Dissociation of immunologic and virologic responses to highly active antiretroviral therapy

OBJECTIVE: Immunologic markers, levels of HIV DNA, and infectious HIV were compared in partial responders (PR) to HAART who had high plasma HIV RNA levels but stable or increasing levels of CD4+ peripheral blood mononuclear cells (PBMC), and patients with complete failure (CF) who had very low or decreasing levels of CD4+ PBMC and high plasma HIV RNA levels. DESIGN AND METHODS: CD4 and CD8 levels were monitored by flow cytometry. Beta2-microglobulin (beta2M) and neopterin levels were measured by quantitative enzyme immunoassays. Plasma and PBMC from 11 PR and 13 CF were analyzed for infectious HIV levels in limiting dilution cultures. Polymerase chain reaction (PCR) assays were used to quantify cellular HIV DNA and plasma HIV RNA. RESULTS: In comparison with CF, PR had little or no CD4+ cell loss, a substantial increase in CD8+ cells, significantly fewer positive plasma HIV cultures (p = .03), lower frequencies of infectious HIV in total PBMC (p = .005) and in CD4+ PBMC (p < .001), and lower frequencies of HIV DNA in CD4+ PBMC (p = .007). CONCLUSIONS: Lower levels of infectious HIV and a lower frequency of CD4+ PBMC that contain "productive" HIV DNA in PR as compared with CF may contribute to the stable or increasing CD4+ PBMC levels of the PR. However, HAART may also have effects on lymphocyte homeostasis independent of its antiviral activity.     

Long-term immunologic and virologic responses on raltegravir-containing regimens among ART-experienced participants in the HIV Outpatient Study

Objectives:

Raltegravir (RAL)-containing antiretroviral therapy (ART) produced better immunologic and virologic responses than optimized background ART in clinical trials of heavily ART-experienced patients, but few data exist on long-term outcomes in routine HIV care.

Methods:

We studied ART-experienced HIV outpatient study (HOPS) participants seen at 10 US HIV-specialty clinics during 2007–2011.We identified patients who started (baseline date) either continuous ≥?30?days of RAL-containing or RAL-sparing ART, and used propensity score (PS) matching methods to account for baseline clinical and demographic differences. We used Kaplan–Meier methods and log-rank tests for the matched subsets to evaluate probability of death, achieving HIV RNA ??3 during follow-up.

Results:

Among 784 RAL-exposed and 1062 RAL-unexposed patients, 472 from each group were matched by PS. At baseline, the 472 RAL-exposed patients (mean nadir CD4, 205?cells?mm^??3; mean baseline CD4, 460?cells?mm^??3; HIV RNA ??1 in 61%; mean years on prescribed ART, 7.5) were similar to RAL unexposed. During a mean follow-up of over 3?years, mortality rates and immunologic and virologic trajectories did not differ between the two groups. Among patients with detectable baseline HIV RNA levels, 76% of RAL-exposed and 63% of RAL-unexposed achieved HIV RNA ??1 (P?=?0.51); 69 and 58%, respectively, achieved a CD4 increase ≥?50?cells?mm^??3 (P?=?0.70).

Discussion:

In our large cohort of US ART-experienced patients with a wide spectrum of clinical history, similar outcomes were observed when prescribed RAL containing versus other contemporary ART.     

Long-term clinical,immunologic and virologic impact of glucocorticoids on the chronic phase of HIV infection

Background  

To test the hypothesis of down-regulating the increased immune system activation/destruction process associated with chronic HIV infection, we focused our interest on prednisolone (PDN), because we had showed that, in vitro, PDN had a strong anti-apoptotic activity on activated T cells of HIV-infected patients and no effect on viral replication. We thus designed in 1992 a pilot study to evaluate the clinical, immunologic and virologic effects of PDN. The drug was given to a group of 44 patients with CD4 T cells over 200/μl. After one year, no patient had developed clinical AIDS and the mean CD4 T cell count of the group had increased from 441 ± 21 cells/μl to 553 ± 43 cells/μl. Moreover, markers of immune activation had dropped back to normal levels while the mean viral load of the group had remained unchanged. Here we explore the long-term clinical, immunologic, and virologic impact of prednisolone on the chronic phase of HIV infection.     

