Adequate CD4 Research Articles

Asymptomatic HIV People Present Different Profiles of sCD14, sRAGE, DNA Damage, and Vitamins, according to the Use of cART and CD4+ T Cell Restoration.

We aimed to analyze markers of immune activation, inflammation, and oxidative stress in 92 asymptomatic HIV-infected patients according to the adequate (AR, >500 cells/mm3) or inadequate (IR, <500 cells/mm3) CD4+ T recovery and the presence or absence of antiretroviral treatment (cART). In relation to those newly diagnosed, they were divided into two groups, cART-naïve IR (nIR) and cART-naïve AR (nAR). Among those diagnosed more than five years ago, the following division was made: the cART-naïve long-term nonprogressors (LTNP); patient under cART and AR (tAR); and patients under cART and IR (tIR). We investigated the expression of soluble receptor for advanced glycation end products (sRAGE), high-mobility group-box protein −1 (HMGB1), soluble CD14 (sCD14), IL-8, IL-10, 8-isoprostane, vitamins, and DNA damage. We observed higher levels of sRAGE in tAR as compared to nIR, nAR, LTNP, and more sCD14 than in nIR and nAR. As for IL-10 levels, we found nIR > nAR > LTNP > tAR > tIR. Higher levels of 8-isoprostane were observed in nIR. LTNP presented a higher retinol dosage than tAR and less genotoxic damage induced by oxidative stress than the other groups. We suggest that the therapy, despite being related to lesser immune activation and inflammation, alters the vitamin profile and consequently increases the oxidative stress of patients. In addition, the lowest genotoxic index for LTNP indicates that both VL and cART could be responsible for the increased DNA damage. More studies are needed to understand the influence of cART on persistent immune activation and inflammation.

Increased frequencies of Th17 cells and IL17a-producing regulatory T-cells preceding the immunodiscordant response to antiretroviral treatment

Despite the fact that antiretroviral therapy (cART) suppresses HIV-viremia, an adequate CD4 T-cell recovery is not always achieved (immunodiscordant response to cART). IL17a-producing CD4 T-cells (Th17) constitutes an important subset involved in the preservation of mucosal surfaces integrity, which depletion has been associated with disease progression in HIV-infection. However, whether Th17 frequency at cART initiation is associated with a poor CD4 T-cell recovery has not been yet explored. Our aim was to explore whether the Th17 cells and other IL17a-producing T-cell subsets at cART initiation were associated with a subsequent immunodiscordant response to cART. We selected pre-cART samples of antiretroviral-naïve subjects with and without a low CD4 recovery after cART (LR-subjects and HR-subjects, respectively). Peripheral blood mononuclear cells (PBMCs) were stimulated with PMA/ionomycine, and the production of several cytokines including IL17a was analyzed by flow cytometry. A trend to higher Th17 (p=0.05) and increased frequencies of IL17a-producing Treg (p=0.011) was found in LR-subjects before cART onset. Despite increased frequencies of both Treg and Th17 in LR-subject at cART initiation, no alteration of Treg/Th17 ratio was observed. While polifunctional profile of CD4 T-cells was not different, frequencies of CD4 T-cells producing cytokine-combinations including IL17a were increased in LR-subjects. Increased frequencies of Th17, IL17a-producing Treg and CD4 T-cells producing specific IL17a-containing combinations of cytokines, precede the immunodiscordant response to cART, suggesting a potential contribution of these subsets in such anomalous response to cART.

Modelling adverse treatment outcomes of HIV-infected adolescents attending public-sector HIV clinics in Lusaka

BackgroundIn resource-limited setting, there is scarce evidence comparing antiretroviral therapy (ART) outcomes among HIV-infected adolescents to that of other age groups. Methods and study designWe analysed data from 25 ART facilities in Lusaka District, comparing treatment-naïve ART-eligible young adolescents (10–14 years), older adolescents (15–19) and young adults (20–24 years) initiating first-line ART to those aged 24 years or older. The adjusted relative risk (RR) of failure to achieve an adequate CD4 response (defined as failure to increase CD4 count by ≥ 50 cells/mm3 at 6 months or by ≥ 100 cells/mm3) at 6 or 12 months after ART initiation was modelled using log-binomial regression. The effect of age group on mortality and loss to follow-up (LTFUP; ≥60 days since scheduled visit date) was estimated using adjusted Cox proportional hazards models, respectively. This was a routine retrospective design using program data. ResultsOf the 94,023 patients initiating ART from May 2004 to February 2011, 1303 (1.4%) were young adolescents, 1440 (1.5%) were older adolescents and 5825 (6.2%) were young adults. 85,455 (90.9%) were 24 years or older at the time of ART initiation. Compared with adults, both young adolescents (RR: 0.88, 95% confidence interval [CI]: 0.76–1.01 at 6 months and RR: 0.80, 95% CI: 0.69–0.93 at 12 months) and older adolescents (RR: 0.82, 95% CI: 0.71–0.95 at 6 months) were less likely to achieve adequate CD4 response. No evidence of a difference in mortality risk was observed among older adolescents (hazard ratio [HR] 1.20, 95% CI: 0.93–1.56) compared with adults; however, there was a reduced risk of mortality in young adolescents compared with adults (HR: 0.61, 95% CI: 0.40–0.92). Young adolescents were less likely to be LTFUP following ART initiation (HR: 0.74, 95% CI: 0.59–0.92), while older adolescents and young adults were reported to be more likely to drop out of care (HR: 1.54 95% CI: 1.33–1.78; HR: 1.51 95% CI: 1.40–1.63 respectively). ConclusionOlder adolescents and young adults had poorer ART treatment outcomes, including failure to achieve adequate CD4 recovery and failure to remain in long-term care, when compared with adults. Interventions are necessary to help increase outcomes and retention in care.

