B Gazzard

British HIV Association guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008

This summary document is an update to the full British HIV Association (BHIVA) Treatment Guidelines published in HIV Medicine in July 2005 (Volume 6, Supplement 2). Only the ‘What to start with’ and ‘Treatment-experienced patients’ sections have been completely rewritten. The tables of recommendations (Tables 1–7) have also been updated to include new data. Please refer to the full guidelines for more information.

Immune Reconstitution Inflammatory Syndrome Associated With Kaposi's Sarcoma

PURPOSE A proportion of patients with HIV infection who subsequently receive highly active antiretroviral therapy (HAART) exhibit a deterioration in their clinical status, despite control of virologic and immunologic parameters. This clinical response, known as the immune reconstitution inflammatory syndrome (IRIS), occurs secondary to an immune response against previously diagnosed pathogens. PATIENTS AND METHODS From our cohort of 5,832 patients treated in the HAART era, we identified 150 therapy-naive patients with a first presentation of Kaposis sarcoma (KS). Their clinicopathologic features and progress were recorded prospectively. RESULTS After commencing HAART, ten patients (6.6%) developed progressive KS, which we identify as IRIS-associated KS. In a comparison of these individuals with those whose KS did not progress, we found that IRIS-KS occurred in patients with higher CD4 counts (P = .03), KS-associated edema (P = .01), and therapy with both protease inhibitors and non-nucleosides together (P = .03). Time to treatment failure was similar for both groups, although the CD4 count declined more rapidly at first, in those patients with IRIS-associated KS. Despite this initial decline, in our clinical experience HAART could be successfully continued in those with IRIS-associated KS. CONCLUSION We have identified IRIS-KS in a cohort of HIV patients with KS who start HAART.

Loss of Discrete Memory B Cell Subsets Is Associated with Impaired Immunization Responses in HIV-1 Infection and May Be a Risk Factor for Invasive Pneumococcal Disease

Invasive pneumococcal infection is an important cause of morbidity and mortality in HIV-1-infected individuals. B cells play an important role in maintaining serologic memory after infection. IgM memory B cells are significantly reduced in HIV-1-infected patients and their frequency is similar to that observed in other patient groups (splenectomized individuals and patients with primary Ab deficiency) who are also known to have an increased risk of invasive pneumococcal infection. Antiretroviral therapy does not restore marginal zone B cell percentages. Immunization with the 23-valent polysaccharide pneumococcal vaccine shows that HIV-1-infected patients have impaired total IgM and IgG pneumococcal vaccines compared with healthy controls. Loss of switched memory B cells was associated with impaired tetanus toxoid IgG vaccine responses. Results of this study demonstrate that defects in B cell memory subsets are associated with impaired humoral immune responses in HIV-1 patients who are receiving antiretroviral therapy and may be a contributory factor to the increased risk of invasive pneumococcal infection observed in HIV-1 infection.

