DNA immunization with HIV early genes in HIV type 1-infected patients on highly active antiretroviral therapy

The aim of this study was to evaluate the immunological responses induced by DNA plasmids containing HIV regulatory genes administered in combination in HIV-1-infected patients with pretreatment with highly active antiretroviral treatment (HAART). The study is a double-blind, randomized, and placebo-controlled study, including 15 asymptomatic HIV-1-infected patients on stable HAART for at least 6 months and with plasma HIV RNA levels below 50 copies/ml. Ten patients received a combination of rev, tat, and nef intramuscularly (im) at weeks 0, 4, and 16 at increasing doses giving totals of 300 (100 x 3), 900 (300 x 3), and 1800 (600 x 3) micrograms DNA. Five patients received saline in the same amounts im. Antigen-specific cytotoxic T lymphocyte (CTL) levels were preserved or increased and new T lymphocyte proliferative responses were induced in the group immunized with the HIV DNA genes. No increase in antibody levels was noted. Despite a 10-fold higher vaccine dose, patients on HAART did not respond better to vaccination compared to non-HAART patients included in a previous study where the genes were administered separately. Combining the regulatory genes rev, tat, and nef in increasing doses may reduce the anticipated augmentation of HIV-specific T cell proliferative and CTL responses. Viral suppression did not seem to further improve the initial vaccine responses of patients with comparable CD4 levels.     

Comparative response of African HIV-1-infected individuals to highly active antiretroviral therapy

OBJECTIVE: Few data exist on the virological response to antiretroviral therapy of individuals infected with African HIV-1 subtypes. Our objective was to compare the response, in our clinic, of African HIV-1-infected patients with their British and European contemporaries treated with the same regimes. DESIGN: The St Mary's Hospital HIV database was used to identify drug-naive African and European patients starting a highly active antiretroviral therapy (HAART) regimen. METHODS: HIV-1 subtype was determined by phylogenetic analysis of pol sequences. Kaplan-Meier survival analysis was used to estimate the proportion of patients achieving undetectable viral loads (< 500 copies/ml). The longer-term response to therapy was assessed by changes in CD4 cell counts and viral loads from baseline. RESULTS: A total of 265 patients were classified as 'European' and 97 as 'African', confirmed by sequence. The time to first undetectable viral load was similar for the two groups (P = 0.9). Although there were no statistically significant differences in the CD4 cell count responses (P = 0.11), there was evidence of an increase in viral load after 9 months for the African group, resulting in a widening viral load gap between the two cohorts; the effect of ethnic group was statistically significant (P < 0.001). CONCLUSION: The initial virological and immunological responses of the African and European cohorts to HAART were similar; although the longer-term virological response was poorer in the African cohort, which may be related to adherence. On the basis of these findings, there is no justification for withholding HAART from Africa on virological grounds.     

Virologic and immunologic outcomes after 24 weeks in HIV type 1-infected adolescents receiving highly active antiretroviral therapy

BACKGROUND: Adolescents represent the fastest growing demographic group of new human immunodeficiency virus (HIV) infections in the United States. At present, there is little information available about their response to therapy. METHODS: We studied 120 adolescents infected via high-risk behaviors who began receiving highly active antiretroviral therapy (HAART), to determine their virologic and immunologic response to therapy. RESULTS: Subjects were enrolled at 28 sites of the Pediatric Acquired Immunodeficiency Syndrome Clinical Trials Group. After 16-24 weeks of HAART, 59% of subjects had reproducible undetectable virus loads, according to repeat measurements (virologic success). As enumerated by flow-cytometric analysis, increases in levels of CD4 helper cells (both naive and memory) and decreases in levels of CD8 suppressor cells were observed. Partial restoration of some immunologic parameters for patients who did not achieve virologic success was also observed, but to a more limited extent than for adolescents with virologic success. Adherence to HAART was the only predictor of achieving undetectable virus loads. CONCLUSIONS: Adolescents have the capacity to improve their immunologic status with HAART. Lower than expected success in virologic control is related to lack of adherence, and efforts to improve treatment outcome must stress measures to assure adherence to medication.     

