Raffaella Libertone

Impact of pre-therapy viral load on virological response to modern first-line HAART.

BACKGROUND We tested whether pre-HAART viraemia affects the achievement and maintenance of virological success in HIV-1-infected patients starting modern first-line therapies. METHODS A total of 1,430 patients starting their first HAART (genotype-tailored) in 2008 (median; IQR: 2006-2009) were grouped according to levels of pre-HAART viraemia (≤ 30,000, 30,001-100,000, 100,001-300,000, 300,001-500,000 and > 500,000 copies/ml). The impact of pre-therapy viraemia on the time to virological success (viraemia ≤ 50 copies/ml) and on the time to virological rebound (first of two consecutive viraemia values > 50 copies/ml after virological success) were evaluated by Kaplan-Meier curves and Cox regression analyses. RESULTS Median pre-HAART viraemia was 5.1 log10 copies/ml (IQR 4.5-5.5), and 53% of patients had viraemia > 100,000 copies/ml. By week 48, the prevalence of patients reaching virological success was > 90% in all pre-HAART viraemia ranges, with the only exception of range > 500,000 copies/ml (virological success = 83%; P < 0.001). Higher pre-HAART viraemia was tightly correlated with longer median time to achieve virological success. Cox multivariable estimates confirmed this result: patients with pre-HAART viraemia > 500,000 copies/ml showed the lowest hazard of virological undetectability after adjusting for age, gender, pre-HAART CD4+ T-cell count, transmitted drug resistance, calendar year and third drug administered (adjusted hazard ratio [95% CI]: 0.27 [0.21, 0.35]; P < 0.001). Pre-HAART viraemia > 500,000 copies/ml was also associated with higher probability of virological rebound compared with patients belonging to lower viraemia strata at weeks 4, 12 and 24 (P = 0.050). CONCLUSIONS At the time of modern HAART, and even though an average > 90% of virological success, high pre-HAART viraemia remains an independent factor associated with delayed and decreased virological success. Patients starting HAART with > 500,000 copies/ml represent a significant population that may deserve special attention.

Viral tropism by geno2pheno as a tool for predicting CD4 decrease in HIV-1-infected naive patients with high CD4 counts

OBJECTIVES To investigate the value of tropism (determined by genotypic testing) to predict CD4 depletion in HIV-infected antiretroviral-naive patients with high CD4 counts. METHODS Viral tropism was determined by geno2pheno (false positive rate = 10%) in 223 HIV-infected subjects naive to antiretrovirals with CD4 count ≥350 cells/μL and HIV-RNA >500 copies/mL enrolled in the ICONA Foundation Study for whom a stored plasma sample (baseline) was retrospectively tested. We monitored CD4 cell count and identified predictors of decline before antiretroviral therapy initiation, applying a mixed linear model with covariates (age, gender, tropism, HIV risk factor, calendar year of HIV infection, months from HIV diagnosis to baseline, hepatitis C virus status, CD4 and HIV-RNA at sample collection and duration of follow-up). RESULTS Two hundred and twenty-three subjects met the eligibility criteria; 137 (61%) were male and the median age was 35 (31-40) years. Median follow-up was 16.4 (3.2-37.2) months. Median CD4 decrease during follow-up was -157 (-278 to -13) cells/μL. At baseline, 192 (86%) subjects were defined as harbouring R5 virus and 31 (14%) non-R5. Median CD4 count was 571 (458-729) cells/μL and median HIV-RNA was 4.08 (3.57-4.55) log(10) copies/mL. At multivariable analysis, a greater mean CD4 decrease was associated with non-R5 viral tropism (-159.9 ± 12.22, P = 0.0002) at baseline. Other significant covariates were female gender, older age, intravenous drug use, longer duration of follow-up, and higher CD4 cell count and higher HIV-RNA at sample collection. CONCLUSIONS In patients with CD4 counts ≥350 cells/μL, non-R5 viral tropism by geno2pheno is predictive of CD4 decrease independent of their viral set point and CD4 counts.

HIV pharmacogenetics in clinical practice: recent achievements and future challenges.

