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Biomedical subjects

Nancy Klimas

Publications and source records attributed to Nancy Klimas.

18 recordsLinked to original sources

Impaired natural immunity, cognitive dysfunction, and physical symptoms in patients with chronic fatigue syndrome: preliminary evidence for a subgroup?

OBJECTIVE: The diagnostic criteria of chronic fatigue syndrome (CFS) define a heterogeneous population composed of several subgroups. Past efforts to identify subgroup markers have met with mixed success. This study was designed to examine natural killer cell activity (NKCA) as a potential subgroup marker by comparing the clinical presentations of CFS patients with and without clinically reduced NKCA. METHODS: Forty-one female CFS patients were classified into having either low or normal NKCA levels. These subgroups were then compared on objective measures of cognitive functioning and subjective assessments of fatigue, vigor, cognitive impairment, and daytime dysfunction. RESULTS: Relative to CFS patients in the normal-NKCA subgroup, low-NKCA patients reported less vigor, more daytime dysfunction, and more cognitive impairment. In addition, low-NKCA patients performed less on objective measures of cognitive functioning relative to normal-NKCA patients. CONCLUSIONS: The results are offered as preliminary evidence in support of using NKCA as an immunological subgroup marker in CFS. Findings are also discussed in terms of known associations between dysregulated immune functions, somatic symptoms, and psychological stress.

Adolescent↗

Reductions in depressed mood and denial coping during cognitive behavioral stress management with HIV-Positive gay men treated with HAART.

BACKGROUND: Stress management interventions for HIV-positive persons have been designed to enhance coping skills and encourage health-promoting behaviors with the hope of decreasing distress and slowing disease progression. PURPOSE: We examined the efficacy of a cognitive behavioral stress management (CBSM) intervention in combination with medication adherence training (MAT) in 130 gay and bisexual men living with HIV infection. METHODS: Participants were randomized to either a 10-week CBSM+MAT intervention (n = 76) or a MAT-only condition (n = 54). Measures of self-reported adherence, active cognitive coping (i.e., acceptance and positive reinterpretation), avoidant coping (i.e., denial and behavioral disengagement), and depressed mood were examined over the 10-week intervention period. RESULTS: Men in CBSM+MAT reported reductions in depressed mood and denial coping during the 10-week intervention period, but no changes in active cognitive coping or self-reported adherence were observed. Using path analysis, greater reliance on denial coping at baseline was associated with decreased depressed mood at 10 weeks. We also determined that CBSM+MAT may decrease depressed mood by reducing reliance on denial coping over the 10-week intervention period. CONCLUSIONS: Although denial may be an effective means of distress reduction in the short term, reliance on this coping strategy may result in a decreased capacity to effectively manage a variety of disease-related stressors in the long term. CBSM+MAT addresses this potentially detrimental pattern by teaching stress reduction skills that may decrease depressed mood via reduced reliance on denial coping.

Adaptation, Physiological↗

Gene expression correlates of unexplained fatigue.

Quantitative trait analysis (QTA) can be used to test whether the expression of a particular gene significantly correlates with some ordinal variable. To limit the number of false discoveries in the gene list, a multivariate permutation test can also be performed. The purpose of this study is to identify peripheral blood gene expression correlates of fatigue using quantitative trait analysis on gene expression data from 20,000 genes and fatigue traits measured using the multidimensional fatigue inventory (MFI). A total of 839 genes were statistically associated with fatigue measures. These mapped to biological pathways such as oxidative phosphorylation, gluconeogenesis, lipid metabolism, and several signal transduction pathways. However, more than 50% are not functionally annotated or associated with identified pathways. There is some overlap with genes implicated in other studies using differential gene expression. However, QTA allows detection of alterations that may not reach statistical significance in class comparison analyses, but which could contribute to disease pathophysiology. This study supports the use of phenotypic measures of chronic fatigue syndrome (CFS) and QTA as important for additional studies of this complex illness. Gene expression correlates of other phenotypic measures in the CFS Computational Challenge (C3) data set could be useful. Future studies of CFS should include as many precise measures of disease phenotype as is practical.

Adult↗

Identifying illness parameters in fatiguing syndromes using classical projection methods.