Association between adductor pollicis muscle thickness, anthropometric and immunological parameters in HIV-positive patients

Involuntary weight loss and muscle mass loss among HIV-positive patients are only detectable in late stages, leading poor life quality. The reduction of adductor pollicis muscle thickness (APMT) can be easily and earlier uncovered in those cases. The purpose was to estimate APMT and compare it with immunological and anthropometric parameters of HIV-infected people. A crosssectional study was carried out in an University Hospital including 103 HIV-infected outpatients by subjective global assessment (SGA). Data were compared to APMT for the whole sample and between gender in univariate analysis. Besides that, simple correlation and multiple linear regression were done to check the APMT relation with gender, age, weight body, body mass index, arm circumference, CD4, CD8 and viral load. The APMT average values of the dominant hand (16.2±4.2mm) and non-dominant hand (14.8±4.3mm) were lower than in the healthy population. Through stratified analysis by gender, it was found significant difference in weight, arm muscle circumference, arm muscle area, triceps skinfold thickness and arm fat area (p<0,01 for each). In any age group, men had significantly higher dominant and non-dominant APMT values than women (p<0.001). Although the fair correlation among cited variables and APMT of both hands, there were no correlation and no difference between the genders in regards to immunological markers (CD4, CD8 and viral load). In a prediction model to APMT values, gender was determinant in multiple linear regression. In a well-nourished HIV sample by SGA with adequate CD4 counts, APMT measures of both hands were lower than in healthy people. In both hands, APMT were positively correlated with weight and male, regardless of other anthropometric data and immunologic factors.

Imatinib for highly chemoresistant Kaposi sarcoma in a patient with long-term HIV control: a case report and literature review.

Kaposi sarcoma (ks) is a vascular tumour caused by oncogenic human herpesvirus type 8; it often occurs with hiv-associated immunosuppression. Numerous cellular signalling pathways are involved in the pathogenesis of ks, among which receptor tyrosine kinases such as the c-Kit and platelet-derived growth factor receptors play an important role. Imatinib mesylate, a tyrosine kinase inhibitor, has resulted in partial regression of ks lesions in one third of treated patients, but its mechanism of action remains unclear. Here, we report the case of a white man with recurrent ks despite well-suppressed hiv infection and multiple chemotherapies who received imatinib and showed a complete and sustained tumour response. To our knowledge, this report is the first showing the value of imatinib in the management of ks in the context of long-lasting hiv control with adequate quantitative CD4 recovery. Our case indicates that imatinib can be a treatment option for highly chemoresistant recurrent ks in patients on long-term antiretroviral therapy.

Monitoring of HIV treatment in seven countries in the WHO Region of the Americas.

ObjectiveTo determine the prevalence of adequate monitoring and the costs of measuring CD4+ T-lymphocytes (CD4+ cell) and human immunodeficiency virus (HIV) viral load in people receiving antiretroviral therapy (ART) in seven countries in the WHO Region of the Americas.MethodsWe obtained retrospective, longitudinal data for 14 476 adults who started a first ART regimen at seven HIV clinics in Argentina, Brazil, Chile, Haiti, Honduras, Mexico and Peru between 2000 and 2011. We estimated the proportion of 180-day periods with adequate monitoring, which we defined as at least one CD4+ cell count and one viral load measurement. Factors associated with adequate monitoring were analysed using regression methods. The costs of the tests were estimated.FindingsThe median follow-up time was 50.4 months; the proportion of 180-day periods with adequate CD4+ cell counts was 69% while the proportion with adequate monitoring was 62%. Adequate monitoring was more likely in participants who were older, who started ART more recently, whose first regimen included a non-nucleoside reverse transcriptase inhibitor or who had a CD4+ cell count less than 200 cells/µl at ART initiation. The cost of one CD4+ cell count ranged from 7.37 United States dollars (US$) in Argentina to US$ 64.09 in Chile; the cost of one viral load measurement ranged from US$ 20.34 in Brazil to US$ 186.28 in Haiti.ConclusionIn HIV-infected participants receiving ART in the WHO Region of the Americas, CD4+ cell count and viral load monitoring was often carried out less frequently than regional guidelines recommend. The laboratory costs of monitoring varied greatly.

