Determinants of long-term survival in late HIV presenters: The prospective PISCIS cohort study.

Background: Late HIV diagnosis (i.e CD4≤350 cells/µL) is associated with poorer outcomes. However, determinants of long-term mortality and factors influencing immune recovery within the first years after antiretroviral treatment (ART) initiation are poorly defined. Methods: From PISCIS cohort, we included all HIV-positive adults, two-year survivors after initiating ART between 2005-2019. The primary outcome was all-cause mortality according to the two-year CD4 count. We used Poisson regression. The secondary outcome was incomplete immune recovery (i.e., two-year CD4<500 cells/µL). We used logistic regression and propensity score matching. Findings: We included 2,719 participants (16593·1 person-years): 1441 (53%) late presenters (LP) and 1278 non-LP (1145 non-LP with two-year CD4 count >500 cells/µL, reference population). Overall, 113 patients (4·2%) died. Mortality was higher among LP with two-year CD4 count 200-500 cells/µL (aMRR 1·95[95%CI:1·06-3·61]) or <200 cells/µL (aMRR 4·59[2·25-9·37]).Conversely, no differences were observed in participants with two-year CD4 counts >500 cells/µL, regardless of being initially LP or non-LP (aMRR 1·05[0·50-2·21]). Mortality rates within each two-year CD4 strata were not affected by the initial CD4 count at ART initiation (test-interaction, p = 0·48). The stronger factor influencing immune recovery was the CD4 count at ART initiation. First-line integrase-inhibitor-(INSTI)-based regimens were associated with reduced mortality compared to other regimens (aMRR 0·54[0·31-0·93]) and reduced risk of incomplete immune recovery in LP (aOR 0·70[0·52-0·95]). Interpretation: Two-year immune recovery is a good early predictor of long-term mortality in LP after surviving the first high-risk 2 years. Nearly half experienced a favorable immune recovery with a life expectancy similar to non-LP. INSTI-based regimens were associated with higher rates of successful immune recovery and better survival compared to non-INSTI regimens. Funding: Southern-Denmark University, Danish AIDS-foundation, and Region of Southern Denmark.

Long-lasting adaptive immune memory specific to SARS-CoV-2 in convalescent coronavirus disease 2019 stable people with HIV.

OBJECTIVE: While the course of natural immunization specific to SARS-CoV-2 has been described among convalescent coronavirus disease 2019 (COVID-19) people without HIV (PWOH), a thorough evaluation of long-term serological and functional T- and B-cell immune memory among people with HIV (PWH) has not been reported. METHODS: Eleven stable PWH developing mild ( n  = 5) and severe ( n  = 6) COVID-19 and 39 matched PWOH individuals with mild (MILD) ( n  = 20) and severe (SEV) ( n  = 19) COVID-19 infection were assessed and compared at 3 and 6 months after infection for SARS-CoV-2-specific serology, polyfunctional cytokine (interferon-γ [IFN-γ], interleukin 2 [IL-2], IFN-γ/IL-2, IL-21) producing T-cell frequencies against four main immunogenic antigens and for circulating SARS-CoV-2-specific immunoglobulin G (IgG)-producing memory B-cell (mBc). RESULTS: In all time points, all SARS-COV-2-specific adaptive immune responses were highly driven by the clinical severity of COVID-19 infection, irrespective of HIV disease. Notably, while a higher proportion of mild PWH showed a higher decay on serological detection between the two time points as compared to PWOH, persistently detectable IgG-producing mBc were still detectable in most patients (4/4 (100%) for SEV PWH, 4/5 (80%) for MILD PWH, 10/13 (76.92%) for SEV PWOH and 15/18 (83.33%) for MILD PWOH). Likewise, SARS-CoV-2-specific IFN-γ-producing T-cell frequencies were detected in both PWH and PWOH, although significantly more pronounced among severe COVID-19 (6/6 (100%) for SEV PWH, 3/5 (60%) for MILD PWH, 18/19 (94.74%) for SEV PWOH and 14/19 (73.68%) for MILD PWOH). CONCLUSIONS: PWH develop a comparable short and long-term natural functional cellular and humoral immune response than PWOH convalescent patients, which are highly influenced by the clinical severity of the COVID-19 infection.

Nothing is perfect: the safety issues of integrase inhibitor regimens.

