Disease Progression In HIV-infected Patients Research Articles

Net charge and position 22 of the V3 loop are associated with HIV-1 tropism in recently infected female sex workers in Nairobi, Kenya.

Human immunodeficiency virus (HIV) infection affects around 37 million people worldwide, and in Kenya, key populations especially female sex workers (FSW), are thought to play a substantial role in the wider, mostly heterosexual HIV-1 transmission structure. Notably, HIV tropism has been found to correlate with HIV-1 transmission and disease progression in HIV-infected patients. In this study, recently infected FSWs from Nairobi, Kenya, were assessed for HIV tropism and the factors related to it. We used a cross-sectional study design to analyze 76 HIV-1 positive plasma samples obtained from FSWs enrolled in sex worker outreach program clinics in Nairobi between November 2020 and April 2021. The effects of clinical, demographic, and viral genetic characteristics were determined using multivariable logistic regression. HIV-1 subtype A1 accounted for 89.5% of all cases, with a prevalence of CXCR4-tropic viruses of 26.3%. WebPSSMR5X4 and Geno2Pheno [G2P:10-15% false positive rate] showed high concordance of 88%. Subjects infected with CXCR4-tropic viruses had statistically significant lower baseline CD4+T-cell counts than those infected with CCR5-tropic viruses (P = .044). Using multivariable logistic regression and adjusting for potential confounders, we found that net charge, the amino acid at position 22 of the V3 loop, and the geographic location of the subject were associated with tropism. A unit increase in V3 loop's net-charge increased the odds of a virus being CXCR4-tropic by 2.4 times (OR = 2.40, 95%CI = 1.35-5.00, P = .007). Second, amino acid threonine at position 22 of V3 loop increased the odds of a strain being X4 by 55.7 times compared to the alanine which occurred in CCR5-tropic strains (OR = 55.7, 95%CI = 4.04-84.1, P < .003). The Kawangware sex worker outreach program clinic was associated with CXCR4-tropic strains (P = .034), but there was there was no evidence of a distinct CXCR4-tropic transmission cluster. In conclusion, this study revealed a high concordance of WebPSSMR5X4 and Geno2Pheno in predicting HIV tropism. The most striking finding was that amino acid position 22 of the V3 loop is linked to tropism in HIV-1 subtype A1. Additional studies with a large dataset are warranted to confirm our findings.

Low levels of short- and medium-chain acylcarnitines in HIV-infected patients.

Carnitine plays an essential role in fatty acid metabolism, exerts substantial antioxidant action and regulates immune functions. We hypothesized that a disturbed carnitine metabolism could be involved in progression of HIV infection. Plasma levels of L-carnitine, its precursors, and short-, medium- and long-chain acylcarnitines were analysed with HPLC/mass spectrometry in HIV-infected patients with various disease severities including patients who acquired Mycobacterium avium complex (MAC) infection. In vitro, we examined the MAC-purified protein derivate (PPD)-induced release of TNF-α and IFN-γ in peripheral blood mononuclear cells (PBMCs) from patients with either high or low plasma levels of acylcarnitines. Plasma levels of the short-chain (e.g. propionyl-carnitine) and medium-chain (e.g. octanoyl-carnitine) acylcarnitines were reduced in patients with advanced HIV infection. These acylcarnitines gradually decreased in rapid progressors, while minimal changes were observed in the nonprogressors. Plasma levels of propionyl-carnitine and octanoyl-carnitine significantly increased during antiretroviral therapy (ART). However, ART did not restore levels to those observed in healthy controls. Depletion of propionyl-carnitine and octanoyl-carnitine was observed prior to MAC infection, and the release of TNF-α and IFN-γ from PBMC was decreased after stimulation with MAC-PPD in samples from HIV-infected patients with low levels of propionyl-carnitine or octanoyl-carnitine. Our findings suggest an association between disturbed acylcarnitine metabolism, immune dysregulation and disease progression in HIV-infected patients. Low levels of propionyl-carnitine and octanoyl-carnitine were associated with increased susceptibility to MAC infection in HIV patients with advanced disease.

