Ilaria Izzo

A randomized, pilot trial to evaluate glomerular filtration rate by creatinine or cystatin C in naive HIV-infected patients after tenofovir/emtricitabine in combination with atazanavir/ritonavir or efavirenz

BackgroundGlomerular filtration rate (GFR) estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation based on creatinine or cystatine C may be more accurate methods especially in patients without chronic kidney disease. There is lack of data on GFR estimated by these methods in patients on highly active antiretroviral therapy. MethodsAntiretroviral-naive HIV-infected patients were randomized to tenofovir/emtricitabine in association with atazanavir/ritonavir (ATV/r) or efavirenz (EFV) Patients had to have an actual creatinine clearance >50 mL/minute (24-hour urine collection) and were followed for 48 weeks. ResultsNinety-one patients (48 ATV/r, 43 EFV) were recruited. Using the CKD-EPI creatinine formula, there was a significant decrease in GFR up to week 48 in patients receiving ATV/r (4.9 mL/minute/m2, P = 0.02) compared with a not statistically significant increment in patients prescribed EFV. Using the cystatin C–based equation, we found greater decrease in GFR in both arms, although, in the EFV arm, the decrease was not statistically significant (5.8 mL/minute/m2, P = 0.92). At multivariable analysis, ATV/r was a significant predictor of greater decrease in estimated glomerular filtration rate (eGFR) (P = 0.0046) only with CKD-EPI creatinine. ConclusionsATV/r plus tenofovir caused greater GFR decreases compared with EFV. The evaluation of eGFR by cystatin C confirmed this result, but this method seemed to be more stringent, probably precluding the possibility to detect a significant difference in the pattern of eGFR evolution between the two arms over time. More studies are needed to understand the clinical relevance of these alterations and whether cystatin C is a more appropriate method for monitoring GFR in clinical practice.

Risk of Early Virological Failure of Once-Daily Tenofovir-Emtricitabine plus Twice-Daily Nevirapine in Antiretroviral Therapy-Naive HIV-Infected Patients

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Prospective evaluation of bone markers, parathormone and 1,25-(OH)2 vitamin D in HIV-positive patients after the initiation of tenofovir/emtricitabine with atazanavir/ritonavir or efavirenz

BackgroundIncreased risk of fractures and osteoporosis have been associated with the use of antiretroviral drugs. There is a paucity of prospective evaluations of bone markers after the initiation of drugs currently recommended to treat HIV infection and results on the evolution of these markers are conflicting. Lastly, the effect of tenofovir on 1,25-(OH)2 vitamin D is uncertain.MethodsWe performed a prospective study on the evolution of bone markers, parathormone and 1,25-(OH)2 vitamin D before and after standard antiretroviral regimens. This was a sub-study of a trial conducted in antiretroviral-naïve patients randomized to tenofovir + emtricitabine in combination with either atazanavir/ritonavir (ATV/r) or efavirenz (EFV). Follow-up lasted 48 weeks. The following bone markers were analyzed: C-terminal cross-laps (CTx), osteocalcin (OC), osteoprotegerin (OPG), and receptor activator of nuclear factor κB ligand (RANKL). Mixed-factorial analysis of variance with random-coefficient general linear model was used to compare their trends over time and linear multivariable regression was performed with a backward selection method to assess predictors of their variations from baseline to week 48. Trends of parathormone and 1,25-(OH)2 vitamin D were also evaluated.ResultsSeventy-five patients were studied: 33 received EFV and 42 ATV/r. Significant increases were found for all markers except for RANKL. There was a significant direct association between CTx and OC increases. Multivariable analysis showed that higher glomerular filtration rate (estimated through cystatin C clearance) predicted greater OPG increase, while older age, higher HIV RNA at baseline and use of ATV/r predicted greater CTx increase. A significant increase of parathormone accompanied the evolution of the study markers. 1,25-(OH)2 vitamin D remained stable, though a seasonality variation was demonstrated.ConclusionsThese data demonstrate CTx increase (bone resorption marker) corresponding to OC increase (bone formation marker) early upon HAART initiation. Moreover, predictors of bone marker increases have been suggested, possibly indicating that a stricter monitoring of bone health and pro-active interventions are needed in older patients, those with higher HIV RNA, prescribed ATV/r rather than EFV, and with decreased renal function at baseline. Further studies are needed to clarify the mechanisms responsible for up-regulation of bone turnover markers, as well as to understand if and what markers are best correlated or predictive of pathological fractures.

