The absence of seroconversion after exposition to hepatitis C virus is not related to KIR-HLA genotype combinations (GEHEP-012 study).

BACKGROUND & AIMS: It has been reported that specific killer-cell immunoglobulin-like receptors (KIRs) and HLA genotype combinations, such as KIR2DS4/HLA-C1 with presence of KIRDL2 or KIRDL3, homozygous KIRDL3/HLA-C1 and KIR3DL1/≥2HLA-Bw4, are strongly associated with the lack of active infection and seroconversion after exposition to hepatitis C virus (HCV). OBJECTIVE: To determine whether these KIR-HLA combinations are relevant factors involved in that phenotype. PATIENTS AND METHODS: In this retrospective case-control study, genotype data from a genome-wide association study previously performed on low susceptibility to HCV-infection carried out on 27 high-risk HCV-seronegative (HRSN) individuals and 743 chronically infected (CI) subjects were used. HLA alleles were imputed using R package HIBAG v1.2223 and KIR genotypes were imputed using the online resource KIR*IMP v1.2.0. RESULTS: It was possible to successfully impute at least one KIR-HLA genotype combination previously associated with the lack of infection and seroconversion after exposition to HCV in a total of 23 (85.2%) HRSN individuals and in 650 (87.5%) CI subjects. No KIR-HLA genotype combination analyzed was related to the HRSN condition. CONCLUSIONS: Our results suggest that those KIR-HLA genotype combinations are not relevant factors involved in the lack of infection and seroconversion after exposition to HCV. More studies will be needed to completely understand this phenotype.

Hepatic Steatosis and Weight Gain During the Coronavirus Disease 2019 Pandemic Among People With Human Immunodeficiency Virus: Impact of Therapy With Tenofovir Alafenamide.

Background: Lockdown due to the coronavirus disease 2019 (COVID-19) pandemic led to increases in weight in part of the population. Weight gain leads to hepatic steatosis (HS). Antiretroviral treatment could also influence HS in people with human immunodeficiency virus (PWH). The impact of lockdown on HS in PWH is unknown. The aim of this study was to analyze the changes in HS, as measured by the controlled attenuation parameter (CAP), during the COVID-19 pandemic in PWH. Methods: This was a cohort study that included PWH who attended a tertiary care center in southern Spain from January 2018 to December 2021. The CAP was evaluated by transient elastography. Only those who had a valid CAP before and after March 2020 were included. HS was defined as CAP ≥248 dB/m. Results: Six hundred eighty PWH were attended and 488 (71.8%) were included. Two hundred and fourteen (43.9%) had HS at baseline and 239 (49%) at the end of the follow-up (P = .036). The median change in CAP among PWH taking tenofovir alafenamide (TAF) was 8.5 (interquartile range [IQR], -24 to 46.3) dB/m versus -4 (IQR, -35 to 27) dB/m among PWH receiving TAF-free regimens (P = .003). After multivariate analysis, adjusted by sex and age, weight gain (adjusted odds ratio [AOR], 1.09 [95% confidence interval {CI}, 1.05-1.14]; P < .001), TAF therapy (AOR, 1.59 [95% CI, 1.07-2.35]; P = .021), plasma triglycerides (AOR, 1.01 [95% CI, 1-1.01]; P < .001), and fasting blood glucose (AOR, 1.01 [95% CI, 1-1.02]; P = .027) were associated with HS at the end of follow-up. Conclusions: The frequency of HS increased during the COVID-19 pandemic among PWH. TAF is associated with HS development, regardless of metabolic factors.

Hepatic steatosis after switching to integrase inhibitor-based regimens does not parallel short-term weight gain.

We studied hepatic steatosis in people with HIV (PWH) who switched to an integrase inhibitor (INSTI)-based regimen. One hundred and fifty-four PWH were included. After 48 weeks, median (Q1-Q3) weight gain was 1.2 (-0.6 to 3.8) kg and median (Q1-Q3) controlled attenuation parameter (CAP) change was -4 (-33 to 27) dB/m. Weight gain was weakly correlated with CAP change [R2 95% confidence interval (CI) = 0.144 (-0.014 to 0.296); P = 0.074)]. Changes in hepatic steatosis after switching to INSTI-based regimens do not seem to parallel weight gain after 1 year.

Response to glecaprevir/pibrentasvir in HIV/HCV-coinfected patients in clinical practice.

