Impact of adherence and highly active antiretroviral therapy on survival in HIV-infected patients

OBJECTIVES: To assess the effect of antiretroviral therapy (ART) adherence on survival in HIV-infected patients. DESIGN: Cohort study at a single hospital in Barcelona, Spain. METHODS: Data on HIV-infected patients older than 18 years of age who began ART during the period 1990 to 1999 were analyzed. Patients were considered nonadherent if the total dose of antiretroviral drug was less than 90% of that prescribed. Adherence was assessed through self-report and hospital pharmacy appointments. Cox regression with time-dependent variables was used. RESULTS: A total of 1219 patients were included. The first ART was with monotherapy in 23.7% of cases, with two drugs in 30.5%, and with triple therapy in 45.8%. In multivariate analysis, the variables that presented significant differences with respect to mortality were clinical stage at the beginning of treatment (AIDS: relative hazard (RH) = 2.97; 95% confidence interval [CI]: 2.14-4.13), CD4 cell count (<200 cells/microL: RH = 5.89; CI: 3.44-10.10), type of treatment (monotherapy: RH = 9.76; CI: 4.56-20.90; bi-therapy: RH = 9.12; CI: 4.23-19.64), and adherence (nonadherence: RH = 3.87; CI: 1.77-8.46). CONCLUSIONS: The modifiable factors most strongly associated with survival were type of treatment and adherence. It would be desirable to accompany therapy with intervention strategies intended to improve adherence.     

T-cell re-population in HIV-infected children on highly active anti-retroviral therapy (HAART)

In this pilot study, we address the nature of the re-population of the T-cell compartment in HIV-1+ (Human Immunodeficiency Virus 1), vertically infected children placed on successful regimens of HAART (highly active anti-retroviral therapy) incorporating 2 NRTI and a protease inhibitor. The clonality of the T-cell compartment and the abundance of RTEs (Recent Thymic Emigrants) were determined 2 weeks before and 20 weeks after initiation of HAART in a subgroup of children taking part in the PENTA (Paediatric European Network for the Treatment of AIDS) 5 trial. Analysis of the clonality of the circulating T-cell compartment was assessed using CDR3 spectratyping and analysed using the Kolmogorov-Smirnov two sample test. This revealed that a high degree of T-cell clonal restriction still exists 5 months into therapy, despite the appearance of previously undetectable T-cell clones within the periphery. We detected no increase in RTE abundance in this 5 month period, as determined by PCR detection of TRECs (T-Cell Receptor Excision Circles). We conclude that the observed re-population of T cells within the periphery of treated children is heavily reliant upon the maintenance/expansion of pre-existing cells during the 5 month period immediately following the initiation of therapy.     

Anemia in HIV-infected patients receiving highly active antiretroviral therapy.

BACKGROUND: Anemia is common in HIV infection, particularly in advanced disease states. We wished to determine how highly active antiretroviral therapy (HAART) and other factors affected the level of hemoglobin in HIV infection. METHODS: We analyzed data from 905 patients receiving care at Johns Hopkins in Baltimore, Maryland after July 1, 1996. Analyses were done of hemoglobin levels obtained at baseline and during 1 year of follow-up in patients who received and did not receive a HAART regimen. Use of HAART and other demographic and clinical factors were examined. RESULTS: Eleven percent of patients had a hemoglobin count <10 g/dL, 27% had a hemoglobin count 10 to 12 g/dL, and 21% had a hemoglobin count of >14 g/dL at baseline before HAART was started. During 1 year of follow-up, use of HAART was associated with a hemoglobin levels >14 g/dL in 42% of patients, irrespective of use of zidovudine as part of HAART regimen, compared with 31% of patients who did not use HAART. In multivariate analysis, use of HAART was strongly associated with not having anemia during 1 year of follow-up, adjusting for patient gender, race, injection drug use history, baseline CD4 and HIV-1 RNA levels, and anemia treatments. CONCLUSIONS: HAART is an effective treatment of the anemia of HIV infection. Patients who continue to have symptomatic anemia while receiving HAART may need additional intervention.     

Failure to restore the Vgamma2-Jgamma1.2 repertoire in HIV-infected men receiving highly active antiretroviral therapy (HAART)

Gammadelta (gammadelta) T cells expressing the Vgamma2-Jgamma1.2Vdelta2 (Vgamma9-JPVdelta2, alternate nomenclature) T cell receptor (TCR) constitute the major peripheral blood population of gammadelta T cells in adult humans and are specifically depleted during human immunodeficiency virus (HIV) disease. Vgamma2-Jgamma1.2Vdelta2 T cells provide a convenient model for assessing the impact of antiretroviral therapy on cell populations that are not susceptible to direct infection because they do not express CD4 and depletion occurs by indirect mechanisms. We obtained longitudinal PBMC samples from 16 HIV-infected individuals who enrolled in the Multicenter AIDS Cohort Study (MACS) and were starting highly active antiretroviral therapy (HAART). Vgamma2-Jgamma1.2Vdelta2 T cells were depleted in these individuals as a result of HIV infection. Despite evidence for clinical benefits of HAART, the Vgamma2-Jgamma1.2Vdelta2 T cell repertoire did not recover after HAART initiation irrespective of treatment duration. These studies highlight important defects among cell subsets lost due to indirect effects of HIV.     