INTRODUCTION: Since the administration of the first integrase strand transfer inhibitor (INSTI) in 2007, most international treatment guidelines consider INSTI-based regimens to be the preferred antiretroviral combinations for HIV-1-infected patients as a result of their safety and efficacy profile. INSTIs are generally well tolerated, and reported rates of discontinuation due to drug-related adverse events (AEs) have been very low to date. However, recent reports indicate that physicians should be aware of potential INSTI-related AEs to ensure good clinical practice. AREAS COVERED: The authors performed a critical review of the safety issues affecting INSTIs based on published evidence from original studies and new data from researchers. EXPERT OPINION: Almost all antiretroviral drugs, including INSTIs, are associated with undesirable AEs. Dolutegravir in particular has been associated with more frequent AEs such as neuropsychiatric disorders, neural tube defect in newborns, and weight gain. Data with bictegravir in routine practice are still scarce. While this association and its clinical relevance are not clear, physicians should be alert to the appearance of the aforementioned AEs and others in the future. In the meantime, INSTIs continue to be the preferred option in guidelines on antiretroviral therapy.

Measurement of total and unbound bictegravir concentrations in plasma and cerebrospinal fluid by UHPLC-MS/MS.

Bictegravir is a novel integrase strand transfer inhibitor, administrated in co-formulation with tenofovir alafenamide and emtricitabine (Biktarvy®), indicated in the management of HIV-1 infection in patients not previously treated with antiretroviral therapy. Bictegravir is highly bound to plasma proteins, and this significantly determines its clearance, solubility, and activity. These characteristics are crucial determinants of bictegravir penetration into human body compartments, as the central nervous system. We developed and validated UHPLC-MS/MS procedures to measure total and unbound bictegravir concentrations in plasma and cerebrospinal fluid. Simple protein precipitation with acetonitrile was implemented to prepare plasma and cerebrospinal fluid samples. Sample preparation was preceded by ultrafiltration for measuring unbound bictegravir concentrations. Chromatographic separations were achieved on an Acquity® UHPLC® BEHTM (2.1 × 100 mm id, 1.7 µm) reverse-phase C18 column using an isocratic mobile phase 20:80 (v/v) water/acetonitrile with 0.1% formic. Bictegravir and its internal standard (bictegravir-15N d2) were detected by electrospray ionization mass spectrometry in positive and multiple reaction monitoring modes, using transitions of 450.2→289.2/145.4 and 453.2→289.2, respectively. Ultrafiltration procedures presented non-specific bindings of (8.6 ±â€¯1.2) % for bictegravir in plasma and (26.6 ±â€¯3.1) % for bictegravir in cerebrospinal fluid. Linearity was observed between (10.70-8560) µg/L, (1.07-856.0) µg/L for total and unbound bictegravir in plasma, and 0.107-26.75 µg/L for total and unbound bictegravir in cerebrospinal fluid. Imprecisions, absolute relative biases, normalized-matrix factors, and normalized-recoveries were ≤14.4%, ≤13.8%, (97.4-102.5) %, and (99.8-105.1) %, respectively. No significant interferences and carry-over were observed. The validated UHPLC-MS/MS procedures could be useful for pharmacokinetic and pharmacodynamic studies.

Long-term fat redistribution in ARV-naïve HIV+ patients initiating a non-thymidine containing regimen in clinical practice.

INTRODUCTION: Lipodystrophy is still a matter of concern in HIV+ patients receiving ART. However, long-term fat change in patients taking non-thymidine regimens is not well known. MATERIALS AND METHODS: A prospective ongoing fat change assessment including clinical evaluation and dexa scans (Hologic QDR 4500) is being conducted in all consecutive patients initiating ART from January 2008. Arm, leg, trunk and total fat as well as fat mass ratio (FMR=% trunk fat/% leg fat) were determined. Patients with data at baseline (BL), 12 and 36 m are included in this analysis. ITT and OT were performed. Multivariate general linear models were used to assess changes in fat measures. RESULTS: One hundred patients were included. 81% men, 42.9 years, 18% AIDS, CD4 218.5 (6-756), viral load 5 log (2.9-6.8), leg fat 4644g, trunk fat 6693g, FMR 0.94. Around 40 patients (40%) initiated a PIr (17 LPVr, 11 ATVr, 9 DRVr, 3 FPVr), 34 (34%) NVP and 21 (21%) EFV. About 83% received TDF/FTC and 10% ABC/3TC. Groups were comparable at BL except for a lower viral load in NVP patients (p=0.047) and lower c-LDL in PI patients (p=0.043). After 36 m, no patient presented a clinically evident lipodystrophy. At 12 m, an overall significant increase was found from baseline in trunk, leg and FMR (median 759 g, 479.4 g and 0.03, respectively, p<0.05) and at 36 m in trunk and leg fat (median 989.9 g, 566 g, respectively, p<0.05). According to ART, at 12 m a significant increase in trunk and leg fat was observed in EFV and PIr. At 36 m, in NVP patients trunk and leg fat as well as FMR increased, whereas in PIr patients only leg fat increased (see figure). In ITT analysis, adjusted by age, sex, risk practice and BL CD4, EFV was associated with a greater increase in FMR (p=0.036) at 36 m vs PIr. In OT analysis, at 12 m, NVP was associated with a smaller percentage increase in trunk fat (vs PIr and EFV, p=0.006) and in leg fat (vs PIr, p=0.046). These differences did not persist at 36 m. CONCLUSIONS: In this cohort of patients taking non-thymidine-based regimens, after 36 m without a clinically evident lipodystrophy, no significant changes in FMR were observed. However, some differences in fat redistribution according to ART were present: PIr was associated with an initial and continuous increase in trunk and leg fat, NVP with a slower and progressive increase in both fat compartments, while in EFV patients, the initial fat increase was followed by a decrease in peripheral fat at 36 m. Longer follow up will help to confirm these trends.