OBJECTIVES: HIV infection has been associated with lower rates of sustained viral response (SVR) with direct-acting antivirals (DAAs). There are few data on glecaprevir/pibrentasvir (G/P) in HIV/HCV coinfection outside clinical trials. METHODS: The HEPAVIR-DAA cohort, which recruits HIV/HCV-coinfected patients (NCT02057003) and the GEHEP-MONO cohort (NCT02333292), including HCV-monoinfected individuals, are two concurrent ongoing multicentre cohorts of patients receiving anti-HCV treatment. Patients starting G/P included in those cohorts were analysed. Overall SVR (ITT), discontinuations due to adverse effects, and dropouts were evaluated and compared between both cohorts. RESULTS: Of the 644 patients who started G/P with evaluable SVR, 132 were HIV/HCV coinfected. Overall SVR rates were 487/512 (95.1%) in HCV-monoinfected patients versus 126/132 (95.5%) in HIV/HCV-coinfected patients (P = 1.000). One patient (0.8%) relapsed, and another (0.8%) discontinued treatment due to side effects. SVR to 8 or 12 weeks of treatment with G/P was similar in HIV/HCV-coinfected versus HCV-monoinfected patients. The main reason for not reaching SVR among HIV/HCV-coinfected patients was premature dropout linked to active drug use. CONCLUSIONS: G/P in HIV/HCV coinfection was highly effective and tolerable in clinical practice. SVR to 8 or 12 weeks of treatment with G/P was similar in HIV/HCV-coinfected compared with HCV-monoinfected patients but active drug use is still a barrier to reach HCV microelimination.

A metagenome-wide association study of HIV disease progression in HIV controllers.

Some HIV controllers experience immunologic progression with CD4+ T cell decline. We aimed to identify genetic factors associated with CD4+ T cell lost in HIV controllers. A total of 561 HIV controllers were included, 442 and 119 from the International HIV controllers Study Cohort and the Swiss HIV Cohort Study, respectively. No SNP or gene was associated with the long-term non-progressor HIV spontaneous control phenotype in the individual GWAS or in the meta-analysis. However, SNPs previously associated with natural HIV control linked to HLA-B (rs2395029 [p = 0.005; OR = 1.70], rs59440261 [p = 0.003; OR = 1.78]), MICA (rs112243036 [p = 0.011; OR = 1.45]), and PSORS1C1 loci (rs3815087 [p = 0.017; OR = 1.39]) showed nominal association with this phenotype. Genetic factors associated with the long-term HIV controllers without risk of immunologic progression are those previously related to the overall HIV controller phenotype.

Low rate of vaccination and risk of incident hepatitis A among HIV-infected men who have sex with men in Seville, Southern Spain.

BACKGROUND: Periodic outbreaks of hepatitis A (HAV) infection in men who have sex with men (MSM) have been reported. Low vaccination uptake in HIV-infected individuals could drive new outbreaks. We aimed at evaluating the incidence of and risk factors for HAV infection in people living with HIV (PLWH) in our area. We also assessed the rates of HAV vaccination. METHODS: This was a prospective cohort study. 915 patients were included, 272 (30%) of them were anti-HAV seronegative at baseline. RESULTS: Twenty-six (9.6%) susceptible individuals became infected. Incident cases peaked in 2009-2010 and 2017-2018. Incident HAV infection was independently associated with MSM [adjusted odds ratio (95% confidence ratio): 4.39 (1.35-14.27), p=0.014]. One hundred and five (38.6%) HAV seronegative patients were vaccinated, 21 (20%) of them did not respond, and one (1%) patient lost immunity against HAV. Four (29%) non-responders to vaccination showed incident HAV 5-9 years afterwards. CONCLUSIONS: The incidence of HAV infection in a cohort of well-controlled PLWH remains low and stable, with intermittent outbreaks involving mainly non-immunized MSM. A significant proportion of PLWH remain susceptible to HAV infection due to insufficient vaccine uptake and limited response to vaccination. Importantly, patients not responding to HAV vaccination continue at risk of infection.

Poor increase on HAV vaccination coverage among people living with HIV after an immunization-based intervention.

