Controlled HIV Replication Research Articles

Immune Correlates of Herpes Zoster in People Living with HIV on Effective Antiretroviral Therapy.

Herpes zoster (HZ) has high morbidity in people living with HIV (PLHIV). We investigated immunological factors that correlated with the development of HZ in PLHIV with controlled HIV replication on antiretroviral therapy (ART). PLHIV who developed HZ on ART (cases), with undetectable plasma HIV RNA, and CD4 counts ≥200 cells/μL were matched 1:1 to controls by CD4 count, age, gender, race, and duration of ART. Varicella-zoster virus (VZV)-specific T cells and circulating regulatory T cells (Treg) were measured by flow cytometry before and after HZ. Differences between cases and controls were assessed by paired t-tests and longitudinal changes by Wilcoxon signed rank test. HZ cases (N = 31) had higher CD4+FOXP3+CD25+% Treg before HZ compared with 31 controls. After VZV ex vivo restimulation, cases had lower T cell responses, including CD8+perforin+% cytotoxic T lymphocytes (CTLs), CD4+IL10+%, and CD4+TGFβ+% compared with controls. Overall, Treg negatively correlated with VZV-specific Th1 responses. Moreover, Treg decreased over time on ART in HZ cases, VZV-CTLs were stable and did not increase even after HZ. Increased circulating Treg and decreased VZV-specific T cell immune responses were associated with the risk of HZ in PLHIV. The kinetics of Treg over time, but not of VZV-CTLs, paralleled the natural history of HZ, whose incidence decreases over time on effective ART.

Modeling Pharmacodynamics on HIV Latent Infection: Choice of Drugs is Key to Successful Cure via Early Therapy

Highly active antiretroviral therapy has successfully controlled HIV replication in many patients. The treatment effectiveness may depend on the pharmacodynamics of antiretroviral drugs. In this paper, we integrate several drug-related parameters into an HIV infection model to investigate the effects of drug pharmacodynamics on the HIV latent reservoir and viral load dynamics. We showed that pharmacodynamic characteristics of drugs and the dosing schedule can significantly affect the outcome of either early or late treatment. Variations in each of the four studied parameters (the slope of the dose-response curve, the ratio of the maximum dosage to the 50% inhibitory concentration, the drug's half-life, and the dosing interval) can generate either an infection-free steady state or persistent infection when the other parameters remain unchanged. The global stability of the infection-free steady state and the viral persistence are shown to be governed by a viral invasion threshold that depends on the drug ph...

Síndrome de Fanconi induzida pelo uso de Tenofovir em pessoa coinfectada HIV-Hepatite B multirresistente

Introdução: A coinfecção vírus da Hepatite B-vírus da imunodeficiência humana (HIV-HBV) é comum e o Tenofovir (TDF) é droga de eleição porque age contra os dois vírus ao mesmo tempo. Porém, em cerca de 1% dos casos pode induzir Síndrome de Fanconi (SF), levando à insuficiência renal. Relato do caso: Em um homem coinfectado HIV-HBV, com a replicação do HIV controlada, o vírus da Hepatite B foi resistente a todos os fármacos disponíveis, exceto ao TDF. Vinte e dois meses após tratamento antirretroviral composto com esse medicamento, o qual controlou a replicação dos dois vírus ao mesmo tempo, desenvolveu insuficiência renal com perda de solutos reabsorvíveis em túbulo contornado proximal, diagnosticada como SF induzida por TDF. Diante do dilema de suspender o TDF para preservar o rim e permitir a replicação do HBV, ou manter o TDF para preservar o fígado e aceitar a degeneração renal, optouse por balancear o tratamento segundo o melhor equilíbrio possível entre a replicação do HBV e a preservação do rim, ajustando-se a posologia dos medicamentos de acordo com os indicadores clínicos e laboratoriais do risco hepático e do funcionamento renal. Conclusão: A única possibilidade terapêutica disponível atualmente para pessoas coinfectadas HIV-HBV multirresistente que desenvolvem insuficiência renal por TDF consiste no ajuste da dose do TDF segundo o clearance de creatinina, no tratamento sintomático, na reposição de perdas urinárias com repercussão metabólica e no monitoramento clínico e laboratorial da infecção pelo HIV, da Hepatite B, da insuficiência renal e da remodelação óssea.

HIV RNA levels in plasma and cervical-vaginal lavage fluid in elite controllers and HAART recipients.

