Evolving treatment implementation among HIV-infected pregnant women and their partners: results from a national surveillance study in Italy, 2001-2015.

BACKGROUND: The current global and national indications for antiretroviral treatment (ART, usually triple combination therapy) in adolescent and adults, including pregnant women, recommend early ART before immunologic decline, pre-exposure chemoprophylaxis (PrEP), and treatment of HIV-negative partners in serodiscordant couples. There is limited information on the implementation of these recommendations among pregnant women with HIV and their partners. METHODS: The present analysis was performed in 2016, using data from clinical records of pregnant women with HIV, followed between 2001 and 2015 at hospital or university clinics within a large, nationally representative Italian cohort study. The study period was divided in three intervals of five years each (2001-2005, 2006-2010, 2011-2015), and the analysis evaluated temporal trends in rates of HIV diagnosis in pregnancy, maternal antiretroviral treatment at conception, prevalence of HIV infection among partners of pregnant women with HIV, and proportion of seronegative and seropositive male partners receiving antiretroviral treatment. RESULTS: The analysis included 2755 pregnancies in women with HIV. During the three time intervals considered the rate of HIV diagnosis in pregnancy (overall 23.3%), and the distribution of HIV status among male partners (overall 48.7% HIV-negative, 28.6% HIV-positive and 22.8% unknown) remained substantially unchanged. Significant increases were observed in the proportion of women with HIV diagnosed before pregnancy who were on antiretroviral treatment at conception (from 62.0% in 2001-2005 to 81.3% in 2011-2015, P < 0.001), and in the proportion of HIV-positive partners on antiretroviral treatment (from 73.3% in 2001-2005 to 95.8% in 2011-2015, P = 0.002). Antiretroviral treatment was administered in 99.1% of the pregnancies that did not end early because of miscarriage, termination, or intrauterine death, and in 75.3% of those not ending in a live birth. No implementation of antiretroviral treatment was introduced among male HIV-negative partners. CONCLUSIONS: The results suggest good implementation of antiretroviral treatment among HIV-positive women and their HIV-positive partners, but no implementation, even in recent years, of Pre-Exposure Prophylaxis (PrEP) among uninfected male partners. Further studies should assess the determinants of this occurrence and clarify the attitudes and the potential barriers to PrEP use.

Impact of antiretroviral medications on fasting lipid parameters.

It is widely accepted that metabolic disease in human immunodeficiency virus (HIV) develops at the intersection of traditional risk factors and HIV-specific contributors, but in observational studies it is difficult to dissect the contribution of the two. This review describes the metabolic impact of antiretroviral medications recommended in the first-line treatment in HIV-infected naive patients. At a clinical level, coronary heart disease screening and management will continue to be of paramount importance in the long-term management of HIV-positive patients on antiretroviral therapy.

Metabolic alterations in HIV-infected pregnant women: moving to metabolic tailoring of antiretroviral drugs.

The most striking effect of increased survival and improved quality of life in HIV-infected women undergoing antiretroviral therapy is the feasibility of motherhood-desire satisfaction. However, such advantages are often associated with drug-related metabolic toxicities, particularly relevant in the pregnancy context. Recent guidelines provide recommendations and trends for the use of antiretroviral therapy in pregnant women, but current literature falls short of providing specific insights on the need for metabolic monitoring and treatment in HIV-infected pregnant women. In this review we provide specific insight into the state-of-the-art of: detection, evaluation, and management of metabolic alterations in this special population. Pregnancy is in fact a metabolic transition process, potentially associated with specific diseases in the mother, in the newborn, and in the adulthood of the child. We will not simply discuss antiretroviral therapy metabolic toxicities, but rather their interaction with the physiological metabolic changes occurring during pregnancy. Close monitoring is needed to diagnose metabolic alterations that can lead to adverse outcomes in the mother, in the newborn, and potentially in adulthood. Lifestyle interventions and an appropriate metabolic tailoring of antiretroviral therapy drugs need to be considered in the prevention and treatment of metabolic alteration during pregnancy.

CD8 T-cell activation is associated with lipodystrophy and visceral fat accumulation in antiretroviral therapy-treated virologically suppressed HIV-infected patients.