OBJECTIVES: To examine the potential of multivariate projection methods in identifying common patterns of change in clinical and gene expression data that capture the illness state of subjects with unexplained fatigue and nonfatigued control participants. METHODS: Data for 111 female subjects was examined. A total of 59 indicators, including multidimensional fatigue inventory (MFI), medical outcome Short Form 36 (SF-36), Centers for Disease Control and Prevention (CDC) symptom inventory and cognitive response described illness. Partial least squares (PLS) was used to construct two feature spaces: one describing the symptom space from gene expression in peripheral blood mononuclear cells (PBMC) and one based on 117 clinical variables. Multiplicative scatter correction followed by quantile normalization was applied for trend removal and range adjustment of microarray data. Microarray quality was assessed using mean Pearson correlation between samples. Benjamini-Hochberg multiple testing criteria served to identify significantly expressed probes. RESULTS: A single common trend in 59 symptom constructs isolates of nonfatigued subjects from the overall group. This segregation is supported by two co-regulation patterns representing 10% of the overall microarray variation. Of the 39 principal contributors, the 17 probes annotated related to basic cellular processes involved in cell signaling, ion transport and immune system function. The single most influential gene was sestrin 1 (SESN1), supporting recent evidence of oxidative stress involvement in chronic fatigue syndrome (CFS). Dominant variables in the clinical feature space described heart rate variability (HRV) during sleep. Potassium and free thyroxine (T4) also figure prominently. CONCLUSION: Combining multiple symptom, gene or clinical variables into composite features provides better discrimination of the illness state than even the most influential variable used alone. Although the exact mechanism is unclear, results suggest a common link between oxidative stress, immune system dysfunction and potassium imbalance in CFS patients leading to impaired sympatho-vagal balance strongly reflected in abnormal HRV.

Adult↗

Exploration of statistical dependence between illness parameters using the entropy correlation coefficient.

UNLABELLED: The entropy correlation coefficient (ECC) is a useful tool for measuring statistical dependence between variables. We employed this tool to search for pairs of variables that correlated in the chronic fatigue syndrome (CFS) Computational Challenge dataset. Highly related variables are candidates for data reduction, and novel relationships could lead to hypotheses regarding the pathogenesis of CFS. METHODS: Data for 130 female participants in the Wichita (KS, USA) clinical study [1] was coded into numerical values. Metric data was grouped using Gaussian mixture models; the number of groups was chosen using Bayesian information content. The pair-wise correlation between all variables was computed using the ECC. Significance was estimated from 1000 iterations of a permutation test and a threshold of 0.01 was used to identify significantly correlated variables. RESULTS: The five dimensions of multidimensional fatigue inventory (MFI) were all highly correlated with each other. Seven Short Form (SF)-36 measures, four CFS case-defining symptoms and the Zung self-rating depression scale all correlated with all MFI dimensions. No physiological variables correlate with more than one MFI dimension. MFI, SF-36, CDC symptom inventory, the Zung self-rating depression scale and three Cambridge Neuropsychological Test Automated Battery (CANTAB) measures are highly correlated with CFS disease status. DISCUSSION: Correlations between the five dimensions of MFI are expected since they are measured from the same instrument. The relationship between MFI and Zung depression index has been previously reported. MFI, SF-36, and Centers for Disease Control and Prevention (CDC) symptom inventory are used to classify CFS; it is not surprising that they are correlated with disease status. Only one of the three CANTAB measures that correlate with disease status has been previously found, indicating the ECC identifies relationships not found with other statistical tools. CONCLUSION: The ECC is a useful tool for measuring statistical dependence between variables in clinical and laboratory datasets. The ECC needs to be further studied to gain a better understanding of its meaning for clinical data.

Adult↗

Spouses of Persian Gulf War I veterans: medical evaluation of a U.S. cohort.

Ten years after the 1991 Persian Gulf War (GW I), a comprehensive evaluation of a national cohort of deployed veterans (DV) demonstrated a higher prevalence of several medical conditions, in comparison to a similarly identified cohort of nondeployed veterans (NDV). The present study determined the prevalence of medical conditions among nonveteran spouses of these GW I DV and NDV. A cohort of 490 spouses of GW I DV and 537 spouses of GW I NDV underwent comprehensive face-to-face examinations. No significant differences in health were detected except that spouses of DV were less likely to have one or more of a group of six common skin conditions. We conclude that, 10 years after GW I, the general physical health of spouses of GW I DV is similar to that of spouses of NDV.