It has long been recognized that drug metabolism and drug toxicity may vary greatly between individuals, affecting both efficacy and toxicity. Pharmacogenetics could benefit HIV therapeutics because of the high prevalence of drug-related adverse events and the long term nature and complexity of combination therapy. In recent years a number of associations between human genetic variants and predisposition to drug toxicity and risk of virologic failure have been described. This review summarizes the existing literature on pharmacogenetic determinants of antiretroviral drug exposure, toxicity, and activity. Studies across the world have consistently demonstrated that HLA-B*5701 predicts the likelihood of hypersensitivity reactions to abacavir. As a consequence, pharmacogenetic screening for HLA-B*5701 has entered routine clinical practice and is recommended in most guidelines before starting an abacavir containing regimen. Moreover, prospective clinical trials and cohort studies have identified a number of associations between human genetic variants, drug metabolism and toxicity. These include nevirapine hypersensitivity and hepatotoxicity, efavirenz plasma levels and central nervous system side effects, indinavir- and atazanavir-associated hyperbilirubinemia, antiretroviral drug-associated peripheral neuropathy, lipodystrophy and hyperlipidaemia, NRTI-related pancreatitis, and tenofovir-associated renal proximal tubulopathy. Thus, pharmacogenetics is expected to play an important role in HIV treatment in the near future. The aim of the present paper is to provide HIV clinicians with a comprehensive review of recent achievements and future prospects for HIV pharmacogenetics.

Muscle symptoms and creatine phosphokinase elevations in patients receiving raltegravir in clinical practice: Results from the SCOLTA project long-term surveillance

Muscle alterations ranging from asymptomatic creatine phosphokinase (CPK) increases to rhabdomyolysis and central nervous system (CNS) symptoms have been reported in patients receiving raltegravir. Muscle symptoms and CPK increases were investigated in a cohort of HIV-infected patients receiving raltegravir-based antiretroviral therapy, and possible associated predictors were evaluated. The SCOLTA Project is a prospective, observational, multicentre study created to assess the incidence of adverse events in patients receiving new antiretroviral drugs in clinical practice. In total, 496 HIV-infected patients were enrolled [333 (67.1%) male]. CDC stage was C in 196 patients (39.5%). Mean age at enrolment was 45.9 ± 9.3 years. Median follow-up was 21 months. Twenty-six patients (5.2%) reported muscle symptoms (16 muscle pain and 17 weakness; 7 had both). Of 342 patients with normal baseline CPK values, 72 (21.1%) had a CPK increase. Seven patients (1.4%) discontinued raltegravir because of muscular events (three for muscle pain/weakness and four CPK increases). No cases of rhabdomyolysis were observed. Patients with muscle symptoms were more frequently receiving in their regimen than those not receiving atazanavir (P=0.04) and were more likely to also report CNS symptoms (P<0.0001). Significant predictors of muscle symptoms were CNS symptoms and use of atazanavir. Female sex was associated with a reduced risk of CPK increase. In conclusion, muscle symptoms and CPK elevations occurred frequently and caused most discontinuations due to adverse events. Their monitoring in patients receiving raltegravir should be considered, especially when co-administered with atazanavir or when CNS symptoms are also present.

Cognitive function in treated HIV patients

Although highly active antiretroviral therapy (HAART) has reduced the incidence of HIV-associated dementia, the overall prevalence of HIV-associated neurocognitive disorders (HAND) has increased. Since treatment and prevention of HAND are becoming an increasing concern, management strategies for cognitive impairment in patients living with HIV are expected to play an important role in the near future. This review summarizes the existing literature on studies investigating cognitive functions in patients receiving antiretroviral (ARV) treatment. Most studies indicate that HAART use results in improvement of neurocognitive functions, yet milder forms of HAND are not only prevalent, but also incident in patients with persistently undetectable plasma HIV RNA. We performed a systematic review on all studies performed in patients receiving ARV treatment that included neurocognitive evaluations as study end points. Thirty-six studies were examined. Study methodology varied from cross-sectional to double- blind, randomized, controlled designs. Aside from historic zidovudine monotherapy trials, in most studies, ARV schemes varied considerably, and in some cases, ARV regimens were not reported in detail. Only a few articles included virological studies on cerebrospinal fluid. Study duration was ,2 years in most cases. Differences in study design and presence of study limitations may account for difficulties in understanding the impact of HAART on cognition and in evaluating the effect of an individual agent or ARV regimen on cognitive functioning. The aim of the present article is to provide HIV clinicians with a comprehensive review of recent achievements and future prospects for ARV treatment and prevention of cognitive dysfunctions

