A patient-centred approach to deprescribing antiretroviral therapy in people living with HIV.

Only a few studies have explored the benefit of deprescribing in people living with HIV (PLWH), focusing on the discontinuation of non-antiretrovirals (non-ARVs) used for HIV-associated comorbidities (co-medications), or the management of drug-drug interactions (DDIs) between ARVs or between ARVs and co-medications. The availability of modern single-tablet regimens, two-drug regimens and long-acting therapy opens a discussion regarding ARV deprescribing strategies. The objective of this article is to discuss ARV deprescribing strategies in the context of medication-related burden and patients' lived experience with medicine (PLEM) and to suggest indications for whom, when, how and why to consider these ARV options in PLWH. A PLEM construct helps to better interpret these strategies and provides a patient-centred precision-medicine approach. There are several safe and virologically effective ARV deprescribing strategies, but the ultimate benefits of these interventions still need to be further explored in terms of the overall health and quality of life of patients.

Evidence-based renewal of the Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons.

The Italian Society for Infectious and Tropical Diseases (SIMIT) in collaboration with the Technical Health Committee (Sections L and M) of the Italian Ministry of Health have supported the renewal of the recommendations for the Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons. This publication summarizes the latest updates to the 2017 version of the Italian Guidelines for the management of HIV-1 infected patients and the use of antiretroviral drugs. New recommendations were released framing the clinical questions the use of antiretrovirals according to the Patient Intervention Comparator Outcome (PICO) methodology and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Diagnostic tools for immunological and virological monitoring, when to start, what to start, optimization and therapeutic failure were updated in order to include the recommendation obtained with these newly developed methods. For a complete review of clinical and therapeutic relevant topics we refer the reader to the extended version of the Guidelines.

Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons. Update 2016.

The Italian Society of Infectious and Tropical Diseases (SIMIT) of the Technical Health Committee, Ministry of Health (Sections L and M) of Italy have supported recommendations for the Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons. This publication summarizes the latest updates to the 2016 version of the Italian Guidelines for the management of HIV-1 infected patients and the use of antiretroviral drugs. In particular, new recommendations were released concerning the following topics: estimate of the HIV continuum of care in Italy, optimal timing and preferred drug combinations for starting antiretroviral therapy, treatment optimization, and pre-exposure prophilaxis (PrEP). For a complete review of clinical and therapeutic relevant topics we refer the reader to the extended version of the Guidelines.

Long-acting agents for HIV infection: biological aspects, role in treatment and prevention, and patient's perspective.

Current cART regimens are highly potent and well tolerated, but long-term toxicities, drug-drug interactions, lifetime costs and scarce option for multiclass failed patients could limit the efficacy of treatment itself. Long-acting formulations of antiretrovirals, which could potentially replace daily tablets, have been developed and are under investigation for prevention and treatment of HIV infection. Cabotegravir and rilpivirine represent the first drugs studied in this context. The aim of this review is to summarize the biological bases, the available information on completed and ongoing clinical trials and the potential development of long-acting regimens for the treatment and prevention of HIV infection.

An update on integrase inhibitors: new opportunities for a personalized therapy? The NEXTaim Project.

Thanks to the development of antiretroviral agents to control HIV replication, HIV infection has turned from a fatal disease into a treatable chronic infection. The present work collects the opinions of several experts on the efficacy and safety of recently approved second generation of integrase inhibitors and, in particular, on the role of this new class of drugs in antiretroviral therapy. The availability of new therapeutic options represents an opportunity to ameliorate the efficacy of cART in controlling HIV replication also within viral reservoirs. The personalization of the treatment driven mainly by the management of comorbidities, HIV-HCV co-infections and aging, will be easier with antiretroviral drugs without drug-drug interactions and with a better toxicity and tolerability profile. Future assessment of economic impact for the introduction of new innovative drugs in the field of antiretroviral therapy will likely need some degree of adjustment of the evaluation criteria of costs and benefit which are currently based almost exclusively on morbidity and mortality.

Increased incidence of sexually transmitted diseases in the recent years: data from the ICONA cohort.