OBJECTIVE: HIV-infected patients receiving antiretroviral treatment frequently accumulate fat at the abdominal level. It is unknown whether T-cell activation and immune phenotypes are associated with fat accumulation. Thus, the aim of the study was to search for an association between the presence of clinical lipodystrophy (LD), visceral and subcutaneous abdominal adipose tissue amount (VAT and SAT), and peripheral T-cell immune phenotypes. DESIGN: Cross-sectional study including 87 HIV-infected antiretroviral therapy-treated virologically suppressed and immune-reconstituted patients. METHODS: The patients were evaluated for clinical LD, VAT, SAT, homeostasis model of insulin resistance, and coronary artery calcium score (>10). T-cell activation (CD8/CD38), differentiation (CD4/CD8/CCR7/CD45RA), and expression/activation of the interleukin-7 (IL-7)/IL-7R system (CD4/CD8/CD127, IL-7, and CD4/CD8/pStat-5) were assessed by cytometry. RESULTS: In multivariable analyses, CD8 T-cell activation (CD38) was associated with lipoatrophy and central fat accumulation (respectively, ß = 5.63, P = 0.005, and ß = 4.19, P = 0.020). This was also the case for IL-7R expressing CD8⁺ T cells (CD127⁺) for lipoatrophy ß = 12.8, P = 0.003, and for central fat accumulation ß = 9.45, P = 0.016. CD8⁺ T-cell activation was also associated with VAT/total adipose tissue (ß = 0.01, P = 0.002) and SAT/VAT ratios (ß = -0.014, P = 0.015). As expected, VAT/total adipose tissue was an independent risk factor for homeostasis model of insulin resistance (r = 0.364, P = 0.028) and cardiovascular risk (coronary artery calcium, r = 0.406, P = 0.002). CONCLUSIONS: CD8⁺ T-cell activation was associated with LD and the relative amount of VAT in antiretroviral therapy-controlled, virologically suppressed, HIV-infected patients. We propose that CD8 activation may be involved in the accumulation of central fat frequently observed in these patients, with resulting increased cardiometabolic risk.

Effects of pregnancy on endothelial function and cardiovascular disease risk in HIV-infected women.

OBJECTIVE: This study assessed flow-mediated vasodilation (FMD) and brachial artery diameter (BAD) in HIV-infected pregnant women compared to healthy pregnant controls, and determined their relationships to variables of interest, including the HIV status. METHODS: Subjects were enrolled prospectively for this longitudinal, observational study. Body mass index (BMI), blood pressure (BP), fasting lipoprotein profiles, homeostasis model assessment of insulin resistance (HOMA-IR), FMD, and BAD were assessed at 10-12, 20-22, and 32-35weeks gestation in HIV-infected women and healthy controls aged 18-45years with singleton pregnancies. RESULTS: Fourteen HIV-infected women and 19 controls were enrolled. Groups were similar at baseline except there were more Caucasians in the control group (P<0.01). FMD and BAD did not change during pregnancy in either group, and there were no differences between groups. In multivariable regression analysis, FMD was associated with BAD (P=0.002), but not with age, BMI, BP, TC, TG, HOMA-IR, or HIV status. No variables were associated with BAD. CONCLUSION: No differences were observed in FMD or BAD between HIV-infected and healthy pregnant women, and neither measure changed significantly during pregnancy. HIV status did not affect endothelial function or brachial artery diameter. Pregnancy does not appear to further increase the CVD risk associated with HIV infection.

T-cell phenotypes, apoptosis and inflammation in HIV+ patients on virologically effective cART with early atherosclerosis.

