[Show abstract][Hide abstract] ABSTRACT: Introduction
Switch to Stribild (STB) was non-inferior to continuation of a non-nucleoside reverse transcriptase inhibitor (NNRTI) with emtricitabine and tenofovir DF (FTC/TDF) at week 48 in virologically suppressed HIV adults . We report the Week 48 efficacy and safety of STB versus nevirapine (NVP) or rilpivirine (RPV) with FTC/TDF in suppressed subjects.
Materials and Methods
Virologically suppressed subjects on an NNRTI with FTC/TDF regimens for ≥6 months were randomized (2:1) to switch to STB versus continue their NNRTI regimen. Eligibility criteria included no documented resistance to FTC and TDF, no history of virologic failure and eGFR ≥70 mL/min. The primary endpoint was the proportion of subjects in the modified ITT population who maintained HIV-1 RNA <50 copies(c)/mL at Week 48 by FDA snapshot algorithm (12% non-inferiority margin). Subgroup analysis by non-EFV NNRTI use (NVP ; RPV ; etravirine ) at screening was pre-specified.
The mITT population included 433 subjects who were randomized and treated. In the non-EFV NNRTI subgroup, 59 switched to STB; 37 continued a non-EFV NNRTI (27 NVP, 10 RPV) with FTC/TDF. At week 48, 97% STB versus 95% non-EFV NNRTI maintained HIV-1 RNA <50 c/mL. No emergent resistance was detected in either group. No difference in median increases from baseline in CD4 count at week 48 (cells/µL): 25 STB versus 55 non-EFV NNRTI (p=0.78). No discontinuation due to adverse events; no cases of proximal renal tubulopathy. As expected, there were no significant changes in the frequency of neuropsychiatric symptoms (i.e. anxiety, insomnia, dizziness, vivid dreams, weird/intense dreams, and nightmares) reported on the HIV Symptom Index at week 48 compared to baseline after switching to STB. There was a greater but non-progressive decrease from baseline in eGFR in the STB versus non-EFV NNRTI group; median changes (mL/min) at week 48: −9.1 versus −1.4. Switch to STB was associated with a higher treatment ease (convenience, flexibility, demand, lifestyle, understanding) score (range: −15 to 15) at week 4 (median: 14 vs 11; p=0.047) and week 24 (median: 14 vs 12.5; p=0.038).
In this small group of virologically suppressed subjects, switch to STB vs continuation of NVP or RPV with FTC/TDF was safe, well-tolerated, and associated with a high rate of virologic suppression at week 48. There was more treatment ease with STB use.
Journal of the International AIDS Society 11/2014; 17(4(Suppl 3)):19793. DOI:10.7448/IAS.17.4.19793 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the efficacy and safety of antiretroviral simplification from a ritonavir-boosted protease inhibitor-based regimen [protease inhibitor+RTV+two nucleos(t)ide reverse transcriptase inhibitors (NRTIs); ≥6 months of exposure prior to study entry with no prior treatment failure] to the single-tablet regimen (STR) rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) in virologically suppressed, HIV-1-infected participants.
Phase 3b, randomized, open-label, international, 48-week switch study.
Participants were randomized 2 : 1 to switch to RPV/FTC/TDF immediately or stay on their baseline protease inhibitor+RTV+2NRTIs regimen with a delayed switch to RPV/FTC/TDF at week 24. The primary endpoint was noninferiority (12% margin) of RPV/FTC/TDF compared with protease inhibitor+RTV+ two NRTIs in maintaining plasma HIV-1 RNA less than 50 copies/ml at week 24 by Snapshot analysis.
A total of 476 participants were randomized and received at least one dose of study drug. Demographics and baseline characteristics were similar between arms. The primary objective of noninferiority at week 24 was met: HIV-1 RNA less than 50 copies/ml by Snapshot analysis, 93.7% of RPV/FTC/TDF versus 89.9% of protease inhibitor+RTV+ two NRTIs (difference 3.8%, 95% confidence interval -1.6 to 9.1%). Through week 48, 89.3% of participants in the immediate switch group maintained virologic suppression. High rates of suppression were maintained with RPV/FTC/TDF regardless of participant's pre-antiretroviral HIV-1 RNA level. Overall development of resistance mutations after switching to RPV/FTC/TDF was low. Decreases in total cholesterol, low-density lipoprotein (LDL), and triglycerides were significantly greater among RPV/FTC/TDF recipients than those in the protease inhibitor+RTV+ two NRTIs group.