Primary isolate neutralization by HIV type 1-infected patient sera in the era of highly active antiretroviral therapy

Sera from highly selected HIV-1-positive patients are known to have the ability to neutralize a diverse array of primary isolates of HIV-1. The human osteosarcoma cell line that expresses CD4 and chemokine receptors (GHOST cells) was adapted to study HIV-1 neutralization in 37 HIV-1-infected individuals who were selected because of slow disease progression or nonprogression. Many of these individuals were receiving combination drug therapy. Molecularly cloned HIV-1 JR-FL and NL4-3 viruses were used as prototypes to define assay conditions. Sera were then tested at a 1:40 dilution against six additional primary isolates, three of which utilized CCR5 and three of which used both CCR5 and CXCR4. The assay was highly reproducible and independent of viral input titer, with a readout at 48 hr equivalent to that at later time points. As previously reported, neutralization sensitivity was entirely independent of coreceptor usage. Only a few sera from slow progressors were able to neutralize a broad array of primary isolates at a 1:40 dilution, and the best clinical predictor of broadly neutralizing antibody for primary isolates was the present use of antiretroviral agents. In further studies it was found that purified antibody accounted for the majority of the measured neutralization. However, experiments with exogenous addition of antiviral agents showed that the use of nucleosides also greatly contributed to the measured neutralization in some patients. Measurement of neutralization of HIV-1 primary isolates by sera from patients receiving antiretroviral therapy must be carried out with some caution.     

Recovery of replication-competent HIV type 1-infected circulating monocytes from individuals receiving antiretroviral therapy

The affect of antiretroviral therapy (ART) on HIV-1 recovery from blood monocytes was determined in purified peripheral blood monocyte-derived macrophage (MDM) cultures from HIV-1-infected subjects with undetectable plasma viremia or active viral replication. Additionally, the association between replication-competent HIV-1-infected MDM and neurocognitive status was examined. Fifty-two individual with previous AIDS-defining illnesses receiving nucleoside analogues with and without protease inhibitors or no ART were followed for up to 1.5 years. Detection of plasma viremia significantly correlated with the occurrence of infected monocytes. Viral replication was detected in less than 10% of the MDM cultures from 23 individuals receiving effective antiretroviral therapy. In contrast, approximately 50% of the MDM cultures from 29 individuals with active viral replication and evidence of decreased immune function, including all individuals with neurocognitive impairment, produced detectable virus indicating that a lack of adequate ART results in increased abundance of replication-competent blood monocytes. Proviral DNA levels were a minimum of 13-fold higher in MDM from subjects with active viral replication. The infrequent detection of viral DNA in cultures from individuals receiving effective ART suggested low levels of circulating monocytes harboring replication-incompetent virus. These studies demonstrate that HIV-infected individuals on ART with breakthrough viremia have significantly higher levels of circulating infected monocytes, the precursors of tissue macrophages.     

Gender differences in clinical progression of HIV-1-infected individuals during long-term highly active antiretroviral therapy

OBJECTIVE: To assess gender differences in the long-term clinical, virological and immunological outcomes during highly active antiretroviral therapy (HAART). METHODS: This longitudinal observational multicentre study followed 2460 HIV-infected patients who had begun a protease inhibitor-based regimen for a median period of 43 months. Outcome measures were virological suppression (< 500 copies/ml), confirmed virological rebound after suppression, and death or new AIDS-defining illness (ADI). RESULTS: At baseline, 690 female patients (28.0%) had significantly lower age, higher prevalence of heterosexual contact and lower prevalence of intravenous drug use as risk factors for HIV infection compared with males. Furthermore, females had a lower number of AIDS-defining illnesses, higher CD4 cell counts and lower viral loads.No gender differences were reported in terms of proportion of patients achieving viral suppression or exhibiting rebound after achieving viral suppression. Female patients experienced reduced clinical progression during follow-up compared with males (P = 0.008) by Kaplan-Meier analysis; however this difference was not significant in an adjusted analysis. In a multivariate model, the interaction between gender and risk factor for HIV or viral load showed that female drug users and female patients with a baseline HIV RNA viral load of 10(4)-10(5) copies/ml had a favourable clinical outcome compared with males (P = 0.035 and P = 0.015, respectively). CONCLUSION: No differences were found between genders in terms of virological and immunological outcomes during long-term HAART. Nevertheless, a lower risk of clinical progression was reported among female patients with intermediate baseline viral load than in males.     