Adult↗

Gulf War veterans' health: medical evaluation of a U.S. cohort.

BACKGROUND: United States military personnel reported various symptoms after deployment to the Persian Gulf during the 1991 Gulf War. However, the symptoms' long-term prevalence and association with deployment remain controversial. OBJECTIVE: To assess and compare the prevalence of selected medical conditions in a national cohort of deployed and nondeployed Gulf War veterans who were evaluated by direct medical and teledermatologic examinations. DESIGN: A cross-sectional prevalence study performed 10 years after the 1991 Gulf War. SETTING: Veterans were examined at 1 of 16 Veterans Affairs medical centers. PARTICIPANTS: Deployed (n = 1061) and nondeployed (n = 1128) veterans of the 1991 Gulf War. MEASUREMENTS: Primary outcome measures included fibromyalgia, the chronic fatigue syndrome, dermatologic conditions, dyspepsia, physical health-related quality of life (Short Form-36 [SF-36]), hypertension, obstructive lung disease, arthralgias, and peripheral neuropathy. RESULTS: Of 12 conditions, only 4 conditions were more prevalent among deployed than nondeployed veterans: fibromyalgia (deployed, 2.0%; nondeployed, 1.2%; odds ratio, 2.32 [95% CI, 1.02 to 5.27]); the chronic fatigue syndrome (deployed, 1.6%; nondeployed 0.1%; odds ratio, 40.6 [CI, 10.2 to 161]); dermatologic conditions (deployed, 34.6%; nondeployed, 26.8%; odds ratio, 1.38 [CI, 1.06 to 1.80]), and dyspepsia (deployed, 9.1%; nondeployed, 6.0%; odds ratio, 1.87 [CI, 1.16 to 2.99]). The mean physical component summary score of the SF-36 for deployed and nondeployed veterans was 49.3 and 50.8, respectively. LIMITATIONS: Relatively low participation rates introduce potential participation bias, and deployment-related illnesses that resolved before the research examination could not, by design, be detected. CONCLUSIONS: Ten years after the Gulf War, the physical health of deployed and nondeployed veterans is similar. However, Gulf War deployment is associated with an increased risk for fibromyalgia, the chronic fatigue syndrome, skin conditions, dyspepsia, and a clinically insignificant decrease in the SF-36 physical component score.

Adult↗

Increases in a marker of immune system reconstitution are predated by decreases in 24-h urinary cortisol output and depressed mood during a 10-week stress management intervention in symptomatic HIV-infected men.

BACKGROUND: Stress management interventions reduce distress symptoms and hypothalamic-pituitary-adrenal (HPA) axis hormones such as cortisol, which has been related to a down-regulation of immune system components relevant to the human immunodeficiency virus (HIV) infection. We previously showed that HIV+ men assigned to a 10-week cognitive behavioral stress management (CBSM) intervention showed more CD4+CD45RA+CD29+ lymphocytes, an indicator of immune system reconstitution, at a 6- to 12-month follow-up compared with controls. Here, we tested whether reductions in urinary cortisol output and depressed mood during the 10-week CBSM intervention period mediated its effects on this immune system reconstitution marker at follow-up. METHODS: Twenty-five HIV-infected men randomized to either a 10-week CBSM intervention or a wait-list control provided 24-h urine samples and psychological responses pre- to postintervention, which were related to changes in immune status over a 6- to 12-month follow-up period. RESULTS: Greater reductions in cortisol output and depressed mood during CBSM appeared to mediate the effects of this intervention on this indicator of immune system reconstitution over the 6- to 12-month follow-up period. Changes in mood were maintained over the follow-up period, although these did not add explanatory information beyond the cortisol and mood changes that were observed during the 10-week intervention period. These findings were not explained by the changes in medications or health behaviors during follow-up. CONCLUSION: A time-limited CBSM intervention may affect the rate of immune system reconstitution in HIV-infected men by modifying the stress of symptomatic disease. This intervention may work by decreasing depressed mood and normalizing HPA axis functioning.

Adolescent↗

Development and implementation of a medication adherence training instrument for persons living with HIV: the MATI.

