Hypofibrinolytic state in HIV-1-infected patients treated with protease inhibitor-containing highly active antiretroviral therapy

Decreased insulin sensitivity, hyperlipidemia, and body fat changes are considered as risk factors for coronary heart disease (CHD). A clustering of such factors (metabolic syndrome [MSDR]) exponentially increases the risk. Impaired fibrinolysis and increased coagulation are additional independent risk factors for CHD. We studied the effects of protease inhibitor (PI)-containing highly active antiretroviral therapy (HAART) on metabolic and hemostatic parameters in 363 HIV-infected individuals, of whom 266 were receiving PI-containing HAART and 97 were treatment naive. The fasting plasma levels of insulin, glucose, triglycerides, cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, plasminogen activator inhibitor type 1 (PAI-1), and fibrinogen were evaluated together with the areas of visceral adipose tissue and the visceral adipose tissue/subcutaneous adipose tissue area ratio. The levels of insulin, triglycerides, cholesterol, and low-density lipoprotein cholesterol; visceral adipose tissue area; low-density lipoprotein/high-density lipoprotein ratio; and visceral adipose tissue/subcutaneous adipose tissue area ratio were significantly increased in patients receiving PI-containing HAART compared with treatment-naive patients. The levels of PAI-1 and fibrinogen were significantly higher in patients receiving PI-containing HAART. PAI-1 levels were higher in individuals with MSDR but also in patients without MSDR who were receiving PI-containing HAART. PAI-1 was independently correlated to use of PI-containing HAART, triglyceride level, insulin level, and body mass index (p <.001). These findings suggest that patients receiving PI-containing HAART have decreased fibrinolysis and increased coagulability, which may thus represent additional risk factors for cardiovascular disease in this patient group.     

Modeling the time course of CD4 T-lymphocyte counts according to the level of virologic rebound in HIV-1-infected patients on highly active antiretroviral therapy

OBJECTIVE: To study the influence of the level of virologic rebound during combination antiretroviral therapy on the time course of the CD4 count. METHODS: Between January 1997 and December 1999, we enrolled 3736 patients from the French Hospital HIV Database who had an undetectable viral load on a first course of highly active antiretroviral therapy (HAART). Four levels of virologic rebound were defined on the basis of viral load values during the year following initial undetectability on HAART: group 1, all viral loads <500 copies/mL; group 2, all viral loads <5000 copies/mL; group 3, all viral loads <10,000 copies/mL; and group 4, at least 1 viral load >10,000 copies/mL. We developed a continuous time-homogeneous Markov process with 5 reversible stages defined by CD4 count intervals. RESULTS: CD4 counts increased continuously over time in each group. The smaller the virologic rebound, the stronger was the increase in the CD4 count (P < 0.0001). The mean CD4 cell count increments between months 2 and 6 were 26, 20, 11, and 2 cells/mm3 in groups 1, 2, 3, and 4, respectively. The rate of gain fell after month 6 and was almost nil in group 4. CONCLUSION: After achieving an undetectable viral load on HAART, immunologic reconstitution is possible whatever the subsequent level of viral replication, except among patients with high-level rebound, meaning that in patients with a long history of antiretroviral therapy and a reduced choice of antiretroviral drugs due to acquisition of resistances, delay in antiretroviral therapy switch can be possible in patients with low or intermediate rebound.     

Soluble urokinase receptor levels in plasma during 5 years of highly active antiretroviral therapy in HIV-1-infected patients

High blood levels of the soluble urokinase receptor (suPAR) strongly predict increased mortality in human immunodeficiency virus-1 (HIV-1)-infected patients. This study investigated the plasma concentration of suPAR in 29 treatment-naive HIV-1-infected patients during 5 years treatment with highly active antiretroviral therapy (HAART). Plasma suPAR decreased after introducing HAART, most pronounced during the first treatment year. The change in plasma suPAR was independent of changes in viral replication and CD4+ cells but it was strongly correlated with plasma levels of the soluble TNF receptor II. Compared with healthy individuals, plasma suPAR and sTN-FrII was increased in untreated patients. After initiating HAART, plasma sTNFrII remained increased whereas plasma suPAR decreased to a level comparable with healthy individuals. The present data indicate that the circulating suPAR level is linked to inflammation in untreated as well as HAART-treated HIV-1-infected patients.     

