Helen Devereux

The progression of HCV-associated liver disease in a cohort of haemophilic patients

We have studied morbidity and mortality related to hepatitis C virus infection in haemophilic patients treated at our centre. 11/255 HCV seropositive patients have developed hepatic decompensation. 20 years after first exposure to lyophilized clotting factor concentrate the risk of hepatic decompensation is estimated to be 10.8% (95% CI 3.8‐17.8%). There is a significantly increased risk associated with HIV infection, and also with increased age. For HIV seropositive patients the rates of decline in CD4 lymphocyte count and the development of p24 antigenaemia are significant risk factors for hepatic decompensation. Cirrhosis was seen in 9/19 HIV seropositive patients at post mortem. There was an association of cirrhosis with increased age but not with CD4 count, p24 antigenaemia or AIDS. In conclusion, HCV infection is associated with serious liver disease in haemophilic patients, but so far this has been restricted to a minority of those at risk. HIV coinfection accelerates progression to hepatic decompensation, and we speculate that this is probably due to enhanced HCV replication in the presence of immune deficiency.

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.

Course of viral load throughout HIV-1 infection

Summary: HIV‐1 RNA levels are routinely monitored as part of patient management. However, little is known about the course of HIV‐1 RNA levels over the entire period of infection. The aim of this study was to investigate the course of HIV‐1 RNA levels in a cohort of men with hemophilia who were observed for up to 17 years after HIV‐1 seroconversion, and to assess the risk of HIV disease progression at any HIV‐1 RNA level. Viral loads were measured on annual stored serum samples in 107 men with hemophilia A using the Roche Amplicor Monitor assay with non‐B primers. On average, HIV‐1 RNA levels increased significantly by 0.11 log10 per year over the course of HIV infection. This rate of increase was significantly faster in those who developed AIDS or died over the subsequent 12 to 17 year period, and in those who were older at HIV‐1 seroconversion. The risk of developing AIDS and death remained low when the HIV‐1 RNA level was below 4 log10 copies/ml, but increased rapidly thereafter, supporting current guidelines for the initiation of antiretroviral therapy after the viral load has exceeded this level.

HCV RNA levels and HIV infection: evidence for a viral interaction in haemophilic patients

Summary. In order to investigate a possible interaction between HIV and HCV infections, we compared HCV RNA levels in 29 matched pairs of haemophilic patients seropositive for HCV and serodiscordant for HIV. Levels were assayed using the new Chiron Quantiplex bDNA assay and were found to be significantly higher in HIV seropositive patients. There was no association between HCV RNA and age, duration of HCV infection, concentrate usage, markers of HIV progression, or use of zidovudine. Our study supports the hypothesis that HIV infection facilitates HCV replication and leads to more severe liver damage.

Gender differences in virologic response to treatment in an HIV-positive population : A cohort study

Objective: To establish whether a gender difference in virologic response to highly active antiretroviral treatment (HAART) exists. Methods: A cohort of HIV‐positive individuals was examined. Outcomes: Achievement of viral load <500 copies/ml and “failure” (failure to suppress viral load <500 copies/ml after 24 weeks or two consecutive measurements above this level after having suppressed below it). Hazard ratios (HRs) comparing the rate in women to that in men were derived using the Cox model. Results: Of 366 male subjects, 79% were white and 82% were homosexual. Sixtythree percent of the 91 female subjects were African and 87% were heterosexual. The median follow‐up after HAART was 94 weeks. The baseline CD4 count was higher in men (228 × 106 per liter) than in women (171 × 106 per liter) (p = .01), but the viral load was similar (p = .88). The median time to <500 copies/ml was 16 weeks. Women achieved a viral load of <500 copies/ml at a faster rate than men, with an adjusted HR of 1.46 (95% confidence interval [CI]: 0.99‐2.16; p = .06). Some 261 patients failed treatment (58% of men and 53% of women) with an HR of 0.78 (95% CI: 0.51‐1.21; p = .27). Conclusions: Women may achieve virologic suppression at a faster rate than men and have a more durable response. Further research should examine these responses in conjunction with clinical outcomes, because gender differences in virologic response may ultimately be of little relevance if clinical outcomes are similar.

Substantial correlation between HIV type 1 drug-associated resistance mutations in plasma and peripheral blood mononuclear cells in treatment-experienced patients

The correlation of detectable HIV-1 drug resistance mutations in plasma and PBMCs in patients extensively treated with all antiretroviral drug classes has not been fully elucidated. The detection of mutations in PBMCs may reveal resistant HIV-1 associated with past therapies. In addition, these measures in PBMCs may have a practical value when plasma virus is at low levels that are difficult to detect with current assays. The reverse transcriptase (RT) and protease (P) genes were analyzed for drug resistance, using an in-house method carried out on 36 paired samples of plasma and PBMCs from 12 treatment-experienced patients in order to investigate resistance in the two compartments. When viruses in plasma and PBMCs were analyzed by patient, the mean of the Cohen kappa values was 0.728 (substantial agreement). When viruses were analyzed by codon the mean of the Cohen kappa values was 0.715 (substantial agreement). Baseline samples were concordant at 280 of 288 (97%) codons analyzed. This study shows that a minority of mutations associated with previous therapy can be detected in PBMCs and not in plasma. Overall, mutations in plasma and PBMCs showed a substantial correlation in extensively treated patients, suggesting that either compartment is suitable for the detection of mutations as a virological guide for clinical care.