Long-Term Persistence of Hepatitis A Antibodies in Pediatric HIV-Infected Patients after Primary Immunization: Association with Immunological Profile and Response to Revaccination

Background: We analyzed the persistence of hepatitis A virus (HAV) antibodies 7 years after primary immunization in pediatric HIV-positive patients and its association with the immunological profile. Methods: 29 vertically HIV-infected adolescents (median age, 12.9 years) were enrolled. All of them had been HAV-vaccinated with two HAV vaccine doses 7 years before and all had seroconverted. HAV antibodies were measured by electrochemiluminescence. Lymphocyte immunophenotyping was performed by flow cytometry. Adolescents who lost HAV antibodies were revaccinated. Results: 23/29 patients (79.3%) persisted HAV seropositive (HAV antibodies≥20mlU/mL) 7 years after primary immunization. Age, gender, clinical progression of HIV infection, median viral load, and antiretroviral therapy were similar between those who persisted HAV seropositive and those who lost seropositivity. HIV adolescents who lost HAV antibodies had lower median CD4+ T cells/mm3 (200 vs. 634, p=0.004), lower median B cells/mm3 (103 vs. 335, p<0.001), lower median NK cells/mm3 (67 vs. 209, p=0.002), lower median percentage of naive CD4+ T cells (20% vs. 30%, p=0.026), lower median percentage of naive B cells (52% vs. 68%, p=0.009), higher median percentage of activated memory B cells (19% vs. 7%, p=0.004), higher median percentage of activated CD8+ T cells (51% vs. 22%, p=0.002), and higher median percentage of exhausted memory B cells (23% vs. 8%, p=0.031) than HAV-positive adolescents. 83.3% adolescents responded to revaccination. Conclusion: Persistence of HAV antibodies occurred in 79.3% of patients. Both antibody maintenance and response to revaccination are closely associated with low immune activation and adequate CD4+ T and B cell levels.

Atypical Presentation of PKDL due to Leishmania infantum in an HIV-Infected Patient with Relapsing Visceral Leishmaniasis.

We describe the case of an Italian patient with HIV infection who developed an atypical rash resembling post-kala-azar dermal leishmaniasis (PKDL) when receiving liposomal Amphotericin B (L-AMB) for secondary prophylaxis of visceral leishmaniasis (VL). At the time of PKDL appearance, the patient was virologically suppressed but had failed to restore an adequate CD4+ T-cell count. Histology of skin lesions revealed the presence of a granulomatous infiltrate, with lymphocytes, plasma cells, and macrophages, most of which contained Leishmania amastigotes. Restriction fragment length polymorphism-polymerase chain reaction was positive for Leishmania infantum. Paradoxically, cutaneous lesions markedly improved when a new relapse of VL occurred. The patient received meglumine antimoniate, with a rapid clinical response and complete disappearance of cutaneous rash. Unfortunately, the patient had several relapses of VL over the following years, though the interval between them has become wider after restarting maintenance therapy with L-AMB 4 mg/kg/day once a month. Even if rare, PKDL due to Leishmania infantum may occur in Western countries and represents a diagnostic and therapeutic challenge for physicians. The therapeutic management of both PKDL and VL in HIV infection is challenging, because relapses are frequent and evidence is often limited to small case series and case reports.

Treatment Outcomes of HIV-Infected Adolescents Attending Public-Sector HIV Clinics Across Gauteng and Mpumalanga, South Africa

There is little evidence comparing treatment outcomes between adolescents and other age groups, particularly in resource-limited settings. A retrospective analysis of data from seven HIV clinics across urban Gauteng (n=5) and rural Mpumalanga (n=2), South Africa was conducted. The analysis compared HIV-positive antiretroviral treatment (ART)-naive young adolescents (10-14 years), older adolescents (15-19), and young adults (20-24 years) to adults (≥25 years) initiated onto standard first-line ART between April 2004 and August 2010. Log-binomial regression was used to estimate relative risk (RR) of failure to suppress viral load (≥400 copies/ml) or failure to achieve an adequate CD4 response at 6 or 12 months. The effect of age group on virological failure, mortality, and loss to follow-up (LTFU; ≥90 days since scheduled visit date) was estimated using Cox proportional hazards models. Of 42,427 patients initiating ART, 310 (0.7%) were young adolescents, 342 (0.8%) were older adolescents, and 1599 (3.8%) were young adults. Adolescents were similar to adults in terms of proportion male, baseline CD4 count, hemoglobin, and TB. Compared to adults, both older adolescents (6 months RR 1.75 95% CI 1.25-2.47) and young adults (6 months RR 1.33 95% CI 1.10-1.60 and 12 months RR 1.64 95% CI 1.23-2.19) were more likely to have an unsuppressed viral load and were more likely to fail virologically (HR 2.90 95% CI 1.74-4.86; HR 2.94 95% CI 1.63-5.31). Among those that died or were LTFU, the median time from ART initiation until death or LTFU was 4.7 months (IQR 1.5-13.2) and 10.9 months (IQR 5.0-22.7), respectively. There was no difference in risk of mortality by age category, compared to adults. Young adolescents were less likely to be LTFU at any time period after ART initiation (HR 0.43 95% CI 0.26-0.69) whereas older adolescents and young adults were more likely to be LTFU after ART initiation (HR 1.78 95% CI 1.34-2.36; HR 1.63 95% CI 1.41-1.89) compared to adults. HIV-infected adolescents and young adults between 15 and 24 years have poorer ART treatment outcomes in terms of virological response, LTFU, and virological failure than adults receiving ART. Interventions are needed to help improve outcomes and retention in care in this unique population.