Immune correlates of virological response in HIV-positive patients after highly active antiretroviral therapy (HAART)

Correlates of immune reconstitution after highly active antiretroviral therapy (HAART) are not completely understood, in particular as far as viro-immunological discordant responses are concerned. HIV-positive patients on stable HAART for > or = 1 year were recruited. Viro-immunological responses were categorized according to positive or negative area under the curve (AUC) variations for HIV plasma viral load (pVL) and CD4+ T-cell counts measured at least every 4 months. The following parameters were evaluated: lymphocyte spontaneous apoptosis (LSA), intracellular Bcl-2 expression in both CD4-CD45RA+ and CD4-CD45R0+, IL-7 and IL-15 plasma concentrations, and lymphocyte TRECs levels. Sixty-one patients were enrolled. A significant inverse correlation was found between CD4+ T-cell count and pVL AUC (r = 0.45; p = 0.0003). Patients with pVL response had higher levels of Bcl-2 in CD4-CD45R0+ (mean 65,409 MESF vs. 54,018 MESF; p = 0.089) and higher IL-15 (mean 1.34 pg/mL vs. 1.05 pg/mL; p = 0.069, respectively). Higher LSA and lower TRECs levels were found in viro-immunological non-responder patients with respect to those who had viro-immunological response (mean 24.84% vs. 14.89%; p = 0.01, and mean 17,796 copies/10(6) cells vs. 29,251 copies/10(6) cells; p = 0.68, respectively). Virological suppression may allow Bcl-2 and IL-15 hyperexpression during incomplete immune-reconstitution phase, while more complete immune reconstitution appeared to be marked by both high TRECs and low LSA levels, possibly indicating both central and peripheral CD4+ T-cell repopulations at this stage.     

Sexual dysfunction in HIV-infected patients treated with highly active antiretroviral therapy

Sexual disturbances develop in some patients treated with highly active antiretroviral therapy (HAART). To evaluate sexual dysfunction and the influence that different antiretrovirals could have on those parameters, we conducted a prospective study in patients with stable clinical condition attending an HIV outpatient clinic. A total of 351 evaluations were performed in 189 HIV-infected men, who were interviewed about symptoms of sexual dysfunction. Sexual hormones as well as other clinical and laboratory parameters were also measured at the time of each evaluation. The mean CD4 count was 451.1 x 10(6) cells/L, and viral load was undetectable in two thirds of the determinations. The prevalence of sexual dysfunction was 19.5% overall, but it was influenced by treatment, particularly (although not exclusively) by protease inhibitors (PIs) (27.1% vs. 3.8% for untreated patients). Sexual dysfunction was not related to hypophyseal or gonadal hormonal values. Although several parameters were associated with sexual dysfunction in the univariate analysis, only antiretroviral treatment was significantly predictive of this disorder in a logistic regression analysis. Sexual dysfunction is common in HIV-infected patients in stable clinical condition receiving HAART, and all antiretroviral drugs, particularly PIs, seem to be related to it. Sexual dysfunction in these patients is not related to hormonal causes.     

Non-AIDS-defining malignancies among HIV-infected patients in the highly active antiretroviral therapy era

In the highly active antiretroviral therapy (HAART) era, the incidence of AIDS-defining malignancies (ADMs) has declined significantly. On the other hand, the incidence of other malignancies not known to be associated with immunosuppression (non-ADMs) has not changed and remains significantly higher than in the general population. Some recent controlled studies even suggest that the incidence of selected non-ADMs has increased in the HAART era. These trends warrant a high index of suspicion for malignancies among HIV care providers and a renewed focus on understanding the mechanisms underlying the increased rates. Potential explanations for the higher non-ADM rates include longer survival of patients with HIV on HAART, with only partial immune recovery achieved in most patients; high incidence of human papillomavirus, Epstein-Barr virus, and hepatitis C virus coinfection in patients with HIV infection; and potential oncogenicity of long-term HIV infection or of long-term HAART.     

Cytomegalovirus disease in the era of highly active antiretroviral therapy (HAART).