OBJECTIVES: To assess HAV serologic and vaccination status among people who live with HIV (PLWH), and to evaluate the impact of a vaccination-based strategy on HAV-negative patients in Seville, Spain. METHODS: Study with two time-overlapping phases: (i) cross-sectional study of HAV immunity prevalence among PLWH followed at a Spanish hospital between August 2019 and March 2020. (ii) Patients seronegative for HAV, reliably unvaccinated were included in a before-and-after quasi-experimental study, with an intervention focused on HAV vaccination according to national recommendations in force. RESULTS: Six hundred and fifty-six patients were included, of which 111 [17%, 95% confidence interval (95% CI) 14-20%] were seronegative for HAV. Of these, 48 [43% (95% CI, 34-53%)] individuals were MSM. The absence of HAV immunity was attributed in 69 [62% (95% CI, 52-71%)] patients to non-referral to vaccination, followed by lack of achievement of a correct vaccination scheme [n=26; 23% (95% CI, 16-32%)]. After the program implementation, 96 [15% (95% CI, 12-18%)] individuals were seronegative (17% vs. 15%, p=0.256), of whom 42 [41% (95% CI, 32-51%)] were MSM. The absence of immunity after the intervention was mainly attributed to: adherence failure in 23 [24.0% (95% CI, 15.8-33.7%)] patients, on-course immunization scheme in 34 [33% (95% CI, 24-43%)] individuals and pending appointment at the vaccine delivery unit in 20 [20.8% (95% CI, 13.2-30.3%)] patients. CONCLUSIONS: A sizeable proportion of PLWH remains susceptible for HAV infection in future outbreaks. A program based on referral to the vaccine delivery unit yields poor results, largely due to program adherence failures. New strategies are needed to increase HAV vaccination coverage.

Poor increase on HAV vaccination coverage among people living with HIV after an immunization-based intervention / Pobre incremento de la cobertura vacunal frente al VHA en personas que viven con el VIH, tras una intervención basada en la inmunización

Objectives: To assess HAV serologic and vaccination status among people who live with HIV (PLWH), and to evaluate the impact of a vaccination-based strategy on HAV-negative patients in Seville, Spain. Methods: Study with two time-overlapping phases: (i) cross-sectional study of HAV immunity prevalence among PLWH followed at a Spanish hospital between August 2019 and March 2020. (ii) Patients seronegative for HAV, reliably unvaccinated were included in a before-and-after quasi-experimental study, with an intervention focused on HAV vaccination according to national recommendations in force. Results: Six hundred and fifty-six patients were included, of which 111 [17%, 95% confidence interval (95% CI) 14–20%] were seronegative for HAV. Of these, 48 [43% (95% CI, 34–53%)] individuals were MSM. The absence of HAV immunity was attributed in 69 [62% (95% CI, 52–71%)] patients to non-referral to vaccination, followed by lack of achievement of a correct vaccination scheme [n=26; 23% (95% CI, 16–32%)]. After the program implementation, 96 [15% (95% CI, 12–18%)] individuals were seronegative (17% vs. 15%, p=0.256), of whom 42 [41% (95% CI, 32–51%)] were MSM. The absence of immunity after the intervention was mainly attributed to: adherence failure in 23 [24.0% (95% CI, 15.8–33.7%)] patients, on-course immunization scheme in 34 [33% (95% CI, 24–43%)] individuals and pending appointment at the vaccine delivery unit in 20 [20.8% (95% CI, 13.2–30.3%)] patients. Conclusions: A sizeable proportion of PLWH remains susceptible for HAV infection in future outbreaks. A program based on referral to the vaccine delivery unit yields poor results, largely due to program adherence failures. New strategies are needed to increase HAV vaccination coverage.(AU)

Objetivos: Evaluar la prevalencia de inmunidad frente al VHA en personas que viven con VIH así como el impacto de una intervención basada en la vacunación de pacientes seronegativos frente al VHA. Métodos: Estudio con dos fases solapadas en el tiempo: 1) transversal de prevalencia de inmunidad frente al VHA en personas que viven con VIH seguidas en un hospital de tercer nivel, entre agosto de 2019 y el inicio de las medidas nacionales de contención de la epidemia por SARS-CoV-2, marzo de 2020. 2) Cuasiexperimental, con una intervención centrada en la vacunación frente a VHA de pacientes seronegativos, en la unidad responsable de esta. Resultados: Ciento once (17%, [95% IC, 14-20%]) de los 656 pacientes incluidos eran seronegativos frente al VHA. Las principales causas de la ausencia de inmunidad fueron: 69 (62% [95% IC, 52-71%]) individuos no derivados a la unidad responsable de la vacunación; 26 pacientes (23% [95% CI, 16-32%]) no completaron el esquema vacunal. Tras la intervención, 96 (15% [95% IC, 12-18%]) pacientes continuaron siendo seronegativos frente al VHA (comparada con la prevalencia basal, p=0,256), 42 (18% [95% IC, 13-23%]) eran HSH. Las principales causas de la ausencia de inmunidad fueron: 26 (23% [95% IC, 15-32%]) individuos presentaron fallos de adherencia al circuito vacunal; 34 (33% [95% IC, 24-43%]) pacientes habían recibido una sola dosis; 22 (22% [95% IC, 14-31%]) seguían sin una primera valoración por parte de la unidad responsable de la vacunación. Conclusiones: Una proporción considerable de personas que viven con VIH, particularmente HSH, sigue siendo susceptible a la infección por VHA. La derivación sistemática a la unidad responsable de la vacunación se traduce en modestos incrementos de la prevalencia de inmunidad. Son necesarias nuevas estrategias para aumentar la cobertura vacunal.(AU)

