ATV Yes 29/76.1 38.1 (24.2-52.0) 1.61 (1.10-2.35) No 585/2527.3 23.1 (21.3-25.0) 1.00 P-value 0.008 0.0142 Rates given per 100 person-years. aHR= hazard ratio adjusted for ART history, gender, ethnicity, VL and CD4. • Although managing drug drug interactions (DDI) is ingrained into daily HIV clinical care, there are few data to support the true clinical implications or outcomes of many of these.

There is increasing concern that HIV treatment failure may result from inadequate central nervous system (CNS) penetration of antiretroviral drugs, allowing compartmentalized viral replication and development of resistance. We discuss a patient who maintained a suppressed plasma viral load for four years on antiretroviral therapy (ART) before developing HIV encephalitis with a cerebrospinal fluid (CSF) HIV viral load of 861 copies/mL and newly detectable plasma viral load of 68 copies/mL. Identification of major resistance mutations to his combination therapy supported concerns that resistant HIV had developed within the CNS. His ART was changed to optimize CNS penetration, leading to maintained clinical improvement. Imaging presented demonstrates corresponding radiological improvement. The report illustrates the need to exclude CNS viral rebound or incomplete suppression in HIV patients with neurological symptoms, and suggests that the extent of this emerging problem is only beginning to be recognized as the implications of long-term peripheral HIV suppression unfold.

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

Objective More and more highly treatment‐experienced patients are achieving viral suppression. However, the durability of suppression remains unclear. Methods Patients from Royal Free Hospital (London, UK) and JW Goethe University Hospital (Frankfurt, Germany) who had failed ≥1 antiretroviral (ARV) regimen in all three main drug classes and ≥3 previous ARV regimens and subsequently achieved viral load <50 HIV‐1 RNA copies/mL were included. They were followed until stopping pre‐combination antiretroviral therapy, end of follow‐up or viral rebound (two viral loads >400 copies/mL). Results Two hundred and forty‐seven patients contributed 723 person‐years and 114 viral rebounds [rate=15.8 per 100 person‐years; 95% confidence interval (CI) 12.9–18.7]. More recent calendar years of viral suppression [relative risk (RR)=0.90 per year later; 95% CI 0.81–1.00; P =0.05] and greater number of ARVs in the regimen not previously failed (RR=0.78 per 1 ARV more; 95% CI 0.65–0.95; P =0.01) were associated with lower viral rebound rates. At 0–1, 1–2, 2–3 and >3 years after achieving suppression, the rebound rates were 30.9, 9.2, 4.3 and 3.5 per 100 person‐years, respectively. Compared to 0–1 years, the adjusted RRs (95% CIs) after 1–2, 2–3 and >3 years were 0.33 (0.18–0.58), 0.21 (0.09–0.48) and 0.14 (0.06–0.33), respectively ( P <0.0001). Conclusions Although rebound rates are high, especially in the first year after viral suppression, this risk reduces substantially if highly treatment‐experienced patients can maintain viral suppression.

Objective To describe outcomes in patients starting first‐line antiretroviral regimens including lopinavir/ritonavir (LPV/r) in a routine clinic setting. Methods Previously naïve patients starting LPV/r‐containing antiretroviral therapy were included in the study. Virological failure was defined as the first of two viral loads >500 HIV‐1 RNA copies/mL more than 6 months after starting LPV/r. Cumulative percentages experiencing virological failure were calculated using Kaplan–Meier methods. Results A total of 195 individuals had a median follow‐up time of 1.7 years. At 48 weeks, 87.9, 77.4 and 71.6% of patients with pretreatment CD4 counts of <50, 50–200 and >200 cells/μL, respectively, remained on LPV/r. By 48, 72 and 96 weeks, 2.2, 3.0 and 5.0% of patients, respectively, had experienced virological failure, ignoring treatment changes but censoring follow‐up at discontinuation of all antiretrovirals; these percentages became 24.0, 33.7 and 42.3% when LPV/r discontinuation was considered as virological failure. Censoring those who stopped LPV/r with a viral load <50 copies/mL and considering as virological failures those who stopped LPV/r with a viral load >50 copies/mL gave 12.1, 14.6 and 17.0% virological failure at 48, 72 and 96 weeks, respectively. Median CD4 count increases at 24, 48 and 72 weeks were 167, 230 and 253 cells/μL, respectively. Conclusions Few patients experienced virological failure whilst on a LPV/r‐based regimen, although it was not uncommon for patients in our clinic with higher baseline CD4 counts to discontinue LPV/r.

