High plasma levels of soluble fas in HIV type 1-infected subjects are not normalized during highly active antiretroviral therapy

Plasma levels of soluble Fas (sFas) are elevated in human immunodeficiency virus type 1 (HIV-1) infection, indicating dysregulation of the Fas apoptosis pathway and chronic immune activation. We performed a retrospective study to investigate the effects of HAART on plasma levels of sFas. A cross-sectional study of 27 drug-naive infected subjects and 49 patients under antiretroviral treatment showed that plasma levels of sFas were higher in HIV-1-infected subjects than in 52 HIV-1-negative controls, independently of the treatment status. In a longitudinal study of 69 patients undergoing HAART, we observed a minimal, but significant decrease in sFas plasma levels after 1 year of therapy. Levels of sFas, however, remained still higher than physiologic values. Patients undergoing HAART were further classified as nonresponders or responders on the basis of viremia suppression; no significant changes in plasma levels of sFas were observed between the two groups. These findings show that 1 year of HAART has a minor effect on the sFas levels in plasma. Long-term HAART may be required to normalize the dysregulation of the Fas apoptotic pathway and the persistent immune activation initiated by HIV-1.     

IL-7 and Flt-3L plasma levels are increased during highly active antiretroviral therapy-associated IL-2 therapy

IL-2 is used in conjunction with highly active antiretroviral therapy to increase the CD4 cell count in HIV-positive patients. The mechanisms involved remain ill-defined. Here we show that during the first cycle of IL-2 therapy, IL-7 and Flt-3L plasma levels are increased, whereas levels of stem cell factor are unchanged. This supports the hypothesis that aside from stimulating CD4 T cells IL-2 may also indirectly affect lymphocyte production through the stimulation of lymphopoietic cytokines.     

Effects of highly active antiretroviral therapy on paediatric metabolite levels

OBJECTIVES: Highly active antiretroviral therapy (HAART) has extended survival of HIV-infected children into adulthood, raising concerns about long-term metabolic changes in childhood. METHODS: A longitudinal study of metabolite levels in paediatric HIV-infected patients before and after starting HAART (January 2000 to June 2003). The effects of HAART on nonfasting blood levels of total (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol, cholesterol ratio and lactate were analysed using mixed-effects regression. RESULTS: A total of 146 children attended 1208 appointments (median 6.7/child). Of these, 99 (68%) were African. At baseline, 75 (51%) were on HAART and had higher TC (4.19 vs 3.49 mmol/L, P<0.0001), HDL (1.03 vs 0.82 mmol/L, P<0.0001), and LDL (2.54 vs 2.11 mmol/L, P=0.0003) than those not on HAART. Metabolites increased with time on HAART exposure and then stabilized. At 2 years, TC had increased by 0.93 mmol/L (P<0.0001), with 29 children (20%) having repeated TC levels above the 95th centile. LDL and HDL had increased by 0.69 and 0.31 mmol/L at 2 years, respectively (both P<0.0001). Lactates declined with increasing age (-0.06 mmol/L/year, P=0.0001). CONCLUSIONS: This is the first cohort study to demonstrate significant elevations of HDL as well as LDL in children on HAART. This rise in cardio-protective HDL may represent a positive effect of treatment.     

Ferritin levels during structured treatment interruption of highly active antiretroviral therapy

Objective

The aim of the study was to investigate the influence of highly active antiretroviral therapy (HAART) on iron status and, conversely, the influence of iron status on the response to HAART.

Methods

Ferritin levels were retrospectively determined in stored plasma from 138 HAART‐naïve, moderately immunosuppressed HIV‐infected Thai patients participating in a structured treatment interruption trial. Ferritin levels were determined at three predefined time‐points: (1) HAART initiation; (2) HAART discontinuation; and (3) HAART resumption.