Vitamin D deficiency among HIV type 1-infected individuals in the Netherlands: effects of antiretroviral therapy

Vitamin D regulates bone metabolism but has also immunoregulatory properties. In HIV-infected patients bone disorders are increasingly observed. Furthermore, low 1,25(OH)(2)D(3) levels have been associated with low CD4(+) counts, immunological hyperactivity, and AIDS progression rates. Few studies have examined the vitamin D status in HIV-infected patients. This study will specifically focus on the effects of antiretroviral agents on vitamin D status. Furthermore, the effect of vitamin D status on CD4 cell recovery after initiation of HAART will be evaluated. Among 252 included patients the prevalence of vitamin D deficiency (<35 nmol/liter from April to September and <25 nmol/liter from October to March) was 29%. Female sex, younger age, dark skin, and NNRTI treatment were significant risk factors in univariate analysis, although in multivariate analyses skin pigmentation remained the only independent risk factor. Median 25(OH)D(3) levels were significantly lower in white NNRTI-treated patients [54.5(27.9-73.8) nmol/liter] compared to white PI-treated patients [77.3 (46.6-100.0) nmol/liter, p = 0.007], while among nonwhites no difference was observed. Both PI- and NNRTI-treated patients had significantly higher blood PTH levels than patients without treatment. Moreover, NNRTI treatment puts patients at risk of elevated PTH levels (>6.5 pmol/liter). Linear regression analysis showed that vitamin D status did not affect CD4 cell recovery after initiation of HAART. In conclusion, 29% of the HIV-1-infected patients had vitamin D deficiency, with skin color as an independent risk factor. NNRTI treatment may add more risk for vitamin D deficiency. Both PI- and NNRTI-treated patients showed higher PTH levels and might therefore be at risk of bone problems. Evaluation of 25(OH)D(3) and PTH levels, especially in NNRTI-treated and dark skinned HIV-1-infected patients, is necessary to detect and treat vitamin D deficiency early.     

Etravirine-based highly active antiretroviral therapy in HIV-1-infected paediatric patients

Background

We evaluated the efficacy, safety and tolerability of etravirine in paediatric patients vertically infected with HIV‐1.

Methods

A multicentre retrospective study of 23 multidrug‐resistant paediatric patients (five children and 18 adolescents) enrolled in the study from 1 September 2007 to 28 February 2010 was carried out. We performed a longitudinal analysis of immunological, virological and clinical data.

Results

The median age of the patients was 14.2 years [interquartile range (IQR) 12.5–15.8 years]. At baseline, the median HIV‐1 RNA was 29 000 (4.5 log₁₀) HIV‐1 RNA copies/mL (range 4300‐83 000 copies/mL), the median CD4 T‐cell count was 445 cells/μL (range 221–655 cells/μL) and the median CD4 percentage was 19.6% (IQR 13.0‐31.0). Remarkably, 16 of 23 patients (70%) harboured one or more etravirine‐associated resistance mutations. The backbone regimen included at least two fully active drugs in 91% of patients. After etravirine‐based therapy, 20 patients (87%) achieved HIV‐1 RNA<400 copies/mL and 18 of 23 (78%) achieved HIV‐1 RNA<50 copies/mL: three (13%) within the first month, seven (30%) within the first 4 months, and six (26%) between the 5th and 8th months. CD4 T‐cell recovery was observed in 19 patients (83%). The median follow‐up time was 48.4 weeks (IQR 35.7–63.4 weeks); four patients (17%) were exposed to etravirine for >120 weeks. Three mild/short‐term and two moderate skin rashes were observed in the adolescents. Laboratory abnormalities included hypercholesterolaemia (11 of 23 patients), hypertriglyceridaemia (eight of 23 patients), and reduced high‐density lipoprotein cholesterol (10 of 23 patients). Adherence was complete in seven patients (30%). No patients showed complete resistance to etravirine after follow‐up. However, three of 21 patients (14%) who initially showed intermediate resistance interrupted etravirine treatment because of virological failure.

