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We estimated the dynamics of the neutralizing response against XBB sublineages and T cell response in persons with HIV (PWH) with previous AIDS and/or CD4 < 200/mm3 receiving the bivalent original strain/BA.4-5 booster dose in fall 2022. Samples were collected before the shot (Day 0), 15 days, 3, and 6 months after. PWH were stratified by immunization status: hybrid immunity (HI; vaccination plus COVID-19) versus nonhybrid immunity (nHI; vaccination only). Fifteen days after the booster, 16% and 30% of PWH were nonresponders in terms of anti-XBB.1.16 or anti-EG.5.1 nAbs, respectively. Three months after, a significant waning of anti-XBB.1.16, EG.5.1 and -XBB.1 nAbs was observed both in HI and nHI but nAbs in HI were higher than in nHI. Six months after both HI and nHI individuals displayed low mean levels of anti-XBB.1.16 and EG.5.1 nAbs. Regarding T cell response, IFN-γ values were stable over time and similar in HI and nHI. Our data showed that in PWH, during the prevalent circulation of the XBB.1.16, EG.5.1, and other XBB sublineages, a mRNA bivalent vaccine might not confer broad protection against them. With a view to the 2023/2024 vaccination campaign, the use of the monovalent XBB.1.5 mRNA vaccine should be urgently warranted in PWH to provide adequate protection.
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COVID-19 , Infecções por HIV , Humanos , COVID-19/prevenção & controle , Programas de Imunização , RNA Mensageiro , Estações do Ano , Vacinas de mRNA , Anticorpos Neutralizantes , Anticorpos AntiviraisRESUMO
Background: Pre-exposure vaccination with MVA-BN has been widely used against mpox to contain the 2022 outbreak. Many countries have defined prioritized strategies, administering a single dose to those historically vaccinated for smallpox, to achieve quickly adequate coverage in front of low supplies. Using epidemiological models, real-life effectiveness was estimated at approximately 36%-86%, but no clinical trials were performed. Few data on MVA-BN immunogenicity are currently available, and there are no established correlates of protection. Immunological response in PLWH in the context of the 2022 outbreak was also poorly described. Methods: Blood samples were collected from participants eligible for pre-exposure MVA-BN vaccination before (T1) receiving a full course of vaccine (single-dose for vaccine-experienced or smallpox-primed and two-dose for smallpox vaccine-naïve or smallpox non-primed) and one month after the last dose (T2 and T3, respectively). MPXV-specific IgGs were measured by in-house immunofluorescence assay, using 1:20 as screening dilution, MPXV-specific nAbs by 50% plaque reduction neutralization test (PRNT50, starting dilution 1:10), and IFN-γ-producing specific T cells to MVA-BN vaccine, by ELISpot assay. Paired or unpaired t-test and Wilcoxon or Mann-Whitney test were used to analyse IgG and nAbs, and T-cell response, as appropriate. The probability of IgG and nAb response in vaccine-experienced vs. vaccine-naïve was estimated in participants not reactive at T1. The McNemar test was used to evaluate vaccination's effect on humoral response both overall and by smallpox vaccination history. In participants who were not reactive at T1, the proportion of becoming responders one month after full-cycle completion by exposure groups was compared by logistic regression and then analysed by HIV status strata (interaction test). The response was also examined in continuous, and the Average Treatment Effect (ATE) of the difference from baseline to schedule completion according to previous smallpox vaccination was estimated after weighting for HIV using a linear regression model. Self-reports of adverse effects following immunization (AEFIs) were prospectively collected after the first MVA-BN dose (T1). Systemic (S-AEFIs: fatigue, myalgia, headache, GI effects, chills) and local (L-AEFIs: redness, swelling, pain) AEFIs were graded as absent (grade 0), mild (1), moderate (2), or severe (3). The maximum level of severity for S-AEFIs and L-AEFIs ever experienced over the 30 days post-dose by vaccination exposure groups were analysed using a univariable multinomial logistic regression model and after adjusting for HIV status; for each of the symptoms, we also compared the mean duration by exposure group using an unpaired t-test. Findings: Among the 164 participants included, 90 (54.8%) were smallpox vaccine-experienced. Median age was 49 years (IQR 