Laboratory and Clinical Predictors of Disease Progression following Initiation of Combination Therapy in HIV-Infected Adults in Thailand

BackgroundData on determinants of long-term disease progression in HIV-infected patients on antiretroviral therapy (ART) are limited in low and middle-income settings.MethodsEffects of current CD4 count, viral load and haemoglobin and diagnosis of AIDS-defining events (ADEs) after start of combination ART (cART) on death and new ADEs were assessed using Poisson regression, in patient aged ≥18 years within a multi-centre cohort in Thailand.ResultsAmong 1,572 patients, median follow-up from cART initiation was 4.4 (IQR 3.6–6.3) years. The analysis of death was based on 60 events during 6,573 person-years; 30/50 (60%) deaths with underlying cause ascertained were attributable to infections. Analysis of new ADE included 192 events during 5,865 person-years; TB and Pneumocystis jiroveci pneumonia were the most commonly presented first new ADE (35% and 20% of cases, respectively). In multivariable analyses, low current CD4 count after starting cART was the strongest predictor of death and of new ADE. Even at CD4 above 200 cells/mm3, survival improved steadily with CD4, with mortality rare at ≥500 cells/mm3 (rate 1.1 per 1,000 person-years). Haemoglobin had a strong independent effect, while viral load was weakly predictive with poorer prognosis only observed at ≥100,000 copies/ml. Mortality risk increased following diagnosis of ADEs during cART. The decline in mortality rate with duration on cART (from 21.3 per 1,000 person-years within first 6 months to 4.7 per 1,000 person-years at ≥36 months) was accounted for by current CD4 count.ConclusionsPatients with low CD4 count or haemoglobin require more intensive diagnostic and treatment of underlying causes. Maintaining CD4≥500 cells/mm3 minimizes mortality. However, patient monitoring could potentially be relaxed at high CD4 count if resources are limited. Optimal ART monitoring strategies in low-income settings remain a research priority. Better understanding of the aetiology of anaemia in patients on ART could guide prevention and treatment.

HIV Infection and Progression of Carotid and Coronary Atherosclerosis: The CARE Study

Progression of carotid intima-media thickness (c-IMT) and coronary artery calcium (CAC) are increasingly used as surrogates for vascular risk. We assessed the predictors of c-IMT and CAC progression in a large longitudinal cohort of HIV-infected adults. c-IMT, CAC scores, and vascular and HIV risk factors were evaluated at baseline and at 3-year follow-up in 255 HIV-infected adults. Multivariate regression was used to determine the predictors of atherosclerotic progression. The mean change in c-IMT per year of follow-up was 0.016 mm for the common and 0.020 mm for the internal. Significant predictors of yearly progression were age, systolic blood pressure, triglycerides, and insulin for common c-IMT and triglycerides >=150 mg/dL, glucose >126 mg/dL, use of glucose-lowering medications, quantitative insulin sensitivity check index, high waist circumference, and current smoking for internal c-IMT. Twenty-eight percent had CAC progression. Of those with zero CAC at baseline, 32% had detectable scores at follow-up. Of those with detectable CAC at baseline, 26% had progression at follow-up. For CAC score, quantitative insulin sensitivity check index, apolipoprotein B, and triglycerides predicted progression. Those with abnormal surrogate markers at baseline were more likely to have the metabolic syndrome reversed and be started on antihypertensive medications over the 3-year follow-up period than those who had no abnormalities at baseline. Although c-IMT and CAC progression rates in HIV-infected patients appear higher than expected for this age and risk groups, traditional cardiovascular risk factors remain the strongest determinants of carotid and coronary atherosclerotic disease progression in HIV-infected patients. Aggressive cardiovascular risk reduction is effective at slowing the atherosclerotic progression in those with preexisting disease.

