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Background and Objectives: Since the introduction of highly active antiretroviral therapy (HAART), non-AIDS defining malignancies including colorectal cancer (CRC) have emerged as major health concerns for people living with HIV., Methods: From a prospective database of 11,112 HIV seropositive individuals, we identified 11 patients with CRC. Clinicopathological details on the presentation, treatment and outcomes were collected., Results: All were male with a median age of 50 years (range 36-67) and median duration of HIV infection of 7.2 years (range 0-21). Five had metastatic disease at presentation, including 1 patient with a small cell cancer of the rectum. Patients were treated along conventional lines for CRC with concomitant HAART and opportunistic infection prophylaxis. During treatment, median CD4 cell counts fell from 357/mm(3) at CRC diagnosis to 199/mm(3), although no opportunistic infections were recorded. Three patients have died and the 5-year overall survival measured 65% (95% confidence interval 32-98%)., Conclusions: Treatment for CRC reduces cellular immunity and potentially puts HIV patients at risk of opportunistic infections; knowledge of HIV status prior to starting treatment is essential. This risk may be reduced by concomitant HAART and prophylaxis. Clinicians managing CRC should consider screening patients for HIV before starting chemotherapy or radiotherapy., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

HIV-associated multicentric Castleman disease (HIV-MCD) is a rare lymphoproliferative disorder caused by infection with human herpesvirus-8. The disease follows a relapsing and remitting clinical course, with marked systemic symptoms during an active attack, which can prove fatal. Its incidence is rising, and new data indicate the utility of the anti-CD20 monoclonal antibody rituximab at inducing remissions in both first- and second-line settings, although biomarkers associated with relapse have not been previously identified. In 52 individuals with a histologic diagnosis of HIV-MCD, we performed univariate and multivariate analyses to predict factors associated with an HIV-MCD attack. Although a younger age (< 50 years) was associated with an attack, the strongest association was observed with plasma levels of human herpesvirus-8 DNA. Rising levels predicted an attack (hazard ratio = 2.9; 95% confidence interval, 1.3-6.7), and maintenance therapy with rituximab should be considered in these individuals.

Purpose: To describe clinical features, treatment outcomes and relapse rates in HIV-associated multicentric Castleman's disease (MCD) in a sizeable mature cohort., Methods: From a prospective database, we identified 61 HIV-seropositive patients with histologically confirmed MCD (median follow-up, 4.2 years). Since 2003, 49 patients with newly diagnosed MCD have been treated with rituximab with (n = 14) or without (n = 35) etoposide., Results: At MCD diagnosis, 55 (90%) of 61 patients met proposed clinical criteria defining an attack. Four patients (7%) had histologic evidence of coexisting lymphoma, and one developed lymphoma 2 years after treatment. The incidence of lymphoma is 28 per 1,000 patient years. With rituximab-based treatment, the overall survival was 94% (95% CI, 87% to 100%) at 2 years and was 90% (95% CI, 81% to 100%) at 5 years compared with 42% (95% CI, 14% to 70%) and 33% (95% CI, 6% to 60%) in 12 patients treated before introduction of rituximab (log-rank P < .001). Four of 49 rituximab-treated patients have died; three died as a result of MCD within 10 days of diagnosis, and one died as a result of lymphoma in remission of MCD. Eight of 46 patients who achieved clinical remission suffered symptomatic, histologically confirmed MCD relapse. The median time to relapse was 2 years, and all have been successfully re-treated and are alive in remission. The 2- and 5-year progression-free survival rates for all 49 patients treated with rituximab-based therapy were 85% (95% CI, 74% to 95%) and 61% (95% CI, 40% to 82%), respectively., Conclusion: HIV-associated MCD is a remitting-relapsing disease. The outlook has improved dramatically in recent years with the introduction of rituximab-based therapy and yields high overall survival rates.