Signatures of CD4 T-cell help and CD8 exhaustion predict clinical outcome in autoimmunity, infection, and vaccination

Autoimmune diseases are common and debilitating, but their severe manifestations could be reduced if biomarkers were available to allow individual tailoring of the potentially toxic immunosuppressive therapy required for their control. Gene expression-based biomarkers have been identified and translated into clinical practice in cancer, but not autoimmunity. We show that transcriptional profiling of purified CD8 T cells, which avoids the confounding influences of unseparated cells, identifies two distinct patient subgroups predicting long-term prognosis in four distinct autoimmune diseases: anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, systemic lupus erythematosus, ulcerative colitis, and Crohn's disease.While the correlation of this signature with prognosis raises the prospect of individualised therapy in autoimmunity, the biological mechanism underlying its association with relapsing disease may indicate novel therapeutic targets. Acute exposure to foreign antigen results in persistent antigen-specific cellular immunity, but during chronic viral infection persistent antigen exposure may exhaust that response. This exhausted CD8 T-cell phenotype may itself be defined by a distinct transcriptional signature. We show that the same signature seen in chronic viral infection can be seen in chronic self antigen exposure during autoimmunity, with one exception: whereas exhaustion results in viral persistence it predicts favourable outcome in autoimmunity. Provision of adequate CD4 help can prevent or overcome the development of CD8 exhaustion resulting in clearance of chronic viral infection. Consistent with this observation, we show that the CD8 exhaustion signature in autoimmunity is inversely correlated with that of concurrent CD4 help and can be robustly identified in mixed cell populations. This has allowed independent validation of this marker on published datasets, confirming prediction of clinical outcome in a total of 1070 samples from 429 individuals spanning infection (HIV, dengue virus, hepatitis C), vaccination (yellow fever, malaria, influenza), and autoimmunity (type 1 diabetes, ANCA–associated vasculitis, systemic lupus erythematosus, Crohn's disease, and ulcerative colitis). FundingWellcome Trust.

Increased risk of mortality and loss to follow-up among HIV-positive patients with oropharyngeal candidiasis and malnutrition before antiretroviral therapy initiation: a retrospective analysis from a large urban cohort in Johannesburg, South Africa

We investigated the effect of oropharyngeal candidiasis (OC) and body mass index (BMI) before antiretroviral therapy (ART) initiation on treatment outcomes of human immunodeficiency virus (HIV)-positive patients. Treatment outcomes included failure to increase CD4 count by ≥50 or ≥100 cells/μL or failure to suppress viral load (<400 copies/mL) at 6 or 12 months in addition to loss to follow-up (LTFU) and mortality by 12 months. Risk and hazard ratios (HRs) were estimated with the use of log-binomial regression and Cox proportional hazards models, respectively. Baseline CD4 <100 cells/μL, low BMI (<18.5 kg/m(2)), low hemoglobin, and elevated aspartate transaminase were associated with OC at ART initiation. Patients with low BMI with and without, respectively, OC were at risk of mortality (HR 2.42, 95% CI 1.88-3.12; HR 1.87, 95% CI 1.54-2.28) and LTFU (HR 1.36, 95% CI 1.02-1.82; HR 1.55, 95% CI 1.30-1.85). Low BMI (with/without OC) at ART initiation was associated with poor treatment outcomes. Conversely, normal BMI with OC was associated with adequate CD4 response and reduced LTFU compared with without OC.

HIV disease progression despite suppression of viral replication is associated with exhaustion of lymphopoiesis

AbstractThe mechanisms of CD4+ T-cell count decline, the hallmark of HIV disease progression, and its relationship to elevated levels of immune activation are not fully understood. Massive depletion of CD4+ T cells occurs during the course of HIV-1 infection, so that maintenance of adequate CD4+ T-cell levels probably depends primarily on the capacity to renew depleted lymphocytes, that is, the lymphopoiesis. We performed here a comprehensive study of quantitative and qualitative attributes of CD34+ hematopoietic progenitor cells directly from the blood of a large set of HIV-infected persons compared with uninfected donors, in particular the elderly. Our analyses underline a marked impairment of primary immune resources with the failure to maintain adequate lymphocyte counts. Systemic immune activation emerges as a major correlate of altered lymphopoiesis, which can be partially reversed with prolonged antiretroviral therapy. Importantly, HIV disease progression despite elite control of HIV replication or virologic success on antiretroviral treatment is associated with persistent damage to the lymphopoietic system or exhaustion of lymphopoiesis. These findings highlight the importance of primary hematopoietic resources in HIV pathogenesis and the response to antiretroviral treatments.