BACKGROUND:We obtained estimates of the incidence of tuberculosis (TB) among patients receiving HAART and identified determinants of the incidence. METHODS:We analyzed the incidence of TB during the first 3 years after initiation of HAART among 17,142 treatment-naive, AIDS-free persons starting HAART who were enrolled in 12 cohorts from Europe and North America. We used univariable and multivariable Poisson regression models to identify factors associated with the incidence. RESULTS:During the first 3 years (36,906 person-years), 173 patients developed TB (incidence, 4.69 cases per 1000 person-years). In multivariable analysis, the incidence rate was lower for men who have sex with men, compared with injection drug users (relative rate, 2.46; 95% confidence interval [CI], 1.51-4.01), heterosexuals (relative rate, 2.42; 95% CI, 1.64-3.59), those with other suspected modes of transmission (relative rate, 1.66; 95% CI, 0.91-3.06), and those with a higher CD4+ count at the time of HAART initiation (relative rate per log2 cells/microL, 0.87; 95% CI, 0.84-0.91). During 28,846 person-years of follow-up after the first 6 months of HAART, 88 patients developed TB (incidence, 3.1 cases per 1000 person-years of follow-up). In multivariable analyses, a low baseline CD4+ count (relative rate per log2 cells/microL, 0.89; 95% CI, 0.83-0.96), 6-month CD4+ count (relative rate per log2 cells/microL, 0.90; 95% CI, 0.81-0.99), and a 6-month HIV RNA level >400 copies/mL (relative rate, 2.21; 95% CI, 1.33-3.67) were significantly associated with the risk of acquiring TB after 6 months of HAART. CONCLUSION:The level of immunodeficiency at which HAART is initiated and the response to HAART are important determinants of the risk of TB. However, this risk remains appreciable even among those with a good response to HAART, suggesting that other interventions may be needed to control the TB epidemic in the HIV-infected population.

Background It has been suggested that a lower pre-highly active antiretroviral therapy (HAART) CD4 count nadir may lead to a greater risk of experiencing HAART-related toxicity. We investigated the relationship between the pre-HAART CD4 count nadir, HAART and the occurrence of laboratory-defined toxicities. Methods Previously antiretroviral-naive individuals starting HAART at the Royal Free Hospital, London, UK, were included. Drug discontinuation, increases in total cholesterol (by >1mmol/l), alanine aspartate transferase/ alanine aminotransferase (AST/ALT) (by >2.5 times the upper limit of normal), bilirubin (by >2.5 times the upper limit of normal), triglycerides (by >1 mmol/l) and decreases in haemoglobin (by >2 g/dl) were assessed. Results 377/847 (45%) individuals starting HAART stopped at least one antiretroviral within the first 48 weeks. Lower CD4 nadirs were not associated with a greater rate of discontinuing antiretrovirals (adjusted hazard ratio (HR)=1.04 per 100 cells/mm3 higher; 95% confidence intervals (CI) 0.99–1.10; P=0.15). 70/297 (24%), 39/192 (20%) and 73/358 (20%) with a CD4 cell nadir of 0–100, 100–200 and 200+ cells/mm3, respectively, stopped for toxicity reasons; 11/297 (4%), 5/192 (3%) and 3/358 (1%) stopped for reasons of insufficient efficacy; 63/297 (21%), 33/192 (17%) and 80/358 (22%) stopped for other reasons ( P=0.1). Reasons for stopping were similar between CD4 nadir groups. Lower CD4 nadirs were not associated with an increased risk of hypercholesterolaemia, anaemia, hypertriglyceridaemia or increases in AST/ALT but were associated with increased incidence of hyperbilirubinaemia (HR=0.67 per 100 cells/mm3 higher; 95% CI 0.49–0.92; P=0.01). Discussion Lower CD4 nadirs were not found to be associated either with discontinuing an antiretroviral or with a higher risk of toxicity, except for an increased risk of experiencing an increase in bilirubin levels.

