of the maternal response to vaccination, the efficiency of IgG transfer, and the persistence of antibodies in infants to optimize maternal immunization regimens.

T helper profile in pregnant women recovered from COVID-19.

T helper (Th) cell subsets play distinct and important roles during pregnancy. This work was focused on investigating the Th and cytokine profile in pregnant women recovered from COVID-19. To this aim, the frequency of Th1, Th2, Th17 subsets and the level of associated cytokines were analysed in pregnant women recovered from COVID-19 and in matched non-pregnant women. Principal component analysis highlighted a significant impact of pregnancy on Th profile with an increase of ex-Th17 subset and a parallel decrease of Th1 population. These modulations may participate in both preserving the pregnancy and reducing the risk of severe infection.

Glucose plasma levels and pregnancy outcomes in women with HIV.

BACKGROUND: There is limited information on the relation between glucose levels in pregnancy and adverse perinatal outcomes in HIV-infected pregnant women. OBJECTIVE: To evaluate the potential impact of fasting glucose levels on pregnancy outcomes in a large sample of pregnant women with HIV from a national study, adjusting for potential confounders. METHODS: Data from the Italian National Program on Surveillance on Antiretroviral Treatment in Pregnancy were used. The main outcomes evaluated in univariate and multivariable analyses were birthweight for gestational age>90th percentile (large for gestational age [LGA]), nonelective cesarean delivery, and preterm delivery. Glucose measurements were considered both as continuous and as categorical variables, following the HAPO study definition. RESULTS: Overall, 1,032 cases were eligible for the analysis. In multivariable analyses, a birthweight>90th percentile was associated with increasing fasting plasma glucose levels (adjusted odds ratio [AOR] per unitary (mg/dL) increase, 1.04; 95% CI, 1.01-1.06; P=.005), a higher body mass index, and parity of 1 or higher. A lower risk of LGA was associated with smoking and African ethnicity. A higher fasting plasma glucose category was significantly associated with LGA occurrence, and AORs for the glucose categories of 90-94 mg/ dL and 95-99 mg/dL were 3.34 (95% CI, 1.09-10.22) and 6.26 (95% CI, 1.82-21.58), respectively. Fasting plasma glucose showed no association with nonelective cesarean section [OR per unitary increase, 1.00; 95% CI, 0.98-1.02] or preterm delivery [OR per unitary increase, 1.00; 95% CI, 0.99-1.02]. CONCLUSIONS: In pregnant women with HIV, glucose values below the threshold usually defining hyperglycemia are associated with an increased risk of delivering LGA infants. Other conditions may independently contribute to adverse perinatal outcomes in women with HIV and should be considered to identify pregnancies at risk.

Association of COVID-19 case fatality rate with disease burden: an ecological analysis in Italy during the first wave.

OBJECTIVES: In Italy, the case fatality rate (CFR) of coronavirus disease 2019 (COVID-19) during the first wave of the pandemic showed significant geographic heterogeneity. The aim of this study was to explore the possible association between the CFR and measures of disease burden in the Italian regions using an ecological approach. METHODS: Cumulated regional data for the period February 24 to May 11, 2020 were analysed to assess the association of the CFR with the cumulative incidence of COVID-19 and the ratio between the maximum number of COVID-19 patients in intensive care units (ICU) and ICU beds available before the pandemic (ICU load), adjusting for median age of the patients at disease onset, number of nasopharyngeal swabs performed per confirmed case, and prevalence of chronic diseases . RESULTS: During the study period, the COVID-19 CFR in the Italian regions ranged between 5.0% and 18.4%. On multivariable regression analysis, the CFR was found to be significantly associated with the cumulative incidence (relative rate (RR) 1.02 per 100 cases/1 million increase), median patient age (RR 1.07 per 1 year increase), and ICU load (RR 1.72, 2.18, and 2.57, for >40-70% vs ≤40%, 70-140% vs ≤40%, and ≥140 vs ≤40%, respectively). CONCLUSIONS: A high burden of COVID-19 may contribute to increased disease fatality, possibly as a result of the increasing demand for care of critically ill patients beyond health system capability.

Role of NEDD8 in HIV-associated lipodystrophy.

The pathogenetic bases of HAART-associated lipodystrophy are still poorly known, even if it is clear that adipose tissue and its metabolism are sensitive to antiretroviral therapy alone and/or in combination with HIV infection. The NEDD8 system is essential for the regulation of protein degradation pathways involved in cell cycle progression, morphogenesis and tumorigenesis. We investigated the possible involvement of NEED8 in adipogenesis and, consequently, in HIV-related lipodystrophy. One hundred HIV-1-infected patients were included in the study. Using an in vitro model of adipogenesis we evaluated the effects on adipogenesis of the forced expression of NEDD8 together with efavirenz, stavudine, saquinavir, amprenavir and indinavir, belonging to the three main classes of anti-HIV medications. We showed that NEDD8 expression level is higher in the peripheral blood of HIV patients developing lipodystrophy. Coherently, forced expression of NEDD8 in an in vitro model of adipogenesis was able to perturb expression of some key proteins involved in adipogenesis, such as C/EBPalpha and PPARgamma, possibly acting throughout the NEDD8/p27/beta-catenin pathway. Moreover, three out of five evaluated drugs were able to affect adipocyte differentiation: efavirenz, stavudine and saquinavir. Finally, we have shown that NEDD8 was expressed in the fat tissue of lipodystrophic patients, being significantly higher in the lipodystrophic patients with respect to the controls, thus further confirming the altered NEDD8 expression in the fat tissue of HIV-infected patients affected by lipodystrophy. Taken together, our data support the hypothesis of an implication of NEDD8 through p27 and beta-catenin pathways in the disruption of adipogenesis and consequent lipodystrophy in patients affected by HIV infection under HAART therapy with qualitative and quantitative differences according to diverse antiretroviral treatments. These evidences indicate the NEDD8/beta-catenin/p27 pathway as a possible molecular target for prevention of lipodystrophy development in patients under HAART therapy.