Brief Communication: Rituximab in HIV-Associated Multicentric Castleman Disease

Context Castleman disease is a rare lymphoproliferative condition. Risk for the condition is elevated in people with HIV infection. Case reports and series suggest that rituximab shows some therapeutic promise in patients previously treated with chemotherapy, but data on initial therapy with rituximab are lacking. Contribution This uncontrolled case series suggests that initial treatment with rituximab can achieve better overall and disease-free survival than that anticipated in untreated patients. Laboratory measures improved with therapy. Caution The absence of a control group precludes definitive assessment of the efficacy or safety of rituximab in treating HIV-associated Castleman disease. The Editors Multicentric Castleman disease is a rare lymphoproliferative disorder that is increasingly occurring in people with HIV infection. It is associated with Kaposi sarcoma, sharing an etiologic agent, Kaposi sarcomaassociated herpesvirus (KSHV), also known as human herpesvirus-8 (1, 2). The gold-standard therapy for HIV-associated multicentric Castleman disease is yet to be established. The use of an anti-CD20 monoclonal antibody, rituximab, to target KSHV-infected plasmablasts in multicentric Castleman disease is a novel and potentially beneficial approach. It has been the subject of case reports and clinical series, in which patients were often pretreated with chemotherapy and follow-up was brief (310). We investigated the efficacy and safety of rituximab as initial monotherapy and correlate clinical findings with immune subset, plasma cytokine, and HIV and KSHV virologic variables. Methods Between 2003 and 2006, 21 patients (18 men) with multicentric Castleman disease were treated prospectively in a nonrandomized, open-label, phase II study with 4 infusions of rituximab at a standard dose of 375 mg per m2 of body surface area at weekly intervals. All biopsy specimens were reviewed and confirmed to be plasmablastic variants of multicentric Castleman disease with no microlymphoma, as defined by previous studies (11, 12). The plasmablasts showed immunoglobulin light chain restriction, were KSHV latent nuclear antigenpositive, and expressed CD20 on immunohistochemistry. Patients were recruited from 3 HIV and cancer centers, where local ethics review committees approved the study and patients gave informed consent. Toxicity was recorded at each visit and was graded by using the Common Terminology Criteria for Adverse Events, version 3.0 (13). We measured plasma KSHV DNA viral load at diagnosis and at 1 and 3 months after rituximab therapy by using Lightcycler quantitative polymerase chain reaction (Roche, Lewis, United Kingdom) on DNA extracted from whole blood using primers specific to KSHV ORF-7 gene, as described elsewhere (14). We assessed progression-free and overall survival by using the KaplanMeier method (15) and used the Wilcoxon rank-sum test to assess the statistical significance of changes in hematologic, biochemical, and immunologic variables. Summaries of data that were not normally distributed are presented as medians with interquartile ranges. All P values are 2-sided (Statview, version 4.57, Abacus Concepts, Berkeley, California). Role of the Funding Source Support for the cytokine assays was provided by St. Stephens AIDS Trust, a national charity supporting clinical research in HIV/AIDS, which had no role in the design, conduct, or reporting of this review or in the decision to publish the manuscript. Results We enrolled 21 patients with a histologically confirmed plasmablastic variant of multicentric Castleman disease without microlymphoma. Their median age was 37 years (range, 31 to 69 years), 9 (43%) patients had a previous AIDS-defining diagnosis, and 13 (62%) patients were receiving highly active antiretroviral therapy (HAART) at diagnosis of multicentric Castleman disease. The median CD4 cell count at diagnosis was 0.30109 cells/L (range, 0.08 to 0.73109 cells/L). Four patients had a plasma HIV-1 viral load less than 50 copies/mL, and 5 other patients had a viral load less than 400 copies/mL (Table 1). Table 1. Hematologic, Biochemical, and Immunologic Variables at Presentation and Change from Baseline 1 Month after Completion of Rituximab Therapy* At diagnosis, the median duration of symptoms was 4 months (range, 0.5 to 24 months), all patients had significant lymphadenopathy, 20 (95%) patients had fever of unknown origin, 18 of 20 (90%) patients had splenomegaly (1 had had splenectomy), and 11 (52%) patients had cutaneous Kaposi sarcoma. Ninety-five percent of the patients had an increased erythrocyte sedimentation rate (ESR) (>20 mm/h), 82% had an increased C-reactive protein (CRP) level (>10 mg/L), 67% were anemic (hemoglobin level <100 g/L), 67% were hypoalbuminemic (serum albumin level <30 g/L), and 14% were thrombocytopenic (platelet count <100109 cells/L). All patients had polyclonal hypergammaglobulinemia, and 2 patients had a serum IgG monoclonal paraprotein band (Table 1). One patient who was receiving intensive care at diagnosis died of progressive disease before completing the rituximab course. All 20 remaining patients achieved resolution of symptoms and fever by the end of rituximab treatment. Of the 21 patients, 14 (67%) had a partial response and 6 (29%) had stable disease according to the radiologic Response Evaluation Criteria in Solid Tumors. The median follow-up was 12 months (range, 1 to 49 months). The 2-year overall survival rate was 95% (95% CI, 86% to 100%), and the relapse-free survival rate was 92% (CI, 75% to 100%) at 1 year and 79% (CI, 52% to 100%) at 2 years. One month after completion of rituximab therapy, 0 of 20 patients were anemic, 0 of 20 were thrombocytopenic, 11 of 17 had an increased ESR, 2 of 16 had an increased CRP level, and 1 of 20 had hypoalbuminemia. Hemoglobin level, platelet count, and serum albumin level increased, whereas ESR and CRP level decreased, 1 month after rituximab treatment (Table 1). Quantitative polymerase chain reaction for KSHV was available for 11 patients at diagnosis and was detectable in 9 patients (median, 700 copies/mL; range, 0 to 400000 copies/mL). One month after treatment, only 2 of 10 (20%) patients had detectable KSHV (Table 1). In both cases, the titer was only 100 copies/mL. Three months after rituximab therapy, only 1 of 10 (10%) patients had detectable KSHV DNA, and once again the titer was only 100 copies/mL (P= 0.018). Serum IgG and IgM levels decreased 1 month after rituximab therapy, but IgA levels did not change (Table 1). Similarly, the CD19 cell count decreased, which persisted at 3 months (median decrease from baseline, 104 cells/mL; interquartile range, 14 to 350 cells/mL; P= 0.002), but the CD19 cell count had recovered to prerituximab levels by 12 months. We performed immune subset analysis on the 13 patients who were already receiving HAART at the time of rituximab therapy. The CD4, CD8, CD56 (natural killer) cell subsets, or HIV viral load did not change during this period. No Common Terminology Criteria for Adverse Events grade 3 or 4 toxicities were recorded with rituximab therapy; however, Kaposi sarcoma progressed during rituximab therapy in 4 of 11 (36%) patients who had cutaneous Kaposi sarcoma at diagnosis. We also measured 15 plasma cytokines: interleukin (IL)1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 p40/p70, IL-13, IL-15, IL-17, interferon-, interferon-, tumor necrosis factor-, and granulocyte macrophage colony-stimulating factor, before and after rituximab therapy and again 3 months after the completion of rituximab therapy. Most patients had elevated plasma cytokine levels at presentation, and the proportion with increased levels declined on completion of therapy (Table 2). Table 2. Proportion of Patients with Elevated Plasma Cytokine Levels at Diagnosis and Changes during Treatment* Discussion Rituximab therapy seems to be a promising first-line treatment for HIV-associated multicentric Castleman disease: Patients completing 4 weekly infusions achieved a clinical and biochemical remission within 1 month, and the radiologic response rate was 67%. Plasma KSHV viral load significantly decreased in individuals with this measurement (P= 0.018). The 2-year overall survival rate was 95% (CI, 86% to 100%), and the relapse-free survival rate was 79% (CI, 52% to 100%). This compares favorably with the median survival of 14 months recorded for 20 patients from the pre-HAART era (16). The clinical response to rituximab occurred within 1 month of completing therapy, and normalization of acute-phase inflammatory markers, such as ESR, CRP, and albumin, occurred by this point. Plasma KSHV DNA viral load was measured before, during, and after treatment and decreased dramatically with treatment and increased at relapse. The high plasma titers of KSHV reflect lytic replication, which is not a feature of Kaposi sarcoma but correlates with disease activity in multicentric Castleman disease. Indeed, KSHV-infected B-lymphocytes from lymph nodes in patients with multicentric Castleman disease are known to express KSHV lytic gene products (17, 18). Rituximab produced a decrease in CD19-positive B-lymphocytes, as would be expected, but was well tolerated in patients with HIV-related multicentric Castleman disease, with no grade 3 or 4 toxicities. In addition, rituximab did not seem to cause exacerbation of HIV infection, with no adverse effect on the immune T-cell subsets, including CD4 cell count or HIV viral load. However, Kaposi sarcoma progressed in 36% of patients with this disease, a phenomenon that has been recorded previously (4). The reason for this is unclear, but the rapid decrease in B-lymphocytes observed with rituximab therapy may play a role in the progression of Kaposi sarcoma (19). Because rituximab has also been associated with an increased risk for death from infection in AIDS-related non-Hodgkin lymphoma (20), the data we present should provide reassurance to clinicians. A recent trial i

