Unexpected CD4 decay, hidden adherence gaps, resilience, and the need for long-acting therapy in a single HIV outpatients' cohort.

This single-centre, single-cohort study examines hidden non-adherence to antiretroviral therapy in a setting of persistent optimal viral suppression but concordant absolute and percent CD4 decay by >10% from the previous test. After the finding of important drug holidays in two virologically suppressed patients, between January 2021 and January 2022 all PLWH who fulfilled CD4 decay criteria were asked for how long therapy was interrupted, how many days before re-testing CD4 and HIV RNA was it resumed and the reason for interruption. Of 668 HIV-infected subjects, 61 fulfilled the pre-specified criteria for significant CD4 decay and 15 (2.25% of the total, 25% of the CD4 decay group) admitted long-lasting treatment interruptions, compensated by treatment resumption before the subsequent testing. Eleven treatment interruptions exceeded 28 days, and none was shorter than 15 days. CD4 recovery was worse at 6 months in non-adherent subjects (-0.5 vs + 16/mmc, p < 0.0001) and in non adherence vs immune decay time-related with COVID-19 (0 vs + 22/mmc, p < 0.0001). Reasons for interrupting treatment were travel, psychological, poverty-related, addiction and sentimental sphere problems. Long-acting regimens, with stringent control of precision in timely administration, may protect PLWH from damaging their health status and possibly transmit HIV.

Short-term inhibition of SARS-CoV-2 by hydrogen peroxide in persistent nasopharyngeal carriers.

Asymptomatic and convalescent coronavirus disease 2019 (COVID-19) subjects may carry severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for months in their upper respiratory ways. Desiring to permanently clean the mucosal surfaces, we investigated the chemical agents that fit to rapidly degrade the virus. Among these, hydrogen peroxide, initially tested by two of us for tolerability, showed both good performance and acceptable side effects (burning sensation for 15-20 s). We contacted circles of family physicians and the ATS Milano (Territorial Assistance and Prevention Service), and we tested this procedure on eight persistent carriers of SARS-CoV-2, performing swabs before the procedure and after it until the reappearance of the virus or until 14 days (the incubation period), keeping the surfaces clean with a hypertonic solution. Our patients had a median time from exposure or symptom onset of 111 days, and three had relapsed after being declared "cured" (two consecutive negative swabs after quarantine). One patient had a baseline negative swab and was excluded, and two successfully ended the 14 days' course, four suppressed viral elimination for 72 h, and one for 48 h, all rebounding to weak positive (cycle thresholds above 24). Although temporarily effective, such measures may have some place in the control of viral shedding to protect the most fragile subjects.

A dual regimen of ritonavir/darunavir plus dolutegravir for rescue or simplification of rescue therapy: 48 weeks' observational data.

BACKGROUND: Dolutegravir (DTG) plus darunavir/ritonavir (DRV/r) is a simple combination of drugs that has the best genetic barrier to HIV-1 resistance and may be fit for salvage therapy. METHODS: All HIV-1-infected subjects treated with DTG plus DRV/r between March 2014 and September 2015 in eight Italian centres were included in the analysis. The main metabolic data, efficacy parameters and safety data routinely collected were provided. This observational study is aimed to assess the efficacy of such approach. The primary end-point was the proportion of subjects achieving or maintaining virologic suppression <50 copies/mL at week 24. Secondary end points were maintaining virologic suppression in the follow-up (weeks 48 and 96) and safety. RESULTS: One hundred and thirty subjects were followed for a median of 56 months. Reasons for switching were simplification (44.6%), viral failure (30%), toxicity (16.9%), non-adherence (4.6%), persistent low-level viremia (3.1%), and drug-drug interaction (0.8%). At baseline, 118 subjects had documented resistance to 1 to 5 antiretroviral classes while 12 had viral rebound at a time when genotypic tests were not yet available. Seventeen and 14 subjects took DRV/r and DTG twice daily, respectively. One subject was lost to follow-up, one discontinued for liver enzymes' elevation, one died of illicit drug abuse and one of cancer-related complications. The proportion of subjects with ongoing HIV replication dropped from 40% to 6.1%. Those with undetectable viral load increased from 38.5% to 76.2%. At week 48, 17.7% had HIV RNA between 1 and 49 copies/mL. The number of subjects with altered serum glucose, creatinine, ALT, AST, total-, HDL- and LDL-cholesterol, triglycerides and MDRD <90 mL/min decreased by week 48, while those having MDRD <60 mL/min remained 4.6%. Overall 90/283 baseline laboratory alterations returned to normality. CONCLUSIONS: Switching to DTG plus DRV/r proved to be safe, suppressing viral replication without metabolic impact.