Identification of PD-1 as a Unique Marker for Failing Immune Reconstitution in HIV-1–Infected Patients on Treatment

PD-1 expression on T cells correlates with T-cell exhaustion and disease progression in HIV-infected patients. Previous studies have shown that combinational antiretroviral therapy induced viral suppression results in immune restoration and reduced PD-1 expression. However, a significant number of patients fail to restore CD4 T cells despite suppression of HIV replication below limit of quantification. In this study, we have analyzed PD-1 expression on CD4 and CD8 T cells in patients with poor immune reconstitution despite successful highly active antiretroviral therapy. We found that T cells of such patients express significantly higher levels of PD-1 than patients who had normal recovery of CD4 cells after treatment. In contrast, failing immune reconstitution was not associated with the expression of activation markers, indicating that PD-1 is a unique marker for failing immune reconstitution despite viral suppression. Furthermore, we show that T cells from patients with poor immune recovery differ from T cells of elderly in respect of their marker profile. PD-1 expression negatively correlated with individual CD4 cell counts, and PD-1 expressing T cells were more prone to programmed death ligand-mediated inhibition of T-cell proliferation, indicating that PD-1-mediated T-cell suppression may have a role in impaired immune reconstitution in HIV patients.

Harmful alcohol consumption and patterns of substance use in HIV-infected patients receiving antiretrovirals (ANRS-EN12-VESPA Study): relevance for clinical management and intervention

Alcohol abuse affects secondary prevention and disease progression in HIV-infected patients, and adherence and response to treatment in those chronically treated. The objective of this study was to estimate the prevalence of harmful alcohol consumption (HAC) using various indicators and identify which groups of patients may require specific targeted interventions for HAC risk reduction. A cross-sectional survey, based on a random sample representative of people living with HIV/AIDS (PLWHA) was carried out in 102 French hospital departments delivering HIV care. As alcohol abuse is particularly detrimental to patients receiving highly active antiretroviral therapy (HAART), we focused only on those individuals receiving HAART with complete alcohol assessment (CAGE, AUDIT-C, regular binge drinking, N=2340). Collected information included medical and socio-demographic data, HIV risk behaviors, adherence to treatment and substance and alcohol use, together with depression, anxiety, and experience of attempted suicide or sex work. HAC prevalence was evaluated as follows: 12% (CAGE score ≥2), 27% (AUDIT-C), and 9% (regular binge drinking). Three groups were at higher risk of HAC: men who have sex with men using stimulants, polydrug users, and to a lesser degree, ex-drug users. Innovative intervention strategies to reduce HAC and improve HIV prevention and HAART adherence in various PLWHA populations need urgent testing and implementation. Such interventions for alcohol risk reduction remain central to promoting improved HIV prevention and assuring HAART effectiveness in these populations.

Relationship of CD4+ CD25hi regulatory T (Treg) cells to disease progression in HIV-infected patients

Analyzing the relationships between peripheral blood CD4+ CD25hi regulatory T (Treg) cells and peripheral blood immune status or plasma HIV-lviral load in HIV-infected individuals,so as to determine whether Treg were related to the progression of HIV-infected disease. 116 HIV-infected patients in different stages and 21 healthy control individuals were included in this study. The CD4+ and CD8+ T cell counts were determined by a standard 4-color flow cytometry technique. The Treg cells were examined with 3-color immune staining flow cytometry. The plasma HIV-1 viral load was detected by real time PCR. The frequencies of Treg cells decreased in HIV-infected individuals with high CD4+ T cell counts( > 300/microl) compared with normal controls. With the progression of disease the frequencies of Treg cells were raised gradually, until were increased in HIV-infected individuals with low levels of CD4+ T cell counts ( < 100/microl). In addition, the frequencies of Treg cells were inversely related to CD4+ T cell counts and CD4+ /CD8+ ratio, data showed a statistically significant (respectively, r = -0.564, P < 0.001; r = -0.377, P < 0.001). Furthermore, the proportions of Treg cells were closely related to plasma HIV-1 RNA viral load (r = 0.514, P < 0.001). CD4 CD25hi Treg cells should be a kind of important cells participating the immunopathogenesis of AIDS. It may play different roles in different stages of HIV-infected disease. The exact mechanism of Treg cells in the progression of the HIV-infected disease needs to be investigate further.