Recent advances in the medical management of HIV offer the potential for increased longevity, improved quality of life, and the treatment of HIV as a chronic, rather than terminal, illness. The advent of highly active antiretroviral therapy (HAART) has required the necessity of strict adherence to complex medication regimens. As a vital factor in the successful outcome of HAART therapy, adherence-focused treatment represents a teaching opportunity for practitioners involved in the care and management of persons who are HIV positive. Scores of articles have been published regarding nonadherence, and numerous strategies have been employed to encourage adherence. Despite these efforts, medication adherence continues to present problems for patients and health care providers. This article discusses prior and existing adherence interventions for people living with HIV and outlines the rationale related to the development of a structured protocol, the Medication Adherence Training Instrument (MATI), for the evaluation and enhancement of HIV medication adherence by health care providers. The key components to the MATI throughout all sessions are to provide information, enhance motivation, and assess current levels of adherence and HIV-related knowledge.

Adult↗

Cognitive behavioral stress management effects on mood, social support, and a marker of antiviral immunity are maintained up to 1 year in HIV-infected gay men.

Numerous herpesvirus infections are associated with clinically relevant outcomes as well as an accelerated HIV replication rate and subsequent disease progression. Stress management interventions may improve markers of cellular immune control over latent herpesvirus infections and these changes appear to be mediated by perceptions of increased social support availability. We examined the effects of a group-based cognitive behavioral stress management (CBSM) intervention on distress, dysphoria, perceived social support, and herpesvirus immunoglobulin G (IgG) antibody titers during the 6 to 12 months following the intervention. Of those who were initially randomized, 49 HIV-infected men were followed during the 6- to 12-month period after randomization to either a 10-week CBSM intervention (n = 31) or a modified wait-list control condition (n = 18). Measures of distress, dysphoria, social support, and blood samples for herpesvirus IgG titers were taken at baseline, immediately following CBSM and at 6- to 12-month follow-up. Men in CBSM displayed maintenance of previously observed intervention effects on dysphoria, reliable alliance support, and herpesvirus IgG antibody titers (i.e., Epstein-Barr virus capsid antigen; EBV-VCA). Intervention-related changes in EBV-VCA were unrelated to changes in lymphocyte subsets (i.e., CD4+, CD8+, and CD4+:CD8+) or changes in measures of dysphoria and social support during the investigation period. Data indicate that HIV-infected men participating in a CBSM intervention maintain better psychosocial status and immunologic control of latent EBV infection up to 1 year after its conclusion.

Adult↗

Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution.

BACKGROUND: Chronic fatigue syndrome (CFS) is defined by symptoms and disability, has no confirmatory physical signs or characteristic laboratory abnormalities, and the etiology and pathophysiology remain unknown. Difficulties with accurate case ascertainment contribute to this ignorance. METHODS: Experienced investigators from around the world who are involved in CFS research met for a series of three day workshops in 2000, 2001 and 2002 intended to identify the problems in application of the current CFS case definition. The investigators were divided into focus groups and each group was charged with a topic. The investigators in each focus group relied on their own clinical and scientific knowledge, brainstorming within each group and with all investigators when focus group summaries were presented. Relevant literature was selected and reviewed independent of the workshops. The relevant literature was circulated via list-serves and resolved as being relevant by group consensus. Focus group reports were analyzed and compiled into the recommendations presented here. RESULTS: Ambiguities in the current CFS research definition that contribute to inconsistent case identification were identified. Recommendations for use of the definition, standardization of classification instruments and study design issues are presented that are intended to improve the precision of case ascertainment. The International CFS Study Group also identified ambiguities associated with exclusionary and comorbid conditions and reviewed the standardized, internationally applicable instruments used to measure symptoms, fatigue intensity and associated disability. CONCLUSION: This paper provides an approach to guide systematic, and hopefully reproducible, application of the current case definition, so that case ascertainment would be more uniform across sites. Ultimately, an operational CFS case definition will need to be based on empirical studies designed to delineate the possibly distinct biological pathways that result in chronic fatigue.

Cognition↗

Stress as a predictor of symptomatic genital herpes virus recurrence in women with human immunodeficiency virus.