The future of long-acting cabotegravir plus rilpivirine therapy: deeds and misconceptions.

HIV infection is currently managed as a chronic disease because of improvements in antiretroviral therapy (ART). Switching to a new regimen is a natural event during long-term therapy to avoid problems related to toxicity, adherence, failure, and potential selection of drug resistance. The development of co-formulations of multiple agents in one pill, and novel drug classes and drugs with a high genetic barrier to resistance have been important in this context. The approval of the long-acting, once-monthly or bimonthly injectable combination of the second-generation strand transfer integrase inhibitor (InSTI), cabotegravir (CAB) together with the non-nucleoside reverse transcriptase inhibitor (NNRTI), rilpivirine (RPV) represents the most recent achievement in the search for potent and convenient ART. Several pivotal trials (such as LATTE-2, ATLAS, FLAIR, and ATLAS-2M) showed the high efficacy and safety of this long-acting formulation used as an induction-maintenance strategy. Few confirmed virological failures (CVF) have been observed. The combination of at least two of the following baseline factors, HIV-1 subtype A6/A1, a body mass index (BMI) ≥30 kg/m2, and RPV resistance-associated mutations, was associated with an increased risk of CVF at week 48. The data indicate that this long-acting therapeutic strategy is attractive and potent; therefore, defining the most appropriate patient for this treatment and how to handle practical issues is warranted.

Decay rate of antiS1/S2 IgG serum levels after 6 months of BNT162b2 vaccination in a cohort of COVID-19-naive and COVID-19-experienced subjects.

Vaccination toward SARS-CoV-2 reduced mortality and 'boosters' are being implemented. We offer scientific contribution about IgG production in the COVID-19 experienced population. From January 2021 to March 2021, 183 residents and staff from the Elderly Nursing Home "San Giuseppe Moscati" who had received two doses of the BNT162b2 vaccine were enrolled. The antibody response was assessed by the DiaSorin LIAISON-CLIA S1/S2® IgG solution. Cutoff levels for response (>39 BAU/mL) and neutralizing activity (>208 BAU/mL) were derived from DiaSorin official data. Serology was assessed before and after the first vaccination, and 2 weeks and 6 months after the second vaccination. Anti-S IgG in COVID-19 experienced, baseline IgG producers spiked after the first vaccination to median 5044 BAU/mL and decayed at 6 months to 2467.4 BAU/mL. Anti-S IgG in COVID-19 experienced, baseline IgG non-producers spiked after the second vaccination to median 1701.7 BAU/mL and decayed at 6 months to 904.8 BAU/mL. Anti-S IgG in COVID-19 naïve subjects spiked after the second vaccination to median 546 BAU/mL and decayed at 6 months to 319.8 BAU/mL. The differences between sequential timepoint levels in each group were statistically significant (p < .0001). Serology analysis revealed different kinetics between COVID-19 experienced subjects depending on baseline response, possibly predicting different IgG persistence in blood.

One-year durability of anti-spike IgG to SARS-CoV-2: Preliminary data from the anticrown prospective observational study one year durability of COVID-19 anti-spike IgG.

Data are presented of 368/503 post-COVID-19 outpatients followed within the AntiCROWN Cohort who have a one-year control and a baseline assessment of anti-S1/S2 antibodies, detected with the The LIAISON® SARS-CoV-2 S1/S2 IgG solution by DiaSorin. Loss of response occurred in 4 subjects having a baseline level below 50 AU/mL.

Anti-inflammatory effect of maraviroc in an HIV-infected patient with concomitant myositis: a case report.

We report the surprising yet sought impact that an antiretroviral (ARV) regimen containing maraviroc had on an HIV-infected and heavily highly active antiretroviral therapy (HAART)-experienced patient with chronic polymyositis. The patient had elevated creatine kinase (CK) levels in serum for 6 years, reaching peaks over 900 U/L and showing only partial response to high-dose steroids, not responding to HAART withdrawal. The disease started while on second-line HAART and gradually impaired his muscular function, leading to the absolute loss of the ability to stand on his legs. Atherosclerosis and hypertension contributed to the development of myocardial infarction. The association of unboosted atazanavir (ATV) plus maraviroc was designed hoping in a protective role on the cardiovascular system and in an anti-inflammatory effect that some authors have hypothesized. After only 3 months the patient's CK levels had normalized and with the help of rehabilitation he recovered the ability to walk, which he still maintains at the one year of observation.