Controlled attenuation parameter-insulin resistance (CIR) score to predict non-alcoholic steatohepatitis.

The diagnosis of non-alcoholic steatohepatitis (NASH) requires liver biopsy. Patients with NASH are at risk of progression to advanced fibrosis and hepatocellular carcinoma. A reliable non-invasive tool for the detection of NASH is needed. We aimed at developing a tool to diagnose NASH based on a predictive model including routine clinical and transient hepatic elastography (TE) data. All subjects undergoing elective cholecystectomy in our center were invited to participate, if alcohol intake was < 30 g/d for men and < 15 g/d for women. TE with controlled attenuation parameter (CAP) was obtained before surgery. A liver biopsy was taken during surgery. Multivariate logistic regression models to predict NASH were constructed with the first 100 patients, the elaboration group, and the results were validated in the next pre-planned 50 patients. Overall, 155 patients underwent liver biopsy. In the elaboration group, independent predictors of NASH were CAP value [adjusted OR (AOR) 1.024, 95% confidence interval (95% CI) 1.002-1.046, p = 0.030] and HOMA value (AOR 1.847, 95% CI 1.203-2.835, p < 0.001). An index derived from the logistic regression equation to identify NASH was designated as the CAP-insulin resistance (CIR) score. The area under the receiver operating characteristic curve (95%CI) of the CIR score was 0.93 (0.87-0.99). Positive (PPV) and negative predictive values (NPV) of the CIR score were 82% and 91%, respectively. In the validation set, PPV was 83% and NPV was 88%. In conclusion, the CIR score, a simple index based on CAP and HOMA, can reliably identify patients with and without NASH.

High efficacy of glecaprevir/pibrentasvir for HCV-infected individuals with active drug use.

OBJECTIVES: Real world data on glecaprevir/pibrentasvir (G/P) among active drug users are scarce. We evaluated the sustained virological response (SVR) rates of G/P among individuals with and without active drug use in routine clinical practice. METHODS: Two ongoing prospective multicenter cohorts of individuals starting G/P were analyzed. Overall SVR intention-to-treat (ITT), discontinuations due to adverse effects and dropouts were evaluated. Results in patients with active, past and without active drug use were compared. RESULTS: Overall, 644 individuals started G/P and have reached the date of SVR evaluation. Of them, 613 (95.2%) individuals achieved SVR. There were two (0.3%) relapses, one (0.2%) discontinuation due to side effects and 35 (5.4%) dropouts. SVR rates for patients with active drug use, past drug use and those who never used drugs were 85.4%(n/N = 70/82), 96.1%(n/N = 320/333) and 97.4%(n/N = 223/229) respectively (p < 0.001). After adjustment by sex, age, HCV genotype and opioid agonist therapy, active drug use was the only factor independently associated with SVR (ITT) [adjusted OR (95%confidence interval): 0.29(0.09-0.99),p = 0.048]. CONCLUSIONS: Active drug use was independently associated with lower SVR rates to G/P, mainly due to voluntary dropout. G/P could be particularly beneficial in this scenario but specific strategies designed to increase the retention in care are needed.

A Genome-Wide Association Study on Liver Stiffness Changes during Hepatitis C Virus Infection Cure.