Tuberculosis antigen-specific immune responses can be detected using enzyme-linked immunospot technology in human immunodeficiency virus (HIV)-1 patients with advanced disease

There are limited data on the efficacy of T cell‐based assays to detect tuberculosis (TB) antigen‐specific responses in immune‐deficient human immunodeficiency virus (HIV) patients. The aim of this study is to determine whether TB antigen‐specific immune responses can be detected in patients with HIV‐1 infection, especially in those with advanced disease (CD4 T cell count < 300 cells/µl). An enzyme‐linked immunospot (ELISPOT) assay, which detects interferon (IFN)‐γ secreted by T cells exposed to TB antigens, was used to assess specific immune responses in a prospective study of 201 HIV‐1‐infected patients with risk factors for TB infection, attending a single HIV unit. The performance of the ELISPOT assay to detect TB antigen‐specific immune responses is independent of CD4 T cell counts in HIV‐1 patients. The sensitivity and specificity of this assay for the diagnosis of active tuberculosis does not differ significantly from values obtained in immunocompetent subjects. The negative predictive value of the TB ELISPOT test is 98·2%. A positive predictive value of 86% for the diagnosis of active tuberculosis was found when the combined number of early secretory antigen target‐6 (ESAT‐6) and culture filtrate protein‐10 (CFP‐10) IFN‐γ spots to CD4 T cell count ratio was > 1·5. TB antigen‐specific immune responses can be detected in HIV patients with low CD4 T cell counts using ELISPOT technology in a routine diagnostic laboratory and is a useful test to exclude TB infection in immune‐deficient HIV‐1 patients. A combination of TB antigen‐specific IFN‐γ responses and CD4 T cell counts has the potential to distinguish active tuberculosis from latent infection.