An evaluation of elvitegravir plus cobicistat plus tenofovir alafenamide plus emtricitabine as a single-tablet regimen for the treatment of HIV in children and adolescents.

INTRODUCTION: Approximately 2.1 million of the estimated 36 million infected with HIV are children or adolescents. International guidelines for HIV-1 Infection suggest starting antiretrovirals (ARV) at the moment of diagnosis. Many factors limit the optimization of antiretroviral therapy in children and adolescents: lack of pediatric formulations, poor adherence, metabolic and pharmacokinetic changes associated withnormal child development and puberty. Areas covered: Three integrase inhibitors are approved by the US Food and Drug Administration and by European Medical Agency for children and adolescents with HIV-1 infection. Raltegravir is approved for children aged 4 weeks to 18 years, while dolutegravir and elvitegravir co-formulated with cobicistat, emtricitabine, and tenofovir alafenamide (E/C/FTC/TAF) are approved for children from 6 years of age. This article evaluates E/C/FTC/TAF as a treatment option. Expert opinion: E/C/FTC/TAF was well tolerated, and the antiretroviral activity and tolerability data of this combination support the use in children and adolescents. However, the studies regarding E/C/FTC/TAF in children and adolescents are scant. Consequently, additional studies investigating its safety and efficacy in children are paramount.

Dolutegravir plus rilpivirine dual therapy in treating HIV-1 infection.

INTRODUCTION: The HIV-infected population is aging and comorbidities and polypharmacological regimens are increasing. To reduce toxicity and drug burden researchers are evaluating the efficacy, safety and durability of dual therapies as a switch option in subjects who have achieved stable virologic suppression. Initially effective dual combinations relied on protease inhibitors but when dolutegravir, the first integrase inhibitor to display a high genetic barrier, became commercially available, many physicians began to use it in a variety of dual regimens, generating several observational cohorts. Areas covered: This review covers the most recent data from observational cohorts and randomized clinical trials concerning the switch to the dual combination of dolutegravir plus rilpivirine and the reasons that lead to consider this option. Also, viral failures, due to poor adherence or to other factors, and drug resistance are investigated. Articles which are searchable on MEDLINE/PubMed and from the main national/international congresses in the field of HIV therapy are reviewed. Expert opinion: The observation period for this regimen is getting longer and data showing its efficacy in maintaining HIV-1 RNA < 50 copies/mL are now consolidated. Metabolic data suggest some benefit in the lipid profile, improvement in bone mineral density and reduced bone reabsorption.

Durability of dolutegravir plus boosted darunavir as salvage or simplification of salvage regimens in HIV-1 infected, highly treatment-experienced subjects.

BACKGROUND: Dolutegravir (DTG) plus boosted darunavir (bDRV) is a compact, adherence-friendly salvage regimen with the highest genetic barrier to HIV-1 resistance. OBJECTIVE: Aim of the present study is to assess the long term (96-week) safety and efficacy of DTG + bDRV in a of multidrug-experienced HIV-1 infected patients, simplifying or building rescue regimens. METHODS: All HIV-1-infected subjects from eleven Italian centers switched to DTG + bDRV between March 2014 and September 2015 were included and followed for minimum 96 weeks. RESULTS: The cohort comprises 130 subjects, switched from 42 different, complex or at least twice-daily regimens, mainly for simplification (44.6%), viral failure (30.0%) or toxicity (16.6%). At baseline 118 had documented resistance to 1-5 antiretroviral classes and 12 lacked genotypic results either for historical reasons or for problems with primer annealing; 52 (40%) had uncontrolled viral replication, three above 500.000 copies/mL. At week 96 two showed ≥50 HIV-1 RNA copies/mL, 23 had 1-49 copies/mL and 101 had no virus detected. The proportion of subjects presenting abnormal values at baseline significantly decreased for serum glucose, creatinine, AST, total cholesterol and triglycerides. CONCLUSIONS: These long-term data confirm the reliability of the two-drug regimen consisting of bDRV plus DTG in salvage settings in HIV-1 infection.

Pharmacokinetic drug evaluation of dolutegravir plus rilpivirine for the treatment of HIV.