Raltegravir Intensification Therapy in Two Human Immunodeficiency Virus‐Infected Patients with Undetectable Viremia and Discordant CD4+ Response

Immunologic failure is characterized by the inability to maintain an adequate CD4+ cell count despite human immunodeficiency virus (HIV) suppression below standard limits of detection. With no consensus on the most efficacious treatment for poor immunologic response, intensification of a given antiretroviral therapy regimen with an additional antiretroviral agent has been proposed. We describe the responses to intensification therapy with raltegravir to increase CD4+ cell count in two HIV‐infected patients who were receiving optimized antiretroviral therapy but experienced discordant immunologic response. In both patients, HIV RNA remained undetectable for at least 70 weeks. The first patient demonstrated no clinically significant change in absolute CD4+ count over baseline (‐2 cells/mm3) as well as a net decrease in CD4+ percentage (‐3%). The second patient demonstrated a robust increase in absolute CD4+ count over baseline (+61 cells/mm3) and a clinically significant increase in CD4+ percentage (+3%). Therefore, conflicting immunologic responses to raltegravir intensification occurred in these two patients with undetectable HIV RNA who were receiving optimized background therapy. Management strategies for immunologic failure and results of the few studies on intensification with antiretrovirals in virologically suppressed patients are discussed. Further prospective trials confirming the immunologic benefits of raltegravir intensification are required before this strategy can be routinely recommended.

A retrospective analysis of HIV-associated Kaposi's sarcoma in patients with non-detectable HIV viral loads and CD4+ counts greater than 300 cells/μL

In the HAART era, the incidence of HIV-associated Kaposi's sarcoma (KS) has declined precipitously for countries with ready access to anti-retrovirals. Patients with newly diagnosed KS typically have low CD4+counts and high HIV viral loads (VLs). Several recently published reports (NEJM 2007;357:1352–3, NEJM 2008;358:535–6, AIDS 2008;22:551–2) suggest that patients with KS may require treatment despite effective HAART and that KS may progress even in the setting of suppressed HIV VLs and adequate CD4+ counts. To investigate this further, we examined the demographic and HIV-related clinical data of 91 KS patients attending our HIV outpatient clinic between 1996 and 2008. Twenty of the 91 patients (22%) had either newly diagnosed KS or persistent or progressive disease despite CD4+ counts >300 cells/μL and undetectable HIV VLs. Nineteen of these 20 patients were males. The median age was 43 years (range 25 to 59), the median time since onset of HIV infection was 156 months (range 24 to 276) and the median duration of HAART was 60 months (range 12 to 144). Nine (45%) patients had a KS stage of T0S0, five (25%) had T1S0, three (15%) had T0S1, three (15%) had T1S1; no patient had KS visceral involvement. All 20 patients received specific anti-KS treatment in addition to HAART including liposomal doxorubicin (65%), paclitaxel (15%), radiation (20%) and novel clinical agents (25%). After a median follow up of 52 months (range 6 to 120), eight (40%) had complete regression of KS, six (30%) had partial regression, one (5%) had stable disease and five (25%) had KS progression. In this retrospective analysis, a substantial proportion of KS patients had undetectable HIV VLs and CD4+counts greater than the level typically associated with opportunistic infections and required systemic anti-ks therapy. This raises important questions regarding the mechanisms of KS progression and the management of KS in such patients.

Maraviroc and CD4+ cell count recovery in patients with virologic suppression and blunted CD4+ cell response

We wish to comment on the recent Editorial review on maraviroc by Soriano et al.[1]. Their suggestion that the drug could be used for managing the subset of patients unable to show an adequate CD4 cell recovery despite achieving sustained virological suppression with highly-active antiretroviral therapy (HAART) [1] has been tested in a recent nonrandomized, prospective, open-label, proof-of-concept pilot study with a minimum follow-up of 150 days, where maraviroc 300 mg was added to an ongoing HAART regimen in nine HIV-infected individuals on stable HAART with HIV-1 RNA less than 50 copies/ml for at least 1 year and a stable CD4+ cell count of less than 250 cells/mm3[2]. Although two patients showed dramatic increases in CD4 cell counts (+112 and +130), the average change was +14 cells for all patients, and was not statistically significant (P > 0.39). Obviously, further studies with a longer follow-up will be required to eventually demonstrate a significant effect of maraviroc. Importantly, Soriano et al.[1] failed to discuss possible drawbacks of maraviroc use in certain HIV-infected individuals. A significant increase in CCR5Δ32 allele prevalence has been found in patients with tickborne encephalitis (TBE, an often fatal infection caused by the TBE virus, TBEV), compared with that in patients with non-TBE aseptic meningoencephalitis and in healthy control individuals seronegative for TBEV [3]. In addition, functional CCR5 seems to be required to prevent symptomatic disease after infection with West Nile virus (WNV), an RNA flavivirus that can cause neuroinvasive disease, particularly in patients with impaired cellular immunity [4]. Indeed CCR5 is specifically required for central nervous system leukocyte trafficking for the purpose of viral clearance, as shown in mouse models [5]. We think that attention needs to be drawn to this possible caveat of maraviroc use, considering the diffusion of TBEV in Eastern Europe, a region where HIV infection is still on the rise, and of WNV in USA. Acknowledgements None of the authors have any conflict of interest. Massimiliano Lanzafame, Emanuela Lattuada and Sandro Vento contributed to the concept and writing of the article. All authors have read and approved the text.