Differentiation of Monocytes Into CD1a− Dendritic Cells Correlates With Disease Progression in HIV-Infected Patients

Monocyte differentiation into dendritic cells (DCs) depends on microenvironmental conditions. In this study, the capacity of human monocytes to differentiate into mature DCs and their ability to induce an antiviral immune response was investigated in HIV-infected patients. In healthy subjects, monocytes differentiate into CD1a+ DCs in the presence of granulocyte macrophage colony-stimulating factor and interleukin (IL)-4 and matured in the presence of lipopolysaccharide. Here, we found that in 30% and 45% of HIV-infected white and African subjects, respectively, monocytes gave rise to a homogeneous CD1a* DC population. In the patients who gave rise only to the CD1a* DCs, this population spontaneously produced IL-10 but not IL-12, and induced a T helper 2-like immune response when cultured with human T cells isolated from cord blood mononuclear cells. In patients with monocytes differentiated into CD1a* DCs, a high percentage of HIV-specific CD4 T cells producing IL-4 were seen in the peripheral blood. Furthermore, differentiation of monocytes into DCs with CD1a* phenotype correlated with low CD4 T-cell counts and high viral loads in HIV-infected subjects. These results suggest that the differentiation of monocytes into CD1a* DCs may be a phenotypic marker associated with progression of the disease.

Short-term clinical disease progression in HIV-1-positive patients taking combination antiretroviral therapy: the EuroSIDA risk-score

To derive and validate a clinically applicable prognostic score for predicting short-term disease progression in HIV-infected patients taking combination antiretroviral therapy (cART). Poisson regression was used to identify prognostic markers for new AIDS/death in patients taking cART. A score was derived for 4169 patients from EuroSIDA and validated on 5150 patients from the Swiss HIV Cohort Study (SHCS). In EuroSIDA, 658 events occurred during 22 321 person-years of follow-up: an incidence rate of 3.0/100 person-years of follow-up [95% confidence interval (CI), 2.7-3.3]. Current levels of viral load, CD4 cell count, CD4 cell slope, anaemia, and body mass index all independently predicted new AIDS/death, as did age, exposure group, a prior AIDS diagnosis, prior antiretroviral treatment and stopping all antiretroviral drugs. The EuroSIDA risk-score was divided into four strata; a patient in the lowest strata would have predicted chance of new AIDS/death of 1 in 801, 1 in 401 and 1 in 201 within the next 3, 6 or 12 months, respectively. The corresponding figures for the highest strata were 1 in 17, 1 in 9 and 1 in 5, respectively. A single-unit increase in the risk-score was associated with a 2.70 times higher incidence of clinical progression (95% CI, 2.56-2.84) in EuroSIDA and 2.88 (95% CI, 2.75-3.02) in SHCS. A clinically relevant prognostic score was derived in EuroSIDA and validated within the SHCS, with good agreement. The EuroSIDA risk-score will be made available publicly via an interface that will perform all calculations for the individual.

Cost-Effectiveness of Genotypic Antiretroviral Resistance Testing in HIV-Infected Patients with Treatment Failure