The introduction of HAART leads to control of HIV replication to less than 50 copies/ml, similar to levels in 'elite controllers'. Low-level viral replication may be one of the contributing factors to persistent immune activation/inflammation in HAART-treated individuals. There are still gaps in our knowledge of whether low-level replication persists in systemic versus mucosal sites. Participants for this study were recruited from the Women's Interagency HIV Study. We evaluated 33 'elite controllers' who naturally controlled HIV replication and 33 matched HAART-suppressed recipients. This study employed a sensitive target-capture transcription-mediated-amplification assay to compare low-level virus concentrations in plasma and cervical-vaginal lavage (CVL) samples from HIV-positive HAART recipients and 'elite controllers'. The median (interquartile range) plasma viral load signal/cut-off (S/Co) for 'elite controllers' was 10.5 (3.9-21.1), which was significantly (P < 0.001) higher than the S/Co for HAART recipients [2.0 (1-4.9)]. The majority of CVL samples from both groups had undetectable HIV RNA and the proportion of CVL samples with a cut-off more than 1.0 was not different between 'elite controllers' and HAART-suppressed recipients. This study demonstrated persistent low-level HIV replication in 'elite controllers', suggesting potential value of HAART treatment for these individuals. Absent or very low levels of HIV RNA in CVL indicate very low risk of secondary sexual transmission for both groups.

HIV: An underrecognized secondary cause of osteoporosis?

HIV: An underrecognized secondary cause of osteoporosis?

High levels of atazanavir and darunavir in urine and crystalluria in asymptomatic patients

Atazanavir has been associated with kidney stones and renal failure. We measured urine and plasma concentrations of recent protease inhibitors (PIs) and searched for PI crystals in the urine of asymptomatic patients. A cross-sectional analysis of HIV-infected patients taking ritonavir-boosted atazanavir 300 mg/day (ATV300/r), unboosted atazanavir 400 mg/day (ATV400), ritonavir-boosted darunavir at either 800 mg/day (DRV800/r) or 1200 mg/day (DRV1200/r) or ritonavir-boosted lopinavir 800 mg/day was performed. Plasma and urine were collected and PI levels measured using HPLC. Crystals were detected and identified in urine using polarized microscopy. PI levels were measured in 266 patients, 142 of whom were assessed for urinary crystals. Their mean age was 46 years. The mean duration of HIV infection was 10.5 years and the mean duration of the current PI-containing regimen was 22.5 months. The mean CD4 cell count was 494 cells/mm(3); 74% showed controlled HIV replication. Median urinary PI levels were 22.3, 14.3, 26.9 and 29.7 mg/L for ATV300/r, ATV400, DRV800/r and DRV1200/r, respectively, significantly higher than plasma levels, which were all <5 mg/L (P < 0.001). In contrast, median urinary lopinavir concentrrations did not significantly differ from plasma concentrations (4.2 and 6.4 mg/L, respectively; P = 0.7) and were significantly lower than those of other PIs (P < 0.001). Atazanavir crystals were found in 7/78 patients receiving ATV300/r (8.9%; 95% CI = 2.6%-15.2%) and darunavir crystals were found in 4/51 patients receiving darunavir (7.8%; 95% CI = 0.4%-15.2%). Longer exposure to atazanavir was the only risk factor associated with the presence of atazanavir crystalluria (P = 0.04). Unlike lopinavir, atazanavir and darunavir reached high concentrations in urine. Urinary crystals were found in a few patients receiving ritonavir-boosted atazanavir or darunavir and may favour nephrolithiasis.

Controlled HIV viral replication, not liver disease severity associated with low bone mineral density in HIV/HCV co-infection

To evaluate the prevalence and risk factors for low bone mineral density (BMD) in persons co-infected with HIV and Hepatitis C. HIV/HCV co-infected study participants (n=179) were recruited into a prospective cohort and underwent dual-energy X-ray absorptiometry (DXA) within 1 year of a liver biopsy. Fibrosis staging was evaluated according to the METAVIR system. Osteoporosis was defined as a T-score ≤-2.5. Z-scores at the total hip, femoral neck, and lumbar spine were used as the primary outcome variables to assess the association between degree of liver disease, HIV-related variables, and BMD. The population was 65% male, 85% Black with mean age 50.3 years. The prevalence of osteoporosis either at the total hip, femoral neck, or lumbar spine was 28%, with 5% having osteoporosis of the total hip, 6% at the femoral neck, 25% at the spine. The mean Z-scores (standard deviation) were -0.42 (1.01) at the total hip, -0.16 (1.05) at the femoral neck, and -0.82 (1.55) at the lumbar spine. In multivariable models, controlled HIV replication (HIV RNA <400 copies/ml vs. ≥400 copies/ml) was associated with lower Z-scores (mean ± standard error) at the total hip (-0.44 ± 0.17, p = 0.01), femoral neck (-0.59 ± 0.18, p = 0.001), and the spine (-0.98 ± 0.27, p = 0.0005). There was no association between degree of liver fibrosis and Z-score. Osteoporosis was very common in this population of predominately African-American HIV/HCV co-infected patients, particularly at the spine. Lower BMD was associated with controlled HIV replication, but not liver disease severity.