CCR5 antagonists may provide a well-tolerated switch option for patients experiencing tolerability or toxicity of their antiretroviral regimen. We analyzed stored samples from patients undergoing planned treatment interruptions for reasons other than virological failure, in order to analyze tropism evolution during fully suppressive antiretroviral therapy (ART). Two of 37 patients showed evidence of switching. Tropism switching after suppressive ART was uncommon in this cohort. Pretreatment human immunodeficiency virus (HIV) RNA tropism testing may help guide the switch to CCR5 antagonists in patients with undetectable HIV RNA.

Background: Human immunodeficiency virus (HIV)-infected individuals are at increased risk for primary lung cancer (LC). We wished to compare the clinicopathologic features and treatment outcome of HIV-LC patients with HIV-indeterminate LC patients. We also sought to compare behavioral characteristics and immunologic features of HIV-LC patients with HIV-positive patients without LC., Patients and Methods: A database of 75 HIV-positive patients with primary LC in the HAART era was established from an international collaboration. These cases were drawn from the archives of contributing physicians who subspecialize in HIV malignancies. Patient characteristics were compared with registry data from the Surveillance Epidemiology and End Results program (SEER; n = 169,091 participants) and with HIV-positive individuals without LC from the Adult and Adolescent Spectrum of HIV-related Diseases project (ASD; n = 36,569 participants)., Results: The median age at HIV-related LC diagnosis was 50 years compared with 68 years for SEER participants (P < .001). HIV-LC patients, like their SEER counterparts, most frequently presented with stage IIIB/IV cancers (77% vs. 70%), usually with adenocarcinoma (46% vs. 47%) or squamous carcinoma (35% vs. 25%) histologies. HIV-LC patients and ASD participants had comparable median nadir CD4+ cell counts (138 cells/µL vs. 160 cells/µL). At LC diagnosis, their median CD4+ count was 340 cells/µL and 86% were receiving HAART. Sixty-three HIV-LC patients (84%) received cancer-specific treatments, but chemotherapy-associated toxicity was substantial. The median survival for both HIV-LC patients and SEER participants with stage IIIB/IV was 9 months., Conclusion: Most HIV-positive patients were receiving HAART and had substantial improvement in CD4+ cell count at time of LC diagnosis. They were able to receive LC treatments; their tumor types and overall survival were similar to SEER LC participants. However, HIV-LC patients were diagnosed with LC at a younger age than their HIV-indeterminate counterparts. Future research should explore how screening, diagnostic and treatment strategies directed toward the general population may apply to HIV-positive patients at risk for LC.

AIDS-associated lung cancer has an increasing incidence, unaccounted for by smoking, and occurs consistently at a younger age than matched controls. We investigated whether known and new cancer-associated polyomaviruses, including the newly identified Merkel cell virus, may play a role in its etiopathogenesis. Although viruses target conserved pathways in cellular evolution, we are unable to suggest that the viruses studied here induce novel mechanisms of oncogenic dysregulation in AIDS-associated lung cancer.

Therapy for infection with HIV-2 remains limited. We report an HIV-2-infected patient in whom genotyping demonstrated PI, NRTI and NNRTI resistance, with a subsequent response to raltegravir- and maraviroc-based therapy. Further studies are required to assess the clinical efficacy of maraviroc in HIV-2 infection.