BackgroundGenotypic antiretroviral resistance testing (GRT) in HIV infection with drug resistant virus is recommended to optimize antiretroviral therapy, in particular in patients with virological failure. We estimated the clinical effect, cost and cost-effectiveness of using GRT as compared to expert opinion in patients with antiretroviral treatment failure.MethodsWe developed a mathematical model of HIV disease to describe disease progression in HIV-infected patients with treatment failure and compared the incremental impact of GRT versus expert opinion to guide antiretroviral therapy. The analysis was conducted from the health care (discount rate 4%) and societal (discount rate 2%) perspective. Outcome measures included life-expectancy, quality-adjusted life-expectancy, health care costs, productivity costs and cost-effectiveness in US Dollars per quality-adjusted life-year (QALY) gained. Clinical and economic data were extracted from the large Swiss HIV Cohort Study and clinical trials.ResultsPatients whose treatment was optimized with GRT versus expert opinion had an increase in discounted life-expectancy and quality-adjusted life-expectancy of three and two weeks, respectively. Health care costs with and without GRT were $US 421,000 and $US 419,000, leading to an incremental cost-effectiveness ratio of $US 35,000 per QALY gained. In the analysis from the societal perspective, GRT versus expert opinion led to an increase in discounted life-expectancy and quality-adjusted life-expectancy of three and four weeks, respectively. Health care costs with and without GRT were $US 551,000 and $US 549,000, respectively. When productivity changes were included in the analysis, GRT was cost-saving.ConclusionsGRT for treatment optimization in HIV-infected patients with treatment failure is a cost-effective use of scarce health care resources and beneficial to the society at large.

Clearance of GB virus C during highly active antiretroviral therapy and course of HIV disease progression in HIV-infected patients with hemophilia

Clearance of GB virus C during highly active antiretroviral therapy and course of HIV disease progression in HIV-infected patients with hemophilia

HAART and the HCV-infected liver: friend or foe?

HAART and the HCV-infected liver: friend or foe?

The chemokine receptor CX3CR1 controls homing and anti-viral potencies of CD8 effector-memory T lymphocytes in HIV-infected patients.

We have recently reported that the polymorphism of the fractalkine receptor, CX3CR1, provides a new marker for prognosis in HIV disease. In order to understand the mechanism by which CX3CR1 participates in the regulation of HIV-immune responses, we investigated its expression and role on T lymphocytes in HIV-infected patients. For that purpose, we analysed the expression of CX3CR1 on CD4 and CD8 effector-memory subsets in HIV-positive individuals by flow cytometric analyses, and studied its potential role in the migration and function of CD8 effector cells. We observed an increased frequency of CD8 cells expressing CX3CR1 that was correlated with disease progression in HIV-infected patients compared with normal individuals. CX3CR1+ was expressed mainly on activated and differentiated CCR7-CD45RA-negative memory lymphocytes. Interestingly, CX3CR1 appeared as the main homing receptor of these cells that have downmodulated most other chemokine receptors. The CD8+CX3CR1+ lymphocytes were engaged in the cytotoxic lineage (perforin+, CD27-negative and CD57+). Ex-vivo analysis showed that CX3C ligand-1 inhibits IFNgamma production in response to T cell receptor engagement. CX3CR1 and its ligand could contribute to the specific migratory pattern of late-stage differentiated CD8 cells and participate in the regulation of effector function of CD8 lymphocytes during HIV infection.

High Frequencies of the CCR2b-64I and SDF1-3'A Mutations with HIV Infection in Koreans

Background: Host genetic polymorphisms in the HIV-1 co-receptor CCR5 and CCR2b and SDF-1, ligand for co-receptor CXCR4, have been known to be associated with the resistance of HIV infection and/or the delayed disease progression in HIV-infected patients. Methods: We examined the frequencies of SDF1-3’A and CCR2b-64I alleles of 354 Koreans including 100 HIV-uninfected persons, 13 discordant spouses of HIV-infected persons, and 241 HIV-infected persons. The genotyping assays of SDF1 and CCR2b genes were carried out by polymerase chain reaction-restriction fragment length polymorphism. Results: The frequencies of CCR2b-64I and SDF1-3’A alleles in Koreans were very high compared with Caucasians and blacks. Observed frequencies of CCR2b-64I and SDF1-3’A allelic variants were 25.1% and 28.7%, respectively. The frequency of the CCR2b-64I allele in Koreans was 2~4 times higher than those of other ethnic groups with the exception of Asian. The frequencies of CCR2b-64I and SDF13’A genotypes did not show the significant difference between HIV-infected and uninfected Koreans. However, the prevalence of CCR2b-64I genotype of the LTNP group was about two times higher than that of the remainder group (P< 0.05). Four (45%) out of 9 LTNPs (long-term nonprogressors) showed having the SDF1-3’A allele and 7 (78%) out of 9 LTNPs carried the CCR2b-64I allele. 3 (33%) out of 9 LTNPs had both SDF1-3’A and CCR2b-64I alleles. But none of 5 RPs (rapid progressors) appeared to have both SDF1-3’A and CCR2b-64I alleles. Conclusion: The different genetic backgrounds in study populations may affect the disease progression and the AIDS epidemic in each country. Further studies need to define whether high frequencies of CCR2b-64I and SDF1-3’A allelic variants may affect the HIV disease progression. (Immune Network 2002;2(2):86-90)