GBV-C co-infection in HIV patients downregulates CCR5 and CXCR4 surface expression on CD4 cells

Aims: The flavivirus GB virus-C (GBV-C), thus far not known to cause any disease, has been shown to be associated with delayed progression of HIV disease. Recently, in vitro studies demonstrated down-regulation of CCR5 as a potential mechanism of GBV-C to modulate HIV disease progression. We therefore studied surface expression of the two major HIV co-receptors, CCR5 and CXCR4, on CD4+ and CD8+ T-cells in 110 HIV patients stratified with respect to their GBV-C status and immune function. Methods: GBV-C infection was studied in 110 HIV patients by RT-PCR. CCR5Δ32 mutation was analyzed by real time PCR. FACS analysis was used to measure CCR5 and CXCR4 surface expression on CD4+ and CD8+ T-cells. Results: GBV-C RNA replication was detected in 31% (34/110) of patients. Fourteen patients were excluded from the analysis because of reduced CCR5 surface expression due to a heterozygous CCR5Δ32 mutation. In the remaining HIV/GBV-C co-infected patients with CD4 <350/μl CCR5 and CXCR4 expression on CD4+ T-cells was significantly reduced to 77% and 80%, respectively, of the levels measured in HIV mono-infected patients (p<0.05). In contrast, HIV-monoinfected and HIV/GBV-C co-infected patients did not differ with respect to CCR5 and CXCR4 expression on CD4+ T cells in the subgroup with preserved immune function (CD4>350/µl) and on CD8+T cells independent of immune function. Of note, we also found significant downregulation of CXCR4 (78%; p<0.05), but not CCR5 expression on CD4+ T-cells in HIV/GBV-C co-infected patients with detectable HIV replication compared to HIV mono-infected patients. Conclusions: GBV-C co-infection is common in HIV infected patients and is associated with reduced expression of both major HIV co-receptors on CD4+ T-cells in the subset of HIV patients with poorly controlled HIV replication and advanced immunodeficiency. Therefore, the molecular and cellular mechanisms underlying down-regulation of HIV co-receptors by GBV-C merit further investigation.

Retrospective Analysis of Suspending HAART in Selected Patients with Controlled HIV Replication

We sought to determine the consequences of stopping highly active antiretroviral therapy (HAART) in a group of 41 HIV-infected individuals with undetectable HIV viral loads and CD4+ counts greater than 500 cells per microliter for 6 months or more. Clinical and laboratory parameters were monitored, as was the time to HAART reinitiation. Three months after HAART interruption, the median CD4+ count declined by 162 cells per microliter and HIV viral load increased by 24,000 copies per milliliter. Over the next year, CD4+ counts continued to decrease by an average of 11 cells per microliter per 3-month intervals. In contrast, HIV viral loads remained stable over the same period. Five of 7 patients (71%) with elevated cholesterol levels and 6 of 13 patients (46%) with elevated triglyceride levels had these values normalize after stopping HAART. After a median of 21 months follow-up, 26 of 41 patients (63%) have restarted HAART. Patients with Centers for Disease Control (CDC) HIV/AIDS C classification were more likely to restart HAART than those with A or B classification (p = 0.008). Reasons for HAART restart included clinical events in 8 patients. Fifteen patients restarted HAART for immunologic reasons: CD4+ count less than 300 cells per microliter (n = 7); HIV viral load greater than 55,000 copies per milliliter (n = 3); or both (n = 5). Three patients restarted HAART because of personal preference. Within 4 months, all 26 patients who restarted HAART achieved HIV viral loads less than 50 copies per milliliter. Although patients were able to rapidly achieve nondetectable HIV viral loads after restarting HAART, the inability to foresee clinical events among 8 patients (20%) is disconcerting. We advise caution before HAART interruption, particularly for those patients with a preceding history of significant HIV-related complications.

Nadir CD4+ T-cell count and numbers of CD28+ CD4+ T-cells predict functional responses to immunizations in chronic HIV-1 infection.