Plasma levels of intact and cleaved urokinase receptor decrease in HIV-1-infected patients initiating highly active antiretroviral therapy

Elevated blood levels of soluble urokinase receptor (suPAR) measured by ELISA decrease in human immunodeficiency virus‐1 (HIV‐1)‐infected patients initiating highly active antiretroviral therapy (HAART). As the suPAR ELISA measures both three‐ and two‐domain suPAR [suPAR(I–III), suPAR(II–III)] and suPAR(I–III)–ligand complexes, the amount by which the individual suPAR forms (suPAR(I–III), suPAR(II–III) and one‐domain suPAR [suPAR(I)]) decrease in plasma in HIV‐1‐infected patients initiating HAART is unknown. Consequently, the objective of this study was to investigate HAART‐induced changes in the individual plasma suPAR forms in HIV‐1‐infected patients. Plasma suPAR was measured by three time‐resolved fluorescence immunoassays detecting suPAR(I–III), suPAR(I–III) + suPAR(II–III) and suPAR(I) in 29 treatment‐naïve HIV‐1‐infected patients followed annually for 5 years after initiation of HAART and in 20 age‐ and gender‐matched healthy individuals. In addition, plasma levels of the following inflammatory markers were also investigated: soluble tumour necrosis factor receptor (sTNFr)‐II, TNF‐α, interleukins (IL)‐10, IL‐6, IL‐4, IL‐2 and interferon (IFN)‐γ. In HIV‐1‐infected patients, plasma suPAR(I–III), suPAR(II–III) and suPAR(I) decreased within the first treatment year (all P < 0.05) and suPAR(I–III) and suPAR(II–III) remained above normal throughout follow‐up (both P < 0.05). Plasma sTNFrII, IL‐6, IFN‐γ and IL‐10 also decreased during HAART (all P < 0.05). In HIV‐1‐infected patients, sTNFrII correlated with all suPAR forms before (all P < 0.01) and after 5 years HAART (all P < 0.001), whereas sTNFrII and suPAR did not correlate in healthy individuals. Intact and cleaved plasma suPAR decreased in HIV‐1‐infected patients initiating HAART but remained above normal. The positive correlation with sTNFrII suggests that the individual plasma suPAR forms are linked to immune activation in HIV‐1 infection.     

Psychiatric illness and virologic response in patients initiating highly active antiretroviral therapy

BACKGROUND: Mental illness (MI) and substance abuse (SA) are common in HIV-positive patients. MI/SA consistently predict poorer antiretroviral adherence, suggesting that affected patients should be at higher risk of poor virologic and immunologic response to highly active antiretroviral therapy (HAART). PARTICIPANTS: 198 HAART-naive patients initiated HAART at an academic medical center serving a heterogeneous population. METHODS: Participants were assigned a predicted probability from 0 to 1 of having each of the following: (1) any mood, anxiety, or substance use disorder; (2) clinically relevant depression; (3) alcohol abuse/dependence; and (4) drug abuse/dependence. Probabilities were based on responses to questions on an MI/SA screening instrument (Substance Abuse and Mental Illness Symptoms Screener [SAMISS]) and other clinical and sociodemographic characteristics and were derived using predictive logistic regression modeling from a separate validation study of the SAMISS compared with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnoses. Using survival analysis techniques, we assessed baseline predicted probability of psychiatric illness as a predictor of time from HAART initiation to virologic suppression (first viral load [VL] <400 copies/mL), from HAART initiation to overall virologic failure (first VL >or=400 copies/mL after suppression, time set to 0 for patients never achieving suppression), from virologic suppression to virologic rebound (first VL >or=400 copies/mL), and from HAART initiation to immunologic failure (first CD4 cell count lower than baseline). RESULTS: A higher predicted probability of any psychiatric disorder was associated with a slower rate of virologic suppression (adjusted hazard ratio [aHR] = 0.86 per 25% increment, 95% confidence interval [CI]: 0.75 to 0.98) and a faster rate of overall virologic failure (aHR = 1.22, 95% CI: 1.06 to 1.40). Associations with other outcomes were consistent in direction but not statistically significant. Predicted probability of depression was associated with slower virologic suppression (aHR = 0.79, 95% CI: 0.63 to 0.98), and predicted probabilities of alcohol and drug abuse/dependence was associated with faster overall virologic failure (aHR = 1.37, 95% CI: 1.08 to 1.74 and aHR = 1.18, 95% CI: 1.00 to 1.39, respectively). CONCLUSIONS: These results are consistent with an inferior virologic response to first HAART among patients with concurrent mood, anxiety, and substance use disorders, suggesting a clinical benefit to identification and treatment of psychiatric illness among patients initiating antiretroviral therapy.     