41-55). Among the 76 (46%) PLWH, 76% had a CD4 count >500 cells/µL. There was evidence that both the IgG and nAbs titers increased after administration of the MVA-BN vaccine. However, there was no evidence for a difference in the potential mean change in humoral response from baseline to the completion of a full cycle when comparing primed vs. non-primed participants. Similarly, there was no evidence for a difference in the seroconversion rate after full cycle vaccination in the subset of participants not reactive for nAbs at T1 (p = 1.00 by Fisher's exact test). In this same analysis and for the nAbs outcome, there was some evidence of negative effect modification by HIV (interaction p-value = 0.17) as primed people living with HIV (PLWH) showed a lower probability of seroconversion vs. non-primed, and the opposite was seen in PLWoH. When evaluating the response in continuous, we observed an increase in T-cell response after MVA-BN vaccination in both primed and non-primed. There was evidence for a larger increase when using the 2-dose vs. one-dose strategy with a mean difference of -2.01 log2 (p ≤ 0.0001), after controlling for HIV. No evidence for a difference in the risk of developing any AEFIs of any grade were observed by exposure group, except for the lower risk of grade 2 (moderate) fatigue, induration and local pain which was lower in primed vs. non-primed [OR 0.26 (0.08-0.92), p = 0.037; OR 0.30 (0.10-0.88), p = 0.029 and OR 0.19 (0.05-0.73), p = 0.015, respectively]. No evidence for a difference in symptom duration was also detected between the groups. Interpretation: The evaluation of the humoral and cellular response one month after the completion of the vaccination cycle suggested that MVA-BN is immunogenic and that the administration of a two-dose schedule is preferable regardless of the previous smallpox vaccination history, especially in PLWH, to maximize nAbs response. MVA-BN was safe as well tolerated, with grade 2 reactogenicity higher after the first administration in vaccine-naïve than in vaccine-experienced individuals, but with no evidence for a difference in the duration of these adverse effects. Further studies are needed to evaluate the long-term duration of immunity and to establish specific correlates of protection. Funding: The study was supported by the National Institute for Infectious Disease Lazzaro Spallanzani IRCCS "Advanced grant 5 × 1000, 2021" and by the Italian Ministry of Health "Ricerca Corrente Linea 2".
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OBJECTIVES: To investigate immunogenicity of SARS-CoV-2 vaccine third booster dose (3BD; fifth dose) with bivalent vaccine original/BA4/5 vaccine in people living with HIV (PLWH). METHODS: This is an observational cohort study to evaluate the outcomes of SARS-CoV-2 vaccination (HIV-VAC study). We analyzed microneutralization assay and interferon-γ production in 48 PLWH on antiretroviral therapy with clusters of differentiation (CD4) count <200 cell/mm3 and/or previous AIDS according to immunization status: vaccinated PLWH who had a previous SARS-CoV-2 infection (hybrid immunization, HI) vs those only vaccinated (non-hybrid immunization, nHI) and current CD4 count. RESULTS: After 15 days from its administration (T1), the 3BD bivalent messenger RNA vaccine elicited a statistically significant increase of neutralizing antibodies (nAbs) geometric mean titers from T0 to T1 against W-D614G (fold increase 4.8; P <0.0001), BA.5 (8.6 P <0.0001), BQ.1.1 (6.4, P <0.0001) and XBB.1 (6.5, P <0.0001). When compared to BA.5, nAbs geometric mean titers against BQ.1.1 and XBB.1 decreased by 3.5 and 4.1-fold, respectively. After controlling for age, years from AIDS diagnosis, CD4 count at administration and CD4 count nadir, the fold change reduction in nAbs response to other variants of concerns as compared to BA.1, was larger in participants with HI vs those nHI: 0.59 lower (95% confidence interval 0.36-0.97, P = 0.04) for BQ.1.1 and 0.67 lower (95% confidence interval: 0.47-0.96, P = 0.03) for XBB.1. In contrast, the analysis carried little evidence for an association between current CD4 count and response to the fifth dose of bivalent vaccine. Furthermore, cell-mediated immunity remained stable. CONCLUSION: Our data support the current recommendation of offering bivalent mRNA vaccine booster doses to PLWH with low CD4 count or previous AIDS at first vaccination, especially in those who never previously acquired SARS-CoV-2 and regardless of current CD4 count.