INTRODUCTION: Sexually transmitted diseases (STDs) data collected in HIV+ patients could be used as indicator of risky sexual behaviour possibly linked to HIV transmission. We described the STDs incidence over time and identified higher incidence factors. METHODOLOGY: All patients in the ICONA Foundation Study enrolled after 1998 were included. STDs considered: any-stage syphilis, human papilloma virus (HPV) diseases, gonococcal and non-gonococcal urethritis, herpes simplex virus (HSV) genital ulcers, vaginitis and acute hepatitis B virus (HBV), hepatitis A virus (HAV), and hepatitis C virus (HCV) infections (only for non-IVDU (intravenous drug user) patients). STDs incidence rate (IR): number of STDs divided by person years of follow-up (PYFU). Calendar periods: 1998-2002, 2003-2007 and 2008-2012. Predictors of STDs occurrence were identified using Poisson regression and sandwich estimates for the standard errors were used for multiple STD events. RESULTS: Data of 9,168 patients were analyzed (median age 37.3 (SD=9.3), 74% male, 30% MSM). Over 46,736 PYFU, 996 episodes of STDs were observed (crude IR 17.3/1,000 PYFU). Median (IQR) CD4/mmc and HIV-RNA/mL at STD: 433 (251-600) and 10,900 (200-63,000). Highest crude IRs were observed for any-stage syphilis (3.95, 95% CI 3.59-4.35), HPV diseases (1.96, 1.71-2.24) and acute hepatitis (1.72, 1.49-1.99). At multivariable analysis (variables of adjustment shown in Figure 1), age (IRR 0.82 per 10 years younger, 95% CI 0.77-0.89), MSM contacts (IRR 3.03, 95% CI 2.52-3.64 vs heterosexual) and calendar period (IRR 1.67, 95% CI 1.42-1.96, comparing 2008-2012 with 1998-2002) significantly increased the risk of acquiring STDs. Moreover, having a HIV-RNA >50 c/mL (IRR 1.44, 95% CI 1.19-1.74 vs HIV-RNA <50 c/mL) and current CD4+ cell count <100/mmc (IRR 4.66, 95% CI 3.69-5.89, p<0.001 vs CD4+ cell count >500) showed an increased risk of STDs. Being on ARV treatment significantly reduced the risk of developing an STD (IRR 0.37, 95% CI 0.32-0.43) compared to ART-naïve people, even in the situation of temporary interruption of treatment (IRR 0.51, 95% CI 0.39-0.43) (see Figure 1). CONCLUSIONS: The overall incidence of STDs has been increasing in the recent years. Interventions to prevent STDs and potential further spread of HIV infection should target the recently HIV diagnosed, the young population and MSM. Being on ARV treatment (potentially an indicator of whether a person is regularly seen for care) seems to reduce the risk of acquiring STDs independently of its viro-immunological effect.

Challenges in HIV Vaccine Research for Treatment and Prevention.

Many attempts have been made or are ongoing for HIV prevention and HIV cure. Many successes are in the list, particularly for HIV drugs, recently proposed also for prevention. However, no eradication of infection has been achieved so far with any drug. Further, a residual immune dysregulation associated to chronic immune activation and incomplete restoration of B and T cell subsets, together with HIV DNA persistence in reservoirs, are still unmet needs of the highly active antiretroviral therapy, causing novel "non-AIDS related" diseases that account for a higher risk of death even in virologically suppressed patients. These "ART unmet needs" represent a problem, which is expected to increase by ART roll out. Further, in countries such as South Africa, where six millions of individuals are infected, ART appears unable to contain the epidemics. Regretfully, all the attempts at developing a preventative vaccine have been largely disappointing. However, recent therapeutic immunization strategies have opened new avenues for HIV treatment, which might be exploitable also for preventative vaccine approaches. For example, immunization strategies aimed at targeting key viral products responsible of virus transmission, activation, and maintenance of virus reservoirs may intensify drug efficacy and lead to a functional cure providing new perspectives also for prevention and future virus eradication strategies. However, this approach imposes new challenges to the scientific community, vaccine developers, and regulatory bodies, such as the identification of novel immunological and virological biomarkers to assess efficacy end-points, taking advantage from the natural history of infection and exploiting lessons from former trials. This review will focus first on recent advancement of therapeutic strategies, then on the progresses made in preventative approaches, discussing concepts, and problems for the way ahead for the development of vaccines for HIV treatment and prevention.