Clinical outcome of HIV-infected antiretroviral-naive patients with discordant immunologic and virologic responses to highly active antiretroviral therapy

BACKGROUND: The prognostic significance of a response to highly active antiretroviral therapy (HAART) that is immunologically and virologically discordant is not well understood. METHODS: Four hundred four antiretroviral-naive patients initiating HAART at an urban HIV outpatient clinic in 1995 to 2004 were analyzed. The association of treatment responses at 3 to 9 months after HAART initiation with time to development of an opportunistic infection (OI) or death was determined using Cox proportional hazards modeling. Logistic regression modeling was used to examine the association between discordant responses and patient characteristics. RESULTS: Of 404 patients, 70.5% experienced favorable concordant responses (CD4 cell count [CD4]+/viral load [VL]+: increase in CD4 count of >or=50 cells/microL and achievement of undetectable plasma HIV RNA level), 15.8% an immunologic response only (CD4+/VL(-)), 8.7% a virologic response only (CD4(-)/VL+), and 5.0% a concordant unfavorable response (CD4(-)/VL(-)). Both types of discordant responses (CD4+/VL(-) and CD4(-)/VL+), nonresponse (CD4(-)/VL(-)), and baseline CD4 cell count were significantly associated with earlier development of an OI or death (relative hazard [RH] = 2.81, 95% confidence interval [CI]: 1.31 to 3.97; RH = 4.83, 95% CI: 2.10 to 11.12; and RH = 0.93, 95% CI: 0.88 to 0.99, respectively). CD4+/VL(-) and CD4(-)/VL(-) were associated with nonwhite race in multivariate logistic regression models (adjusted OR = 2.83, 95% CI: 1.46 to 5.47 and adjusted OR = 6.50, 95% CI: 1.65 to 25.69, respectively). CONCLUSION: Discordant immunologic and virologic responses at 3 to 9 months after HAART initiation play important roles in predicting long-term clinical outcomes in treatment-naive patients.     

Iron deficiency anemia in HIV infection: immunologic and virologic response

We report the immunologic and virologic response of iron deficiency anemia in two cases of human immunodeficiency virus (HIV)-infected individuals. The findings of this report suggest that caution be exercised in prescribing iron supplements to HIV-infected patients. The treatment of iron deficiency anemia should be combined with antiretroviral agents in people living with HIV/AIDS to avoid adverse immunologic and virologic consequences.     

Pretreatment factors associated with 3-year (144-week) virologic and immunologic responses to potent antiretroviral therapy

OBJECTIVE: To examine pretreatment factors associated with longer term (144 weeks) responses to antiretroviral therapy (ART). METHODS: Of 1498 ART-naive subjects randomized to ART regimens, including > or =3 agents, 1083 patients who had plasma HIV RNA (vRNA) levels and CD4 cell counts at baseline and week 144 were analyzed. Primary baseline factors evaluated were CD4 cell count, vRNA level, gender, race, and age, using multivariable Cox, log-binomial, and linear regression models. RESULTS: Shorter time to achieving a vRNA level <50 copies/mL was associated with lower baseline vRNA level (P < 0.001), older age (P = 0.007), and lower baseline CD4 cell count (P = 0.055). After adjusting for race, gender, and baseline CD4 cell count, older age was associated with a vRNA level <50 copies/mL at week 144 (P = 0.018). Greater CD4 count increases from baseline to week 144 (mean = 284 cells/microL) were seen in younger men, blacks, and subjects with higher pretreatment vRNA levels; the effect of pretreatment vRNA level was most apparent in women. CONCLUSIONS: Older age was the most important baseline predictor of a vRNA level <50 copies/mL at week 144; lower pretreatment vRNA level and older age were the most important predictors of time to a vRNA level <50 copies/mL. The influence of pretreatment factors on increases in CD4 cell counts differed between men and women.     