OBJECTIVE: We investigated the potential relationship between T-cell phenotype, inflammation, endotoxemia, and atherosclerosis evaluated by carotid intima-media thickness (IMT) in a cohort of HIV-positive patients undergoing long-term virologically suppressive combination antiretroviral therapy (cART). DESIGN: We studied 163 patients receiving virologically suppressive cART. METHODS: We measured IMT (carotid ultrasound); CD4+/CD8+ T-cell activation (CD38, CD45R0), differentiation (CD127), apoptosis (CD95), and senescence (CD28, CD57) (flow cytometry); plasma sCD14, IL-6, TNF- α, sVCAM-1, hs-CRP, anti-CMV IgG (ELISA); LPS (LAL). The results were compared by Mann-Whitney, Kruskal-Wallis or Chi-square tests, and factors associated with IMT were evaluated by multivariable logistic regression. RESULTS: Of 163 patients, 112 demonstrated normal IMT (nIMT), whereas 51 (31.3%) had pathological IMT (pIMT: ≥1 mm). Of the patients with pIMT, 22 demonstrated an increased IMT (iIMT), and 29 were shown to have plaques. These patient groups had comparable nadir and current CD4+, VLs and total length of time on cART. Despite similar proportions of CD38-expressing CD8+ cells (p = .95), pIMT patients exhibited higher activated memory CD8+CD38+CD45R0+ cells (p = .038) and apoptotic CD4+CD95+ (p = .01) and CD8+CD95+ cells (p = .003). In comparison to nIMT patients, iIMT patients tended to have lower numbers of early differentiated CD28+CD57- memory CD4+ (p = .048) and CD28-CD57-CD8+ cells (p = .006), both of which are associated with a higher proliferative potential. Despite no differences in plasma LPS levels, pIMT patients showed significantly higher circulating levels of sCD14 than did nIMT patients (p = .046). No differences in anti-CMV IgG was shown. Although circulating levels of sCD14 seemed to be associated with a risk of ATS in an unadjusted analysis, this effect was lost after adjusting for classical cardiovascular predictors. CONCLUSIONS: Despite the provision of full viral suppression by cART, a hyperactivated, pro-apoptotic T-cell profile characterizes HIV-infected patients with early vascular damage, for whom the potential contribution of subclinical endotoxemia and anti-CMV immunity should be investigated further.

Erectile dysfunction is more common in young to middle-aged HIV-infected men than in HIV-uninfected men.

INTRODUCTION: Erectile dysfunction (ED) is common among elderly men and patients suffering from chronic diseases, the latter probably including also HIV infection. No studies, however, compared the prevalence of ED in HIV-infected and HIV-uninfected individuals using the international index of erectile function (IIEF-15). AIM: The aim of this study is to compare ED prevalence in young to middle-aged men with and without HIV infection using the IIEF-15 questionnaire. METHODS: We conducted a cross-sectional, observational, controlled study on 444 HIV-infected men and 71 HIV-uninfected men. MAIN OUTCOMES MEASURES: The IIEF-15 questionnaire was used to assess ED. A cutoff score of ≤25 of the erectile domain was used to diagnose ED. Serum testosterone, demographic, and anthropometric (weight, height, and body mass index [BMI]) characteristics were obtained from all participants. Statistics included the T-test, the Fisher's test, univariable and multivariable logistic regression, and univariate and multivariate Spearman's correlation analysis. RESULTS: The HIV-uninfected group was significantly younger than the HIV-infected group and presented a higher BMI (P < 0.001). The prevalence of mild, moderate, and severe ED was higher in HIV-infected men than in HIV-uninfected men of all decades of age. In univariate analysis, HIV infection was associated with ED (odds ratio [OR] = 34.19, P < 0.001). In multivariable logistic regression analysis, HIV infection remained the strongest predictors of ED (OR = 42.26, P < 0.001) followed by hypogonadism, after adjusting for age and BMI. CONCLUSIONS: This study demonstrates a clear association between ED and HIV infection, after adjusting for age and BMI. Other than HIV infection, hypogonadism was associated with ED. In addition, the prevalence of ED was higher in HIV-infected men than in HIV-uninfected men, in all decades of age. The early onset of ED in HIV-infected men could be considered a peculiar clinical hallmark of HIV and confirms precocious aging in these patients. ED should be of concern to clinicians when managing HIV-infected men even if the latter are young or middle aged.

Erectile dysfunction is not a mirror of endothelial dysfunction in HIV-infected patients.