Less drug regimens and PI/r-based strategies in HIV infection: focus on best practices using the HIV patient's journey methodology.

During these last two years less drug regimens (LDRs) in HIV, and in particular protease inhibitor (PI)/r-based strategies, have been explored both in clinical trials and in clinical practice. Many results are now available and more is known about how to use them safely and effectively. Understanding that an LDR strategy represents a real tailored therapeutic approach for the patient is crucial for the long-term success and positive management of HIV infection. Trust between patients and HIV specialists and a real focus on the patient's life are key factors for long life treatment success, in particular when using a LDR strategy. This is clearly shown by the HIV patient's journey (HPJ) methodology, used in an Italian national workshop to better define the criteria and challenges of LDR strategies. This paper shows the results of this complex process.

Renal complications in HIV disease: between present and future.

The recent introduction of new antiretroviral drugs, characterized by high efficiency and improved safety profiles, has not reduced the incidence of long-term adverse effects, in some cases manifested as selective organ damage. The presence of organ damage in patients receiving antiretroviral treatment is not only the expression of treatment toxicity, but also a complex interaction between individual risk factors, HIV-correlated effects, and antiretroviral drug toxicity. Kidney damage belongs to these adverse events. Renal function abnormalities are present in a large percentage of patients with HIV infection. Moreover, HIV-associated renal disease seems to be associated with progression to AIDS and death. In this review we address the various aspects of the epidemiology of renal damage, the interaction and the convergent effect of HIV and antiretroviral drugs in the onset of kidney injury, the interplay between kidney function and other organ systems, early clinical management, the monitoring of renal function, and a proposal of clinical approach to kidney disease in daily practice. Finally, we discuss future perspectives of renal damage in HIV patients and evaluate the patient's perspective.

Communication, recruitment and enrolment in the preventative and therapeutic phase I clinical trial against HIV/AIDS based on the recombinant HIV-1 Tat protein.

The role of volunteer recruitment in HIV vaccine trials has recently been considered particularly with respect to critical issues, such as motivation, psychological assessment and social impact. The preventative and therapeutic phase I trials based on the recombinant biologically active Tat vaccine candidate, sponsored in Italy by the Istituto Superiore di Sanità, included a specific centralised procedure (SCP) developed to support both the sponsor and the volunteers during trial enrolment and conduction. This process, which is an integrated, multidisciplinary, biomedical and psycho-socio-behavioural network, represented a novel and important aspect for the conduction and success of the clinical study. A specific flow of information from the sponsor to the population was developed through the SCP which started from the national announcement of the trials (through a press conference and a press release) to the enrolment of the volunteers. To this aim a telephone counselling intervention was performed to supply the scientific information translated in personalised message, allowing to select potential participants prior to the first contact with the clinical sites. Furthermore, the multi-step procedure contributed in reinforcing the motivation to participation and trial retention, providing important hints for the design of standardised enrolment procedures to be used in clinical studies. Indeed, this methodological approach, which foresees the joined participation of researchers and expert of communication, could be followed in future vaccine trials in order to improve the effectiveness of enrolment procedures.

Therapeutic immunization with HIV-1 Tat reduces immune activation and loss of regulatory T-cells and improves immune function in subjects on HAART.

UNLABELLED: Although HAART suppresses HIV replication, it is often unable to restore immune homeostasis. Consequently, non-AIDS-defining diseases are increasingly seen in treated individuals. This is attributed to persistent virus expression in reservoirs and to cell activation. Of note, in CD4(+) T cells and monocyte-macrophages of virologically-suppressed individuals, there is continued expression of multi-spliced transcripts encoding HIV regulatory proteins. Among them, Tat is essential for virus gene expression and replication, either in primary infection or for virus reactivation during HAART, when Tat is expressed, released extracellularly and exerts, on both the virus and the immune system, effects that contribute to disease maintenance. Here we report results of an ad hoc exploratory interim analysis (up to 48 weeks) on 87 virologically-suppressed HAART-treated individuals enrolled in a phase II randomized open-label multicentric clinical trial of therapeutic immunization with Tat (ISS T-002). Eighty-eight virologically-suppressed HAART-treated individuals, enrolled in a parallel prospective observational study at the same sites (ISS OBS T-002), served for intergroup comparison. Immunization with Tat was safe, induced durable immune responses, and modified the pattern of CD4(+) and CD8(+) cellular activation (CD38 and HLA-DR) together with reduction of biochemical activation markers and persistent increases of regulatory T cells. This was accompanied by a progressive increment of CD4(+) T cells and B cells with reduction of CD8(+) T cells and NK cells, which were independent from the type of antiretroviral regimen. Increase in central and effector memory and reduction in terminally-differentiated effector memory CD4(+) and CD8(+) T cells were accompanied by increases of CD4(+) and CD8(+) T cell responses against Env and recall antigens. Of note, more immune-compromised individuals experienced greater therapeutic effects. In contrast, these changes were opposite, absent or partial in the OBS population. These findings support the use of Tat immunization to intensify HAART efficacy and to restore immune homeostasis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00751595.