Background: As human immunodeficiency virus (HIV)-infected individuals are living longer, non-AIDS-defining cancers are becoming increasingly recognized. Primary esophageal tumors in people living with HIV have seldom been reported. We sought to document patient, virologic, and tumor characteristics and clinical outcomes in this patient group., Methods: International physicians involved in the care of AIDS-defining and non-AIDS-defining cancers accrued cases of primary esophageal malignant neoplasms in HIV-infected individuals. Patient demographics, HIV status, cancer risk factors, esophageal tumor characteristics, treatment, and outcomes were analyzed., Results: A total of 19 patients with primary adenocarcinoma and/or squamous cell carcinoma of the esophagus were identified. The median age was 48 years (range, 35-69 years) and the median CD4 lymphocyte count measured 376 cells/microL (range, 42 to >1000 cells/microL) (to convert to x10(9)/L, multiply by 0.001). The majority of patients were men with a history of smoking or considerable alcohol consumption. Prior esophageal disease (reflux, peptic ulcers, and achalasia) was reported in almost half of all patients. Seven patients (37%) underwent surgical resection, 11 (58%) received fluorouracil-based chemotherapy, and 7 (37%) underwent radiotherapy; survival correlated with stage at cancer presentation. While the majority of patients died, only 5 deaths (26%) were attributed to progression of esophageal carcinoma., Conclusions: Primary esophageal carcinoma is another non-AIDS-defining cancer associated with moderate immunosuppression and lifestyle habits including tobacco and alcohol use. The biological behavior, treatment, and outcome of HIV-related esophageal cancer appear similar to the general population with this disease; the same screening and risk moderation strategies are likely to apply.

Objectives: We wished to determine the efficacy of nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens in antiretroviral-naive patients commencing highly active antiretroviral therapy (HAART) and to evaluate the effect of calendar year, nucleoside analogue reverse transcriptase inhibitor (NRTI) backbone, sex, and ethnicity on treatment outcome., Methods: Antiretroviral-naive individuals commencing efavirenz or nevirapine with dual-nucleoside analogue backbones were identified from a prospective database. Virological success was defined as HIV viral load <500 copies per milliliter. Treatment failure was defined as a switch or discontinuation of NNRTI or documented virological failure (2 measurements with viral load >500 copies/mL)., Results: From a cohort of 994 individuals, 73% commenced efavirenz- and 27% nevirapine-containing regimens. We found no differences between the 2 treatment groups for the time to virological success (proportion with virological success: efavirenz 71%, nevirapine 72%, P = 0.77) or treatment failure (proportion failing treatment: efavirenz 23%, nevirapine 26%, P = 0.58). There was a significant difference in the calendar year for commencing HAART for the time to virological success and treatment failure (P < 0.001). In the multivariable model, the likelihood of virological success for stavudine/lamivudine was 52% [relative hazard (RH) 1.52, 95% confidence interval (CI) 1.17 to 1.97, P = 0.002]. The nonthymidine analogue backbones as a group seemed to be least likely associated with virological success (RH 0.62, 95% CI 0.48 to 0.80, P < 0.001). This was however largely driven by tenofovir/didanosine being significantly associated with treatment failure (RH 6.48, 95% CI 3.81 to 11.0, P < 0.001). Sex and ethnicity were not associated with treatment outcome., Conclusions: We found no significant differences between nevirapine and efavirenz for the time to virological success or treatment failure. Calendar year of commencing HAART and NRTI backbones were significant predictors of virological success and treatment failure, explaining differences in data to the 2NN study. The weaker the NNRTI (or the weaker the protease inhibitor) the more important the NRTI backbone becomes.

Recent data highlight the importance of inflammatory markers during human immunodeficiency virus type 1 (HIV) infection. HIV-associated multicentric Castleman disease (HIV-MCD) presents with systemic symptoms attributed to cytokine disarray, and we have previously shown that the use of the anti-CD20 monoclonal antibody rituximab induces clinical remissions. Before and during successful rituximab therapy, 15 plasma cytokines were measured as were adaptive (CD4, CD8, CD19) and innate (CD16/56) immune cell populations and HIV-1 viral loads. A significant reduction from baseline of the CD19 B-cell count, consistent with rituximab's mechanism of action, was observed. Markedly elevated cytokine levels were observed before rituximab therapy, and a reduction from baseline values with rituximab therapy was observed for interleukin (IL)-5, IL-6, and IL-10. Therapies that reduce the inflammatory cytokine response are likely to be successful in a range of diseases, including HIV-MCD, and in the future may be used to guide therapeutic strategies.