Despite the advent of anti-pseudomonal antibiotics, Pseudomonas aeruginosa remains an important pathogen in the immunocompromised. It has emerged as one of the most common causes of Gram-negative bacteraemia in HIV-infected hospitalised patients. Risk factors that have been implicated include recent hospitalisation; blood CD4 count <200×109/l; neutropenia; nebulised pentamidine and corticosteroids. 1 Nelson M.R. Shanson D.C. Barter G.J. Hawkins D.A. Gazzard B.G. Pseudomonas sepsis associated with HIV. AIDS. 1991; 5: 761-763 Crossref PubMed Scopus (49) Google Scholar , 2 Kielhofner M. Atmar R.L. Hamill R.J. Musher D.M. Life-threatening Pseudomonas aeruginosa infections in patients with human immunodeficiency virus infection. Clin Infect Dis. 1992; 14: 403-411 Crossref PubMed Scopus (108) Google Scholar , 3 Sheep D.H. Tang I.T.-L. Ramundo M.B. Kaplan M.K. Serious Pseudomonas aeruginosa infection in AIDS. J Acquir Immune Defic Syndr Hum Retrovirol. 1994; 7: 823-831 Google Scholar The spectrum of dermatological manifestations of Pseudomonas sepsis are well recognized. An important but less reported finding is that of subcutaneous nodules. We describe such a case in an HIV-infected patient with Pseudomonas community-acquired pneumonia and a high blood CD4 count.

ABSTRACTKaposi's sarcoma-associated herpesvirus (KSHV) is the infectious cause of Kaposi's sarcoma (KS) and certain lymphoproliferations particularly in the context of human immunodeficiency virus (HIV) type 1-induced immunosuppression. The introduction of effective therapies to treat HIV has led to a decline in the incidence of KS, suggesting that immune responses may play a role in controlling KSHV infection and pathogenesis. Cytotoxic-T-lymphocyte (CTL) activity against KSHV proteins has been demonstrated; however, the identification of KSHV CTL epitopes remains elusive and problematic. Although the herpesvirus genomic layout is generally conserved, KSHV encodes a unique hypervariable protein, K1, with intense biological selection pressure at specific amino acid sites. To investigate whether this variability is partly driven by cellular immunity, we designed K1 peptides that match only the unique viral sequence for every individual studied here (autologous peptides). We identified functional CTL epitopes within K1's most variable areas, and we show that a given individual responds only to autologous peptides and not to peptides from other individuals. Furthermore, these epitopes are highly conserved sequences within KSHV isolates from a specific strain but are not conserved between different strains. We conclude that CTL recognition contributes to K1, and therefore to KSHV, evolution.

The occurrence of viral breakthrough on treatment was examined in 233 previously antiretroviral-naive HIV-infected patients who started highly active antiretroviral therapy (HAART) and who achieved initial viral suppression to less than 50 copies/ml. The rate of viral breakthrough despite the continuation of therapy was 3.6 per 100 person-years (12 cases occurred during 332.8 person-years of follow-up). Viral suppression on HAART is proving extremely durable in those who can tolerate these regimens over long periods.

10.1128/JVI.77.7.4306-4314.2003. 2003, 77(7):4306. DOI: J. Virol. Kuon, Joachim Sieper, Frances Gotch and Chris Boshoff Tyrer, Mike Youle, Nesrina Imami, Toru Kobu, Wolfgang Stephen Henderson, Ian Williams, Natalie Wilder, Mervyn Justin Stebbing, Dimitra Bourboulia, Margaret Johnson, Autologous K1 Epitopes Target Darwinian Positively Selected Cytotoxic T Lymphocytes Recognize and Kaposi's Sarcoma-Associated Herpesvirus

In most studies, people who have not responded virologically to a protease inhibitor (PI)-containing regimen have tended to experience poor virologic responses to subsequent regimens. We describe the 2-year viral load, CD4 count, and clinical outcome of a multidrug regimen used in 60 people who had not responded virologically to a PI-containing regimen. At baseline, median CD4 count was 126/mm(3) (nadir 30/mm(3)) and median viral load was 320,000 copies/mL. A median of five antiretroviral drugs had previously been used, of which a median of two were PIs. Of these patients, 16% had previously used another nonnucleoside reverse transcriptase inhibitor besides efavirenz. The multidrug regimen (median 5 drugs) started most commonly included efavirenz (100%), at least one PI (92%, usually indinavir/ritonavir), didanosine (78%), and hydroxyurea (74%). At year 2, 5 patients had died and 5 had no measure available. Nine patients developed a new AIDS event and 10 patients Were known to have stopped all antiretroviral therapy. Thirty-one patients (52% of the whole group, 72% of those remaining on therapy With viral load value available) had viral load <50 copies/mL. Thus, a substantial proportion of patients who had failed to respond virologically to PI-containing regimens can achieve profound and sustained virologic suppression with a multidrug regimen.