HIV-infected immunologic non-responders: can we provide a helping hand?

baseline viral load, history of opportunistic infection, co-morbidities, and age. Potential mechanisms underlying the low-level regeneration of CD4 cells in immune non-responders include deficiencies in the regeneration of central memory CD4 cells and excessive apoptosis8. Increased CD4 and CD8 T cell activation at baseline has also been correlated with poor immune responses to HAART9. In one early observational study, no association was found between a specific antiretroviral regimen and the presence of discordant responses5. In recent years, however, a number of reports have described CD4 declines or attenuated gains despite viral suppression in patients receiving a combination of didanosine and tenofovir10. While co-administration of these two agents has been shown to increase the ddI serum concentration, thereby increasing the risk of ddI-associated toxicities, the exact mechanisms leading to the CD4 effects are uncertain. The effect is diminished when a lower ddI dose is used11. Failure to increase CD4 counts may also be associated with additive myelotoxicity of antiretroviral drugs and therapies being administered for the prevention or treatment of opportunistic infection, as, for example, the additive myelosuppression of zidovudine (AZT) and trimethoprim/sulfamethoxazole (TMP/SMX). It has been postulated that ongoing, low-level viral replication, occurring below the limits of assay detection, may contribute to slowed CD4 T-cell recovery. Consequently, one approach has been to change or intensify antiretroviral regimens in an effort to more fully suppress viral replication and allow immune recovery, though available data do not support this practice. Alternative strategies aimed at improving the HIV-induced immunodeficiency utilize immune-based therapies. Potential approaches that have been studied over the years include therapy with cytokines such as interleukin-2 (IL-2), IL-12, IL-7, interpheron alpha, interpheron gamma and GM-CSF, as well as cell-transfer approaches using unmodified or genetically modified CD4 or CD8 cells. Immunosuppressive medications aiming to reduce high level immune activation thought to underlie CD4 cell turnover and death have also been studied, including cyclosporine A, anti-TNF monoclonal antibodies (etanercept), and mycophenolate mofetil. The best-studied and most promising immunotherapy agent for HIV infection that has been investigated to date is IL-2. IL-2 is a cytokine produced by T lymphocytes that is known to promote proliferation and modulate the secretory capacity of lymphocytes, including T, B, and natural killer cells. Numerous randomized trials have demonstrated that intermittent subcutaneous or intravenous administration of cycles of IL-2, in combination with antiHighly active antiretroviral therapy (HAART) has dramatically reduced the morbidity and mortality associated with HIV infection. In most patients receiving HAART, suppression of HIV replication is accompanied by recovery of CD4 T lymphocytes to near normal levels and a substantial reversal of HIV-associated immunologic defects, as is best reflected by the marked decrease in HIV-related opportunistic complications. However, immunologic recovery varies greatly between patients, and a significant proportion of those treated experience only small improvements in CD4 cell counts despite virologic suppression on HAART. These patients, who maintain virologic suppression on HAART but fail to have significant gains in CD4 T-cell counts, are referred to as immunologic non-responders. Estimates of the frequency of immunologic non-response vary depending on the definition used. Based on a number of cohort studies, 10% to 20% of treated patients fail to have an adequate CD4 count increase (e.g > 100 cells/mm3 increase over baseline or an increase to > 200-300 cells/mm3) after 6-12 months of effective HAART1-7. Whereas some patients with a poor initial immune response despite virologic suppression will go on to have an immunologic response over time, others will be stalled at a threshold that potentially puts them at increased risk for opportunistic complications. Observational cohort studies suggest that such patients do in fact have a higher rate of new AIDSdefining events or death than complete responders, though these rates are less than is seen in patients who are both immunologic and virologic non-responders2,6,7. The pathogenesis of discordant responses is poorly understood. The immunologic response to HAART is influenced by a number of viral, host, and treatment-related factors. Immune recovery depends, in part, on the extent and duration of viral load reduction, although the minimum viral suppression necessary for improved immune function and CD4 recovery is debated. Numerous other factors may influence CD4 T cell and immune recovery, including the degree of immunosuppression at HAART initiation (e.g., baseline CD4 count), duration of infection,