Short communication: focal encephalitis related to viral escape and resistance emergence in cerebrospinal fluid in a patient on lopinavir/ritonavir monotherapy with plasma HIV-1 RNA suppression.

Monotherapy with boosted protease inhibitors has emerged as an antiretroviral therapy simplification alternative for selected patients, endorsed by the results of some randomized clinical trials. However, there are some concerns about the efficacy of such a strategy in achieving successful viral suppression in those anatomic compartments or reservoirs in which antiretroviral drug penetration is lower, such as the central nervous system (CNS). Several studies have demonstrated better neurocognitive performance in patients receiving antiretroviral drugs with better cerebrospinal fluid (CSF) penetration. Nevertheless, cases of CSF viral escape accompanied by moderate or severe neurological symptoms have been reported with both standard triple therapy and boosted protease inhibitor (PI) monotherapy, and it is not well established whether ritonavir-boosted protease inhibitor (PI/r) monotherapy is associated with a higher risk of symptomatic CSF viral escape or not. Herein, we present a case of viral rebound and resistance emergence exclusively in CSF associated with an unusual clinical manifestation of focal encephalitis in a patient with plasma HIV-1 RNA suppression while receiving lopinavir/ritonavir monotherapy. Clinical resolution and CSF viral suppression were observed after switching to a genotype-guided combined antiretroviral regimen with good CSF penetration.

[Consensus statement on the clinical management of human immunodeficiency virus-associated neurocognitive disorders]. / Documento de consenso sobre el manejo clínico de los trastornos neurocognitivos asociados a la infección por el virus de la inmunodeficiencia humana (enero 2013).

OBJECTIVE: To develop a consensus document containing clinical recommendations for the management of human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND). METHODS: We assembled a panel of experts appointed by GeSIDA and the Secretariat of the National AIDS Plan (PNS), including internal medicine physicians with expertise in the field of HIV, neuropsychologists, neurologists and neuroradiologists. Scientific information was reviewed to October 2012 in publications and conference papers. In support of the recommendations using two levels of evidence: the strength of the recommendation in the opinion of the experts (A, B, C) and the level of empirical evidence (I, II, III), two levels based on the criteria of the Infectious Disease Society of America, already used in previous documents GeSIDA/SPNS. RESULTS: Multiple recommendations for the clinical management of these disorders are provided, including two graphics algorithms, considering both the diagnostic and possible therapeutic strategies. CONCLUSIONS: Neurocognitive disorders associated with HIV infection is currently highly prevalent, are associated with a decreased quality of life and daily activities, and given the possibility of occurrence of an increase in the coming years, there is a need to adequately manage these disorders, from a diagnostic as well as therapeutic point of view, and always from a multidisciplinary perspective.

Community associated methicillin-resistant Staphylococcus aureus in HIV-infected patients.

Until recently, methicillin-resistant Staphylococcus aureus was considered an uncommon community pathogen, almost exclusively associated with healthcare exposure. Over the last decade, however, methicillin-resistant S. aureus infection, particularly skin and soft tissue infection, has emerged in healthy individuals with no traditional risk factors for its acquisition. Several risk factors, including certain lifestyle behaviors, have been associated with community-acquired methicillin-resistant S. aureus colonization and infection. Regardless of other concurrent risk factors, HIV-infected patients have an increased risk for acquiring this pathogen. This article summarizes the current knowledge regarding associated risk factors, clinical manifestations, and management of community-acquired methicillin-resistant Staphylococcus aureus infections in HIV-infected patients.

Maraviroc concentrations in cerebrospinal fluid in HIV-infected patients.