Liver stiffness (LS) at sustained virological response (SVR) after direct-acting antivirals (DAA)-based therapy is a predictor of liver events in hepatitis C virus (HCV)-infected patients. The study aim was to identify genetic factors associated with LS changes from the moment of starting anti-HCV therapy to SVR. This prospective study included HCV-infected patients from the GEHEP-011 cohort who achieved SVR with DAA-based therapy, with LS pre-treatment ≥ 9.5 kPa and LS measurement available at SVR. Plink and Magma software were used to carry out genome-wide single-nucleotide polymorphism (SNP)-based and gene-based association analyses, respectively. The ShinyGO application was used for exploring enrichment in Gene Ontology (GO) categories for biological processes. Overall, 242 patients were included. Median (quartile 1, quartile 3) LS values at pre-treatment and at SVR were 16.8 (12, 28) kPa and 12.0 (8.5, 19.3) kPa, respectively. Thirty-five SNPs and three genes reached suggestive association with LS changes from the moment of starting anti-HCV therapy to SVR. GO categories related to DNA packaging complex, DNA conformation change, chromosome organization and chromatin organization were significantly enriched. Our study reports possible genetic factors associated with LS changes during HCV-infection cure. In addition, our results suggest that processes related to DNA conformation are also involved in these changes.

Similar incidence of coronavirus disease 2019 (COVID-19) in patients with rheumatic diseases with and without hydroxychloroquine therapy.

BACKGROUND: Hydroxychloroquine is not efficacious as post-exposure prophylaxis against coronavirus disease 2019 (COVID-19). It is not known whether as pre-exposure prophylaxis it may prevent COVID-19. OBJECTIVE: To compare the incidence of COVID-19 in Spanish patients with autoimmune rheumatic diseases treated with and without hydroxychloroquine. PATIENTS AND METHODS: Retrospective electronic record review, from February 27th to June 21st, 2020, of patients with autoimmune inflammatory diseases followed at two academic tertiary care hospitals in Seville, Spain. The cumulative incidence of confirmed COVID-19, by PCR or serology, was compared between patients with and without hydroxychloroquine as part of their treatment of autoimmune inflammatory diseases. RESULTS: Among 722 included patients, 290 (40%) were receiving hydroxychloroquine. During the seventeen-week study period, 10 (3.4% [95% CI: 1.7%-6.7%] cases of COVID-19 were registered among patients with hydroxychloroquine and 13 (3.0% [1.6%-5.1%]) (p = 0.565) in those without hydroxychloroquine. COVID-19 was diagnosed by PCR in four (1.4%, 95% CI 0.38%-3.5%) subject with hydroxychloroquine and six (1.4%, 95% CI 0.5%-3.0%) without hydroxychloroquine (p = 0.697). Three patients on hydroxychloroquine and four patients without hydroxychloroquine were admitted to the hospital, none of them required to be transferred to the intensive care unit and no patient died during the episode. CONCLUSIONS: The incidence and severity of COVID-19 among patients with autoimmune rheumatic diseases with and without hydroxychloroquine was not significantly different.

Impact of recent drug use on the efficacy of elbasvir/grazoprevir for HCV-infected people on opioid agonist therapy.

Elbasvir/grazoprevir (EBR/GZR) use in drug users on opiate agonist therapy (OAT) is supported by the C-EDGE Co-STAR trial. SVR rates in this study were within those found in the rest of patients included by the EBR/GZR development programme. In clinical practice, however, efficacy could theoretically be lower. Thus, we aimed at evaluating the SVR rates of EBR/GZR among people who injected drugs (PWID) with and without OAT in clinical practice. Patients starting EBR/GZR included in the HEPAVIR-DAA (NCT02057003), recruiting HIV/HCV-coinfected patients or the GEHEP-MONO (NCT02333292), including HCV-monoinfected individuals, prospective cohorts were analysed. Overall SVR12 (ITT), discontinuations due to adverse effects and drop-outs were evaluated. The same analysis was carried out for PWID with and without OAT. 336 patients had started EBR/GZR and reached the SVR12 evaluation date. 318 [95%, 95% confidence interval (95% CI): 92%-98%] patients achieved SVR12. SVR12 was 97% (95% CI: 93%-99%, n/N = 141/145) among people who never used injecting drugs, 94% (95% CI: 88%-97%, n/N = 117/125) among PWIDs without OAT and 91% (95% CI: 81%-97%, n/N = 60/66) among PWIDs with OAT (p = 0.134). Five (1.5%) patients showed relapses, and two (0.6%) individuals showed viral breakthrough. The SVR12 rate for recent drug users was 69% (n/N = 18/26) compared with 97% (n/N = 276/284) for individuals without recent drug use (in the prior year) (p < 0.001). Among recent drug users, three (12%) showed relapses, and five (19%) were lost-to-follow-up. The SVR rates achieved with EBR/GZR were high in real-world conditions of use. However, PWID with recent drug use reach suboptimal response rates with EBR/GZR.