Sub-optimal CD4 reconstitution despite viral suppression in an urban cohort on Antiretroviral Therapy (ART) in sub-Saharan Africa: Frequency and clinical significance

BackgroundA proportion of individuals who start antiretroviral therapy (ART) fail to achieve adequate CD4 cell reconstitution despite sustained viral suppression. We determined the frequency and clinical significance of suboptimal CD4 reconstitution despite viral suppression (SO-CD4) in an urban HIV research cohort in Kampala, UgandaMethodsWe analyzed data from a prospective research cohort of 559 patients initiating ART between 04/04–04/05. We described the patterns of SO-CD4 both in terms of:- I) magnitude of CD4 cell increase (a CD4 count increase < 50 CD4 cells/μl at 6 months, <100 cells/μl at 12 months; and <200 cells/μl at 24 months of ART) and II) failure to achieve a CD4 cell count above 200 cells/μl at 6,12 and 24 months of ART. Using criteria I) we used logistic regression to determine the predictors of SO-CD4. We compared the cumulative risk of clinical events (death and/or recurrent or new AIDS-defining illnesses) among patients with and without SO-CD4.ResultsOf 559 patients initiating ART, 386 (69%) were female. Median (IQR) age and baseline CD4 counts were 38 yrs (33–44) and 98 cells/μl (21–163) respectively; 414 (74%) started a d4T-based regimen (D4T+3TC+NVP) and 145 (26%) a ZDV-based regimen (ZDV+3TC+EFV). After 6, 12 and 24 months of ART, 380 (68%), 339 (61%) and 309 (55%) had attained and sustained HIV-RNA viral suppression. Of these, 78 (21%), 151 (45%) and 166 (54%) respectively had SO-CD4 based on criteria I), and 165(43%), 143(42%) and 58(19%) respectively based on criteria II). With both criteria combined, 56 (15%) and 129 (38%) had SO-CD4 at 6 and 12 months respectively. A high proportion (82% and 58%) of those that had SO-CD4 at 6 months (using criteria I) maintained SO-CD4 at 12 and 24 months respectively. There were no statistically significant differences in the incidence of clinical events among patients with [19/100PYO (12–29)] and without SO-CD4 [23/100PYO (19–28)].ConclusionUsing criteria I), the frequency of SO-CD4 was 21% at 6 months. Majority of patients with SO-CD4 at 6 months maintained SO-CD4 up to 2 years. We recommend studies of CD4 T-cell functional recovery among patients with SO-CD4.

Mycobacterium avium complex immune reconstitution inflammatory syndrome: Long term outcomes

BackgroundTo describe long term outcomes of Mycobacterium avium complex (MAC) immune reconstitution inflammatory syndrome (IRIS).MethodsCases of MAC IRIS were retrospectively identified at four HIV clinics (Michigan, Maryland, Rhode Island, and Indiana) from 1996–2004. Patients were included if they were initially diagnosed with AIDS and found to have evidence of focal MAC infection documented by tissue culture or PCR after initiating HAART, and at least 6 months of follow up.ResultsAmong the 20 patients included, the mean age was 40 years, mean CD4 cell count was 24/mm3 at pretreatment baseline and 100/mm3 at time of MAC IRIS diagnosis. Sites of disease included lymph nodes (15 patients [8 peripheral, 8 abdominal and 1 peripheral and abdominal]), gastrointestinal tract (7) and liver (3). Sixteen patients (80%) responded to treatment and were disease free after a mean of 17.4 months of therapy for MAC IRIS; IRIS therapy was withdrawn in 6 without relapse. Four patients (non-responder group) had persistent or relapsing disease despite 27 months of ongoing MAC IRIS treatment. At the time of resolution or last follow-up, the mean CD4 cell count and viral load was 143/mm3 and 7,000 c/mL for responders, and 65/mm3 and 17,000 c/mL for non-responders, respectively. Most patients with peripheral adenopathy were responders (7/8; 88%); many with abdominal adenopathy (4/8; 50%) were nonresponders.ConclusionThe majority of patients with MAC IRIS eventually responded to treatment. Our sample size was not adequate to perform statistical analysis, but there was a tendency towards adequate CD4 response to HAART and peripheral rather than intraabdominal adenopathy among responders.