Increased body mass index does not alter response to initial highly active antiretroviral therapy in HIV-1-infected patients

BACKGROUND: Body mass index (BMI) can influence drug metabolism, thus affecting efficacy and risk for toxicities. Hypothesizing that persons with an increased BMI and larger volumes of distribution may experience a suboptimal response to highly active antiretroviral therapy (HAART), we evaluated the effect of BMI on virologic and immunologic response in previously ART-naive patients initiating therapy. METHODS: Using data from the HIV Outpatient Study, we analyzed the statistical association of BMI and other selected demographic variables with achieving an undetectable viral load and experiencing a CD4 cell count increase of more than 100 cell/microL after 3 to 9 months of therapy among antiretroviral-naive patients initiating HAART. RESULTS: Among 711 patients included in analysis, 43% had a BMI of more than 25 (overweight-obese). Higher BMI was associated with being female, having black or Hispanic race/ethnicity, being heterosexual, and using injection drugs (all P<0.001). The patients in BMI groups did not differ significantly by baseline CD4 cell count or the duration of the initial HAART regimen. Although median baseline viral loads were significantly lower in obese participants (P=0.008), overweight or obese BMI did not significantly alter the likelihood of achieving an undetectable viral load and a CD4 cell count increase of more than 100 cells/microL compared with normal weight persons. CONCLUSION: A substantial proportion of HIV-infected outpatients in this cohort were overweight or obese. Increased BMI was not associated with decreased virologic and immunologic responses to initial HAART. Responses were equivalent and within expected ranges between normal weight patients, overweight patients, and obese patients at 3 to 9 months of observation.     

Virologic and immunologic response to highly active antiretroviral therapy in indigenous and nonindigenous HIV-1-infected patients in the Netherlands

OBJECTIVE: To compare the results of antiretroviral treatment (highly active antiretroviral therapy [HAART]) in indigenous Dutch (ID) and nonindigenous HIV-1-infected patients in Amsterdam, the Netherlands. We focused on the largest groups of nonindigenous people visiting our outpatient clinic: patients from other industrialized countries (western), from Surinam/Netherlands Antilles (SNA), and from sub-Saharan Africa (SSA). DESIGN: Retrospective cohort analysis of 692 therapy-naive HIV-1-positive individuals who visited our outpatient clinic for the first time between July 1, 1996 and December 31, 2001. METHODS: We compared the groups at the time of their first visit to our clinic; at the start of HAART; and according to the virological, immunologic, and clinical treatment response during the 96 weeks after the start of HAART. RESULTS: Of the patients starting antiretroviral therapy, 362 were ID, 84 were western, 72 were from SNA, and 110 were from SSA. SNA and SSA patients had a lower CD4 cell count at first visit (ID = 330 cells/mm(3), western = 330 cells/mm(3), SNA = 250 cells/mm(3), and SSA = 170 cells/mm(3); P = 0.0002). Treatment in SNA and SSA patients was also started at a lower CD4 cell count, but the plasma HIV-1 RNA level was comparable. After the start of HAART, a similar rise in CD4 cell count was seen in the 4 groups (P = 0.33), but the baseline difference in CD4 cell count remained present during the follow-up period of 96 weeks. After adjusting for variables potentially influencing treatment outcome, the proportion of patients not reaching a plasma HIV-1 RNA level <400 copies/mL was not different for the 4 groups in contrast to the percentage not reaching a plasma HIV-1 RNA level <50 copies/mL (at 48 weeks: ID = 4.8%, western = 27.5%, SNA = 23.1%, and SSA = 24.2%; P = 0.017 over the 96-week time period). After the start of HAART, nonindigenous patients also more often had progression to Centers for Disease Control and Prevention (CDC) stage C or died (P = 0.006). CONCLUSIONS: In nonindigenous patients, treatment with HAART was equally successful in terms of the increase in CD4 cell count but was substantially less effective in achieving a plasma HIV-1 RNA level below 50 copies/mL. Further investigations should explore differences in adherence and pharmacokinetics in these patient groups.     