Purpose: The effect of highly active antiretroviral therapy (HAART) on the incidence of non-AIDS-defining cancers (NADCs) is unclear., Methods: We have investigated the occurrence of NADCs in a prospective cohort of 11,112 HIV-positive individuals, with 71,687 patient-years of follow-up. Standardized incidence ratios (SIRs) were calculated using general population incidence data. We investigated the effect of calendar period, HIV parameters, and immunologic and treatment-related factors on the incidence of these cancers using univariate and multivariate analyses., Results: The SIR for all NADCs was 1.96 (95% CI, 1.66 to 2.29). There was no significant excess in incidence in the pre-HAART era (1983 to 1995; SIR, 0.95; 95% CI, 0.58 to 1.47). However, the incidence increased in the early HAART period (1996 to 2001) and remains elevated in the most recent established HAART period (2002 to 2007; SIR, 2.05; 95% CI, 1.51 to 2.72, and SIR 2.49; 95% CI, 2.00 to 3.07, respectively). Multivariate analysis showed that use of HAART (hazard ratio [HR] = 1.64; 95% CI, 1.13 to 2.39) and a nadir CD4 count less than 200/microL (HR = 1.67; 95% CI, 1.10 to 2.54) were associated with an increased risk. Only the non-nucleoside reverse transcriptase inhibitors (NNRTIs) were associated with a significantly increased risk of NADCs (HR = 1.45; 95% CI, 1.01 to 2.08). Much of this association was attributable to an increased risk of Hodgkin's lymphoma with NNRTIs (HR = 2.20; 95% CI, 1.03 to 4.69)., Conclusion: Since the introduction of HAART, there has been a significantly increased risk of NADCs, which has now stabilized. A number of factors are associated with this increased risk, including HAART use. There may be an association between the use of NNRTIs and the development of Hodgkin's lymphoma.

Objective: The spectrum of diseases associated with human immunodeficiency virus (HIV) infection has changed dramatically following the introduction of highly active antiretroviral therapy (HAART). Non-AIDS-defining cancers, including renal cell carcinoma (RCC), are being recognized increasingly in this population. Our aim was to describe the risk factors, clinical findings, pathology, and response to therapy of RCC in patients infected with HIV., Patients and Methods: We identified 9 men with HIV infection who developed RCC. Data regarding their HIV status, RCC risk factors, clinical presentation, and pathology were collected. A detailed retrospective chart review focusing on the course of their malignancy, response to therapy, and outcome was performed., Results: Renal cell carcinoma was diagnosed in patients with a median age of 48 years, and most had a history of tobacco use. No association between HIV-related immunosuppression (mean CD4 count, 301 cells/mm3) and the development, clinical presentation, pathology, or behavior of RCC was identified. Long-term survival correlated with early nephrectomy, and the use of interleukin-2 therapy for advanced RCC was not additive. A total of 5 patients died, 1 from a pulmonary embolism and 4 from disseminated RCC., Conclusion: Renal cell carcinoma should be included in the expanding array of non-AIDS-defining malignancies that develop during the course of HIV infection. Acknowledging the inherent limitations of our small study, these data show that the clinical presentation and behavior of RCC in patients with HIV appear similar to that of the HIV-negative population and that chronic immunosuppression plays a lesser role than age and exposure to risk factors in this setting.

There are few data regarding hepatitis and HIV coinfection in Africa. In 378 HIV seropositive individuals in Nairobi, 23 (6%) were hepatitis B virus (HBV) and HIV coinfected, four (1%) were hepatitis C virus (HCV) and HIV coinfected and one patient was infected with all three viruses. Coinfected individuals were more likely to be men and older; a lack of HBV vaccination was a risk factor for HIV/HBV coinfection (P = 0.001) and tenofovir containing regimens appeared most effective at reducing HBV viral load.