OBJECTIVE:To assess the occurrence of viral load greater than 50 copies/ml in patients on highly active antiretroviral therapy (HAART) having achieved less than 50 copies/ml and the chance of whether a viral load greater than 50 copies/ml would lead to a sustained and increasing viral load. DESIGN:A cohort of 553 patients on HAART with viral loads of less than 50 copies/ml were followed. RESULTS:Over a median of 56 weeks 35% of patients experienced a transient increase and 8% virological failure (two consecutive viral loads of > 400 copies/ml). Transient increases and virological failure were more common in those with greater drug experience, and those with initial raised viral load values of more than 400 copies/ml were more likely to have a sustained increase and become virological failures. CONCLUSION:Transient increases in viral load are common, mainly in the 50-400 copies/ml range, and the majority of subsequent viral load estimations show a return to less than 50 copies/ml. A single raised viral load should lead to adherence support and intensified monitoring. Subsequent treatment decisions can then be based on evidence of true virological rebound and failure.

ObjectiveTo describe the reasons for, and factors associated with, modification and discontinuation of highly active antiretroviral therapy (HAART) regimens at a single clinic. SubjectsA total of 556 patients who started HAART at the Royal Free Hospital were included in analyses. Modification was defined as stopping or switching any antiretrovirals in the regimen, whereas discontinuation was defined as the simultaneous stopping of all antiretrovirals included in the initial regimen. Reasons were classified as immunological/virological failure (IVF) and toxicities and patient choice/poor compliance (TPC). ResultsThe median CD4 count at starting HAART was 171 × 106 cells/l and viral load 5.07 log copies/ml. During a median follow-up of 14.2 months, 247 patients (44.4%) modified their HAART regimen, 72 due to IVF (29.1%) and 159 due to TPC (64.4%) and a total of 148 patients (26.6%) discontinued HAART. Older patients were less likely to modify HAART [relative hazard (RH), 0.73 per 10 years;P = 0.0008], as were previously treatment-naive patients (RH, 0.65;P = 0.0050), those in a clinical trial (RH, 0.64;P = 0.027) and those who started nelfinavir (RH, 0.57;P = 0.035). Patients who started with four or more drugs (RH, 2.21, P < 0.0001), who included ritonavir in the initial regimen (RH, 1.41;P = 0.035) or who had higher viral loads during follow-up (RH per log increase, 1.51;P < 0.0001) were more likely to modify HAART. ConclusionsThere was a high rate of modification and discontinuation of HAART regimens in the first 12 months, particularly due to toxicities, patient choice or poor compliance.

AIMS:Common variable immunodeficiency (CVID) is the most common serious primary immunodeficiency. This paper describes the immunological consequences of human immunodeficiency virus (HIV) infection in a patient with familial CVID subsequently treated with highly active antiretroviral therapy (HAART).METHODS:Serial measurements over 11 years of serum immunoglobulins, specific antibodies to tetanus toxoid and pneumococcal polysaccharides, lymphocyte phenotypes, and HIV viral load were made.RESULTS:The patient recovered total serum IgG and IgM, but not IgA production, with adequate concentrations of specific antibodies, allowing withdrawal of intravenous immunoglobulin without an increase in infections. T cell numbers gradually declined and the patient developed a high grade B cell lymphoma. After successful chemotherapy, HAART was commenced, viral load fell from 472 000 to < 50 copies/ml, and CD4+ T cell numbers increased from 13 to 661 x 10(6)/litre. Antibody production was maintained after suppression of viral load.CONCLUSIONS:This is the first definitive report of reversal of IgG and IgM deficiency in familial CVID after HIV infection. Failure to normalise IgA supports the concept of separate predisposing genetic factors for selective IgA deficiency, which when combined with others lead to CVID. Furthermore, a persistently high viraemia is not required to maintain the recovery of immunoglobulin values, suggesting this depends either on a transitory effect of a high viral load, or a persistence of low amounts of virus.