Results

At baseline, 31% and 16% of the HIV‐infected patients included in the study had high (>200 ng/mL) and low (<30 ng/mL) ferritin levels, respectively. Ninety‐five per cent of patients with low ferritin levels were female. Ferritin decreased significantly during the interruption phase of HAART (−8.8 ng/mL; P=0.0005) but remained elevated in 62% of the patients with high baseline levels. A low baseline ferritin level was associated with a shorter time (P=0.041) to reach the CD4 cell target for HAART interruption (350 cells/μL), compared with a normal or high baseline ferritin level. Moreover, in a multivariate model, the relative risk (RR) of arriving at this CD4 cell target was significantly higher [RR 1.81; 95% confidence interval (CI) 1.05–3.14] in patients with low baseline ferritin. It is unlikely that inflammation affected ferritin in our patients, as mean levels of C‐reactive protein were not elevated in patients with either high or low ferritin levels.

Conclusions

Both high and low ferritin levels were highly prevalent in moderately immunosuppressed HIV‐positive Thai patients. Structured treatment interruption of HAART resulted in a significant decrease in overall ferritin levels. Furthermore, subjects with low baseline ferritin levels had a faster and greater CD4 response to HAART, suggesting a potential beneficial effect of iron deficiency on immunological recovery after initiation of HAART.

     

Dynamics of plasma hepatitis B virus levels after highly active antiretroviral therapy in patients with HIV infection

BACKGROUND/AIMS: The optimal strategy to prescribe highly active antiretroviral therapy (HAART) in patients infected with both hepatitis B virus (HBV) and human immunodeficiency virus (HIV) remains unsettled. This study aimed to compare the HBV dynamics between HBeAg-positive and HBeAg-negative coinfected patients treated with lamivudine-containing HAART. METHODS: We retrospectively analyzed the serial changes of plasma HBV DNA levels in 24 HBsAg-positive HIV-infected patients who entered the HAART program. A polymerase chain reaction-based assay, capable of quantifying as few as 400 HBV copies/ml, was used. The median follow-up time was 18 months. RESULTS: HAART containing lamivudine 300 mg/day effectively suppressed plasma HBV-DNA to 10(-3)-10(-5)-fold of the baseline levels, but a multi-phasic decay of HBV DNA was observed. The later phases became flat, as a persistent residual HBV viremia, in eight of the studied 10 HBeAg-positive patients; in contrast, residual HBV viremia was not observed in the 10 HBeAg-negative patients studied (8/10 vs. 0/10, P=0.0007, Fisher's exact test). HAART without lamivudine did not suppress plasma HBV DNA levels in the remaining four patients. CONCLUSIONS: HAART containing lamivudine 300 mg/day effectively suppress HBV replication in HBeAg-negative HIV/HBV-coinfected patients. Nevertheless, residual HBV replication persisted in most HBeAg-positive coinfected patients.     

Prognostic value of plasma HIV RNA among highly active antiretroviral therapy users

BACKGROUND: The study objective was to compare the prognostic value of plasma HIV RNA and CD4 cell count at baseline and as time-updated variables in highly active antiretroviral therapy (HAART) users for two outcomes: development of AIDS and change in CD4 cell count. METHODS: The study population comprised 387 men enrolled in the Multicenter AIDS Cohort Study who were AIDS-free and initiated HAART between 1996 and 2001. Follow-up until AIDS diagnosis (n=36, 9%) or the last AIDS-free visit was included. To determine the predictive value of combining HIV RNA and CD4 cell count, regression tree methods using recursive partitioning at pre-specified cut points for both variables were used. RESULTS: Low CD4 cell count was a strong predictor of AIDS among HAART users. However, HIV RNA showed strong prognostic value for AIDS development among those with CD4 cell counts > 250 x 10(6) cells/l, in whom an HIV RNA level > 1000 copies/ml carried a 4.6-fold greater risk of developing AIDS. HIV RNA < 5000 copies/ml was also predictive of subsequent increase in CD4 cell count with significantly higher increases among those with initial CD4 counts > 300 x 10(6) cells/l. CONCLUSION: Although, in HAART users, CD4 cell count was the primordial prognostic marker, an HIV RNA > 1000 copies/ml attained after HAART initiation was a strong predictor of the rate of subsequent CD4 cell count increase and of developing AIDS in patients whose CD4 cell counts were > 250 x 10(6) cells/l.     