Multicentric Castleman's disease (MCD), a relatively rare lymphoproliferative disorder that presents with heterogenous symptoms including fevers, anemia, and multifocal lymphadenopathy, is today most commonly observed in individuals infected with human immunodeficiency virus type-1 (HIV). In such individuals, a lymph node biopsy typically identifies cells that stain for Kaposi's sarcoma-associated herpesvirus proteins, and most HIV-associated MCD features can be attributed to the presence of this gamma-herpesvirus. Surgery and antiviral therapies including highly active antiretroviral therapy, interferon-alpha, foscarnet, ganciclovir, and antibodies to interleukin-6 have proved largely ineffective, and chemotherapy in HIV positive individuals is complicated by limited efficacy and pronounced toxicity. While no randomized trials have been performed, more recently the use of the anti-CD20 monoclonal antibody rituximab in large single center cohorts has been associated with prolonged remissions, radiologic responses, as well as hematologic and serum chemistry normalization of the inflammatory picture observed, at the expense of B cell depletion and flare of Kaposi's sarcoma. MCD represents a model of disease at the interplay between tumor biology, infection, and immunology., (Copyright 2008 Wiley-Liss, Inc.)

Purpose: Preclinical and cohort studies suggest that certain antidepressants are associated with a predisposition to cancer whereas others decrease the risk. We aimed to assess whether different classes of antidepressants were associated with changes in cancer incidence in a population of HIV-1 infected individuals, based on duration of exposure., Methods: Antidepressant exposure was measured from date of first prescription of the antidepressant until the date of last follow-up or cancer diagnosis. Univariate and multivariate analyses were performed to establish the risk of AIDS-related cancers and non-AIDS-related cancers according to whether patients were receiving selective serotonin reuptake inhibitors, tricyclic antidepressants, or other medicines for depression. We analyzed data for time exposed to antidepressants, before and during the era of highly active antiretroviral therapy (HAART)., Results: From a cohort of 10,997 patients representing 52,656 years of follow-up attending a large HIV center during the pre-HAART and HAART eras, a total of 2,004 (18%) were prescribed antidepressants representing 15,850 years exposed. A total of 1,607 (15%) individuals were diagnosed with cancer. There were no significant associations between any class of antidepressant and any type of cancer (P = .19), in either the pre-HAART or HAART era (P = .23), and use of serotonin reuptake inhibitors did not alter the risk of Burkitt lymphoma., Conclusion: Antidepressants, irrespective of their class, do not affect cancer risk in HIV-infected individuals.

The L74V and K65R mutations confer resistance to several nucleoside analogues, and the impact on subsequent regimens is unclear. The risk of developing L74V or K65R mutation in the era of highly active antiretroviral therapy (HAART) was 4.5 and 2.8 cases per 100 person-years, respectively; concomitant receipt of boosted protease inhibitors protected against K65R. High rates of virologic suppression in the presence of either mutation were observed if the next regimen contained at least 2 active agents. If suboptimal HAART was used, patients with K65R experienced significantly higher rates of virologic suppression than did those with L74V (P = .01).

Background: HIV-associated multicentric Castleman disease is a rare lymphoproliferative disorder with marked systemic symptoms attributed to cytokine disarray. Many therapeutic approaches in small series of patients have proved largely unsuccessful to date., Objective: To investigate the efficacy and clinicopathologic variables associated with first-line treatment for HIV-associated multicentric Castleman disease with the anti-CD20 monoclonal antibody rituximab., Design: Single-group, open-label, phase II trial., Setting: 3 teaching hospitals in England., Patients: Previously untreated patients with histologically proven HIV-associated multicentric Castleman disease., Intervention: 4 infusions of rituximab, 375 mg per m2 of body surface area, at weekly intervals., Measurements: Response was evaluated clinically and radiologically and by measuring plasma Kaposi sarcoma-associated herpesvirus viral load., Results: 21 consecutive patients (18 men) with plasmablastic multicentric Castleman disease were recruited. The median follow-up was 12 months (range, 1 to 49 months). One patient died before completing therapy, 20 achieved remission of symptoms, and 14 (67%) achieved a radiologic response. The overall and disease-free survival rates at 2 years were 95% (95% CI, 86% to 100%) and 79% (CI, 49% to 100%), respectively. Plasma acute-phase proteins, immunoglobulins, and Kaposi sarcoma-associated herpesvirus viral load decreased after rituximab therapy. The main adverse effect was reactivation of Kaposi sarcoma., Limitation: The study had no comparison group., Conclusion: Rituximab may be clinically valuable as initial therapy for HIV-associated multicentric Castleman disease.