OBJECTIVE: Genital herpes (Herpes Simplex Virus Type 2, HSV-2) is a significant public health problem for HIV+ women, who have high rates of HSV-2 seropositivity and elevated risk for HSV-2 associated morbidity and mortality. Life stress has been identified as a co-factor in genital herpes recurrence. However, no research has evaluated the relationship between stress and genital herpes recurrences in HIV+ women. The purpose of this study was to determine whether stress was associated with symptomatic genital herpes recurrences in women seropositive for HIV and HSV-2. METHODS: Thirty-four HIV-infected African-American and Caribbean-American women underwent a psychosocial interview, blood draw and gynecologic examination to assess gynecologic symptoms (including genital herpes) at study entry. Life stress was measured using a 10-item modified version of the Life Experiences Survey (LES). Genital herpes recurrence over 1-year follow-up was abstracted using medical chart review. RESULTS: Using hierarchical linear regression analysis, life stress at study entry was significantly associated with number of genital herpes recurrences during 1-year follow-up (beta=.38, P=.03) after controlling for HIV disease variables and relevant behavioral factors. Recent life stress, in particular, was highly predictive of genital herpes recurrence during follow-up (beta=.57, P=.002). The relationship between life stress and genital herpes recurrence persisted after controlling for HSV-2 viral reactivation (i.e., HSV-2 IgG titers) at study entry. CONCLUSION: These findings suggest that stress may be a significant predictor of genital herpes recurrence in women with HIV and HSV-2. Stress management interventions may buffer HSV-related morbidity and mortality in women with HIV.

Adolescent↗

Sleep disturbance mediates the association between psychological distress and immune status among HIV-positive men and women on combination antiretroviral therapy.

OBJECTIVES: This study examined the relationship between psychological distress, subjective sleep disturbance and immune status among HIV-positive men and women. METHODS: Fifty-seven participants (41 men, 16 women) without AIDS-related illness and currently on combination antiretroviral therapy were recruited through community advertisement and physician referral. Participants completed the Impact of Events Scale (IES) to assess symptoms of psychological distress and the Pittsburgh Sleep Quality Index (PSQI) to assess quality of sleep over the past month. T-lymphocyte subpopulations were also assessed from early morning blood samples. RESULTS: Participants reporting greater psychological distress also reported more pronounced sleep disruption. Higher levels of distress and greater sleep disturbance were also significantly related to lower T-cytotoxic/suppressor (CD3+CD8+) cell counts. Path analysis revealed that the association between distress level and CD3+CD8+ cell counts was mediated by poorer subjective sleep quality. CONCLUSIONS: These findings suggest that psychological distress may impact upon the immune system through its effects on sleep quality.

Adult↗

Stress management and immune system reconstitution in symptomatic HIV-infected gay men over time: effects on transitional naive T cells (CD4(+)CD45RA(+)CD29(+)).

OBJECTIVE: Changes in immunologic status were evaluated in 25 HIV-infected men randomly assigned to a 10-week stress management intervention or a wait-list control condition. METHOD: The authors monitored changes in number of transitional naive T cells (CD4(+)CD45RA(+)CD29(+)) over 6-12 months after the completion of the intervention. RESULTS: Men receiving stress management had higher CD4(+) CD45RA(+)CD29(+) cell counts at follow-up than did the control subjects. This difference was independent of initial number of naive T cells and HIV virus load. CONCLUSIONS: Stress management is associated with immunologic reconstitution in HIV-positive gay men.

Adolescent↗

Chronic fatigue syndrome: probable pathogenesis and possible treatments.

Chronic fatigue syndrome (CFS) belongs in the medically unexplained illnesses. It affects approximately 0.2-0.7% of the population in Western countries. It is characterised by unexplained fatigue, lasting 6 months or more, impairment of neurocognitive functions and quality of sleep, and of somatic symptoms, such as recurrent sore throat, muscle aches, arthralgias, headache and postexertional malaise. No link between infections and CFS has been clearly established but the immune system is activated, there are aberrations in several hypothalamic-pituitary axes and involvement of other parts of the central nervous system. No specific treatment has been found. Cognitive behavioural therapy is established to be of value to improve quality of life. More effective treatment should result, as advances in biomedical as well as psychological research continue.

Adjuvants, Immunologic↗

Life stress and cervical squamous intraepithelial lesions in women with human papillomavirus and human immunodeficiency virus.