Cytomegalovirus (CMV) infection was one of the most important opportunistic infections in HIV-infected patients before the introduction of highly active antiretroviral therapy (HAART), i.e. the combination of at least three antiretroviral drugs of different classes. Thereafter, life expectancy and quality of life increased dramatically with the persistent suppression of HIV viremia and a significant reduction in incidence of CMV disease. Nevertheless, evidence for a multitude of direct and indirect effects of CMV on HIV progression is accumulating. Even in the era of HAART, a considerable number of HIV-infected patients have a CD4 cell count below <100 mm(-3), which involves a high risk for CMV disease. The focus of the present review is on interpretation of test results, their predictive value for CMV disease, and guidance for the rational use of diagnostic assays in HIV-infected patients. Identification of patients at immediate risk for CMV disease may be accomplished by detection of CMV-DNA in leucocytes or plasma. Evidence is growing that CMV genotypes may be also relevant for the risk of CMV disease. Diagnosis of CMV disease requires in most instances demonstration of virus in biopsy specimen from the affected organ because presence of CMV in blood may not be causally related to symptoms observed. Clinical symptoms and patient characteristics are essential in the interpretation of laboratory test results and may guide the rational collection of clinical specimen and use of laboratory assays. As a consequence, a reliable diagnosis of CMV disease and early identification of patients at high risk for CMV disease requires an integrated interpretation of clinical and virological information.     

HIV-associated bacteremia: how it has changed in the highly active antiretroviral therapy (HAART) era

To evaluate the changing characteristics of HIV-associated bacteremia in the highly active antiretroviral therapy (HAART) era, we conducted a prospective case control study, comparing two periods of time, before (period A) and after (period B) the introduction of HAART. In total, 174 patients with bacteremia and 348 controls were studied. By comparing incidence in periods A and B, a statistically significant reduction of bacteremia, from 11.8 to 6.3/100 person-years (PY), was observed (p = .0001). Incidence of hospital-acquired bacteremia decreased from 5.8 episodes/100 PY in period A to 2.4/100 PY in period B (p = .0005). A similar trend was also observed for community-acquired episodes of bacteremia, with a value close to statistical significance. Logistic regression analysis indicated that intravenous drug abuse, central venous catheter (CVC) use, high value on APACHE III score, and neutropenia were independent risk factors for bacteremia in both the study periods. Interestingly, comparing the prevalence of bacteremia risk factors in the two study periods, we observed a significant reduction in the use of CVC (p = .04, period A versus period B) and in neutropenia (p = .04). The crude mortality rate was 31% in period A and 23% in period B (p = not significant [ns]). Logistic regression analysis indicated that an high value of Acute Physiology and Chronic Health Evaluation III (APACHE III) score (p < .001) predicted an increased risk of death. Analysis of prognostic factors of bacteremia did not significantly differ in both the study periods. We conclude that HAART has determined a significant reduction of the incidence and a modification of the characteristics of bacteremia. This reduced incidence may produce a substantial impact on future morbidity and health care costs of patients with HIV.     

Significant decrease of the enhancement/neutralization index in HIV patients during highly active antiretroviral therapy (HAART)

Authors studied the effect of highly active antiretroviral therapy (HAART) on balance of the antibodies that enhance or neutralize growth of HIV-1(IIIB) strain in MT-4 cells in the presence or absence of human complement. Sequential serum samples were collected from 28 patients in advanced stage of HIV disease before and during HAART. The balance of the enhancing and neutralizing antibodies was expressed by an index value (E/N I). Samples with an E/N I of <0.5 (twofold decrease in virus production) were considered as neutralizing, whereas samples with an E/N I>2.0 (twofold increase in virus production) were considered as enhancing. At the beginning of HAART serum samples from eight patients enhanced, and samples from only two patients neutralized the virus in the presence of complement, median (25th-75th percentile) value of E/N I was 1.32 (0.79-2.29). E/N I significantly (P<0.0001) dropped to 0.37 (0.19-0.57) during the follow-up period of 18.5 (10.5-23.5) months under HAART. Similar changes were detected when serum samples were tested with no complement added. The E/N I values were also markedly decreased when cultures inoculated with mixtures of HIV and purified IgG prepared from serum pools taken before and during HAART, respectively, were compared. In the last samples of 20/28 patients, neutralization was measured even in the presence of complement while enhancement was found with none of these samples. These findings suggest that HAART results in disappearance of enhancing antibodies and switches the E/N I toward neutralization.     

Public health consequences of screening patients for adherence to highly active antiretroviral therapy

Improvements in HIV antiretroviral therapy (ART) have been accompanied by increasing recognition of the importance of adherence to treatment regimens for maximizing patient benefits while minimizing the emergence of drug-resistant virus. Whether clinicians should screen patients for adherence and only administer therapy to those believed likely to adhere has not been resolved. We first examine the implications of data drawn from a recent study reporting physicians' ability to predict whether patients will adhere to highly active antiretroviral therapy (HAART) or not. We then extend previously developed mathematical models of ART to include screening for adherence and focus on resulting drug resistance as well as on HIV and AIDS incidence at the population level. We show that although screening for adherence is likely to reduce the level of drug resistance compared with a policy of treating all HIV patients with HAART, rates of new HIV infections and AIDS cases in the population would likely increase unless screening accuracy is extremely (perhaps implausibly) high.