Few data exist regarding the resistance profile in individuals receiving atazanavir. We found that ritonavir-boosted atazanavir is not associated with the development of primary genotypic resistance in individuals failing this combination, without previous protease inhibitor failure. It is rarely associated with the acquisition of primary mutations in individuals with previous protease inhibitor exposure. This is particularly important because of the increasing use of atazanavir monotherapy, and implies that treatment failure is caused by lack of potency.

A number of cancers occur with increased frequency in individuals with HIV infection. There is a debate as to whether or not hepatocellular cancer is one of these tumors. This article reviews the current data regarding incidence etiology, treatment and outcome for HIV-related hepatocellular cancer. It also attempts to predict future areas of importance in the management of these patients in the era of highly active antiretroviral therapy.

The involvement of the CNS in individuals with non-Hodgkin's lymphoma is a well-recognised complication. Despite the progress that has been made in controlling cancer at most sites in the body, the outcome of individuals affected by meningeal infiltration is dismal and few patients survive for more than a few months. There are few studies that have addressed the management of CNS disease in AIDS-associated non-Hodgkin's lymphoma, and treatment algorithms have been formulated secondary to protocols in immunocompetent individuals. The prevention and treatment of CNS disease is an important aspect of lymphoma management, and new medications, such as a sustained-release formulation of intrathecal cytarabine, will have an increasingly relevant role.

Physicians prescribing drugs are routinely confronted with the balance between efficacy and toxicity. Pharmacogenetics involves the study of how inheritance influences response to drugs, and its goal is to enable the appropriate selection of these individuals, thus eliminating unpredictable responses. Pharmacogenetics can be used to identify target populations that either will have minimal benefit or a better outcome including better survival or improvement in surrogate end points. As we move towards common use of targeted therapies, the future of medicine will involve an examination of the interplay between multiple genetic factors, as the response to drugs is likely to be complex and polyfactorial especially in chronic diseases. There has already been some success in situations where single genes play a large role in the overall drug response, and this is discussed with reference to commonly used cytotoxics and anti-retrovirals, encompassing the major principles of pharmacogenetics.

Few genetic markers are used routinely to predict clinical effectiveness and toxic effects despite the fact that physicians and their patients are consistently confronted with this balance. Because one of the goals of pharmacogenomics is to identify individuals and target populations that might have adverse outcomes, pharmaceutical companies have been reluctant to use a strategy that might identify patients who are not eligible for a particular treatment. This view is changing because drug-discovery programmes and treatments that target specific pathways, are showing improvements in surrogate and survival endpoints. HIV and cancer are now regarded as chronic diseases, which commonly need life-long systemic treatment from the time of diagnosis. HIV and cancer medicine have used pharmacogenomics to some extent in clinical care. Common and classic features of pharmacogenomics that are related to both antiretroviral treatment and to cytotoxic treatment are discussed in this review, providing a framework for individual treatment of these diseases.

Fewer than one million HIV infected individuals are currently receiving antiretroviral therapy. Present antiretroviral therapy costs between 10,000 dollars and 20,000 dollars per year, which provides excellent value for money in developed countries with a cost of about 10,000 dollars per life year saved; this compares very favourably with other therapies in chronic use. Recent studies have demonstrated a dramatic decline in HIV and AIDS related morbidity and mortality across developed countries and these reductions have been sustained since the introduction of highly active antiretroviral therapy (HAART) since 1996. The use of HAART has been associated with specific toxicities related to the drug class, problems with adherence with the subsequent emergence of viral isolates and resistance associated mutations. The replacement of older therapies with newer drugs that avoid cross resistance even within the same class of antiretroviral, represents a new hope in retroviral targeting.