Changes in CCR5 and CXCR4 expression and beta-chemokine production in HIV-1-infected patients treated with highly active antiretroviral therapy

The effect of highly active antiretroviral therapy (HAART) on the expression of CCR5 and CXCR4 HIV coreceptors and the production of the beta-chemokines regulated upon activation, normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta has been investigated in 30 HIV-1-infected individuals during 12-36 months of therapy. CCR5 expression was increased in both CD4 + and CD8 + subsets, whereas CXCR4 expression was upregulated only in CD4 + cells. CCR5 levels normalized during 36 months of therapy and positively correlated with the levels of memory, CD95 +, and HLA-DR + T cells. In contrast, the frequency of CXCR4-expressing cells was not significantly modified by HAART, although a downregulation was observed early after starting treatment. CXCR4 levels were significantly associated with the frequencies of naive T cells and negatively correlated with plasma viral load, CD95, and HLA-DR expression. An increased production of both spontaneous and lectin-induced RANTES, MIP-1alpha, and MIP-1beta was found at baseline in HIV-infected individuals. The spontaneous beta-chemokines production was not modified by 12 months of HAART, although a significant reduction was seen during the first months of therapy. A transient decrease of lectin-stimulated RANTES production was also observed, whereas the reduction of lectin-induced MIP-1alpha persisted for up to 12 months of therapy. In contrast, MIP-1beta secreted by phytohemagglutinin antigen-stimulated peripheral blood mononuclear cells progressively increased during HAART. In conclusion, our data indicate a normalization of CCR5 but not CXCR4 expression during suppressive therapy and changes in beta-chemokine production that may play a part in dictating the efficiency of viral infection and consequently the disease course.     

T cell proliferation and apoptosis in HIV-1-infected lymphoid tissue: impact of highly active antiretroviral therapy.

T cell turnover was studied in situ in tonsillar lymphoid tissue (LT) from HIV-1-infected individuals during 48 weeks of highly active antiretroviral therapy (HAART) and compared to that of HIV-1-negative controls. Prior to therapy, CD4 cell proliferation (%CD4+ Ki67+) and apoptosis (%CD4+ TUNEL+) were increased in HIV-1-infected LT and both parameters correlated with tonsillar viral load. CD8 cell proliferation (%CD8+ Ki67+) was increased 4- to 10-fold, mainly in the germinal centers. Apoptotic CD8+ T cell levels (%CD8+ TUNEL+) were raised preferentially in the tonsillar T cell zone. The frequency of CD8+ Ki67+ and CD8+ TUNEL+ T cells correlated with tonsillar viral load and with the fraction of CD8(+) T cells expressing activation markers. During HAART, CD4 cell turnover normalized while CD8 cell turnover was dramatically reduced. However, low level viral replication concomitant with slightly elevated levels of CD8 cell turnover indicated a persistent cellular immune response in LT. In conclusion, enhanced T cell turnover may reflect effector cells related to HIV-1 infection.     

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.     

Changes in circulating levels of soluble cell adhesion molecules following highly active antiretroviral treatment of HIV-1-infected patients

Increased levels of soluble cell adhesion molecules (sCAM) have been reported in HIV-1 infection and may possibly contribute to altering the adhesion mechanisms of phagocytic cells. We evaluated the effect of highly active antiretroviral therapy (HAART) on plasma levels of sL-selectin, sE-selectin, intercellular cell adhesion molecule-1 (sICAM-1), sICAM-3, and vascular cell adhesion molecule-1 (sVCAM-1). Study participants included 22 HIV-1-infected patients with a CD4+ T-cell count/microl below 500 who were started on a HAART regimen and followed up for 9 months. After the initiation of therapy, plasma sL-selectin concentrations progressively decreased to normal ranges in the majority of our patients (P < 0.001), while no changes in sE-selectin were found. In all patients sICAM-1 remained relatively constant at significantly elevated concentrations during the 9 months of therapy. A significant reduction in plasma concentrations of both sICAM-3 and sVCAM-1 was found; however, the levels of these sCAM were not normalized by HAART and remained significantly elevated throughout the study (P < 0.001). The reduced release of sL-selectin could improve the ability of phagocitic cells to migrate in response to chemotactic stimuli after starting HAART. On the other hand, the persistent elevation of sICAM-1, sICAM-3, and sVCAM-1 could reflect continuous HIV-1-mediated immune activation, despite adequate control of plasma HIV-1 replication by therapy.