INTRODUCTION: The penis has been compared to a barometer of endothelial health, erectile dysfunction (ED) being an early sign of endothelial dysfunction. AIM: The aim of the study was to investigate the extent of the association between ED and endothelial dysfunction in patients with human immunodeficiency virus (HIV) infection on antiretroviral therapy. METHODS: In this observational cross-sectional study, we evaluated the prevalence and factors associated with ED in a cohort of 133 HIV-infected men. MAIN OUTCOME MEASURES: The International Index of Erectile Function, ultrasound assessment of brachial artery flow mediated dilatation (FMD), and multi-slice computed tomography for coronary artery calcifications (CAC) as surrogates of endothelial dysfunction, the Adult Treatment Panel III criteria to diagnose metabolic syndrome (MS), plasma total testosterone (hypogonadism), and a visual analogue scale (VAS) of aesthetic satisfaction of the face and of the body (psychological distress associated with lipodystrophy). RESULTS: Thirty-nine (29.32%) patients had mild ED, 14 (10.52%) patients had moderate ED, and 26 (19.55%) patients had severe ED. Prevalence of ED ranged from 45% to 65%, respectively, in patients less than 40 and more than 60 years old. MS was present in 20 (25%) patients with ED and 13 (24%) patients without ED (P value = 0.87). Prevalence of ED neither appeared to be associated with MS as a single clinical pathological entity nor with the numbers of its diagnostic components. FMD < 7% was present in 25 (32%) patients with ED and 18 (33%) patients without ED (P value = 0.83), and CAC > 100 was present in 8 (10%) patients with ED and 5 (9%) patients without ED (P value = 0.87). A stepwise multivariable logistic regression analysis was used to find predictors of ED. Independent predictors were VAS face (odds ratio [OR] = 0.85, 95% confidence interval [CI] 0.73-0.99, P = 0.049) and age per 10 years of increase (OR = 1.73, 95% CI 1.02-2.94, P = 0.04). CONCLUSIONS: Age constituted the most important risk factor for ED, which was related to aesthetic dissatisfaction of the face leading to negative body image perception.

Morphological and metabolic components of lipodystrophy in various nevirapine-based highly active antiretroviral therapy (HAART) regimens: a cross-sectional, observational study.

BACKGROUND: Morphological abnormalities (lipoatrophy and central fat accumulation) and metabolic changes (dyslipidaemia and glucose regulation impairment) have emerged as components of lipodystrophy and as major tolerability issues with long-term use of highly active antiretroviral therapy (HAART) in HIV-positive patients. Protease inhibitors (PIs) are recognized as having the greatest impact in terms of metabolic complications, followed by nucleoside reverse transcriptase inhibitors, while the non-nucleoside reverse transcriptase inhibitors (NNRTIs) have the least impact. In particular, regimens based on the NNRTI nevirapine have been shown to achieve significant metabolic benefits and may help to improve dyslipidaemia. Improvements in body shape changes associated with lipodystrophy have also been reported when nevirapine replaced a PI in long-term triple therapy. OBJECTIVE: The objective of this cross-sectional observational ('real-world') study was to investigate the effect of three HAART regimens plus stable nevirapine therapy on morphological and metabolic components of lipodystrophy in HIV-infected patients. METHODS: Consecutive patients (aged >18 years) with serologically documented HIV infection, who had received HAART for at least 2 years and who had been diagnosed with lipodystrophy, were followed up as outpatients at the metabolic clinic of the University of Modena and Reggio Emilia, Modena, Italy. Patients received stable nevirapine therapy plus fixed-dose combinations of tenofovir disoproxil fumarate plus emtricitabine (Truvada(®); TVD), zidovudine plus lamivudine (3TC) [Combivir(®); CBV], or abacavir plus lamivudine (Kivexa(®); KVX). Multivariate regression analyses were performed to analyse predictors of four components of lipodystrophy: lipoatrophy using leg fat mass measured by dual-emission x-ray absorptiometry (DXA), fat accumulation using waist circumference, dyslipidaemia using apolipoprotein (Apo)B/ApoA1 ratio, and glucose intolerance using the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). RESULTS: Overall, 101 patients were enrolled (TVD group = 61, CBV group = 20, KVX group = 20); 191 observations were analysed. Male sex was associated with reduced leg fat mass, while age and body mass index (BMI) were associated with increased leg fat mass (all p < 0.05). Leg fat mass and male sex were associated with increased waist circumference (p < 0.001 for both). Leg fat mass predicted reduced ApoB/ApoA1 ratio, while age and BMI predicted increased ApoB/ApoA1 ratio (all p < 0.05). BMI predicted HOMA-IR increase (p = 0.0017). No differences in lipoatrophy, central fat accumulation, dyslipidaemia or glucose metabolism were observed among any of the three different nevirapine plus nucleoside backbone groups (TVD, CBV or KVX). CONCLUSION: HAART including nevirapine has a limited impact on components of lipodystrophy in patients with HIV infection. Further studies are needed to verify if nevirapine overcomes the expected distinct lipodystrophy risk profile associated with different nucleoside backbone therapies.