Adherence and plasma drug concentrations are predictors of confirmed virologic response after 24-week salvage highly active antiretroviral therapy

Data from 197 patients for whom highly active antiretroviral therapy (HAART) failed, who started a new regimen chosen under the guide of resistance testing results interpreted by experts, were retrospectively studied, provided that at least 2 determinations of adherence and plasma drug concentrations were performed during the follow-up. Univariate and multivariable logistic regression analyses were conducted, using confirmed virologic response at week 24 as outcome measure (i.e., achievement of undetectable HIV plasma viral load at any time point before week 24 and its maintenance up to week 24). Suboptimal drug concentrations (odds ratio [OR]: 0.3; 95% confidence interval [CI] 0.2-0.7; p = 0.006) and suboptimal adherence (OR: 0.4; 95% CI 0.2-0.8; p = 0.014) were both negative independent predictors of sustained virologic response, while the use of boosted protease inhibitor-containing regimens resulted to be protective (OR: 2.4; 95% CI 1.1-5.3; p = 0.032).     

IL-23 and IFN-gamma deficiency in immunodeficient HIV patients who achieved a long-term increase in CD4 T-cell counts on highly active antiretroviral therapy

The pathogenesis of HIV infection and the susceptibility to opportunistic infections has been associated with poor type 1 cytokine production. In severely immunodeficient HIV patients who achieved increased CD4 T-cell counts on longterm highly active antiretroviral therapy, we observed reduced expression of IL-23p19 and IFN-gamma messenger RNA. Impaired IL-23-induced IFN-gamma production by memory T cells might thus contribute to opportunistic infections in a minority of patients with substantial CD4 T-cell recovery.     

Naive CD4+ T lymphocytes express high levels of Bcl-2 after highly active antiretroviral therapy for HIV infection

The mechanism causing the increasing number of peripheral T cells after highly active antiretroviral therapy (HAART) is still unclear. The bcl-2 oncogene prevents spontaneous apoptosis (SA) in lymphocytes. Spontaneous apoptosis could be a determinant of HIV immunodeficiency and can be reversed by HAART including protease inhibitors (PI-HAART). The aims of our study were to measure Bcl-2 protein expression in memory (CD45RO+) and naive (CD45RO-) CD4+ and CD8+ T lymphocytes of HIV+ patients and to correlate it with efficacy of PI-HAART. Forty-nine HIV+ patients (cases) and 26 HIV- individuals (controls) were evaluated. Patients receiving PI-HAART, and who had undetectable HIV plasma viral load (VL-, n = 21), had higher levels of Bcl-2 than did VL+ patients (n = 28), both in CD4+ cells (p < 0.0001) and in CD8+ cells (p < 0.001). VL+ patients had lower Bcl-2 levels than did controls in CD8+ cells (p = 0.02), but not in CD4+ cells (p > 0.05). Interestingly, VL- patients had higher Bcl-2 expression than did controls both in CD4+ cells (p < 0.0001) and in CD8+ cells (p = 0.03). In a subcohort of the same patients, Bcl-2 was significantly higher in VL- patients (n = 10) than in controls (n = 12), both in naive CD4+ cells (p < 0.0001) and in naive CD8+ cells (p = 0.01). Naive CD4+ cells had higher Bcl-2 expression in VL- than in VL+ patients (p = 0.01). In a subsequent longitudinal study of nine HIV patients, naive CD4+ cells increased after effective PI-HAART (p = 0.03), which paralleled an increase in Bcl-2 expression in the same cells (p = 0.02). In conclusion, upregulation of bcl-2 could be a mechanism of immune reconstitution of naive CD4+ T cells induced by PI-HAART.     