Chronic erosive herpes simplex virus infection of the penis, a possible immune reconstitution disease

Objective To report a novel clinical presentation: a chronic erosive herpes simplex virus (HSV) infection of the penis which developed in AIDS patients following the commencement of highly active antiretroviral therapy (HAART). The lesions were unresponsive to antiviral treatments which had previously been effective, and this could not be accounted for in terms of increased antiviral resistance.

Rate of AIDS diseases or death in HIV-infected antiretroviral therapy-naive individuals with high CD4 cell count.

Objective:To assess the absolute rate of AIDS and death in antiretroviral therapy (ART)-naive patients with a high CD4 cell count. Such information would be helpful in the design of a trial investigating early initiation of ART. Design:Analysis of data from an ongoing HIV cohort study. Methods:The rate of (severe) AIDS or death and death alone was evaluated in ART-naive patients according to the current CD4 cell count, focusing on CD4 cell counts ≥ 350 cells/μl among patients in the UK CHIC Study. Results:In a total of 30 313 person-years of follow-up, there were 1557 AIDS or death events. The rate of AIDS or death in persons with most recent CD4 cell count 350–499, 500–649 and > 650 cells/μl was 2.49, 1.54 and 0.96 per 100 person-years, respectively. The rate ratio for those with CD4 cell count 500–649 cells/μl compared with those with CD4 cell count ≥ 650 cells/μl was 1.55 [95% confidence interval (CI), 1.11–2.17; P = 0.01]. In a Poisson regression model based on person years with CD4 cell count ≥ 350 cells/μl, there was a strong effect of CD4 cell count on rate of AIDS or death (rate ratio, 0.84; 95% CI, 0.76–0.93; P = 0.001), independent of viral load and age. Conclusions:The trend of decreasing rate of AIDS and death with higher CD4 cell count is present throughout the CD4 cell count ≥ 350 cells/μl range in ART-naive people.

Better maintained adherence on switching from twice‐daily to once‐daily therapy for HIV: a 24‐week randomized trial of treatment simplification using stavudine prolonged‐release capsules

Adherence to antiretroviral therapy is critical to treatment outcomes. Adherence studies in other therapeutic areas of medicine suggest that once‐daily regimens support improved adherence when compared to twice‐daily therapy. An expansion in the range of once‐daily antiretrovirals is making once‐daily therapy possible for persons with HIV infection.

A compartmental pharmacokinetic evaluation of long-acting rilpivirine in HIV-negative volunteers for pre-exposure prophylaxis.

Rilpivirine long‐acting (RPV‐LA) is a parenteral formulation enabling prolonged plasma exposure. We explored its multiple‐compartment pharmacokinetics (PK) after a single dose, for pre‐exposure prophylaxis. Sixty‐six HIV‐negative volunteers were enrolled: women received an intramuscular dose of 300, 600, or 1,200 mg, with plasma and genital levels measured to 84 days postdose; men receiving 600 mg had similar PK determined in plasma and rectum. Ex vivo antiviral activity of cervicovaginal lavage (CVL) was also assessed. After a single dose, RPV concentrations peaked at days 6–8 and were present in plasma and genital‐tract fluid to day 84. Vaginal and male rectal tissue levels matched those in plasma. At the 1,200 mg dose, CVL showed greater antiviral activity, above baseline, at days 28 and 56. All doses were well tolerated. All doses gave prolonged plasma and genital‐tract rilpivirine exposure. PK and viral inhibition of repeated doses will be important in further dose selection.

Impact of antiretroviral choice on hypercholesterolaemia events: the role of the nucleoside reverse transcriptase inhibitor backbone

The use of highly active antiretroviral therapy (HAART) has profoundly altered the life expectancy of individuals infected with HIV. Metabolic abnormalities associated with antiretrovirals and cumulative exposure to combination antiretroviral therapy, including dyslipidaemia and insulin resistance, have been linked to an increased risk of myocardial infarction.