INTRODUCTION: The search for simple, potent, metabolic-friendly and nucleoside/nucleotide sparing antiretroviral regimens has led clinical investigators to move steps towards dual therapies. Among these the association of rilpivirine and dolutegravir is emerging as a twin randomized clinical trial (SWORD1&2) and at least three observational cohort describe it as a safe and highly effective regimen for switch from other therapies Areas covered: We review the evidence supporting the use of dolutegravir plus rilpivirine for the treatment of HIV in virologically suppressed patients taking other antiretroviral regimens. The reasons for the switch in clinical practice may range from simplification to tolerability/toxicity issues, to the prevention of future metabolic damage, to predicted drug-drug interactions when treatment of HCV co-infection is planned. Articles searchable on MEDLINE/PubMed and from the main international congresses in the field of HIV therapy were reviewed to provide context for use of dolutegravir plus rilpivirine Expert opinion: This treatment is highly effective in maintaining HIV-1 RNA <50 copies/mL. Although the studies up to date requested patient to switch to drugs they had no experience of, a predictable 'radical change' effect did not impact negatively on the results. Further data from these studies may help elucidate the possible advantage in terms of safety and metabolic effect in the next few months.

Salvage therapy or simplification of salvage regimens with dolutegravir plus ritonavir-boosted darunavir dual therapy in highly cART-experienced subjects: an Italian cohort.

BACKGROUND: Dolutegravir plus darunavir provide a high genetic barrier to HIV-1 resistance and are suitable for simple salvage regimens. METHODS: All HIV-1-infected subjects treated with dolutegravir plus boosted darunavir dual therapy between March 2011 and September 2015 were included in an observational cohort. Data were collected at baseline and at weeks 4, 12, 24 and 48. RESULTS: We enrolled 113 subjects. After week 24, one was lost at follow-up, one dropped out for grade 2 elevation of liver enzymes, one died from illicit drug abuse and one from cancer-related sepsis. The mean age was 51, 26.5% were female and 9.7% were non-Caucasian. Twenty had never experienced failure. A total of 99 had reverse-transcriptase (RT) mutations, 87 had protease inhibitor mutations and 12 had integrase strand transfer inhibitor (INSTI) mutations. Viraemic patients declined from baseline to week 24 from 43.4% to 6.2%, the remainder being due to high baseline viraemia or adherence issues. The proportion of subjects with viraemia 1-49 copies/ml remained at 20.4% while those in whom no virus was detected (NVD) increased from 36.3% to 73.5% by week 24. All the 47 subjects who had a 48-week follow-up had <50 copies/ml and 42 (89.4%) had NVD. 18 subjects had reduced sensitivity to darunavir (Stanford median score 15, range 15-40), but none rebounded, 6 having a 24-week and 7 a 48-week follow-up. The median variation in serum creatinine was -0.01 (range +0.2 to -0.21) mg/dl. CONCLUSIONS: This dual regimen provides a simple salvage regimen and proved safe and effective in this cohort.

Switch to Dolutegravir plus Rilpivirine Dual Therapy in cART-Experienced Subjects: An Observational Cohort.

INTRODUCTION: Little information is available on the efficacy and safety of the dual combination of ripivirine plus dolutegravir. This work aims at beginning to fill this gap. METHODS: All HIV-1 infected subjects treated with ripivirine plus dolutegravir between October 2014 and September 2015 in eight Italian centres were included in an observational cohort. Data were collected at baseline and at weeks 4, 12, 24 and 48. RESULTS: One hundred and thirty-two subjects were followed for a median of 24 months, mean 33 months. One subject discontinued the study drug at week 24 for headache, one for drug interaction and one died after week 24 of illicit drug abuse. The mean age was 51.8, females 31.7% and non-caucasians 10%. Fifty-seven (43.2%) had at least one failure in their treatment history. Reasons for switching were simplification (53.0%), toxicity (34.8%), drug interactions (n = 7), persistent low-level viremia (n = 4), non-adherence (n = 3) and viral failure (n = 2). Sixty patients (45.5%) had reverse transcriptase (RT) mutations and 69 (44,7%) had protease (PR) mutations. Sixteen had baseline viral replication, 27 had < 50 HIV-1 RNA copies/mL and in 89 (67.4%) no virus was detected (NVD, 0 copies/mL). At w4, 114 (86.4%) had NVD, 15 had 1 to 49 HIV-1 RNA copies/mL and 3 had 50 to 57 copies/mL. At week 24 one subject had viral rebound without mutations due to missed drug refill, 19 had 1 to 49 copies/mL, and 112 had NVD. All 132 subjects were tested at weeks 4 and 24. Of the 50 subjects who had a 48-week follow-up, one had a treatment interruption, four had 1 to 49 copies/mL and 45 had NVD. Among the entire population, one subject had low-level, one intermediate and 4 high-level resistance to rilpivirine: none failed by week 48. Mean serum creatinine increased by +0.1 mg/dL. During the follow-up one patient reported headache and insomnia. CONCLUSIONS: Ripivirine plus dolutegravir proved safe and effective in this cohort of non-naïve HIV-1 infected subjects.