Emergence of Exhausted B Cells in Asymptomatic HIV-1-Infected Patients Naïve for HAART is Related to Reduced Immune Surveillance

Alterations of B cell subpopulations have been described up to date as characterizing advanced stage of HIV-1 infection. However, whether such defects are relevant in subjects with a preserved number of CD4+ T cells (>350 cells/μL) is unclear. In a cross-sectional study, we investigated if signs of B cells exhaustion and impaired viral immune surveillance are present in a cohort of 43 asymptomatic HIV-1-infected patients with preserved CD4+ T cell counts (>350 cells/μL) and highly active antiretroviral therapy (HAART) untreated. A dramatic expansion of exhausted tissue-like memory B cells (CD10−CD21lowCD27−) was observed. B cells alteration was related to an increase in Torque teno virus (TTV) load, used as surrogate marker of immune function. Successfully HAART-treated patients showed normalization of B cell subpopulations frequency and TTV load. These results provide new insights on B cell in HIV-1 infection and show that development of B cell abnormalities precedes CD4+ T cell decline.

Clinical Evaluation of the Potential Utility of Computational Modeling as an HIV Treatment Selection Tool by Physicians with Considerable HIV Experience

The HIV Resistance Response Database Initiative (RDI), which comprises a small research team in the United Kingdom and collaborating clinical centers in more than 15 countries, has used antiretroviral treatment and response data from thousands of patients around the world to develop computational models that are highly predictive of virologic response. The potential utility of such models as a tool for assisting treatment selection was assessed in two clinical pilot studies: a prospective study in Canada and Italy, which was terminated early because of the availability of new drugs not covered by the system, and a retrospective study in the United States. For these studies, a Web-based user interface was constructed to provide access to the models. Participating physicians entered baseline data for cases of treatment failure and then registered their treatment intention. They then received a report listing the five alternative regimens that the models predicted would be most effective plus their own selection, ranked in order of predicted virologic response. The physicians then entered their final treatment decision. Twenty-three physicians entered 114 cases (75 unique cases with 39 entered twice by different physicians). Overall, 33% of treatment decisions were changed following review of the report. The final treatment decisions and the best of the RDI alternatives were predicted to produce greater virologic responses and involve fewer drugs than the original selections. Most physicians found the system easy to use and understand. All but one indicated they would use the system if it were available, particularly for highly treatment-experienced cases with challenging resistance profiles. Despite limitations, the first clinical evaluation of this approach by physicians with substantial HIV-experience suggests that it has the potential to deliver clinical and economic benefits.

Updated Prevalence of Genotypic Resistance Among HIV-1 Positive Patients Naïve to Antiretroviral Therapy : A Single Center Analysis