Discordant immunologic and virologic responses to highly active antiretroviral therapy are associated with increased mortality and poor adherence to therapy

OBJECTIVE: To examine the independent association of discordant virologic and immunologic responses to highly active antiretroviral therapy (HAART) with mortality. METHODS: A population-based study of 1527 treatment-naive individuals initiating HAART used Cox proportional hazards modeling to determine the independent association of treatment response at 3 to 9 months with nonaccidental mortality. Logistic regression was used to examine associations with discordant responses. RESULTS: Viral load (VL)/CD4 discordant responses were seen in 235 (15.4%) of subjects, and VL/CD4 responses were seen in 179 (11.7%) of subjects. In adjusted Cox regression models, discordant responses were found to be independently associated with an increased risk of mortality (VL/CD4: relative hazard [RH] = 1.87, 95% confidence interval [CI]: 1.15 to 3.04; VL/CD4: RH = 2.47, 95% CI: 1.54 to 3.95). VL/CD4 discordance was found to be associated with increasing age, baseline HIV RNA load <100,000 copies/mL, baseline CD4 counts <50 cells/muL, the use of lamivudine (3TC)/zidovudine (ZDV), and poor adherence to therapy. VL/CD4 discordance was associated with younger age; injection drug use; baseline HIV RNA load >100,000 copies/mL; the use of 3TC/ZDV, didanosine (ddI)/3TC, or ddI/stavudine; and poor adherence to therapy. CONCLUSION: Discordant responses are independently associated with an increased risk of mortality and are, in turn, associated with poor adherence to therapy.     

Clinical, biologic, and behavioral predictors of early immunologic and virologic response in HIV-infected patients initiating protease inhibitors

Predictors of virologic (plasma HIV RNA viral load [VL] < 500 copies/ml) and immunologic (rise in CD4+ cell count > 50 cells/mm3) response after 4 months of therapy (M4) were studied in 750 HIV-1-infected patients prospectively enrolled at the initiation of a protease inhibitor (PI)-containing regimen. A virologic response was observed in 80% of patients, and an immunologic response was observed in 64%. Sixty-two percent of patients self-reported full adherence to therapy at 1 month of therapy (M1) and M4. In multivariate analysis, a virologic response was more frequent in fully adherent patients (odds ratio [OR] = 2.0; p =.001). An immunologic response was associated with age < 36 years (OR =1.4; p =.03), baseline VL (OR = 1.5 per 1 log10 copies/ml higher; p <.01), decrease in VL at M1 (OR = 1.5 per 1 log10 copies/ml decrease; p <.01), baseline total lymphocyte count (OR = 1.7 per 50% lower; p <.001), and baseline CD4+ cell percentage > or = 20% (OR =1.9; p <.001) but not with adherence to therapy. Full adherence seems to be a major predictor of a virologic response to PI-containing triple therapy. An immunologic response may be possible despite incomplete adherence, at least early in therapy.     

Impact of Baseline Virologic,Immunologic, and Demographic Characteristics on Virologic Responses in the Gemini Study

Abstract

Purpose: To determine the impact of baseline viral load (VL) and CD4+ cell count, race/ethnicity, and gender on response in a post hoc analysis of the Gemini study.Methods: In this 48-week study, treatment-naïve, HIV-infected participants received as initial therapy twice-daily saquinavir/ritonavir (SQV/r) 1000/100 mg (n=167) or lopinavir/ritonavir (LPV/r) 400/100 mg (n=170), each with emtricitabine 200 mg/tenofovir 300 mg daily. The proportion of participants achieving HIV RNA<50 copies/mL (primary endpoint) and median change from baseline in CD4+ cell count were compared by baseline VL (>100,000 vs ≤100,000 copies/ mL) and CD4+ cell count (>100 vs ≤100 cells/µL). The impact of baseline and demographic variables on virologic response was assessed by logistic regression analysis.Results: Responses were similar between arms (SQV/r vs LPV/r) with or without stratification. In a pooled analysis of SQV/r and LPV/r arms, CD4+ cell count >100 cells/µL (odds ratio [OR], 1.628;P = .0416), non-Thai/non-Black versus Black race (OR, 1.518;P = .0023), and non-Thai/non-Black versus Thai (OR, 0.467;P = .0046) were significant predictors of virologic response.Conclusions: Treatment groups had similar efficacy. Baseline CD4+ cell count and race/ethnicity were independent predictors of virologic response, whereas baseline VL and gender were not.     