Late presenters in the era of highly active antiretroviral therapy: uptake of and responses to antiretroviral therapy

OBJECTIVES: To investigate the characteristics and clinical, immunological and virological outcomes for individuals presenting for care with low CD4 cell counts. METHODS: Individuals aged > 16 years presenting for care for the first time were identified between 1 January 1996 and 31 December 2002. Late presenters were those with CD4 cell count < 50 x 10(6) cells/l. Follow-up was until last contact, death or 31 December 2002. RESULTS: Late presenters formed 15.3% (110) of the group; they were more likely to be female (35% versus 24%), heterosexual (53% versus 38%), and of Black-African ethnicity (39% versus 27%) than other individuals. Over a median follow-up of 2.5 years, 13% of late presenters died. Ninety-nine patients started antiretroviral treatment; Of the 11 patients who did not start antiretroviral treatment, eight died within 3 months of presentation. Among those starting treatment, 87 (87.9%) achieved a viral load < 400 copies/ml and median CD4 cell counts increased from 43 x 10(6) cells/l at 0-2 months after presentation to 204 x 10(6) cells/l at 1 year. Over the first year, 71 patients attended at least one outpatient visit (median, 4.5; range, 0-39), 21 attended at least one day case visit (median, 0; range, 0-15) and 49 were admitted as an inpatient (median, 0; range, 0-4). CONCLUSIONS: Those presenting for care with very low CD4 cell counts may make large demands on clinical resources, particularly over the first few months. While some patients do have a poor outcome on highly active antiretroviral therapy, many will benefit from this therapy and will experience good immunological and virological responses.     

Decreased recovery of CD4 lymphocytes in older HIV-infected patients beginning highly active antiretroviral therapy

Among virological responders, the area under the curve of the CD4 count minus baseline (AUCMB) after 3, 9, 15 and 18 months of highly active antiretroviral therapy (HAART) was less in individuals 55 years or older (P < 0.05). Fewer older individuals achieved increases of 50, 100, or over 150 CD4 cells/l. A random quadratic time course model estimated that the AUCMB decreased 35 cells/year for each 10 years of additional age during the first 12 months after HAART (P < 0.005).     

HIV infection: pre-highly active antiretroviral therapy IL-7 plasma levels correlate with long-term CD4 cell count increase after treatment

Highly active antiretroviral therapy (HAART) in HIV patients generally increases the CD4 cell count, but the level of CD4 cell restoration remains very heterogeneous. IL-7 is the main cytokine controlling the size of the T-cell pool. We assessed the hypothesis that pre-HAART IL-7 plasma levels may affect CD4 cell restoration after treatment. A positive correlation was found in a cohort of 18 patients between pre-HAART IL-7 plasma levels and CD4 cell increases after 20 +/- 7.8 months of HAART.     

Absolute count and percentage of CD4+ lymphocytes are independent predictors of disease progression in HIV-infected persons initiating highly active antiretroviral therapy

BACKGROUND: Highly active antiretroviral therapy (HAART) is recommended when the absolute CD4(+) T lymphocyte count is <200 cells/mm(3), and it should be considered when that count is > or =200, although the optimal timing when it is > or =200 is unclear. Because preliminary data had suggested that a low CD4(+) T lymphocyte percentage (%CD4) is associated with disease progression in persons initiating HAART who have a higher absolute CD4, we sought to further characterize the predictive utility of %CD4. METHODS: We conducted an observational study of persons in Collaborations in HIV Outcomes Research/US cohort who initiated their first HAART regimen between 1997 and 2004, received > or =30 days of therapy, and had baseline values of absolute CD4, %CD4, and HIV-1 RNA. Cox proportional-hazards models determined associations between %CD4 and disease progression (to either a new AIDS-defining event [ADE] or death). RESULTS: Of 1891 persons, 11% were female and 18% were African American; the median age was 38 years. Median follow-up was 55 months (interquartile range, 23-83 months), and 468 (25%) had disease progression. Multivariable analysis including age, race, sex, HIV-1 RNA, prior antiretroviral therapy, probable route of infection, prior ADE, absolute CD4, and %CD4 was performed; prior ART (P<.0001), injection-drug use (P=.04), lower absolute CD4 (P=.002), and lower %CD4 (P=.002) predicted disease progression. CONCLUSIONS: %CD4 at initiation of the first HAART regimen predicted disease progression independent of absolute CD4; %CD4 may be used to determine the timing of HAART.