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Síndrome da Imunodeficiência Adquirida , COVID-19 , Humanos , Vacinas contra COVID-19 , Linfócitos T , COVID-19/prevenção & controle , SARS-CoV-2 , Vacinas Sintéticas , Vacinas Combinadas , Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas de mRNARESUMO
Dynamics of human immunodeficiency virus type 1 (HIV-1) tropism after antiretroviral therapy (ART) initiation and their association with disease progression are poorly investigated.This was a cohort study on subjects from the ICONA cohort receiving ART with persistently detectable (PD) or persistently undetectable (PU) viral load (VL) and with stored plasma or peripheral blood mononuclear cell (PBMC) samples at 2 time-points (T1, T2) after ART initiation. HIV-1 co-receptor tropism was determined by V3-loop sequencing and the geno2pheno algorithm. A switch in viral tropism was defined if the tropism classification at T2 differed from that observed at T1. Time to disease progression, defined as the occurrence of a new acquired immune deficiency syndrome (AIDS)-defining event/death from T2, was also evaluated.One hundred ninety-five patients were analyzed (124 PD, 71 PU). Over a median follow-up of 22.6 (19.8-28.1) months, PD and PU patients showed similar rates (95% confidence interval) of switch to a non-R5 virus [PD: 6.9 (3.7-11.2)/100-person-years of follow-up (PYFU); PU: 8.0 (3.4-14.5)/100-PYFU; Pâ=â0.63] and of switch to a R5 virus [PD: 15.4 (7.3-26.4)/100-PYFU; PU: 8.1 (2.5-16.7)/100-PYFU; Pâ=â0.38]. Switch to non-R5 virus was predicted by nadir CD4+ before T1.Twenty-two (18%) PD and 4 (6%) PU subjects experienced disease progression (Pâ=â0.02). The risk of disease progression was independently associated with a switch in co-receptor tropism (adjusted hazard ratioâ=â4.06, 95% CI: 1.20-13.80, Pâ=â0.03) as well as age, AIDS diagnosis, nadir CD4+ before T2, current CD4+, and VL.Switch of HIV-1 tropism under ART occurs in both directions, with similar rates in subjects with PD or PU VL and it might be predictive of future unfavorable clinical outcome.
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Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/fisiologia , Tropismo Viral , Adulto , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Serious non-AIDS events (SNAE) are frequent in HIV patients receiving cART. Current CD4 count was shown to be more strongly associated with infective compared to not-infective SNAE and unable to predict cardiovascular events. We investigated the relationship between baseline and current CD4 count and the risk of both infective and non-infective SNAE in HIV-positive patients according to current ART use. METHODS: We included all HIV-positive persons enrolled in the ICONA Foundation Study cohort who had at least one follow-up visit. SNAE were grouped in infective (pneumonia, sepsis, endocarditis and meningitis) and non-infective (malignancies, chronic kidney disease, cardiovascular events, hepatic events and pancreatitis) aetiology. Incidence of these event groups were calculated overall and according to baseline and current CD4 count (grouped as 0-200, 201-350, 351-500, 501-750, and >750 cells/mm(3)). Participants' follow-up accrued from the date of enrolment (baseline) to a diagnosis of SNAE or their last visit. An event was defined the first time one of the considered SNAE occurred so that each person contributed a single event. A Poisson regression model for each of the two endpoints was used. RESULTS: A total of 10,822 patients were included (25.3% females, 38.2% heterosexuals) and 26.6% had hepatitis co-infections. Median age was 36 (IQR 31-42) years. Overall, 423 not-infective and 385 infective SNAE were included. The most frequent non-infective SNAE were malignancies (n=202) and the most frequent infective SNAE were pneumonia (n=289). Crude rates of non-infective SNAE were 0.78, 1.08 and 0.80/100 PYFU, and those of infective SNAE were 1.00, 0.51 and 0.66/100 PYFU in ART naive, currently off and currently on ART patients, respectively. Higher current CD4 count was associated with reduced risk of both infective and non-infective SNAE in naives and in patients on ART (Table 1). The association was less strong in the group which suspended ART (for non-infective SNAE the p value for interaction between current log-CD4 and ART-status, p=0.004). Conversely, we found no association between baseline CD4 count and risk of non-infective SNAE in people treated with ART (p value for interaction = 0.0001). When CVD were considered separately, there was no association with CD4 count (not shown). CONCLUSIONS: Our findings show that, differently from ART naive, in ART-treated patients, non-infective SNAE are predicted by current but not by baseline CD4, suggesting that immune restoration is crucial to prevent these events.