Switching to the STR RPV/FTC/TDF from an RTV-boosted protease inhibitor regimen in virologically suppressed, HIV-1-infected participants maintained virologic suppression with a low risk of virologic failure, while improving total cholesterol, LDL, and triglycerides.
AIDS (London, England) 01/2014; 28(3):335-44. DOI:10.1097/QAD.0000000000000087 · 5.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Antiretroviral regimen simplification improves quality of life and medication adherence while reducing the risk of HIV virologic failure and long-term drug-related toxicities. Rilpivirine/Emtricitabine/Tenofovir DF (RPV/FTC/TDF) is a well-tolerated, efficacious once daily single-tablet regimen (STR) treatment option.
SPIRIT is a phase 3b, open-label, 48-week study to evaluate the safety and efficacy of simplifying from PI+RTV+2NRTI to RPV/FTC/TDF in virologically-suppressed HIV-1 infected subjects, who were randomized 2:1 to switch to RPV/FTC/TDF at baseline (n=317) or maintain their current PI+RTV+2NRTI regimen until a delayed switch to RPV/FTC/TDF at Week (W) 24 (n=159). The primary endpoint was non-inferiority (12% margin) of RPV/FTC/TDF to PI+RTV+2NRTI in maintaining plasma HIV-1 RNA <50 c/mL (virologic suppression; VS) at W24 by FDA snapshot analysis
The primary endpoint of non-inferiority at W24 was met (VS 93.7% RPV/FTC/TDF vs 89.9% PI+RTV+2NRTI; difference 3.8%, 95% CI [-1.6 to 9.1]). Through W48, 89.3% of subjects simplifying to RPV/FTC/TDF at baseline and 92.1% of subjects who simplified at W24 maintained VS. Changes in fasting lipids and NCEP categories are in the table.
Mean Change from Baseline
% of Patients in National Cholesterol Educational Program (NCEP) Target Categories
W24 – W48
W24 – W48
Through W48, VS was maintained regardless of whether subjects simplified to RPV/FTC/TDF at baseline or W24. Simplifying to RPV/FTC/TDF also led to significant improvement in fasting total cholesterol, LDL, and triglycerides, including significant changes in those NCEP categories.
IDWeek 2013 Meeting of the Infectious Diseases Society of America; 10/2013
[Show abstract][Hide abstract] ABSTRACT: Background
Women and men have diverse responses to many infectious diseases. These differences are amplified following menopause. However, despite extensive information regarding the effects of sex hormones on immune cells, our knowledge is limited regarding the effects of sex and gender on the function of the mucosal immune system. Sex differences also manifest in the prevalence of gut associated inflammatory and autoimmune disorders, including Crohn’s disease, ulcerative colitis and Celiac disease. It is thus hypothesized that a baseline sex-associated difference in immune activation may predispose women to inflammation-associated disease.
Peripheral blood samples and small intestinal biopsies were obtained from 34 healthy men and women. Immunophenotypic analysis of isolated lymphocytes was performed by flow cytometry. Oligonucleotide analysis was used to study the transcriptional profile in the gut mucosal microenvironment while real-time PCR analysis was utilized to identify differential gene expression in isolated CD4+ T cells. Transcriptional analysis was confirmed by protein expression levels for genes of interest using fluorescent immunohistochemistry. Data was analyzed using the GraphPad software package.
Women had higher levels of immune activation and inflammation-associated gene expression in gut mucosal samples. CD4+ and CD8+ T cells had a significantly higher level of immune activation-associated phenotype in peripheral blood as well as in gut associated lymphoid tissue along with higher levels of proliferating T cells. CD4+ T cells that showed upregulation of IL1β as well as the TH17 pathway-associated genes contributed a large part of the inflammatory profile.
In this study, we demonstrated an upregulation in gene expression related to immune function in the gut microenvironment of women compared to men, in the absence of disease or pathology. Upon closer investigation, CD4+ T cell activation levels were higher in the LPLs in women than in men. Sex differences in the mucosal immune system may predispose women to inflammation-associated diseases that are exacerbated following menopause. Our study highlights the need for more detailed analysis of the effects of sex differences in immune responses at mucosal effector sites.