OBJECTIVE: Human immunodeficiency virus (HIV)-infected women are at risk for cervical intraepithelial neoplasia (CIN) and cancer due to impaired immunosurveillance over human papillomavirus (HPV) infection. Life stress has been implicated in immune decrements in HIV-infected individuals and therefore may contribute to CIN progression over time. The purpose of this study was to determine whether life stress was associated with progression and/or persistence of squamous intraepithelial lesions (SIL), the cytologic diagnosis conferred by Papanicolaou smear, after 1-year follow-up among women co-infected with HIV and HPV. METHOD: Thirty-two HIV-infected African-American and Caribbean-American women underwent a psychosocial interview, blood draw, colposcopy, and HPV cervical swab at study entry. Using medical chart review, we then abstracted SIL diagnoses at study entry and after 1-year follow-up. RESULTS: Hierarchical logistic regression analysis revealed that higher life stress increased the odds of developing progressive/persistent SIL over 1 year by approximately seven-fold after covarying relevant biological and behavioral control variables. CONCLUSIONS: These findings suggest that life stress may constitute an independent risk factor for SIL progression and/or persistence in HIV-infected women. Stress management interventions may decrease risk for SIL progression/persistence in women living with HIV.

Black or African American↗

Psychosocial factors predict CD4 and viral load change in men and women with human immunodeficiency virus in the era of highly active antiretroviral treatment.

OBJECTIVE: Most previous longitudinal studies demonstrating relationships between psychosocial variables and human immunodeficiency virus (HIV) disease progression utilized samples of gay men accrued before the era of highly active antiretroviral treatment (HAART), without including viral load (VL) as an indicator of disease progression or assessing the impact of medication adherence. This study sought to determine whether psychosocial variables would predict both CD4 and VL changes in a diverse sample assessed entirely during the era of HAART and accounting for adherence effects. METHODS: This longitudinal study assessed a multiethnic HIV+ sample (n = 177) of men and women in the midrange of illness (CD4 number between 150 and 500; no previous acquired immunodeficiency syndrome [AIDS]-defining symptom) every 6 months for 2 years. Hierarchical linear modeling was used to model change in CD4 and VL controlling for sociodemographics (age, gender, ethnicity, education) and medical variables (baseline CD4/VL, antiretroviral medications at each time point, adherence). RESULTS: Baseline depression, hopelessness, and education predicted the slope of CD4 and VL. Avoidant coping and life event stress predicted VL change. Cumulative variables produced stronger relationships (depression, avoidant coping, and hopelessness with CD4/VL slope and life events stress with VL slope). High cumulative depression and avoidant coping were associated with approximately twice the rate of decline in CD4 as low scorers and greater relative increases in VL. Social support was not significantly related to CD4 or VL slope. CONCLUSIONS: Psychosocial factors contribute significantly to the variance in HIV disease progression (assessed through CD4 number and VL) in a diverse sample, accounting for adherence and do so in the era of HAART.

Adaptation, Psychological↗

Randomized clinical trial of cognitive behavioral stress management on human immunodeficiency virus viral load in gay men treated with highly active antiretroviral therapy.

OBJECTIVE: Human Immunodeficiency Virus (HIV)-positive individuals treated with highly active antiretroviral therapy (HAART) may experience psychological burdens and negative mood states, which could impair their ability to derive maximum benefits from their medical treatment. We tested whether a cognitive behavioral stress management (CBSM) intervention in combination with antiretroviral medication adherence training (MAT) from a clinical pharmacist influences HIV viral load more than MAT alone. METHODS: HIV-positive men who have sex with men were randomized to either a 10-week CBSM + MAT intervention (n = 76) or a MAT-Only condition (n = 54). Data were collected at baseline immediately following the 10-week intervention period, at 9 months postrandomization, and at 15 months postrandomization. RESULTS: We found no differences in HIV viral load among the 130 men randomized. However, in the 101 men with detectable viral load at baseline, those randomized to CBSM + MAT (n = 61) displayed reductions of 0.56 log10 units in HIV viral load over a 15-month period after controlling for medication adherence. Men in the MAT-Only condition (n = 40) showed no change. Decreases in depressed mood during the intervention period explained the effect of CBSM + MAT on HIV viral load reduction over the 15 months. CONCLUSIONS: A time-limited CBSM + MAT intervention that modulates depressed mood may enhance the effects of HAART on suppression of HIV viral load in HIV+ men with detectable plasma levels.

Anti-HIV Agents↗