Conclusions

We observed a sustained antiviral response and improved immunological parameters in multidrug‐resistant paediatric patients, most of whom had received etravirine as part of salvage regimens with at least two fully active drugs.     

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

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

Once-a-day highly active antiretroviral therapy in treatment-naive HIV-1-infected adults in Senegal

OBJECTIVES: To study the effectiveness, adherence and tolerance of a once-a-day highly active antiretroviral therapy regimen in adults in Senegal. DESIGN AND METHODS: In a prospective, open-label one-arm study, 40 treatment-naive HIV-1-infected patients took the following three drugs once a day at bedtime: didanosine, lamivudine and efavirenz. The primary endpoint was the percentage of patients with plasma HIV-1 RNA below 500 copies/ml at 6 months. The analysis was done on an intent-to treat basis. RESULTS: Eighty-five per cent of patients were at Centers for Disease Control and Prevention stage B or C and the plasma HIV RNA level was 5.4 +/- 0.4 log(10) copies/ml at baseline. The percentage of patients with plasma HIV-1 RNA below 500 copies/ml at 6 months was 95% [95% confidence interval (CI), 83-99]. The proportions of patients with plasma HIV-1 RNA below 50 copies/ml at months 3, 6, 9, 12 and 15 were 26% (n = 39; 95% CI, 12-39), 78% (n = 40; 95% CI, 65-90), 70% (n = 40; 95% CI, 56-84), 77% (n = 39; 95% CI, 64-90) and 69% (n = 39; 95% CI, 55-84), respectively. The CD4 cell count was 164 +/- 75 x 106/l at baseline and increased by a mean of 199 +/- 101 x 106/l at month 15. Permanent treatment discontinuation was never necessary for serious adverse effects. Adherence was excellent, as shown by plasma drug concentrations and according to the results of the questionnaire. CONCLUSIONS: The once-daily regimen of didanosine, lamivudine and efavirenz was safe, easy-to-take and demonstrated strong antiretroviral and immunologic effects in African patients with advanced HIV infection.     

Immunopathology as a result of highly active antiretroviral therapy in HIV-1-infected patients

OBJECTIVE: Unusual clinical inflammatory syndromes associated with underlying previously unrecognized opportunistic infections are increasingly being noted shortly after starting highly active antiretroviral therapy (HAART). This study examined the possible relationship between such unexpected disease manifestations and in vitro parameters of microbial antigen-specific immune reactivity in patients infected with HIV-1 who had a Mycobacterium avium intracellulare or Mycobacterium xenopi infection. DESIGN: In vitro T-cell proliferation experiments were performed after specific stimulation of a patient's peripheral blood mononuclear cells (PBMC) with M. avium and M. xenopi antigen and non-specific stimulation with phytohaemagglutinin (PHA). The results were compared with appropriate controls. PATIENTS: Five patients who presented with unusual clinical syndromes associated with M. avium or M. xenopi infection within weeks of experiencing large rises in CD4+ cell counts following the initiation of antiretroviral therapy. RESULTS: In all patients except one, mycobacteria-specific lymphoproliferative responses rose significantly following HAART; this was temporally associated with elevations in CD4+ cell counts and the occurrence of clinical disease. The patient with M. xenopi infection appeared to clear his infection subsequently without antimycobacterial therapy. In three of the four patients with M. avium infection, antimycobacterial treatment could be stopped without recurrence of infection. CONCLUSION: Our findings support the hypothesis that HAART may lead to clinically relevant inflammation as a result of restoration of specific immune reactivity against microbial pathogens that are subclinically present at the time treatment is initiated. Continuation of HAART may subsequently result in protective immunity and clearance of infection.     