Relationship Between Health-Related Quality of Life Measures and High HIV Viral Load in HIV-Infected Triple-Class-Experienced Patients

Abstract Background: Health-related quality of life (HRQoL) has been recognized as a central measure of the overall health status in HIV patients. With the availability of different highly effective drug combinations, maximizing quality-adjusted survival has become a major target of HIV treatment. Although the association of HIV RNA and CD4 cell count with clinical HIV progression has been well established, the relation between these markers and HRQoL measures is still unclear. Method: This cross-sectional study investigated the relationship linking HIV RNA and CD4 to HRQoL measures in 181 triple-class-experienced patients with advanced HIV disease. The instrument used was the ISSQoL, a self-administered and HIV-specific HRQoL questionnaire. Results: Data showed no correlation between HRQoL measures and CD4 counts. Higher HIV RNA levels were, however, associated with poor HRQoL scores in 3 out of 9 scales of social functioning, depression and anxiety, and satisfaction with quality of life. In multivariable analyses, only the satisfaction with quality of life mean score remained significantly lower for the HIV RNA >100,000 copies/mL group compared to the HIV RNA 50 to 10,000 copies/mL group. Conclusions: Although other determinants of HRQoL in people with HIV should also be considered, this finding suggests a negative impact of high viral load on perceived HRQoL that adds to other described determinants of lower quality of life in people with HIV, such as lower social support and self-reported symptoms.

Central nervous system penetration-effectiveness rank does not reliably predict neurocognitive impairment in HIV-infected individuals.

Central nervous system (CNS) penetration‐effectiveness (CPE) rank was proposed in 2008 as an estimate of penetration of ARV regimen into the CNS, and validated as predictor of CSF HIV‐1 replication. Results on predictive role of CPE on neurocognitive and clinical outcome were conflicting.

Response to raltegravir-based salvage therapy in HIV-infected patients with hepatitis C virus or hepatitis B virus coinfection

OBJECTIVES To define the impact of coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) on viroimmunological response to raltegravir-based salvage regimens that also include new HIV inhibitors such as maraviroc, darunavir and etravirine. METHODS We used data from a national observational study of patients starting raltegravir-based regimens to compare virological suppression and CD4 cell change from baseline in patients with and without concomitant HBV or HCV infection. RESULTS Overall, 275 patients (107 coinfected and 168 non-coinfected) were evaluated. Coinfected patients were more commonly former intravenous drug users and had a longer history of HIV infection and higher baseline aminotransferase levels. Both HIV-RNA and CD4 response were similar in the two groups. Mean time to first HIV-RNA copy number <50 copies/mL was 4.1 months (95% CI 3.5-4.6) in non-coinfected patients and 3.9 months (95% CI 3.3-4.5) in coinfected patients (hazard ratio 1.039, 95% CI 0.761-1.418, P = 0.766, log-rank test). The risk of developing new grade 3-4 hepatic adverse events was significantly higher in coinfected patients (hazard ratio 1.779, 95% CI 1.123-2.817, P = 0.009). The two groups of coinfected and non-coinfected patients had similar rates of interruption of any baseline drug (hazard ratio 1.075, 95% CI 0.649-1.781, P = 0.776) and of raltegravir (hazard ratio 1.520, 95% CI 0.671-3.447, P = 0.311). Few AIDS-defining events and deaths occurred. CONCLUSIONS Viroimmunological response to regimens based on raltegravir and other recent anti-HIV inhibitors is not negatively affected by coinfection with HBV or HCV. Liver toxicity, either pre-existing or new, is more common in coinfected patients, but with no increased risk of treatment interruption.

An anal cancer screening program for MSM in Italy: Prevalence of multiple HPV types and vaccine-targeted infections.