Continuous surveillance of HIV primary resistance mutations is highly important due to their potential clinical impact. All patients naïve to antiretrovirals who had ≥1 genotypic resistance testing at the Institute of Infectious Diseases (Brescia, Northern Italy) between 2001 and 2006 were analyzed. Primary resistance mutations were defined using epidemiological and clinical criteria. Mutations were interpreted using the Stanford University Algorithm. Logistic regression analysis was used to assess possible predictors of primary resistance mutations. Among 569 patients, 11% presented ≥1 mutation. Prevalence of primary resistance mutations to nucleoside reverse‐transcriptase inhibitors (NRTI), non‐nucleoside reverse‐transcriptase inhibitors (NNRTI), and protease inhibitors (PI) was 6.3%, 6%, and 1.6%, respectively. The most frequent mutations to NRTI were substitutions at position 215 (215Y in 3 patients, and 215 revertants in 16), 41L (13), 219Q (12), and 210W (10). Among mutations to NNRTI, 103N was found in 21 patients, while 181C, 188L, and 190A/S in 8, 3, and 4 patients, respectively. Fifty‐one patients (9%) had high‐to‐intermediate resistance to ≥1 antiretroviral drug before starting the treatment. Regarding the new generation drugs, nine patients had intermediate resistance to etravirine, five patients had intermediate resistance to tipranavir, while five, one, and seven patients had low resistance to etravirine, tipranavir, and darunavir. Homosexuals were more likely to harbor a virus with primary resistance mutations (OR:2.68; 95% CI:1.44–5.00; P = 0.002) while non‐Italian nationality was protective (OR:0.38; 95% CI:0.17–0.86; P = 0.020). Prevalence of primary resistance mutations suggests that genotypic resistance testing should be performed before starting treatment in naïve patients in Italy, particularly when NNRTI are prescribed. J. Med. Virol. 80:747–753, 2008.

Increase in Standard Cholesterol and Large HDL Particle Subclasses in Antiretroviral-Naïve Patients Prescribed Efavirenz Compared to Atazanavir/Ritonavir

Abstract Background: Cardiovascular risk in HIV-infected patients is related, at least in part, to serum lipid alterations before and after HAART. Lipoprotein-particle subclasses may also have an effect, but comparative data after standard HAART regimens are limited.Methods: This was a substudy of a trial in 91 antiretroviral-naïve patients randomized to tenofovir + emtricitabine + atazanavir/ritonavir (ATV/r) or efavirenz (EFV). Over-time trends from baseline to week 48 in total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), HDL particles (HDLp), and TC:HDL-C and TG:HDL-C ratios were analyzed by analysis of covariance (ANCOVA). Furthermore, confidence intervals for differences between the 2 groups at week 48 were calculated. Indications for lipid-lowering interventions and low HDL-C were also studied.Results: ANCOVA showed that, with respect to patients receiving ATV/r, those prescribed efavirenz (EFV) had greater increases reported as mean differences in lipid values at week 48: 14 mg/dL (95% CI, 0.2 to 27) for TC, 14 mg/dL (95% CI, 4 to 25) for LDL-C, 5 mg/dL (95% CI, 2 to 9) for HDL-C, and 2.2 mg/dL (95% CI, 0.4 to 4) for large HDLp. Proportions of subjects with indications for lipid-lowering interventions and with HDL-C <40 mg/dL did not differ significantly.Conclusions: Patients prescribed EFV had greater increases in TC, LDL-C, and HDL-C. Although no significant differences were detected between the 2 groups for the TC:HDL ratio and for indications to start lipid-lowering interventions, large HDLp increased more in the EFV group compared to the ATV/r group, suggesting a protective effect associated with EFV use.

Screening and Management of HIV-2-Infected Individuals in Northern Italy

There is a lack of updated estimates of HIV-2 infection in Italy. Moreover, lack of standardized HIV-2 viral load (VL) and drug resistance tests challenges clinical practice. Among 2941 HIV-positive patients followed in our center (Brescia, Northern Italy), 220 (7.5%) were African at the beginning of the study period. We assessed a population of 151 HIV-Ab positive patients (141 of African origin), presenting for routine blood testing from January 2006 to May 2007. Those found infected with HIV-2 started an appropriate disease management with HIV-2 VL and genotypic drug resistance testing. Sixteen of 151 (10.6%) patients were positive for HIV-2. Of those 16 patients, 14 came from Africa. Among 7 experienced patients, 1 was responding to nelfinavir and 4 to lopinavir/ritonavir-containing regimens. Two patients were failing treatment: 1 patient was switched to a saquinavir/ritonavir-containing regimen and responded. The remaining patient switched to lamivudine + atazanavir + saquinavir + ritonavir did not respond, having had previous experience to multiple ineffective drugs, resulting in a very complex HIV-2 drug-resistance pattern. Accurate screening programs and integration of virological tools must be implemented urgently, given the high prevalence of HIV-2, particularly in immigrant patients.