To ascertain whether delaying the initiation of highly active antiretroviral therapy (HAART) compromises functional immune reconstitution in HIV-1 infection in persons who regain 'normal' CD4 T-cell counts after suppressive antiretroviral therapies. Prospective open-label study carried out at two University-affiliated HIV-outpatient clinics in the USA. Response to immunization was used as a model for in vivo functional immune competence in 29 HIV-1 infected patients with CD4 T-cell counts > 450 x 106 cells/l and HIV-RNA < 400 copies/ml for > 12 months after HAART and nine HIV-1 seronegative controls. After immunization with tetanus toxoid, diphtheria-toxoid, and keyhole limpet hemocyanin, immune response scores (IRS) were calculated using postimmunization antibody concentrations, lymphocyte proliferation, and delayed-type hypersensitivity responses to vaccine antigens. Despite normal numbers of circulating CD4 T-cells, the CD4 T-cell nadir before HAART initiation predicted the immune response to immunization (rho = 0.5; P < 0.005) while current CD4 T-cell count did not. Likewise, CD4 T-lymphocyte expression of the co-stimulatory molecule CD28 was also an independent predictor of response to immunization (rho = 0.5; P < 0.005). Even among persons who controlled HIV replication and normalized CD4 T-cell counts with HAART, pretreatment CD4 T-cell count and numbers of circulating CD4+CD28+ T-cells at immunization, but not current CD4 T-cell count, predict the ability to respond to vaccination. Delaying the initiation of HAART in chronic HIV-1 infection results in impaired functional immune restoration despite normalization of circulating CD4 T-cell numbers.

Systemic non-Hodgkin lymphoma in HIV-infected patients with effective suppression of HIV replication: persistent occurrence but improved survival.

The incidence of systemic non-Hodgkin lymphoma (NHL) has only slightly decreased since the introduction of highly active antiretroviral therapy (HAART), suggesting that current antiretroviral strategies do not eliminate the lymphoma risk. This study evaluates the evolving characteristics of HIV and NHL between the pre-HAART and the post-HAART periods in 246 HIV-infected NHL patients from a single institution. Major HIV-related characteristics were similar in the two periods. Most patients in the post-HAART period presented with unknown (23%), untreated (16%), or uncontrolled (37%) HIV infection. Despite an increased frequency of advanced stage IV disease in the post-HAART period (68% vs. 53%, p =.03), the overall survival has improved, with a 2-year survival probability of 61.6% versus 35.9%, (p <.001). This was associated with an increased complete remission rate (69% vs. 55%, p =.04) and the generalization of more intensive chemotherapy regimens. Most patients (76%) who developed NHL in the post-HAART period had uncontrolled HIV replication. However, 27 patients (24%) developed NHL despite an effective viral suppression at NHL diagnosis. Patients who were naive to any antiretroviral therapy at NHL diagnosis had an overall survival probability very similar to that of patients with controlled HIV replication. Improvement in the overall survival rate in the post-HAART period was associated with more intensive chemotherapy regimens, increased complete remission rate, and a likely benefit of continuation or introduction of HAART.

Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy.

To describe a severe form of demyelinating HIV-associated leukoencephalopathy in AIDS patients failing highly active antiretroviral therapy (HAART), its relationship to clinical and neuroimaging findings, and suggest hypotheses regarding pathogenesis. AIDS patients who failed HAART and displayed severe leukoencephalopathy were included. All cases had detailed neuromedical, neuropsychological, neuroimaging and postmortem neuropathological examination. Immunocytochemical and PCR analyses were performed to determine brain HIV levels and to exclude other viruses. Seven recent autopsy cases of leukoencephalopathy in antiretroviral-experienced patients with AIDS were identified. Clinically, all were severely immunosuppressed, six (86%) had poorly controlled HIV replication despite combination antiretroviral therapy, and five (71%) had HIV-associated dementia. Neuropathologically, all seven had intense perivascular infiltration by HIV-gp41 immunoreactive monocytes/macrophages and lymphocytes, widespread myelin loss, axonal injury, microgliosis and astrogliosis. The extent of damage exceeds that described prior to the use of HAART. Brain tissue demonstrated high levels of HIV RNA but evidence of other pathogens, such as JC virus, Epstein-Barr virus, cytomegalovirus, human herpes virus type-8, and herpes simplex virus types 1 and 2, was absent. Comparison of the stages of pathology suggests a temporal sequence of events. In this model, white matter damage begins with perivascular infiltration by HIV-infected monocytes, which may occur as a consequence of antiretroviral-associated immune restoration. Intense infiltration by immune cells injures brain endothelial cells and is followed by myelin loss, axonal damage, and finally, astrogliosis. Taken together, our findings provide evidence for the emergence of a severe form of HIV-associated leukoencephalopathy. This condition warrants further study and increased vigilance among those who provide care for HIV-infected individuals.