Mervyn Tyrer

Reasons for modification and discontinuation of antiretrovirals: results from a single treatment centre.

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.

Immunological, virological and clinical response to highly active antiretroviral therapy treatment regimens in a complete clinic population

BackgroundHighly active antiretroviral therapy (HAART) is now widely used in clinical practice and gives rise to a range of immunological, virological and clinical responses. ObjectivesTo describe the immunological, virological and clinical response to HAART and to examine the frequency of modification of the HAART regimen among patients from a single treatment centre. MethodsKaplan–Meier estimation and incidence rates were used to describe responses to HAART (a protease inhibitor or non-nucleoside drug in addition to at least two nucleoside analogues) among 421 patients from the Royal Free Hospital in London. ResultsThe median CD4 cell count at starting HAART was 186 × 106 cells/l [interquartile range (IQR) 76–310] and viral load was 5.13 log10 copies/ml (IQR 4.66–5.56). At 6 months after starting HAART, 51.1% of patients were estimated to have experienced a 100 × 106 cells/l increase in CD4 cell count; the median time for viral load to fall below 400 copies/ml was 3.7 months (95% confidence interval 3.2–4.4). At 6 months after the first viral load was < 400 copies/ml, 16.4% of patients were estimated to have failed on the basis of a single viral load > 400 copies/ml and 12.4% were estimated to have failed if the more stringent definition of two viral loads above the limit of detection was used. Compared with the pre-HAART era, the incidence of death among patients on HAART was one sixth of that level; new AIDS-defining illnesses was one seventh; and hospital admissions was one fifth. In total, 141 patients (33.5%) stopped at least one of the antiretroviral agents included as part of their HAART regimen; the occurrence of side effects was the most common reason (n = 63; 44.7%). ConclusionA good response occurred to an initial HAART regimen. There was a high rate of virological relapse, which varied considerably according to the definition of failure used. Even so, the rates of clinical progression and hospital admissions observed to date were low. Further follow-up of these patients is required to determine their long-term immunological, virological and clinical outcome.

Kaposi's Sarcoma-Associated Herpesvirus Cytotoxic T Lymphocytes Recognize and Target Darwinian Positively Selected Autologous K1 Epitopes

ABSTRACT Kaposis sarcoma-associated herpesvirus (KSHV) is the infectious cause of Kaposis 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 K1s 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.

Raised viral load in patients with viral suppression on highly active antiretroviral therapy: transient increase or treatment failure?

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.

Stability of antiretroviral regimens in patients with viral suppression

Objective:To study the rate of treatment change due to toxicities in patients who achieved viral suppression within 6 months of starting antiretroviral therapy and who have never experienced virological failure. Methods:Included patients attended the Royal Free Hospital in London, started antiretroviral therapy in 2000–2005, and achieved viral suppression within 6 months. Included follow-up (censored at virological failure) was spent on a regimen of lamivudine or emtricitabine, with a second nucleoside/nucleotide reverse transcriptase inhibitor, and either a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor. Results:In 912 person-years, there were 140 treatment changes due to toxicities (rate = 15.4 per 100 person-years, confidence interval = 12.8–17.9). In the multivariable analysis, factors associated with a higher rate of treatment change due to toxicities included increased age (for every 10 years increase: incidence rate ratio = 1.28, confidence interval = 1.04–1.57), being on stavudine compared with zidovudine (incidence rate ratio = 2.04, confidence interval = 1.28–3.26), and being on lopinavir compared with efavirenz (incidence rate ratio = 1.55, confidence interval = 1.04–2.31), whereas factors associated with a lower rate were being on tenofovir compared with zidovudine (incidence rate ratio = 0.46, confidence interval = 0.29–0.73), and being on atazanavir compared with efavirenz (incidence rate ratio = 0.23, confidence interval = 0.06–0.91). Conclusions:In patients who have never experienced virological failure, the rate of treatment change due to toxicities is low, and certain regimens are associated with an even lower rate of change. If virological failure is avoided, some regimens are so far proving to be sufficiently stable to suggest that very long-term use is potentially feasible.