Inflammatory reactions in HIV-1-infected persons after initiation of highly active antiretroviral therapy

PURPOSE: To review reported inflammatory reactions occurring after initiation of highly active antiretroviral therapy (HAART) in persons infected with HIV-1 and to explore the mechanisms leading to these reactions. DATA SOURCES: MEDLINE search of biomedical literature reporting inflammatory reactions after HAART. Bibliographies of retrieved reports were also reviewed. STUDY SELECTION: Articles describing patients infected with HIV-1 who had immunologic and virologic responses to HAART and subsequently developed inflammatory reactions. DATA EXTRACTION: Data on the immune status, clinical characteristics, and therapeutic management of patients who were seropositive for HIV-1 and had inflammatory reactions after HAART. DATA SYNTHESIS: Inflammatory reactions involving opportunistic infections, AIDS-associated malignant conditions, and other noninfectious diseases have recently been described in patients infected with HIV-1. These conditions often appeared shortly after the introduction of HAART and were associated with pronounced reductions in plasma HIV-1 viral load and increases in CD4(+) T-lymphocyte counts. Clinical presentation was often atypical of that in patients with untreated HIV-1 infection, probably because of restored immunity. Most cases improved despite continuation of HAART, although some patients required anti-inflammatory drugs or specific antimicrobial agents. CONCLUSIONS: Clinicians caring for patients who are infected with HIV-1 and receiving HAART must be aware of this new and diverse clinical syndrome. As more HAART recipients are studied, new presentations will probably be observed.     

HIV1 and the gut in the era of highly active antiretroviral therapy

The gut and its gut-associated lymphoid tissue serve as a preferential site for HIV1 entry, active viral replication, reservoir, and HIV-mediated CD4 cell apoptosis. The widespread use of highly active antiretroviral therapy (HAART) has resulted in a significant decrease in the incidence of opportunistic enteric pathogens as a consequence of immune recovery. Nonetheless, patients with advanced HIV1 disease who were recently diagnosed or have poor response to HAART can still suffer from opportunistic infections with pathogens such as Cryptosporidium, microsporidia, Isospora belli, Cyclospora cayetanensis, Mycobacterium avium complex, and cytomegalovirus, among others. This review describes the impact of HIV1 infection on gut immune function, the salient features of the most common opportunistic enteric pathogens and HIV-associated enteropathy, and the effects of immune reconstitution after introduction of HAART.     

Phase I trial of a therapeutic HIV type 1 vaccine,Vacc-4x,in HIV type 1-infected individuals with or without antiretroviral therapy

Highly active antiretroviral therapy (HAART) can effectively suppress HIV-1 replication but, as soon as the drugs are withdrawn, there is a rapid rebound of replicating virus. Severe metabolic toxicities and therapy failures due to the appearance of resistant virus are becoming an increasing problem that precludes long-term continuous medication. Therapeutic immunizations represent a feasible and attractive means of supplementing or, alternatively, replacing current therapies, thereby reducing the potential for emergence of drug-resistant HIV-1 strains. We have performed an open, single-center, phase I safety study of a candidate therapeutic HIV-1 vaccine, Vacc-4x, given to 11 HIV-1-infected individuals with or without antiretroviral therapy. The immunogen consists of four synthetic peptides based on the major core protein p24. To ensure optimal exposure of the immunogen to the antigen-presenting cells (APCs), the vaccine was given intradermally together with granulocyte-macrophage colony-stimulating factor (GM-CSF). Responses to the immunization protocol were determined by delayed-type hypersensitivity (DTH) reaction, interferon gamma-secreting cells in the enzyme-linked immunospot (ELISpot) assay, and antibody production to the p24 protein and the peptides. The vaccine was safe and in general well tolerated. Plasma HIV RNA levels and CD4(+) cell counts did not change appreciably during the study. All patients showed a positive DTH response. For two of the patients, the immunization protocol induced responses to one or two of the tested peptides whereas a third patient showed reactivity to one of the peptides before immunization. A weak antibody response in the peptide-specific enzyme-linked immunosorbent assay could be seen in seven patients.     

Hyperglycosylated ferritin in sera of HIV-1-infected patients treated with highly active antiretroviral therapy

A study was conducted to determine the relationship between ferritin and glycosylated isoforms of ferritin and insulin resistance in 69 HIV-infected men receiving HAART. Ferritin levels were significantly correlated with aspartate aminotransferase, alanine aminotransferase, bilirubin and with insulin resistance. The ferritin isoelectric focusing patterns of five insulin-resistant HIV-infected patients under HAART showed large amounts of hyperglycosylated isoforms, which was not found in 56 control subjects and 46 untreated HIV-1-infected patients.