Viro-immunological dynamics in HIV-1-infected subjects receiving once-a-week emtricitabine to delay treatment change after failure: a pilot randomised trial.

BACKGROUND: In HIV-1-infected patients harbouring the M184V mutation (M184V), lamivudine monotherapy leads to a smaller decrease in CD4 percentages (CD4%) than treatment interruption, possibly due to the reduced fitness of the mutated virus. OBJECTIVE: We assessed whether a minimal dose of a cytidine analogue that is theoretically sufficient to maintain M184V (one emtricitabine tablet once-weekly) may be as effective. STUDY DESIGN: In a proof-of-concept, randomised clinical trial, HIV-1-infected patients with CD4 cells >400/mm(3), failing on lamivudine- or emtricitabine-containing combination antiretroviral therapy (cART), received emtricitabine once-a-week (A), or emtricitabine once-a-day (B), or lamivudine once-a-day (C). The primary endpoint was the proportion of subjects without a 12-week loss in CD4%. The patients resumed cART after 24 weeks or in the case of CD4 cells <350/mm(3). RESULTS: The 38 enrolled patients had similar baseline characteristics across groups. The primary endpoint was reached by 5/13 patients (38.5%) in arm A, 3/13 (23.1%) in arm B, and 3/12 (25%) in arm C (P=0.644), and respectively 4/13 (30.8%), 4/13 (30.8%) and 5/12 (41.7%) had to resume cART within 24 weeks (P=0.805). The immunological changes over 24 weeks were similar in the three groups, but there was a higher median viral rebound in once-weekly treatment recipients (A) than in once-daily (B+C): 0.97 versus 0.52log(10)copies/ml (P=0.033). M184V was maintained in all the participants. CONCLUSIONS: Once-weekly emtricitabine led to a higher viral rebound than once-daily monotherapy, but similar immunological changes, thus suggesting a role of M184V in slowing the decrease in CD4% in treatment failing subjects.

Rate and predictors of self-chosen drug discontinuations in highly active antiretroviral therapy-treated HIV-positive individuals.

Despite the clinical benefits of highly active antiretroviral therapy (HAART), sustained treatment remains a great challenge for HIV-infected people. The rate, consequences, and correlates of self-elected treatment interruptions (TI) are not known. The objectives of the study were to assess the rate of patient-elected TI in a cohort of HIV-infected people taking HAART, to evaluate whether patient-elected TI is correlated with suboptimal nonadherence, and to identify the predictors of self-chosen HAART interruptions. Using a Web-based cross-sectional survey beginning in January 2006 primary outcomes were: (1) reports of having asked their physician to interrupt the current regimen (AskDisc) and (2) reports of at least one interruption of a minimum of 1 day of any of the drugs included in the regimen (INTERR). Three hundred fifty-nine people were enrolled; 296 were taking HAART. Twenty-three percent self-reported suboptimal adherence, 45% reported AskDisc, and 25% INTERR. Forty percent of people reporting INTERR self-reported suboptimal adherence. As expected, AskDisc and INTERR were correlated with suboptimal adherence. The AskDisc group had higher CD4 cell counts and HIV RNA, more symptoms, and took more convenient regimens. The INTERR group had higher HIV RNA, were more likely to smoke, seek more information on HIV/AIDS, and less likely to take non-nucleoside reverse transcriptase inhibitors (NNRTIs). The rate of self-chosen TI was high and often related to suboptimal adherence. These findings may help clinicians to better monitor patients, and identify patients for targeted counseling.