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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.
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OBJECTIVE AND DESIGN: The present study aims at evaluating the influence of genetic polymorphisms on antiretroviral therapy (ART)-associated lipodystrophy. We included in the study 255 ICoNA. patients and we assessed the distribution of Fas -670 AG polymorphism, ApoC3 -455 CT and -482 CT polymorphisms, C161T silent substitution in the PPAR gamma gene, the Adrenergic beta3 Receptor (ARbeta3) codon 64 TC variant, and two polymorphisms in the Adrenergic beta2 Receptor (ARbeta2) codon 16 AG and codon 27 CG. Crude rates of lipoatrophy and fat accumulation and adjusted relative rates were calculated using Poisson regression. RESULTS: In a multivariate model after adjusting for gender, HIV exposure, age, current viral load, hepatitis C virus (HCV) serology, nucleoside reverse-transcriptase inhibitor (NRTI) pair/'third drugs' currently used, months of pre-highly active antiretroviral therapy (HAART) exposures to NRTI, the following genotypes resulted protective against lipoatrophy: ApoC3 -455 CC genotype [adjusted relative risks (ARR) 0.2, 95% confidence interval (CI) 0.046-0.91 vs CT/TT, P = 0.037], ARbeta3 codon 64 TT genotype (ARR 0.39, 95% CI 0.14-1.06 vs TC/CC, P = 0.066), and Fas -670 GG genotype (ARR 0.51, 95% CI 0.26-1.01 vs AG/AA, P = 0.053). With regard to fat accumulation, in the multivariate model, the ARbeta2 codon 27 CC genotype resulted protective (ARR 0.21, 95% CI 0.08-0.51 vs CG/GG, P = 0.0006), whereas the ARbeta2 codon 16 AA genotype resulted associated with higher risk (ARR 3.72, 95% CI 1.58-8.76 vs AG/GG, P = 0.0026). CONCLUSION: Our study suggests that genetic polymorphisms of genes involved in apoptosis and adipocyte metabolism are significantly related to ART associated lipodystrophy. Particularly, we evidenced a role for ApoC3 -455 in lipoatrophy and for the two variants of ARbeta2 in fat accumulation.
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Apoptose/genética , Composição Corporal/genética , HIV-1 , Síndrome de Lipodistrofia Associada ao HIV/genética , Polimorfismo Genético , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adulto , Fatores Etários , Antirretrovirais/uso terapêutico , Apolipoproteína C-III/genética , Feminino , Seguimentos , Frequência do Gene , Genótipo , Síndrome de Lipodistrofia Associada ao HIV/tratamento farmacológico , Síndrome de Lipodistrofia Associada ao HIV/patologia , Humanos , Masculino , Análise Multivariada , PPAR gama/genética , Polimorfismo de Fragmento de Restrição , Regiões Promotoras Genéticas , Receptores Adrenérgicos beta 2/genética , Risco , Fatores Sexuais , Receptor fas/genéticaRESUMO
Recently, it was shown that cirrhotic patients without human immunodeficiency virus (HIV) infection had low CD4 cell counts and normal CD4 cell percentages, suggesting that, for HIV-infected persons, the CD4 cell percentage might be a more accurate marker of disease progression than the absolute CD4 cell count. In cirrhotic HIV-infected persons in the Italian Cohort of Antiretroviral-Naive Patients, the absolute CD4 cell count seemed to be better predictor of the risk of developing an acquired immunodeficiency syndrome-defining illness than the CD4 cell percentage.