Increasing age at HIV seroconversion from 18 to 40 years is associated with favorable virologic and immunologic responses to HAART

BACKGROUND: Studies evaluating the effect of age on response to highly active antiretroviral therapy (HAART) have been limited by their inability to control for duration of human immunodeficiency virus (HIV) infection. We examined the effect of age at HIV seroconversion on response to HAART. METHODS: A retrospective analysis of a longitudinal US military cohort of HIV-infected subjects. Time to and maintenance of viral suppression, rate of CD4 cell increase, and rate of progression to acquired immunodeficiency syndrome or death were compared across age groups using time-to-event methods. RESULTS: Five hundred sixty-three HIV-infected adults who seroconverted after January 1, 1996, and started HAART were included. Increasing age at seroconversion was significantly associated with faster time to viral suppression (P = 0.002). Increasing age also correlated with duration of suppression, with a 35% reduction in risk of viral rebound for every 5-year increase in age above 18 years (hazard ratio: 0.65, 95% confidence interval 0.55 to 0.75). The rate of CD4 cell increase from 6 to 84 months post-HAART was significantly greater in those who seroconverted at older ages (P = 0.0002). Rates of progression to acquired immunodeficiency syndrome or death did not differ between groups. CONCLUSIONS: Increasing age at seroconversion was associated with shorter time to and longer maintenance of viral suppression and a faster increase in CD4 cell count.     

A factor analytic study of the demographic characteristics of incarcerated females

Produced 10 identifiable factors in a factor analytic study of demographic and behavioral variables on female (N = 100) inmates of an adult correctional facility in the South. While the items were those frequently cited as contributory—abuse, neglect, etc.—they did not cluster as expected, but took on a more unitary structure, except for behavioral data from the interviews that were highly interrelated either positively or negatively.     

Impaired CCR7 expression on plasmacytoid dendritic cells of HIV-infected children and adolescents with immunologic and virologic failure

BACKGROUND: Defects of plasmacytoid (p) and myeloid (m) dendritic cells (DCs) occur in HIV infection. The aim of this study was to evaluate the maturation and function of DCs in children with perinatal HIV infection who were on antiretroviral therapy. MATERIALS AND METHODS: Twenty HIV-infected children (median age = 12.9 years) classified as immunologic/virologic responders and failures were evaluated in a whole-blood assay with resiquimod (RSQ), a potent agonist to Toll-like receptors 7 and 8, as the DC stimulant. RESULTS: In comparison to controls, pDC and mDC numbers were decreased in patients, but RSQ stimulation resulted in upregulation of CD83, CD80, and tumor necrosis factor-alpha in both DC subsets and upregulation of interferon (IFN)-alpha in pDCs. Patients with immunologic and virologic failure demonstrated a selective impairment in upregulation of lymph node homing marker CCR7 in pDCs. Plasma virus load was negatively correlated with IFNalpha and CCR7 expression, whereas CD4 percentage correlated only with CCR7 expression in pDCs. CONCLUSIONS: A novel defect of pDCs, impaired CCR7 upregulation, is described in association with immunologic or virologic failure. This deficiency could impair homing of pDCs to lymph nodes, leading to secondary defects of mDC maturation and poor T-cell activation.     

Psychiatric, demographic and personality characteristics of elderly sex offenders

BACKGROUND: Psychiatric disorders are purported to play a role in the aetiology of violent crime, but evidence for their role in sexual offending is less clear. The authors investigated the prevalence of psychiatric morbidity and personality disorders in elderly incarcerated sex offenders compared with elderly non-sex offenders. METHOD: One hundred and one sex offenders and 102 non-sex offenders aged over 59 years wereinterviewed using standardized semi-structured interviews for psychiatric illness (the Geriatric Mental State) and the personality disorder (Structured Clinical Interview for DSM-IV personality disorders). Data on demographic, offence and victim characteristics were collected. RESULTS: Six per cent of the elderly sex offenders had a psychotic illness, 7% a DSM-IV major depressive episode and 33% a personality disorder; and 1% had dementia. These prevalence figures were not different from the elderly non-sex offenders interviewed in this study. Differences emerged at the level of personality traits with sex offenders having more schizoid, obsessive-compulsive, and avoidant traits, and fewer antisocial traits compared with non-sex offenders. CONCLUSIONS: Elderly sex offenders and non-sex-offenders have similar prevalence rates of mental illness. However, elderly sex offenders have increased schizoid, obsessive-compulsive, and avoidant personality traits, supporting the view that sex offending in the elderly is associated more with personality factors than mental illness or organic brain disease.