Pre-AIDS mortality and its association with HIV disease progression in haemophilic men, injecting drug users and homosexual men.

ObjectiveTo study pre-AIDS mortality and its association with HIV disease progression in different exposure groups with known intervals of HIV seroconversion. Design and methodsThe type and rate of pre-AIDS deaths were assessed in 111 HIV-infected haemophilic men followed in London, and 118 injecting drug users and 158 homosexual men followed in Amsterdam. In each group, the association between CD4+ T-cell count, HIV RNA and pre-AIDS mortality was studied using proportional hazards analysis. ResultsBy 10 years after seroconversion 7.3% of the haemophilic men had died without AIDS and 38.2% had developed AIDS. These figures were 20.2 and 30.5% for injecting drug users, and 8.0 and 55.0% for homosexual men. The major causes of pre-AIDS mortality appear to differ in the three exposure groups. The risk of pre-AIDS death tended to increase with decreasing CD4 cell count and increasing HIV RNA levels in injecting drug users and homosexual men. In men with haemophilia the associations were less obvious, although the log-transformed CD4 cell count was predictive for pre-AIDS death. ConclusionsPre-AIDS deaths occur and are at least partially related to HIV disease progression irrespective of how individuals became infected. Because of the longer life expectancy due to highly active antiretroviral therapy (HAART), pre-AIDS deaths are likely to show a further increase. Methods to incorporate these intermediate outcomes should be considered in the estimation of the size of the HIV epidemic and in the survival analysis of HIV-infected individuals. Prevention and treatment of non-AIDS infections, especially hepatitis C virus infection, and cancers will become increasingly important in HIV-infected individuals. The interaction between these therapies and HAART should be closely monitored.

Immune markers and viral load after HIV-1 seroconversion as predictors of disease progression in a cohort of haemophilic men

Objective:To assess the prognostic value of HIV RNA levels measured shortly after HIV seroconversion and whether markers of immune response (CD4+ and CD8+ T-cell counts, IgA and IgG) measured at the same time, continue to provide prognostic information once the HIV RNA level is known. Design and methods:HIV RNA levels were measured approximately 2.5 years after seroconversion in 97 haemophilic men followed for up to 17 years. Levels of CD4+ and CD8+ T cells, IgA and IgG were measured within 1 year of the HIV RNA level. The relationships between these markers and progression to AIDS and death were studied using Kaplan–Meier plots and proportional hazards regression models. Results:High HIV RNA levels were associated with faster progression to AIDS and shorter survival in univariate Cox regression models. High IgA and IgG levels were also associated with faster disease progression. In multivariate models, high HIV RNA levels remained independently associated with faster disease progression [relative hazard (RH), 1.86; P = 0.01 for AIDS; RH, 1.66; P = 0.05 for death]. However, high IgA and IgG levels provided strong independent prognostic information for AIDS and death (IgA: RH, 1.38; P = 0.006 for AIDS; RH, 1.33; P = 0.07 for death; IgG: RH, 1.10; P = 0.02 for AIDS; RH, 1.12; P = 0.01 for death). Conclusions:Our results confirm the importance of the HIV RNA level in assessing the long-term prognosis in individuals infected with HIV. However, our results suggest that immune activation markers, rather than merely reflecting high HIV RNA levels are important in assessing prognosis in their own right. These findings may improve our understanding of HIV pathogenesis and may aid clinical management of patients.

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.

Cytomegalovirus seropositivity and human immunodeficiency virus type 1 RNA levels in individuals with hemophilia

The effect of cytomegalovirus (CMV) seropositivity on the course of human immunodeficiency virus (HIV) type 1 RNA levels and HIV disease progression was assessed in a cohort of 109 hemophilic men infected with HIV-1 for a median of 12.7 years. There was no evidence of higher HIV RNA levels in the first year after HIV seroconversion (P=. 88) or faster rates of increase over infection (P=.20) in the 59 CMV-seropositive individuals than in the CMV-seronegative individuals. In univariate analyses, CMV seropositivity was associated with significantly faster progression to AIDS and death (relative hazards of 1.58 and 2.22, respectively). These effects were unchanged after adjusting for the RNA level, but they were reduced after adjusting for the CD4 cell count, age at seroconversion, and calendar year of follow-up. Thus, the effect of CMV seropositivity on clinical progression remains significant in this cohort but does not appear to be mediated through an increase in HIV RNA levels.