High rate of major drug-drug interactions of lopinavir-ritonavir for COVID-19 treatment.

The impact of drug-drug interactions (DDI) between ritonavir-boosted lopinavir (LPV-r) to treat patients with coronavirus disease 2019 (COVID-19) and commonly used drugs in clinical practice is not well-known. Thus, we evaluated the rate and severity of DDI between LPV-r for COVID-19 treatment and concomitant medications. This was a cross-sectional study including all individuals diagnosed of SARS-CoV-2 infection treated with LPV-r and attended at a single center in Southern Spain (March 1st to April 30th, 2020). The frequency [95% confidence interval (95% CI)] of potential and major DDI were calculated. Overall, 469 patients were diagnosed of COVID-19, 125 (27%) of them were prescribed LPV-r. LPV-r had potential DDI with concomitant medications in 97 (78%, 95% CI 69-85%) patients, and in 33 (26%, 95% CI 19-35%) individuals showed major DDI. Twelve (36%) patients with major DDI and 14 (15%) individuals without major DDI died (p = 0.010). After adjustment, only the Charlson index was independently associated with death [adjusted OR (95% CI) for Charlson index ≥ 5: 85 (10-731), p < 0.001]. LPV-r was discontinued due to side effects in 31 (25%) patients. Management by the Infectious Diseases Unit was associated with a lower likelihood of major DDI [adjusted odds ratio (95% CI): 0.14 (0.04-0.53), p = 0.003). In conclusion, a high frequency of DDI between LPV-r for treating COVID-19 and concomitant medications was found, including major DDI. Patients with major DDI showed worse outcomes, but this association was explained by the older age and comorbidities. Patients managed by the Infectious Diseases Unit had lower risk of major DDI.

A genome-wide association study on low susceptibility to hepatitis C virus infection (GEHEP012 study).

BACKGROUND: A low proportion of individuals repeatedly exposed to the hepatitis C virus (HCV) remain uninfected. This condition could have a genetic basis but it is not known whether or not it is mainly driven by a high-penetrance common allele. OBJECTIVE: To explore whether low susceptibility to HCV infection is mainly driven by a high-penetrance common allele. METHODS: In this genome-wide association study (GWAS), a total of 804 HCV-seropositive individuals and 27 high-risk HCV-seronegative (HRSN) subjects were included. Plink and Magma software were used to carry out single nucleotide polymorphism (SNP)-based and gene-based association analyses respectively. RESULTS: No SNP nor any gene was associated with low susceptibility to HCV infection after multiple testing correction. However, SNPs previously associated with this trait and allocated within the LDLR gene, rs5925 and rs688, were also associated with this condition in our study under a dominant model (24 out of 27 [88.9%] rs5925-C carriers in the HRSN group vs 560 of 804 [69.6%] rs5925-C carriers in the HCV-seropositive group, P = 0.031, odds ratio [OR] = 3.48; 95% confidence interval [CI] = 1.04-11.58; and 24 out of 27 [88.9%] rs688-T carriers in the HRSN group vs 556 of 804 [69.1%] rs688-T carriers in the HCV-seropositive group, P = 0.028, OR = 3.57, 95% CI = 1.65-11.96). CONCLUSIONS: Low susceptibility to HCV infection does not seem to be mainly driven by a high-penetrant common allele. By contrast, it seems a multifactorial trait where genes such as LDLR could be involved.

Genotypic susceptibility score (GSS) and CD4+ T cell recovery in HIV-1 patients with suppressed viral load.