Drugs and cardiotoxicity in HIV and AIDS.

The advent of potent antiretroviral drugs in recent years has had an impressive impact on mortality and disease progression in HIV-infected patients, so that issues related to long-term effects of drugs are of growing importance. Hyperlipidemia, hyperglycemia, and lipodystrophy are increasingly described adverse effects of highly active antiretroviral therapy (HAART), in particular when protease inhibitors are used. Hyperlipidemia is strikingly associated with the use of most available protease inhibitors, with an estimated prevalence of up to 50%. Because of the short observation period and the small number of cardiovascular events, epidemiological evidence for an increased risk of coronary heart disease in HIV-infected patients treated with HAART is not adequate at present; however, it is likely that shortly more data will accumulate to quantify this risk. Before starting HAART and during treatment it is reasonable to evaluate all patients for traditional coronary risk factors, including lipid profile. Among the drugs that are currently used in HIV+ patients, antibacterials, antifungals, psychotropic drugs and anti-histamines have been associated with QT prolongation or torsade de pointe, a life-threatening ventricular arrhythmia. Among the risk factors that may precipitate an asymptomatic electrocardiographic abnormality into a dangerous arrhythmia is the concomitant use of drugs that share the CYP3A metabolic pathway. Since most protease inhibitors are potent inhibitors of CYP3A, clinicians should be aware of this potentially dangerous effect of HAART. Anthracyclines are potent cytotoxic antibiotics that have been widely used for the treatment of HIV-related neoplasms. Their cardiotoxicity is well known, ranging from benign and reversible arrhythmias to progressive severe cardiomyopathy. The increased survival and quality of life of HIV+ patients emphasize the importance of a high awareness of adverse drug-related cardiac effects.

Lipid and acute-phase protein alterations in HIV-1 infected patients in the early stages of infection: correlation with CD4+ lymphocytes