Relapse of HIV-associated nephropathy after discontinuing highly active antiretroviral therapy

F.H., a 53-year-old African American woman presented to her primary care provider with acute renal failure (creatinine 2.7 mg/dl from baseline of 1.3 mg/dl) and proteinuria (1.6 g of protein per 24 h). Her past medical history was significant only for hypertension and asthma. Evaluation revealed a positive HIV antibody and a CD4 cell count of 281 cells/μl. F.H. was started on antiretroviral therapy with zidovudine, and a renal biopsy demonstrated glomerular capillary loop collapse and a tubulointerstitial lymphocyte infiltrate with cystically dilated tubules and atrophy consistent with HIV-associated nephropathy (HIVAN). In addition to her antiretroviral therapy she was treated with an angiotensin-converting enzyme inhibitor and a course of corticosteroids. Her creatinine level peaked at 4.6 mg/dl and proteinuria was at approximately 3 g per 24 h. Over the next 3 years her creatinine and proteinuria levels stabilized as she was treated with zidovudine and lamivudine with a relatively suppressed viral load and rising CD4 cell count (see Fig. 1). In March 1999, she was started on HAART with stavudine, didanosine and efavirenz resulting in complete viral suppression and a rise in the CD4 cell count to approximately 900 copies/μl for 2 years. During this period the creatinine level declined to 1.8 mg/dl and urinary protein dropped to 500 mg per 24 h. In August 2001, F.H. discontinued HAART as a result of the side effects of therapy. Her viral load quickly rose to over 300 000 copies/ml and her renal function worsened, with a creatinine level of 3.8 mg/dl in May 2002. A renal ultrasound revealed small echogenic kidneys, consistent with chronic disease, and renal biopsy confirmed recurrent active HIVAN. F.H. was again treated with corticosteroids and HAART, now consisting of zidovudine/lamivudine/abacavir and efavirenz. Over the next 3 years her viral load was fully suppressed on this regimen and her renal function, although severely compromised, has stabilized (estimated glomerular filtration rate 15 ml/min per 1.73 m2) avoiding the need for renal replacement therapy. In addition, there was a dramatic decline in proteinuria from an estimated 5 g to 1 g per 24 h.Fig. 1: Serum creatinine (mg/dl) and urine protein to creatinine ratio (grams protein/grams creatinine) versus time, during therapy with HAART. The upper bars indicate the antiretroviral treatment regimen during the corresponding time intervals. The fluctuation in HIV viral load in relation to time and treatment is indicated in the upper graph. CD4 cell count (cells/ml) at various points in time is indicated numerically below the treatment bars. The lower graph indicates serum creatinine (▵) and urine protein to creatinine ratios (□) versus time and in relation to the ongoing treatment indicated in the upper treatment bars. ABC, Abacavir; ddI, didanosine; D4T, stavudine; EFV, efavirenz; 3TC, lamivudine; ZDV, zidovudine.Epidemiological studies have shown a correlation between increasing HIV viral load, decreasing CD4 cell count and the occurrence of proteinuria and renal failure [1], as well as a reduction in the incidence of HIVAN in patients treated with HAART [2]. Previous case reports have demonstrated a reversal of acute renal failure and histological changes on biopsy after short courses of antiretroviral therapy [3]. Several observational cohort studies have demonstrated a decreased need for renal replacement therapy for patients treated with antiretroviral therapy compared with those not so treated [4–6]. This case supports the hypothesis that HIVAN can be treated by the suppression of viral replication with HAART, and when initiated early may remove the need for renal replacement therapy and provide long-term stabilization of disease. Unlike the previous reported cases, this case suggests a risk of relapse of disease after discontinuing HAART. This suggests that a history of HIVAN alone may be an indication for indefinite HAART, even with an adequate CD4 cell count and despite mild to moderate side effects.

Long-Term Safety and Efficacy of Nevirapine-Based Approaches in HIV Type 1-Infected Patients

Using a multicenter, cross-sectional, observation study, the long-term safety, metabolic profile, and viral efficacy of nevirapine (NVP)-based approaches in HIV-1-infected patients treated for at least 2 years were assessed. For 4 months, all consecutive HIV-1-infected patients who had been receiving an NVP-containing regimen for at least 2 years were recruited. A total of 613 patients were included with a median follow-up period of 43 months (IQR: 31-51). At baseline, 24.5% (150 patients) were treatment naive, 41.5% (254 patients) switched for simplification purposes, and 34% (209 patients) were failing HAART. Increases by five times or more in AST/ALT values were observed in fewer than 2% of patients. Only 5.7% of all adverse events reported during the investigation were attributable to NVP. The percentage of patients with normal HDL cholesterol levels rose from 17.7% at baseline to 35.4% at the last visit. At the latest time point available for analysis, 76% of naive and 74% of those who had switched had HIV-1 RNA loads of <50 copies/ml, while 59% of salvage patients achieved this level of viral suppression. Factors associated with viral suppression at the latest visit were adequate adherence (OR: 2.58, 95% CI: 0.85-7.78, p < 0.001), first-line treatment (OR: 3.02, 95% CI: 1.52-6.00, p = 0.002), and baseline CD4 cells >400 cells/microl (OR: 2.34, 95% CI: 1.22-4.47, p = 0.010). Exposure to nevirapine for up to 4 years is safe. Liver toxicity is infrequent and generally mild. HDL cholesterol levels consistently increase over time and viral suppression is maintained.