Biology of Sex Differences 05/2013; 4(1):10. DOI:10.1186/2042-6410-4-10 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antiretroviral regimen simplification improves quality of life and medication adherence while reducing the risk of HIV virologic failure (VF) and long-term drug-related toxicities. Emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) is a well-tolerated and efficacious once-daily single-tablet regimen (STR) treatment option. Here we report the Week 48 safety and efficacy results of SPIRIT, the first study to evaluate switching from boosted protease inhibitor (PI+RTV)-based HAART to a simplified regimen of FTC/RPV/TDF STR. SPIRIT is a phase 3b, randomized, open-label, multi-center, international, 48-week study to evaluate the safety and efficacy of switching from PI+RTV regimens to FTC/RPV/TDF in virologically-suppressed HIV-1 infected participants. Participants were randomized 2:1 to switch to FTC/RPV/TDF at baseline or maintain their current PI+RTV regimen with a delayed switch to FTC/RPV/TDF at Week 24. The primary endpoint was non-inferiority (12% margin) of FTC/RPV/TDF relative to PI+RTV regimens in maintaining plasma HIV-1 RNA<50 copies/mL at Week 24 by FDA snapshot analysis. Plasma HIV-1 RNA levels were assessed at screening, baseline, and at Weeks 4, 8, 12, 24, (28 and 32 for delayed switch participants), 36, and 48 or early termination. A total of 476 participants were randomized and received at least 1 dose of study drug (317 FTC/RPV/TDF; 159 PI+RTV+2NRTIs). Baseline characteristics were similar across treatment arms. The primary endpoint of non-inferiority at Week 24 was met (HIV-1 RNA <50 copies/mL by FDA snapshot analysis 93.7% FTC/RPV/TDF vs. 89.9% PI+RTV+2NRTIs; difference 3.8%, 95% CI: -1.6 to 9.1]). Through Week 48, 88.3% of subjects switching to FTC/RPV/TDF at baseline maintained virologic suppression (HIV-1 RNA<50 copies/mL by FDA snapshot analysis). The rate of virologic suppression at Week 48 for the 152 participants who switched to FTC/RPV/TDF at Week 24 was comparable to the rate of virologic suppression at Week 24 for those who switched to FTC/RPV/TDF at baseline (delayed switch to FTC/RPV/TDF 92.1%; baseline switch to FTC/RPV/TDF 93.7%). In the Week 48 analysis of SPIRIT, the first study to evaluate switching to FTC/RPV/TDF STR from a PI+RTV-based regimen in virologically-suppressed, HIV-1-infected participants, virologic suppression was maintained regardless of whether participants switched to FTC/RPV/TDF at baseline or at Week 24.
Journal of the International AIDS Society 11/2012; 15(6):18275. DOI:10.7448/IAS.15.6.18275 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ARTEMIS demonstrated significantly greater efficacy of once-daily darunavir/ritonavir (DRV/r) 800/100 mg versus lopinavir/ritonavir 800/200 mg (total daily dose) in treatment-naïve, HIV-1-infected patients at week 96. The influence of baseline characteristics on efficacy and safety was analyzed in DRV/r patients.
Patients received once-daily DRV/r plus fixed-dose tenofovir/emtricitabine. Week 96 efficacy and safety data were analyzed by gender (males, n=239; females, n=104), age (≤30, n=115; 31-45, n=175; >45, n=53), race (Asian, n=44; Black, n=80; Caucasian/White, n=137; Hispanic, n=77), and hepatitis B and/or C virus coinfection (n=43).
Week 96 virologic response rates (HIV-1 RNA<50 copies/mL) were as follows: gender: 79% for both males and females; age: 72% (≤30), 81% (31-45), and 89% (>45); race: 96% (Asian), 71% (Black), 77% (Caucasian/White), and 79% (Hispanic); coinfection status: 72% (coinfected) and 80% (non-coinfected). The incidence of treatment-related adverse drug reactions (ADRs) and laboratory abnormalities were comparable across gender, age, and race subgroups. Coinfected patients had a higher incidence of liver-related ADRs than non-coinfected patients.