Human immunodeficiency virus type 1 (HIV-1) appears to adversely affect hepatitis C, but whether hepatitis C virus (HCV) has a reciprocal effect on HIV-1 infection remains a point of controversy. In a multivariate analysis of a cohort of 5832 individuals, we found that individuals coinfected with HCV and HIV-1 (prevalence of coinfection, 5.8%) had a CD4+ cell count that decreased at a rate similar to that for individuals infected with HIV-1 alone. However, coinfection was associated with a statistically significant increased likelihood of onset of an acquired immunodeficiency syndromedefining illness or developing a CD4+ cell count of <200 cells/mm3, compared with infection with HIV-1 alone (hazard ratio, 1.52; 95% confidence interval, 1.072.17). Patients who were naive to highly active antiretroviral therapy were significantly less likely to progress to either end point, because of their higher CD4+ cell counts. In conclusion, there was an increased number of adverse events in coinfected individuals, compared with individuals infected with HIV-1 alone.

Immunosuppression induced by the human immunodeficiency virus (HIV) increases the risk of developing non-Hodgkin's lymphoma (NHL). As the hepatitis C virus (HCV) has been implicated in the development of B cell lymphomas, we compared the incidence of systemic NHL during HIV infection compared to HIV and HCV co-infection. Of 5,832 individuals studied during the era of highly active anti-retroviral therapy (HAART), 102 patients were diagnosed with systemic NHL. The incidence of systemic NHL was 6.9 of 10(4) patient years during HIV infection compared to 7.1 of 10(4) patient years during HIV alone (p = 0.9). In this immunocompromised patient population, there was no association between HCV infection and an increased risk of lymphoma., ((c) 2005 Wiley-Liss, Inc.)

Cluster of differentiation (CD) antigens are expressed on cells of myeloid and lymphoid lineages. As most disease processes involve immune system activation or suppression, these antigens offer unique opportunities for monitoring host responses. Immunophenotyping using limited numbers of CD antigens enables differentiation states of immune system cells to be determined. Extended phenotyping involving parallel measurement of multiple CD antigens may help identify expression pattern signatures associated with specific disease states. To explore this possibility we have made a CD monoclonal antibody array and scanner, enabling the parallel immunophenotyping of leukocyte cell suspensions in a single and rapid analysis. To demonstrate this approach, we used the specific example of patients infected with human immunodeficiency virus type-1 (HIV-1). An invariant HIV-induced CD antigen signature has been defined that is both robust and independent of clinical outcome, composed of a unique profile of CD antigen expression levels that are both increased and decreased relative to internal controls. The results indicate that HIV-induced changes in CD antigen expression are disease specific and independent of outcome. Their invariant nature indicates an irreversible component to retroviral infection and suggests the utility of CD antigen expression patterns in other disease settings.

The significantly higher surface expression of the surface heat-shock protein receptor CD91 on monocytes of human immunodeficiency virus type-1 (HIV-1)-infected, long-term nonprogressors suggests that HIV-1 antigen uptake and cross-presentation mediated by CD91 may contribute to host anti-HIV-1 defenses and play a role in protection against HIV-1 infection. To investigate this further, we performed phenotypic analysis to compare CD91 surface expression on CD14(+) monocytes derived from a cohort of HIV-1-exposed seronegative (ESN) subjects, their seropositive (SP) partners, and healthy HIV-1-unexposed seronegative (USN) subjects. The median fluorescent intensity (MFI) of CD91 on CD14(+) monocytes was significantly higher in ESN compared with SP (P = 0.028) or USN (P = 0.007), as well as in SP compared with USN subjects (P = 0.018). CD91 MFI was not normalized in SP subjects on highly active antiretroviral therapy (HAART) despite sustainable, undetectable plasma viraemia. Data in three SP subjects experiencing viral rebounds following interruption of HAART showed low CD91 MFI comparable with levels in USN subjects. There was a significant positive correlation between CD91 MFI and CD8(+) T cell counts in HAART-naïve SP subjects (r = 0.7, P = 0.015). Increased surface expression of CD91 on CD14(+) monocytes is associated with the apparent HIV-1 resistance that is observed in ESN subjects.