Maternal characteristics during pregnancy and risk factors for positive HIV RNA at delivery: a single-cohort observational study (Brescia, Northern Italy)

BackgroundDetectable HIV RNA in mothers at delivery is an important risk factor for HIV transmission to newborns. Our hypothesis was that, in migrant women, the risk of detectable HIV RNA at delivery is greater owing to late HIV diagnosis. Therefore, we examined pregnant women by regional provenance and measured variables that could be associated with detectable HIV RNA at delivery.MethodsA observational retrospective study was conducted from January 1999 to May 2008. Univariate and multivariable regression analyses (generalized linear models) were used, with detectable HIV RNA at delivery as dependent variable.ResultsThe overall population comprised 154 women (46.8% migrants). Presentation was later in migrant women than Italians, as assessed by CD4-T-cell count at first contact (mean 417/mm3 versus 545/mm3, respectively; p = 0.003). Likewise, HIV diagnosis was made before pregnancy and HAART was already prescribed at the time of pregnancy in more Italians (91% and 75%, respectively) than migrants (61% and 42.8%, respectively). A subgroup of women with available HIV RNA close to term (i.e., ≤30 days before labour) was studied for risk factors of detectable HIV RNA (≥50 copies/ml) at delivery. Among 93 women, 25 (26.9%) had detectable HIV RNA. A trend toward an association between non-Italian nationality and detectable HIV RNA at delivery was demonstrated by univariate analysis (relative risk, RR = 1.86; p = 0.099). However, by multivariable regression analysis, the following factors appeared to be more important: lack of stable (i.e., ≥14 days) antiretroviral therapy at the time of HIV RNA testing (RR = 4.3; p < 0.0001), and higher CD4+ T-cell count at pregnancy (per 50/mm3, RR = 0.94; p = 0.038).ConclusionsThese results reinforce the importance of extensive screening for HIV infection, earlier initiation of antiretroviral therapy and stricter monitoring of pregnant women to reduce the risk of detectable HIV RNA at delivery. Public health interventions should be particularly targeted to migrant women who are frequently unaware of their HIV status at the time of pregnancy.

Heterogeneity and penetration of HIV-1 non-subtype B viruses in an Italian province: public health implications

This study assessed changes in prevalence and distribution of HIV-1 non-subtype B viruses in Italian and immigrant patients over two decades in a province in Italy. All HIV-positive patients who underwent genotypic resistance testing were selected. Prevalence of non-subtype B viruses in 3-year periods was calculated. All sequences of non-subtype B and those provided by REGA as unassigned were analysed for phylogenetic relationships. In total, 250/1563 (16%) individuals were infected with a non-subtype B virus. Prevalence increased over time, reaching a peak (31.5%) in 2004-2006. In Italian patients, the most frequent subtypes were B (92.5%) and F1 (4%). F1 subtype was also prevalent in patients from South America (13.6%); in patients of African origin, CRF02_AG (54.9%) and G (12.3%) were the most frequent. HIV-1 non-subtype B infections in Italians were mostly found in patients who acquired HIV sexually. A phylogenetic relationship between F subtypes in Italian and representative HIV-1 sequences from Brazil was found. C subtypes in Italians were phylogenetically related to subtypes circulating in Brazil. Inter-subtype recombinants were also found in the latest years. The HIV-1 epidemic in Brescia province evolved to the point where about 1/3 patients recently diagnosed harboured non-B HIV subtypes. The distribution of HIV-1 non-B subtypes in Italian patients resembled that in South American patients and phylogenetic relatedness between some Italian and South American HIV-1 strains was found. The possible epidemiological link between these two populations would have been missed by looking only at risk factors for HIV acquisition declared by patients. The evidence of inter-subtype recombinants points to significant genetic assortment. Overall our results support phylogenetic analysis as a tool for epidemiological investigation in order to guide targeted prevention strategies.