DRV/r 800/100 mg qd is an effective, well-tolerated treatment option for treatment-naïve patients of different gender, age, race, or coinfection status.
HIV Clinical Trials 11/2011; 12(6):313-22. DOI:10.1310/hct1206-313 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interruption of suppressive highly active antiretroviral therapy (HAART) in HIV-infected patients leads to increased HIV replication and viral rebound in peripheral blood. Effects of therapy interruption on gut-associated lymphoid tissue (GALT) have not been well investigated. We evaluated longitudinal changes in viral replication and emergence of viral variants in the context of T cell homeostasis and gene expression in GALT of three HIV-positive patients who initiated HAART during primary HIV infection but opted to interrupt therapy thereafter. Longitudinal viral sequence analysis revealed that a stable proviral reservoir was established in GALT during primary HIV infection that persisted through early HAART and post-therapy interruption. Proviral variants in GALT and peripheral blood mononuclear cells (PBMCs) displayed low levels of genomic diversity at all times. A rapid increase in viral loads with a modest decline of CD4(+) T cells in peripheral blood was observed, while gut mucosal CD4(+) T cell loss was severe following HAART interruption. This was accompanied by increased mucosal gene expression regulating interferon (IFN)-mediated antiviral responses and immune activation, a profile similar to those found in HAART-naive HIV-infected patients. Sequence analysis of rebound virus suggested that GALT was not the major contributor to the postinterruption plasma viremia nor were GALT HIV reservoirs rapidly replaced by HIV rebound variants. Our data suggest an early establishment and persistence of viral reservoirs in GALT with minimal diversity. Early detection of and therapy for HIV infection may be beneficial in controlling viral evolution and limiting establishment of diverse viral reservoirs in the mucosal compartment.
Journal of Virology 02/2011; 85(10):4772-82. DOI:10.1128/JVI.02409-10 · 4.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human immunodeficiency virus (HIV) infection leads to severe CD4+ T-cell depletion in gut-associated lymphoid tissue (GALT) that persists despite the initiation of highly active antiretroviral therapy (HAART). It is not known whether restoration of gut mucosal CD4+ T cells and their functions is feasible during therapy and how that relates to immune correlates and viral reservoirs. Intestinal biopsies and peripheral blood samples from HIV-infected patients who were either HAART naive or on long-term HAART were evaluated. Our data demonstrated that gut CD4+ T-cell restoration ranged from modest (<50%) to high (>50%), compared with uninfected controls. Despite persistent CD4+ T-cell proviral burden and residual immune activation in GALT during HAART, effective CD4+ T-cell restoration (>50%) was achieved, which was associated with enhanced Th17 CD4+ T-cell accumulation and polyfunctional anti-HIV cellular responses. Our findings suggest that a threshold of>50% CD4+ T-cell restoration may be sufficient for polyfunctional HIV-specific T cells with implications in the evaluation of vaccines and therapeutics.
[Show abstract][Hide abstract] ABSTRACT: Gut-associated lymphoid tissue (GALT) is an early target for human immunodeficiency virus type 1 (HIV-1) infection and is
a site for severe CD4+ T-cell depletion. HIV-associated enteropathy is well-documented in chronic HIV-1 infection. However, the initial host responses
to HIV infection in GALT and the early molecular correlates of HIV enteropathogenesis have not been characterized during primary
HIV infection. In this study, we provide evidence of viral replication in GALT resident CD4+ T cells and macrophages in primary-stage patients and identify early patterns of host mucosal responses and changes in the
molecular microenvironment through gene expression profiling. High levels of viral replication in GALT and marked CD4+ T-cell depletion correlated with decreased expression levels of genes regulating epithelial barrier maintenance and digestive/metabolic
functions. These changes coincided with a marked increase in the transcription of immune activation-, inflammation-, and apoptosis-associated
genes. Our findings indicate that HIV-induced pathogenesis in GALT emerges at both the molecular and cellular levels prior
to seroconversion in primary HIV infection, potentially setting the stage for disease progression by impairing the ability
to control viral replication and repair and regenerate intestinal mucosal tissues.
Journal of Virology 02/2008; 82(1):538-45. DOI:10.1128/JVI.01449-07 · 4.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Matched patients who test positive or negative for human immunodeficiency virus (HIV) who are undergoing comparable operations have similar complication rates and outcomes.