The use of highly active antiretroviral therapy (HAART) has led to the emergence of viral isolates with resistance-associated mutations. Currently, new cases of highly resistant HIV infections associated with rapid progression to AIDS are being reported. The features of a new drug for HIV treatment must include selective potent activity against wild-type virus as well as against mutant virus that has been selected by the use of current antiretroviral treatment regimens. As patients in industrialised countries may live with HIV infection for decades, new drugs must also encourage adherence with simplified dosing regimens associated with favourable toxicity profiles. The replacement of older therapies with newer drugs that avoid cross resistance, even within the same class of antiretroviral, represents a new hope in retroviral targeting.

Cell adhesion molecules are involved in a diverse array of cellular processes. Recent data suggests that human immunodeficiency virus (HIV-1) co-opts their functions, in particular the properties of the intercellular cell adhesion molecules (ICAMs), to enhance viral infection and transmission. To investigate mechanisms that may underlie the non-progression that occurs in immunodeficiency virus-infected chimpanzees, we amplified the protein coding regions of multiple non-human primate ICAMs 1-5 and two ICAM ligands, leukocyte function-associated antigen-1 (LFA-1) and macrophage antigen 1 (Mac-1). We then employed a phylogenetic tree-based approach to comparative genomics, in order to screen for the presence of adaptive changes. Strong Darwinian positive selection in chimpanzee ICAMs 1, 2 and 3 was observed, most markedly in domains that are critical for the integrity and maintenance of ICAM-1 dimerization. As binding of ligands, including the attachment of virions, is influenced by the state of ICAM 1 dimerization, chimpanzee ICAMs may have evolved to modulate their own dimerization. In concert with previous evidence suggesting an ancient retroviral pandemic as a prominent selective force in chimpanzee evolution, adaptation of chimpanzee ICAMs may have effected a mechanism that explains the lack of immunosuppression observed following HIV-1 or simian immunodeficiency virus (SIVcpz) infection.

Background: Evidence from randomized controlled trials supports the use of triple therapy. Research is required on the effectiveness of quadruple therapy in comparison to this and the relative effectiveness of specific highly active antiretroviral therapy (HAART) combinations., Methods: Antiretroviral-naive individuals (n = 53) with an HIV-1 viral load >100 000 copies/mL were randomized to receive three-drug HAART with zidovudine/lamivudine (Combivir) and efavirenz or quadruple therapy with zidovudine/lamivudine/abacavir (Trizivir) and efavirenz (quad regimen). Patients continued on HAART for 48 weeks with regular clinical and immunological assessment. Standard and ultrasensitive (<5 copies/mL) viral load testing was carried out., Results: A DAVG (difference in averages) analysis of the fall in viral load and increase in CD4 count showed no significant differences between regimens. Triple therapy resulted in a -4.17 log change (95% CI, -4.48 to -3.85) and quadruple therapy in a -4.36 log change (95% CI, -4.68 to -4.03) in viral load. For CD4 counts, the triple therapy arm increased by 164 cells/mm(3) (95% CI 112-217) and the quadruple arm by 185 (95% CI, 133-237). In an intent-to-treat analysis, 77% of patients in the triple therapy group reached an undetectable viral load (<50 copies/mL) compared with 84.2% of the quadruple therapy group. For ultrasensitive viral load testing, 23% and 18% of each group, respectively, reached undetectable viral loads. The hazard ratio for attaining a viral load of <5 copies/mL was 0.59 (95% CI, 0.26-1.33) for quadruple versus triple therapy. Three individuals in the triple therapy arm and nine in the quadruple therapy arm discontinued treatment., Conclusions: No differences in any analyses were observed between a standard of care regimen (zidovudine/lamivudine and efavirenz) and the quad regimen (zidovudine/lamivudine/abacavir and efavirenz).