OBJECTIVES: HIV drug resistance, measured by the genotypic susceptibility score (GSS), has a deleterious effect on the virological outcome of HIV-1-infected patients. However, it is not known if GSS retains any predictive value for CD4 recovery in patients with suppressed viral load. METHODS: Four hundred and six patients on virological failure (>500 copies/mL) with GSS : <6 months prior to switch therapy who achieved undetectable plasma viral load (<50 copies/mL) within 1 year, remained undetectable >1 year on an unchanged regimen and had CD4 data available during entire follow-up were included. Adjusted and unadjusted analyses of all characteristics at switch related to CD4 recovery were made for three time frames: (i) 'switch-suppression'; (ii) 'suppression-1 year'; and (iii) 'switch-1 year'. RESULTS: Higher GSS was associated with a greater CD4 recovery between 'switch' and '1 year' in the unadjusted analysis (P = 0.010); however, the effect of GSS was no longer statistically significant after adjusting for pre-switch clinical (CD4 count and plasma viral load) and demographic variables. Furthermore, only a lower pre-switch CD4 count was associated with increased CD4 recovery in the 'suppression-1 year' period in both unadjusted and adjusted models. The main CD4 recovery occurred in 'switch-suppression' and the variables associated, both unadjusted and adjusted, were CD4 and plasma viral load at switch, maintaining a trend for GSS (P = 0.06). CONCLUSIONS: In individuals who re-suppressed HIV viraemia after switching therapy, regimens having a higher GSS were associated with improved CD4 recovery only during the period from switch to virological suppression, but, once viral load is re-suppressed, the GSS of the new regimen has no further effect on subsequent CD4 recovery.

Temporal trends in the discontinuation of first-line antiretroviral therapy.

OBJECTIVES: The aim of this study was to describe the rates and predictors of discontinuing first-line antiretroviral therapy in the different eras of treatment over a nearly 20 year period initiated in British Columbia between 1992 and 2010. METHODS: All naive adults who started antiretroviral therapy (first-line antiretroviral therapy) at any hospital or clinic in British Columbia (Canada) in 1992-2010 were included in this population-based retrospective cohort study. We were primarily interested in whether the era of treatment (1992-95, 1996-2000, 2001-05 and 2006-10) was associated with discontinuation (stopping or switching of initial treatment) within 3 years of starting therapy. Weibull survival analysis was used to model the era of treatment and its association with time to discontinuation. RESULTS: The study included 7901 patients. Overall, the probability of discontinuing at 12, 24 and 36 months of treatment was 52%, 68% and 76%, respectively. In the adjusted model, variables associated with discontinuing were earlier treatment era, younger age, low adherence and lower baseline CD4 count. Regarding the 2006-10 period, the probability of discontinuing at 12, 24 and 36 months was 36%, 47% and 53%, respectively. In the adjusted model, the variables associated with discontinuation were younger age, female gender, AIDS-defining illnesses at baseline, low adherence and a protease inhibitor (PI)-based regimen. CONCLUSIONS: Discontinuation rates of first-line therapy have decreased over time, but are still quite high even for the latest drug combinations. In the most recent era, younger women on a PI regimen and those not achieving optimal adherence had the highest risk of discontinuing first-line antiretroviral therapy.

HIV drug resistance detected during low-level viraemia is associated with subsequent virologic failure.

BACKGROUND: The clinical implications of emergent HIV drug resistance on samples with low-level viraemia (LLV <1000 copies/ml) remain unclear. We undertook the present analysis to evaluate the impact of emergent HIV drug resistance at LLV on the risk of subsequent virologic failure. METHODS: One thousand, nine hundred and sixty-five patients had genotype results at LLV. Risk of virologic failure (≥1000 copies/ml) after LLV was evaluated by Kaplan-Meier analysis and Cox proportional hazards regression. Resistance was assessed using the Stanford algorithm or virtual phenotypes. Patients were grouped into four susceptibility categories ('GSS' or 'vPSS') during LLV, corresponding to the number of 'active' drugs prescribed: <1; 1-1.5; 2-2.5; and ≥3. RESULTS: A total of 1702 patients with follow-up on constant therapy were eligible for analysis. Participants excluded due to changing therapy or loss to follow-up before their next observation had mostly similar characteristics to included participants. There was a 'dose-dependent' increase in the hazard ratio for virologic failure with susceptibility categories at LLV. Compared with a GSS of at least 3, hazard ratios for virologic failure were 1.4 for GSS 2-2.5; 2.0 for GSS 1-1.5; and 3.0 for GSS less than 1 (P < 0.001). Numerous sensitivity analyses confirmed these findings. CONCLUSION: Our results demonstrate that emergent HIV drug resistance at LLV is strongly associated with subsequent virologic failure. Furthermore, we uncovered a 'dose-dependent' increase in the hazard ratio for virologic failure with decreasing GSS estimated at the time of LLV. On the basis of these findings, we propose that resistance genotyping be encouraged for HIV-infected individuals on antiretroviral therapy experiencing low-level viraemia.