Body image is a major determinant of sexual dysfunction in stable HIV-infected women.

BACKGROUND: Prevalence and factors associated with sexual dysfunction in HIV-positive women are poorly known. METHODS: This was a cross-sectional study in a cohort of HIV-infected women. Clinically stable women were invited to participate in a female sexual dysfunction (FSD) evaluation with Female Sexual Function Index (FSFI) exploring desire, arousal, lubrication, orgasm, pain and satisfaction. An FSFI score <23 was used for defining FSD. Variables evaluated included body appearance satisfaction, interference of body changes with habits, social life and attitudinal aspects of body image, health-related quality of life, hormonal assessment, menopause, cumulative exposure to antiretroviral drug classes and immune-virological parameters. Lipodystrophy was defined according to the HIV Outpatient Study definition. RESULTS: A total of 185 women completed the FSFI. The mean (+/-SD) age was 42 years (+/-5), 27% had CDC stage C, the mean (+/-SD) CD4+ T-cell count was 508 cells/microl (+/-251) and median HIV RNA was 1.7 log10 copies/ml (interquartile range 1.7-2.6). Among 161 evaluable patients, 59 (32%) reported FSD. In a multiple linear regression analysis, desire, arousal and satisfaction domains were associated with interference of body changes with habits, social life and attitudinal aspects of body image (beta = 0.22, 95% confidence interval [CI] 0.06-0.37; beta = 0.29, 95% CI 0.10-0.48; and beta = 0.20, 95% CI 0.02-0.38, respectively). Lubrication and orgasm domains were associated with body image satisfaction (beta = -0.49, 95% CI -0.88 - -0.10 and beta = -0.58, 95% CI -1.00 - -0.16, respectively). No significant associations with sex hormones, CDC stage, CD4+ T-cell count, HIV RNA viral load and cumulative exposure to antiretroviral drug classes were found. In women with FSD, severity of self-perceived abdominal fat accumulation showed a trend towards lower FSFI scores (ANOVA P = 0.02). CONCLUSIONS: FSD was highly prevalent in this cohort. Self-perceived body changes was identified as its major determinant.

Sexual dysfunction in HIV-infected men: role of antiretroviral therapy, hypogonadism and lipodystrophy.

BACKGROUND: Both psychological and organic factors have been recognized to be associated with sexual dysfunction in HIV-infected individuals. METHODS: In this cross-sectional study we evaluated the prevalence and factors associated with sexual dysfunction in a cohort of HIV-infected adult men. Evaluation tools included: the International Index of Erectile Function (erectile dysfunction [ED], desire, orgasm, intercourse satisfaction, overall satisfaction), the Assessment of Body Change and Distress (body image satisfaction), the Medical Outcomes Study HIV Health Survey (mental and physical health-related quality of life), and plasma free and total testosterone level (hypogonadism). RESULTS: Three-hundred and fifty-seven men were enrolled. Among 336 patients reporting sexual activities in the 4 weeks before, 94 (29.6%) had mild, 30 (9.4%) moderate and 34 (10.1%) severe dysfunction. The Mental Health Summary score was 2.28 units (95% confidence interval [CI] 1.51, 3.06) lower for each unit higher of body image dissatisfaction and 0.31 units (95% CI 0.27, 0.36) higher for each unit higher of the score for body change interference with habits. At regression analysis, ED was independently related to the body mass index (B = 0.31, 95% CI 0.08, 0.62). Desire, orgasm and overall satisfaction domains were associated with mental health score (B = 0.87, 95% CI 0.47, 1.27; B = 0.75, 95% CI 0.23, 1.26; B = 0.86, 95% CI 0.45, 1.28, respectively). An improved intercourse satisfaction domain was associated with a lower interference of body changes with habits and social life (B = 0.39, 95% CI 0.05, 0.73). Testosterone, metabolic alterations and HAART were not associated with sexual function domains. CONCLUSIONS: Body image and mental health but not HAART or hypogonadism were associated with sexual function domains.