Changes in CD4 lymphocyte counts after interruption of therapy in patients with viral failure on protease inhibitor-containing regimens

ObjectiveTo describe the short-term changes in CD4 lymphocyte counts after the interruption of antiretroviral HIV therapy in order to increase the understanding of CD4 lymphocyte dynamics, and so that appropriate monitoring strategies can be designed. MethodsWe studied 35 HIV-infected patients with late-stage disease who had therapy interruptions leading to high viral load levels, median greater than 750 000 RNA log10 copies/ml, and in whom two CD4 cell counts (median 28 days apart) were available before beginning a salvage regimen. ResultsOverall, there was a substantial decline in CD4 cell counts from a median of 125 to 83 cells/mm3 in the average 28 day period, with median proportionate and absolute losses of 26% and 24 cells/mm3 per month, respectively (P < 0.008). This tended to be greater in individuals studied sooner after interrupting therapy (P = 0.03) and in those with CD4 cell counts above the pre-therapy baseline (P = 0.06). There was a strong negative correlation between the proportionate increase in viral load and the absolute change in CD4 cell count (−0.66, P = 0.0002). ConclusionPatients with relatively advanced HIV infection interrupting antiretroviral therapy after failing a protease inhibitor-containing regimen require frequent monitoring because CD4 cell counts appear to fall quite rapidly, at least in the first few weeks after interruption

Participation in clinical studies among patients infected with HIV-1 in a single treatment centre over 12 years

Objective  To examine a complete population of clinic attenders in order to compare the demographics of patients who participated in a clinical study with those who had not. These were subdivided into trials of antivirals, trials for drugs used in opportunistic infections or symptomatic HIV and epidemiological studies. The setting was an established London teaching hospital. All patients diagnosed HIV‐positive and attending between July 1983 and 1 January 1999 with one measured CD4 count and at least one follow‐up visit were included.

In vivo HIV-1 replicative capacity in early and advanced infection.

OBJECTIVE Previous studies on patients treated with potent antiretroviral therapy have shown that viral clearance rates do not tend to change between early and advanced HIV-1 infection. Our objective was to investigate whether the other major aspect of virus dynamics, viral replicative capacity, does change. In vitro work has indicated that the viral replicative, capacity increases but in vivo evidence has been lacking. METHODS As an in vivo measure of the viral replicative capacity, we studied the rate of rebound of plasma HIV RNA level during a 1-week therapy interruption in previously untreated patients who had received 2 weeks of antiretroviral therapy. RESULTS Such therapy in five previously drug-naive patients with high CD4 lymphocyte counts (mean, 611 x 10(6)/l) and five patients with low counts (mean, 49 x 10(6)/l) led to a mean 2.2 log10 copies/ml decrease in plasma HIV-1 levels (from 5-6 log10 copies/ml) in 2 weeks. This was similar in the two groups. Interruption of therapy for the ensuing week resulted in a stable HIV-1 level for approximately 2 days followed by a rebound towards pretherapy level, which was much more marked in the patients with low CD4 cell counts (estimated mean rise 2.22 log10 versus 1.06 log10 copies/ml; P < 0.02). After restarting therapy, HIV RNA levels returned to pre-interruption levels. CONCLUSIONS These findings need confirmation, but the ability of HIV-1 to replicate in vivo appears to increase during HIV-1 infection. This increased replicative capacity, for which there are several potential explanations, may be the cause of gradual CD4 lymphocyte depletion.

Two-year outcome of a multidrug regimen in patients who did not respond to a protease inhibitor regimen

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.

Factors associated with viral rebound among highly treatment-experienced HIV-positive patients who have achieved viral suppression

More and more highly treatment‐experienced patients are achieving viral suppression. However, the durability of suppression remains unclear.