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Contagem de Linfócito CD4/métodos , Fibrose/complicações , Infecções por HIV/complicações , Infecções por HIV/imunologia , Biomarcadores , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Hospedeiro Imunocomprometido , Masculino , Valor Preditivo dos Testes , RiscoRESUMO
OBJECTIVE: To assess the risk of clinical progression (CP) according to the duration of time spent without complete viral load (VL) suppression compared with that associated with periods of stably suppressed viremia in HIV-infected people who started highly active antiretroviral therapy (HAART) when previously naïve to antiretrovirals. DESIGN: A cohort study of patients having started HAART after enrollment in the Italian Cohort of Antiretroviral-Naive Patients (ICoNA) and being followed for at least 6 months. METHODS: Person-years spent in different categories according to the VL level and the change in VL from the most recent value before the initiation of HAART were calculated. A multivariable Poisson regression model, including potential confounders, was constructed. RESULTS: A total of 3023 patients were studied. The overall rate of CP was 13.4 per 1000 person-years. Evidence for a higher risk of CP was observed for people with a current VL >10,000 copies/mL. For each year longer spent on HAART with a VL >100,000 copies/mL, a 5-fold increased risk was observed (relative risk [RR] = 5.34, 95% confidence interval [CI]: 2.83 to 1.08; P = 0.0001). An increased risk of CP in patients with current suppression <1.5 log10 copies/mL (RR = 2.34, 95% CI: 1.16 to 4.74; P = 0.02) and in those with no suppression or a VL higher than their set point (RR = 2.39, 95% CI: 1.17 to 4.89; P = 0.02) was observed compared with those with suppression of >3 log10 copies/mL, although it was not significant. Longer duration on HAART with a VL suppressed below set point seemed to confer protection against CP. CONCLUSIONS: Virologic failure to antiretroviral drugs is common. The risk of CP may remain low despite a low but detectable level of HIV viremia.
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Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/virologia , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Síndrome da Imunodeficiência Adquirida/fisiopatologia , Estudos de Coortes , Progressão da Doença , Feminino , Infecções por HIV/fisiopatologia , Humanos , Itália , Masculino , Distribuição de Poisson , Análise de Regressão , Fatores de RiscoRESUMO
Objectives of the study were to assess the differences between sexes in the likelihood of starting antiretroviral therapy (ART), in rates of sustained discontinuation from highly active antiretroviral therapy (HAART), and in clinical progression. In a multicenter cohort study (I.Co.N.A. Study), 2323 men and 1335 women previously naive to antiretrovirals were enrolled. As of September 2002, 807 women and 1480 men started ART. The median time to starting ART was 28 weeks for women and 17 weeks for men (P = 0.0003 by log-rank test). This difference was no longer significant after adjusting for either HIV RNA (P = 0.21) or CD4 count (P = 0.28) at enrollment. Women tend to start HAART less frequently than mono/dual ART after adjusting for potential confounders (odds ratio = 0.78, 95% confidence interval [CI]: 0.60-1.01; P = 0.06). Women who started HAART were 1.4 times more likely than men (95% CI: 1.00-1.99; P = 0.05) to interrupt at least 1 drug because of toxicity. Twenty-one percent of women and 19% of men interrupted HAART altogether for more than 3 months (P = 0.3). Clinical progression was observed in 53 women (22.6%) and 137 men (23.4%; P = 0.56). Risk of developing a clinical event was found to be no different between women and men (relative hazard = 0.84, 95% CI: 0.56-1.26; P = 0.40).