Lipid and acute-phase protein alterations have been described in various infection diseases, and they have been recorded during the early stages of HIV infection. Lipid and acute-phase protein profiles also have been correlated with cellular immunological abnormalities. To document these correlations during HIV infection, we studied 75 HIV-infected patients and 26 HIV-negative controls. Patients were classified according to the criteria proposed by the Walter Reed Army Institute: as WR-1 (CD4 lymphocytes, 1154 +/- 268/mm3), WR-2 (CD4, 793 +/- 348/mm3) and WR3/4 (CD4, 287+/-75 mm3). Triglycerides, total cholesterol and HDL-cholesterol concentrations were measured by enzymatic methods. Immunoglobulins (IgA and IgG) and acute-phase proteins (haptoglobin, alpha1-acid glycoprotein, C-reactive protein and transferrin) were determined by immunonephelometry. Haptoglobin levels were significantly increased in HIV-positive patients and correlated with the progression of HIV-infection (control<WR1<WR2<WR3/4). WR-2 and WR-3/4 patients had lower total cholesterol, HDL-cholesterol, and albumin concentrations, however, alpha1-acid glycoprotein and IgA levels were higher, when compared to HIV-negative controls. Elevated triglyceride levels (1.51+/-0.75 mmol/L) were found only in WR3/4 patients, when compared to the control individuals (1.05+/-0.04 mmol/L). No differences were found in transferrin and C-reactive protein concentrations among the studied groups. CD4+ lymphocyte counts were inversely correlated with triglycerides, IgA, alpha1-acid glycoprotein and haptoglobin, and they were positively correlated with albumin, total cholesterol and HDL-cholesterol. Multiple linear regression analysis showed that increased haptoglobin and IgA levels were the best predictive variables of a decreasing CD4+ lymphocyte count. In conclusion, our data showed that: 1) a decrease in total cholesterol, HDL-cholesterol and albumin levels occurred earlier than hypertriglyceridemia in the course of HIV infection; 2) increased levels of haptoglobin occurred earlier than that of alpha1-acid glycoprotein and IgA; 3) haptoglobin and IgA were the best predictive variables of a decreasing CD4+ lymphocyte count. Decreases in HDL-cholesterol and albumin levels with increases in haptoglobin, alpha1-acid glycoprotein, IgA, and triglycerides levels are indications of disease progression in HIV-infected patients.

Increased soluble Fas in HIV-infected hemophilia patients with CD4+ and CD8+ cell count increases and viral load and immune complex decreases.

Previous studies interpreted increases of soluble Fas (sFas) in the plasma during disease progression in HIV-infected patients as evidence of increased apoptosis of CD4(+) lymphocytes. We studied whether sFas and sFas ligand (sFasL) plasma levels are associated with CD4(+) and CD8(+) lymphocyte counts, plasma viral load, and IgM, IgG, C3d, and gp120 complexes on circulating CD4(+) blood lymphocytes in long-term surviving HIV-infected hemophilia patients, most of whom were receiving HAART. Twenty-six hemophilia patients who were infected with HIV in the early 1980s were investigated in 1997, 1998, and 1999. HAART was initiated in 1996 and 1997 in most patients. Lymphocyte subpopulations and immune complex-coated CD4(+) lymphocytes in the blood were investigated by flow cytometry, plasma viral load (HIV-1 mRNA copies/ml plasma) was tested with HIV-1 QT Nuclisens kits, sFas (ng/ml) and sFasL (ng/ml) plasma levels were measured with MBL ELISA kits, and the in vitro response of patient lymphocytes was tested in cell cultures. During the period from 1997 to 1999 we observed an increase in sFas plasma levels (p = 0.003) as well as in CD4(+) (p = 0.004) and CD8(+) (p = 0.023) cell counts; a decrease in IgG (p = 0.047), C3d (p = 0.024), and gp120 (p = 0.001)-coated CD4(+) lymphocytes in the blood; and a decrease in the number of impaired mitogen stimulation assays (p = 0.013). sFas was negatively associated with viral burden (r = -0.662, p = 0.0002) as well as with CD4(+)IgM(+) (r = -0.554, p = 0.004), CD4(+)IgG(+) (r = -0.431, p = 0.031), CD4(+)C3d(+) (r = -0.551, p = 0.041), and CD4(+)gp120(+) (r = -0.430, p = 0.041) blood lymphocytes, CD8(+)DR(+) cell counts (r = -0.700, p = 0.016), and impaired in vitro responses of patient lymphocytes to PHA (r = -0.475, p = 0.016). sFasL was negatively associated with total lymphocyte counts (r = -0.433, p = 0.027), as well as with absolute numbers of CD3(+) (r = -0.492, p = 0.011) and CD8(+) (r = -0.432, p = 0.027) cells. We conclude that, contrary to expectations, sFas plasma levels increased in long-term surviving HIV-infected hemophilia patients receiving HAART, concomitant with increases in CD4(+) and CD8(+) cell counts. Increased sFas may reflect the growing pool of T lymphocytes that recovers because of a decreasing viral burden and a decreasing immune complex load of CD4(+) lymphocytes.