A retrospective study of surgical outcomes in HIV-infected and matched HIV-noninfected patients. Baseline information including HIV-related laboratory results, complications, and mortality was collected from printed and electronic records through 12 postoperative months.
Kaiser Permanente Medical Care Program-Northern California, an integrated health organization with more than 3 million members, including more than 5000 HIV-infected members.
From July 1,1997, through June 30, 2002, HIV-infected members undergoing surgical procedures were matched 1:1 with HIV-noninfected patients undergoing surgical procedures by type, location, and year of surgery as well as by sex and age. Surgical procedures studied included appendectomy, arthrotomy or arthroscopy, bowel resection, cholecystectomy, cardiothoracic procedures, hernia repair, hysterectomy, hip or knee replacement, laparoscopy or laparotomy, and mammoplasty.
Complications and mortality through 12 postoperative months, comparisons between HIV-infected and HIV-noninfected patients using matched-pair analyses, and HIV-infected cohort data were analyzed using the Fisher exact test and logistic regression.
Of 332 HIV-infected-HIV-noninfected pairs (mean age, 46.7 years; male sex, 91%), more than 95.0% were followed up through 12 postoperative months or until their deaths. Pairs had similar comorbidities, length of hospital stay, and number of postoperative surgical visits (P>.05, all variables). Among HIV-infected patients, the median years with HIV infection was 8.4 years; median CD4 T-cell count was 379/microL; 61.5% of these patients had an HIV RNA level less than 500 copies per milliliter; and 68% were receiving highly active antiretroviral therapy. Various complications were no more frequent among HIV-infected than in HIV-noninfected patients (11.1% vs 10.2%; P = .79), except for pneumonia (P = .04). There were more deaths within the 12 postoperative months in HIV-infected patients (10/332 vs 2/332; P = .02); 2 patients died 30 days or less after being operated on. Among HIV-infected patients, viral load of 30 000 copies per milliliter or more was associated with increased complications (adjusted odds ratio, 2.95; P = .007), but a CD4 cell count less than 200/muL was not associated with poorer outcomes.
The HIV-infected patients had more incidences of postoperative pneumonia and higher 12-month mortality, although other operative outcomes were comparable for HIV-infected and HIV-noninfected patients. Viral suppression to fewer than 30 000 copies per milliliter reduced surgical complications.
Archives of Surgery 12/2006; 141(12):1238-45. DOI:10.1001/archsurg.141.12.1238 · 4.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: HIV-1 genotypic resistance test results were obtained on clinical samples from 116 patients with plasma HIV-1 RNA levels of less than 75 copies/mL. Genotype validity was confirmed in 49 of 50 patients with a previous or follow-up genotype. The belief that genotypic resistance testing is unreliable in samples with low-level viremia should be reassessed.
[Show abstract][Hide abstract] ABSTRACT: Although the gut-associated lymphoid tissue (GALT) is an important early site for human immunodeficiency virus (HIV) replication
and severe CD4+ T-cell depletion, our understanding is limited about the restoration of the gut mucosal immune system during highly active
antiretroviral therapy (HAART). We evaluated the kinetics of viral suppression, CD4+ T-cell restoration, gene expression, and HIV-specific CD8+ T-cell responses in longitudinal gastrointestinal biopsy and peripheral blood samples from patients initiating HAART during
primary HIV infection (PHI) or chronic HIV infection (CHI) using flow cytometry, real-time PCR, and DNA microarray analysis.
Viral suppression was more effective in GALT of PHI patients than CHI patients during HAART. Mucosal CD4+ T-cell restoration was delayed compared to peripheral blood and independent of the time of HAART initiation. Immunophenotypic
analysis showed that repopulating mucosal CD4+ T cells were predominantly of a memory phenotype and expressed CD11α, αEβ7, CCR5, and CXCR4. Incomplete suppression of viral replication in GALT during HAART correlated with increased HIV-specific
CD8+ T-cell responses. DNA microarray analysis revealed that genes involved in inflammation and cell activation were up regulated
in patients who did not replenish mucosal CD4+ T cells efficiently, while expression of genes involved in growth and repair was increased in patients with efficient mucosal
CD4+ T-cell restoration. Our findings suggest that the discordance in CD4+ T-cell restoration between GALT and peripheral blood during therapy can be attributed to the incomplete viral suppression
and increased immune activation and inflammation that may prevent restoration of CD4+ T cells and the gut microenvironment.