OBJECTIVE: To determine maraviroc (MVC) concentrations in cerebrospinal fluid (CSF) in HIV-infected patients. METHODS: Twelve CCR5+ HIV-1 adult antiretroviral-experienced patients receiving MVC-containing regimens for at least 1 month were enrolled. Both CSF and blood samples were taken around 12 hours after the last MVC dose. liquid chromatography tandem mass spectrometry was used to determine MVC concentrations, and HIV-1 viral load was determined by real-time polymerase chain reaction, (LOD, 40 copies/mL). RESULTS: Twelve blood and 12 CSF samples were collected. Median CD4 count was 281(120-759) cells per microliter, and median HIV-1 viral load was <40 copies per milliliter. Median time on MVC was 13.5 weeks (4-60). Nucleoside analogues (tenofovir/didanosine) were given in only 1 case. Median MVC concentrations in plasma were 124.75 (7.3-517) ng/mL. In all except one, CSF sample-receiving an erroneous MVC dose while taking concomitantly nevirapine-MVC concentrations [2.58 (<0.5-7.22) ng/mL] were within the EC(90) range (0.06-10.70). Median MVC CSF: plasma ratio was 0.022 (0.004-0.17), and when the free MVC plasma concentration was used, 0.094 (2.58-27.44). CSF viral load was <40 copies per milliliter in all 9 patients with undetectable plasma viral load. CONCLUSIONS: MVC achieves concentrations within the EC(90) range in CSF. All patients with undetectable plasma viral load although receiving nucleoside-sparing regimens including new drugs showed viral suppression in CSF.

Ability of treatment week 12 viral response to predict long-term outcome in genotype 1 hepatitis C virus/HIV coinfected patients.

OBJECTIVE: Guidelines recommendation to extend treatment duration in genotype 1 hepatitis C virus (HCV)/HIV-coinfected patients who clear the virus later than treatment week 4 is not evidence-based. Our main objective was to study the ability of week 12 viral response [early virologic response (EVR)] to predict long-term outcome in patients treated for 48 weeks. DESIGN: Multicenter retrospective cohort analysis. METHODS: Genotype 1 HCV treatment-naive, HIV-coinfected adult patients with compensated liver disease who started combination therapy with fixed-dose pegylated-interferon (pegIFN) alfa-2a or weight-based pegIFN alfa-2b plus ribavirin were included. Univariate and forward stepwise logistic regression analysis were used to identify predictors of sustained viral response (SVR) and relapse. RESULTS: By intention-to-treat analysis, 31.3% (87/278) of patients achieved an SVR. SVR rate was more than three-fold higher in patients who cleared the virus by week 12 of treatment compared with late responders. Among 123 end-of-treatment responders, 36 (29.3%) relapsed. Relapse risk increased in patients with cirrhosis, in those with ribavirin dose reductions and in late responders: more than 65% of patients who cleared the virus between weeks 12 and 24 relapsed following 48 weeks of treatment compared with 10% of those attaining a complete EVR (<15 IU/ml) at treatment week 12 (risk ratio 6.4, 95% confidence interval 2.9-14.4). CONCLUSION: Viral response at treatment week 12 is a strong predictor of long-term outcome. Genotype 1 HCV/HIV-coinfected patients who achieve a complete EVR (<15 IU/ml) are at low risk of viral relapse after completing the standard 48 weeks of therapy.

[Etravirine in highly treatment-experienced patients]. / Etravirina en pacientes ampliamente pretratados.

Etravirine (ETR) has demonstrated efficacy in patients with multiple prior treatments with prior virological failure and resistance mutations to various families of antiretroviral drugs. Most of the evidence concerning this drug has been drawn from the DUET studies, consisting of two multicenter, randomized, double-blind clinical trials with identical designs that included 1,200 patients. These trials showed that ETR obtained a superior virological and immunological response to placebo, reducing the incidence of hospital admissions and progression to AIDS/death. The most frequent adverse effect was rash, which was generally mild to moderate and required treatment discontinuation in only 2%. There were no differences in gastrointestinal, liver or lipid toxicities compared with the placebo arm. Because of the recent development of new drugs, effective regimens are now available for multi-treated patients. The TRIO study evaluated the efficacy and tolerability of one of the regimens most widely used today (ETR/raltegravir/darunavir/r) with excellent virological and immunological response (86% of viral load < 50 copies and CD4 +108 at 48 weeks) and excellent tolerance. ETR is effective and well tolerated and is the first non-nucleoside reverse transcriptase inhibitor (NNRTI) that allows the sequential use of drugs in this family, due to its high genetic barrier compared with firstgeneration NNRTI. Moreover, its long half-life allows once daily administration in patients requiring a QD regimen.