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Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Terapia Antirretroviral de Alta Atividade , Síndrome da Imunodeficiência Adquirida/imunologia , Adolescente , Adulto , Idoso , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Contagem de Linfócito CD4 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de TempoAssuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/prevenção & controle , Terapia Antirretroviral de Alta Atividade/métodos , Esquema de Medicação , Medicina Baseada em Evidências , Humanos , Guias de Prática Clínica como Assunto , Medição de RiscoRESUMO
Definition of the time of loss of virological response is important when designing a viral load endpoint for trials of antiretroviral drugs. We assessed whether, in patients who achieved a viral load below 50 copies/ml, two consecutive values above 50 copies/ml was really indicative of loss of response. It was common for the viral load to return to below 50 copies/ml with no change in regimen, suggesting that a higher threshold for defining the loss of response is required.
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Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Carga Viral , Farmacorresistência Viral , Infecções por HIV/virologia , HIV-1/fisiologia , Humanos , Resultado do TratamentoRESUMO
BACKGROUND: Subpopulations of HIV with mutations associated with resistance to antiretroviral drugs often have reduced replicative capacity, so virus with resistance mutations for all existing and new antiretroviral drugs is likely to be appreciably impaired. Issues of toxicity, quality of life and economics mean that the simultaneous use of all these drugs in combination is unrealistic. We aimed to explore the use of sequential monotherapy regimens using a mathematical model of quasi-species dynamics, to see if these could take advantage of the poor replicative capacity of highly resistant virus. METHODS: We assume for each of seven drugs that a single mutation is associated with the ability to replicate (effective reproductive ratio, R > 1) in the presence of that drug as monotherapy. Parameters included were drug efficacy, the cost of resistance mutations and the number of new target cells arising daily. RESULTS: The use of seven drugs in a daily/weekly sequential monotherapy cycle led to substantial viral suppression (in the presence of all resistant viral subpopulations) for a wider range of parameter values than a continuous five-drug regimen. Although on any one day/week there is a viral subpopulation with R > 1 (e.g. that with resistance only to the current drug), this subpopulation does not have time to grow sufficiently during the short period when that drug is being taken. CONCLUSION: These results provide a rationale for trials of sequential regimens, using as wide a number of drugs with different resistance-associated mutations as possible, as a potential 'resistance-proof' strategy for achieving significant viral load suppression.
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Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Resistência a Múltiplos Medicamentos/genética , Farmacorresistência Viral/genética , Infecções por HIV/genética , Humanos , Modelos Biológicos , Mutação/genéticaRESUMO
BACKGROUND: The effect of chronic coinfection with hepatitis viruses on the response to therapy against human immunodeficiency virus 1 (HIV-1) remains debated. METHODS: In a prospective cohort study, the effect of hepatitis B virus (HBV) and hepatitis C virus (HCV) serostatus on the outcome of potent HIV-1 therapy was analyzed in HIV-1-infected patients previously naive to antiretroviral therapy. Changes from baseline CD4+ cell counts and HIV RNA levels over time were analyzed by linear regression models. Time to clinical progression and time to reach virologic and immunologic response were analyzed by multivariate Cox proportional hazards regression models. RESULTS: We studied 1320 patients, among whom 600 were HCV antibody-positive and 90 were HBV surface antigen-positive. During a median follow-up of 37 months (range, 1-48 months), clinical progression was observed in 99 patients (56 new acquired immunodeficiency syndrome-defining events and 43 deaths). In multivariate models, HCV-positive HBV-negative patients showed a shorter time to clinical progression (hazard ratio, 1.55; 95% confidence interval, 1.00-2.41). Patients who were HCV-positive also showed mean CD4+ recoveries over time that were at least 30 cells/ micro L fewer than those of seronegative patients. Hepatitis virus serostatus did not affect the virologic response to HIV-1 therapy. CONCLUSIONS: Clinical progression of HIV-1 disease after starting potent antiretroviral therapy is accelerated by concomitant infection with HCV. Compared with patients without coinfection, coinfected patients showed impaired CD4+ cell recovery, despite similar virologic response to HIV-1 therapy. These findings may have important implications for the treatment of HCV and for the timing of initiation of HIV-1 therapy in coinfected individuals.