Journal of Virology 09/2006; 80(16):8236-47. DOI:10.1128/JVI.00120-06 · 4.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study examined social support and maladaptive coping as predictors of HIV-related health symptoms. Sixty-five men and women living with HIV/AIDS completed baseline measures assessing coping strategies, social support, and HIV-related health symptoms. The sample was primarily low-income and diverse with respect to gender, ethnicity, and sexual orientation. Three, 6, and 12 months after completing baseline assessments, physical health symptoms associated with HIV disease were assessed. After controlling for demographic characteristics, CD4 T-cell count, and baseline HIV-related health symptoms, individuals reporting lower increase in HIV-related health symptoms used less venting (expressing emotional distress) as a strategy for coping with HIV. However, when satisfaction with social support was added to the model, the use of this coping strategy was no longer significant, and individuals reporting more satisfying social support were more likely to report lower increase in their HIV-related health symptoms, suggesting that social support is a robust predictor of health outcomes over time independent of coping style and baseline medical status. These findings provide further evidence that social support can buffer deleterious health outcomes among individuals with a chronic illness. Future research needs to examine mediating pathways that can explain this relationship.
AIDS PATIENT CARE and STDs 10/2005; 19(9):587-98. DOI:10.1089/apc.2005.19.587 · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. It is important, for drug-resistance surveillance, to identify human immunodeficiency virus type 1 (HIV-1) strains that have undergone antiretroviral drug selection.Methods. We compared the prevalence of protease and reverse-transcriptase (RT) mutations in HIV-1 sequences from persons with and without previous treatment with protease inhibitors (PIs), nucleoside RT inhibitors (NRTIs), and nonnucleoside RT inhibitors (NNRTIs). Treatment-associated mutations in protease isolates from 5867 persons and RT isolates from 6247 persons were categorized by whether they were polymorphic (prevalence, >0.5%) in untreated individuals and whether they were established drug-resistance mutations. New methods were introduced to minimize misclassification from transmitted resistance, population stratification, sequencing artifacts, and multiple hypothesis testing.Results. Some 36 established and 24 additional nonpolymorphic protease mutations at 34 positions were related to PI treatment, 21 established and 22 additional nonpolymorphic RT mutations at 24 positions with NRTI treatment, and 15 established and 11 additional nonpolymorphic RT mutations at 15 positions with NNRTI treatment. In addition, 11 PI-associated and 1 NRTI-associated established mutations were polymorphic in viruses from untreated persons.Conclusions. Established drug-resistance mutations encompass only a subset of treatment-associated mutations; some of these are polymorphic in untreated persons. In contrast, nonpolymorphic treatment-associated mutations may be more sensitive and specific markers of transmitted HIV-1 drug resistance.
The Journal of Infectious Diseases 08/2005; 192(3):456-65. DOI:10.1086/431601 · 6.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Limited information is available on the molecular mechanisms by which long-term HIV-1-infected nonprogressors suppress HIV-1 infection and maintain immune functions. The intestinal mucosal immune system is an early target for HIV-1 infection and severe CD4+ T cell depletion. We evaluated mucosal T lymphocyte subsets, virus-specific cellular responses, gene expression profiles, and viral loads in intestinal mucosal biopsies of long-term nonprogressor (LTNP) patients as compared to chronically HIV-1-infected patients with high viral loads (HVLs) and CD4+ T cell loss, as well as HIV-seronegative healthy individuals. This study aims to identify the mucosal correlates of HIV disease progression and to determine the molecular changes associated with immune and intestinal dysfunction. LTNP patients had undetectable viral loads, normal CD4+ T cell levels, and virus-specific cellular responses in peripheral blood and mucosal compartments. Microarray analysis revealed a significant increase in gene expression regulating immune activation, cell trafficking, and inflammatory response in intestinal mucosa of HVL patients as compared to LTNP patients. Genes associated with cell cycle regulation, lipid metabolism, and epithelial cell barrier and digestive functions were down-regulated in both HVL and LTNP patients. This may adversely influence nutrient adsorption and digestive functions, with the potential to impact the efficacy of antiretroviral therapy. We demonstrate that the maintenance of mucosal T cells, virus-specific responses, and distinct gene expression profiles correlate with clinical outcome in LTNP patients. However, the intestinal mucosal immune system remains an important target of HIV-1 infection in LTNP, and these effects may ultimately contribute toward disease progression.