Elevated concentrations of plasma α-melanocyte stimulating hormone are associated with reduced disease progression in HIV-infected patients

To determine whether concentrations of the anti-inflammatory peptide α-melanocyte stimulating hormone (α-MSH) are associated with accelerated or reduced disease progression in patients with HIV infection, plasma concentrations of α-MSH and two other anticytokine molecules, interleukin-1 receptor antagonist (IL-1 ra) and soluble tumor necrosis factor receptor (s TNF r), were taken repeatedly from HIV-positive patients over a 1-year period. Samples from 87 patients were collected by using special precautions to ensure accurate measurement of the peptide. α-MSH concentrations were determined by radioimmunoassay; IL-1 ra and s TNF r concentrations were measured by using enzyme-linked immunosorbent assays. Clinical and immunologic variables were recorded to determine whether there is an association between cytokine antagonist concentrations and disease progression. Elevated concentrations of circulating α-MSH were associated with reduced progression of the disease. Circulating α-MSH was greater in non-progressors than in progressors; the association between elevated α-MSH and reduced disease progression was even more pronounced in patients with baseline CD4+ T cell counts less than 200/μL. No such association was observed for the other two anticytokine molecules, and there was no significant correlation between the plasma concentration of either cytokine antagonist and α-MSH. The present evidence and previous findings indicate that elevated concentrations of α-MSH are associated with reduced disease progression in HIV-infected patients.

Plasma HIV-1 load and disease progression in HIV-infected patients in Hungary.

Nucleic Acid Sequence Based Amplification (NASBA) is a suitable method for the quantification of HIV-1 RNA in plasma and serum samples. Since determination of the viral load appears to be a valuable marker for the prediction of disease progression and for monitoring the efficiency of antiretroviral therapy, the National AIDS Committee initiated the introduction of NASBA in Hungary at the end of 1996. We obtained plasma samples from patients with ARC and AIDS of the Szt. László Hospital, Budapest. We found an increased viral burden in untreated AIDS (CDC group C) patients compared to untreated ARC (CDC group B) patients. In plasma samples of clinically stable ARC and AIDS patients treated with antiretroviral drugs we detected relatively low HIV-1 RNA copy levels while similarly treated ARC and AIDS patients with progressive disease had high HIV-1 RNA copy numbers. The CD4+ T-cell count was lower in AIDS patients compared to ARC patients, as expected. In general, there was an inverse correlation (r = -0.487, P < 0.0001) between CD4+ T-cell counts and HIV-1 RNA levels. We concluded that measurement of HIV-1 RNA plasma level has an important role in assessing prognosis and effects of antiretroviral therapy in HIV-infected patients.

Viral Resistance and the Selection of Antiretroviral Combinations

Mounting scientific evidence suggests that viral replication and evolution of diversification, with the resulting emergence of variants including drug-resistant strains, is responsible for the gradual destruction of the immune system and is the mechanism of disease progression in HIV-infected patients. Monotherapy does not give long-term suppression of viral replication and evolution, and combination therapy is viewed as a potentially more effective long-term approach based on increased and more durable suppression of HIV replication. Because of the large number of drugs that could be used in combination therapy regimens, it is important to investigate, in clinical studies, only those combinations likely to be most effective. In vitro studies are therefore critical in the selection of such combinations. Resistance mutations to many antiretroviral agents have been documented and their patterns of emergence elucidated. A number of studies have since demonstrated the phenomenon of cross-resistance, in which resistant virus emerging under the selective pressure of one therapy is also cross-resistant to a second antiviral agent. This information can be used to avoid combining agents to which cross-resistance can occur. Suppression or "phenotypic reversal" of zidovudine resistance by the lamivudine-resistance mutation at codon 184 has been demonstrated in in vitro studies. It is encouraging that this finding has led to the clinical evaluation of these two agents with promising results. Moreover, in vitro scientific data are critical in facilitating the identification of potentially effective combination therapies.