BACKGROUND Elevated HPV infection rates have been described in HIV-positive males, placing these subjects at high risk of anal neoplasia. Bivalent, quadrivalent, and nonavalent vaccines to prevent HPV infection have been developed, and recently proposed for gender-neutral immunization programs. OBJECTIVES In order to estimate the benefit that could be obtained by vaccination of HIV-positive men who have sex with men (MSM), we aimed at describing the frequency of multiple and vaccine-targeted HPV infections in MSM enrolled in an anal cancer screening program. STUDY DESIGN The anal cancer screening program was conducted between July 2009 and October 2012. Mucosal anal samples were tested for HPV DNA using MY09/MY11 PCR primers and, if positive, genotyped using the CLART2HPV Clinical Array (35HPV types). RESULTS A total of 220 MSM were screened and 88.6% were positive for HPV DNA: in 86.5% at least one high-risk (HR) type was found and in 13% only low-risk (LR) HPV were found. Multiple infections accounted for 84.5% of HPV DNA-positive cases and overall 160 different HPV genotype combinations were recognized (only three combinations were detected in more than one patient each). Based on strain coverage, at least one vaccine-targeted HPV type was found in 38.9%, 64%, and 78.4% of cases when considering bivalent, quadrivalent and nonavalent vaccines, respectively. At least one HR vaccine-targeted strain was found in 39% of MSM for bivalent and quadrivalent vaccines, and in 64% of cases for nonavalent prevention. CONCLUSIONS Anal HPV infections in unvaccinated mostly HIV-infected MSM are highly prevalent. The majority of this population has multiple infections with an extremely heterogeneous number of genotype combinations. The nonavalent vaccine could theoretically have prevented a minimum of one HR HPV type in two thirds of subjects.

Evaluation of the Prognostic Value of Impaired Renal Function on Clinical Progression in a Large Cohort of HIV-Infected People Seen for Care in Italy

Whilst renal dysfunction, especially mild impairment (60<eGFR<90 ml/min), has been often described in HIV-infected population, its potential contribution to HIV evolution and risk of cerebro-cardiovascular disease (CCVD) has not been clarified. Data from HIV-1 infected patients enrolled in the Italian Cohort of Antiretroviral-Naïve (Icona) Foundation Study collected between January 2000 and February 2014 with at least two creatinine values available. eGFR (CKD-epi) and renal dysfunction defined using a priori cut-offs of 60 (severely impaired) and 90 ml/min/1.73m2 (mildly impaired). Characteristics of patients were described after stratification in these groups and compared using chi-square test (categorical variables) or Kruskal Wallis test comparing median values. Follow-up accrued from baseline up to the date of the CCVD or AIDS related events or death or last available visit. Kaplan Meier curves were used to estimate the cumulative probability of occurrence of the events over time. Adjusted analysis was performed using a proportional hazards Cox regression model. We included 7,385 patients, observed for a median follow-up of 43 months (inter-quartile range [IQR]: 21-93 months). Over this time, 130 cerebro-cardiovascular events (including 11 deaths due to CCVD) and 311 AIDS-related events (including 45 deaths) were observed. The rate of CCVD events among patients with eGFR >90, 60-89, <60 ml/min, was 2.91 (95% CI 2.30-3.67), 4.63 (95% CI 3.51-6.11) and 11.9 (95% CI 6.19-22.85) per 1,000 PYFU respectively, with an unadjusted hazard ratio (HR) of 4.14 (95%CI 2.07-8.29) for patients with eGFR <60 ml/min and 1.58 (95%CI 1.10-2.27) for eGFR 60-89 compared to those with eGFR ≥90. Of note, these estimates are adjusted for traditional cardio-vascular risk factors (e.g. smoking, diabetes, hypertension, dyslipidemia). Incidence of AIDS-related events was 9.51 (95%CI 8.35-10.83), 6.04 (95%CI 4.74-7.71) and 25.0 (95%CI 15.96-39.22) per 1,000 PYFU, among patients with eGFR >90, 60-89, <60 ml/min, respectively, with an unadjusted HR of 2.49 (95%CI 1.56-3.97) for patients with eGFR <60 ml/min and 0.68 (95%CI 0.52-0.90) for eGFR 60-89. The risk of AIDS events was significantly lower in mild renal dysfunction group even after adjustment for HIV-related characteristics. Our data confirm that impaired renal function is an important risk marker for CCVD events in the HIV-population; importantly, even those with mild renal impairment (90<eGFR<60) seem to be at increased risk of cerebro-cardiovascular morbidity and mortality.