Proceedings of the National Academy of Sciences 08/2005; 102(28):9860-5. DOI:10.1073/pnas.0503463102 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This randomized pilot study evaluates whether seropositive patients who are randomly assigned to receive a supportive-expressive group therapy plus education intervention show greater improvements in increased immune function and decreased viral load compared to those randomly assigned to an education-only intervention.
Fifty-nine individuals who had been HIV-seropositive for at least 6 months prior to inclusion in the study and had been receiving standard pharmacologic treatment were entered in a prospective randomized trial of the effects of weekly supportive-expressive group therapy on changes in immune status. Participants were matched for AIDS status and sex and randomized to receive weekly sessions of group psychotherapy plus educational materials on HIV/AIDS, or to receive the educational materials alone. Participants were assessed before treatment and then 12 weeks later.
Individuals who were randomized to group therapy showed a statistically significant increase in CD4 count and decrease in HIV viral load. Among individuals randomized to the education only condition, no significant change occurred in CD4 count or viral load.
These results provide preliminary data suggesting that HIV-seropositive individuals who receive supportive-expressive group psychotherapy may experience concomitant improvements in CD4 cell count and viral load. Further research with a larger sample should examine the possible underlying mechanisms of such benefits.
The International Journal of Psychiatry in Medicine 02/2005; 35(4):349-62. DOI:10.2190/4N6W-BUYY-CFNE-67XH · 0.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gut-associated lymphoid tissue (GALT) harbors the majority of T lymphocytes in the body and is an important target for human
immunodeficiency virus type 1 (HIV-1). We analyzed longitudinal jejunal biopsy samples from HIV-1-infected patients, during
both primary and chronic stages of HIV-1 infection, prior to and following the initiation of highly active antiretroviral
therapy (HAART) to determine the onset of CD4+ T-cell depletion and the effect of HAART on the restoration of CD4+ T cells in GALT. Severe depletion of intestinal CD4+ T cells occurred during primary HIV-1 infection. Our results showed that the restoration of intestinal CD4+ T cells following HAART in chronically HIV-1-infected patients was substantially delayed and incomplete. In contrast, initiation
of HAART during early stages of infection resulted in near-complete restoration of intestinal CD4+ T cells, despite the delay in comparison to peripheral blood CD4+ T-cell recovery. DNA microarray analysis of gene expression profiles and flow-cytometric analysis of lymphocyte homing and
cell proliferation markers demonstrated that cell trafficking to GALT and not local proliferation contributed to CD4+ T-cell restoration. Evaluation of jejunal biopsy samples from long-term HIV-1-infected nonprogressors showed maintenance
of normal CD4+ T-cell levels in both GALT and peripheral blood. Our results demonstrate that near-complete restoration of mucosal immune
system can be achieved by initiating HAART early in HIV-1 infection. Monitoring of the restoration and/or maintenance of CD4+ T cells in GALT provides a more accurate assessment of the efficacy of antiviral host immune responses as well as HAART.
Journal of Virology 12/2003; 77(21):11708-17. DOI:10.1128/JVI.77.21.11708-11717.2003 · 4.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Conclusions • The diverse population of treatment-naïve patients enrolled into ARTEMIS allowed for an exploration of potential gender, age and race effects on efficacy and safety outcomes. • Although some variability was observed, the efficacy (HIV-1 RNA <50 copies/mL) of DRV/r at Week 96 was generally similar across the subgroups (gender: 79%; age: 72–89%; race: 71–96%) and was comparable to the overall population (79%). • No clinically meaningful differences were observed when comparing ADRs and laboratory abnormalities, considered ADRs, with DRV/r 800/100mg qd across gender, age or race subgroups. • Most ADRs and laboratory abnormalities in all subgroups were mild-to-moderate in severity and were infrequently associated with treatment discontinuation. • These results at Week 96 support the findings previously reported at Week 48. 8 • Once-daily DRV/r (800/100mg) is an effective, well-tolerated treatment option for treatment-naïve patients.