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A N Phillips

Publications and source records attributed to A N Phillips.

At least 73 records · Page 4Linked to original sources
PubMed1999

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.

HIV Infections↗
PubMed1999

Interactions between beta-herpesviruses and human immunodeficiency virus in vivo: evidence for increased human immunodeficiency viral load in the presence of human herpesvirus 6.

In vitro, beta-herpesviruses can stimulate or inhibit HIV replication under particular circumstances. In order to investigate the effects of beta-herpesvirus infection on HIV replication and vice versa at an organ level, we determined the quantitative relationships between cytomegalovirus (CMV), human herpesviruses (HHV) 6 and 7, and HIV-1 proviral DNA using quantitative competitive PCR methods in 141 organs collected at autopsy from 11 AIDS patients. The presence of HHV-6 DNA in an organ was significantly associated with elevated HIV-1 proviral DNA (difference in HIV median loads, 1.3 log10 genomes; P = 0.004). Consistent with this, there was a trend for the presence of HIV-1 proviral DNA to be associated with an elevated HHV-6 load (0.44 log10 difference; P = 0.07). In contrast, there were no significant differences between viral loads in the combinations of either CMV or HHV-7 with HIV-1 proviral DNA load. Pairwise combinations of the beta-herpesviruses revealed that the quantity of HHV-7 was increased in the presence of HHV-6 (difference in median loads, 1.3 log10; P = 0.001) and the quantity of HHV-6 was increased in the presence of HHV-7 (difference in median loads, 0.7 log10; P=0.002). These results demonstrate that the presence of HHV-6 in an organ is significantly associated with an elevated HIV-1 proviral load and have implications for understanding HIV pathogenesis in the human host and the role that beta-herpesviruses, especially HHV-6, might play as cofactors in the HIV disease process.

AIDS-Related Opportunistic Infections↗
PubMed1999

Human herpesviruses 6 and 7 as potential pathogens after liver transplant: prospective comparison with the effect of cytomegalovirus.

Because cytomegalovirus (CMV) is an important opportunistic infection after liver transplant, we conducted a prospective study to see if the same applied to human herpesviruses (HHV)-6 and -7. We used polymerase chain reaction (PCR) methods optimised to detect active, not latent, infection and studied patients not receiving antiviral prophylaxis for CMV. Post-transplant, 536 blood samples were tested by PCR (median 7; range 4-50). Active infection with CMV was detected in 28/60 (47%), HHV-6 in 19/60 (32%), and HHV-7 in 29/60 (48%) of patients. The PCR-positive samples were tested by quantitative-competitive PCR to measure the virus load of each betaherpesvirus. The median peak virus load for CMV was significantly greater than that for HHV-6 or HHV-7. Detailed clinicopathological analyses for the whole population showed that CMV and HHV-6 were each significantly associated with biopsy-proven graft rejection. Individual case histories suggested that HHV-6 and HHV-7 may be the cause of some episodes of hepatitis and pyrexia. It is concluded that HHV-6 is a previously unrecognized contributor to the morbidity of liver transplantation, that HHV-7 may also be important and that both viruses should be included in the differential diagnosis of graft dysfunction.

Adult↗
PubMed1999

Bulk culture levels of specific cytotoxic T-cell activity against HIV-1 proteins are not associated with risk of death.

The ability of cytotoxic T lymphocytes (CTL) to control and influence the outcome of human immunodeficiency virus (HIV) infection is not fully understood. The association between HIV-CTL activity and disease progression was evaluated prospectively in 36 HIV-1-infected individuals with a median follow-up of 3.0 years. HIV-CTL activity was measured in a 4 h Cr* release assay using autologous target cells expressing HIV-1 BRU isolate gene products (gp-120, gag, pol, nef) and a bulk culture of autologous effector cells. The CD4 count was measured at enrolment and plasma HIV RNA was measured retrospectively. The present study failed to support the hypothesis that HIV-CTL activity, as measured using the present method, is important in reducing the risk of death in HIV-infected individuals. However, using other approaches and methods could possibly yield other conclusions, and further prospective studies are needed to examine the relationship between CTL and disease progression.

Adult↗
PubMed1999

Changing treatment patterns among patients with HIV: Royal Free Hospital 1987-97.

OBJECTIVE: Following the publication of results of large-scale clinical trials, antiretroviral treatment for HIV has changed dramatically. The aim of this study was to describe changes in antiretroviral treatment and the way treatments were combined among 1806 patients with HIV seen at a single centre at the Royal Free Hospital, London, UK. DESIGN AND METHOD: Each calendar year was divided into quarters, and the number of patients receiving treatment and participating in clinical trials was determined. RESULTS: The proportion of patients on no therapy decreased from over 90% at the beginning of 1988 to under 15% at the end of 1997. Monotherapy was the only form of treatment available before 1992 but its use dropped to 2% by the end of 1997. The standard of care at the end of 1997 was triple combination therapy, used in over 40% of patients. There were dramatic changes in the use of individual agents; use of zidovudine decreased from 50% during 1989 to 25% during 1997, while use of lamivudine and stavudine saw an exponential rise in 1997. The protease inhibitors were used in equal proportions in this clinic population; the use of dual protease therapy began in 1997 and was rising rapidly by the end of the year. CONCLUSIONS: There have been major changes in the use of antiretroviral therapy at this centre, particularly during 1996 and 1997. The long-term cost implications and side-effects of intensive treatment regimens remain to be addressed.

Adult↗
PubMed1999

CD4 lymphocyte count as a predictor of the duration of highly active antiretroviral therapy-induced suppression of human immunodeficiency virus load.

The association between CD4 cell count and duration of virus load suppression was investigated in 558 patients in the Frankfurt HIV Clinic Cohort who had begun highly active antiretroviral therapy and who had virus load declines to </=500 copies/mL. The Kaplan-Meier method estimated viral rebound in 42.5% of patients by 24 weeks and in 64.3% by 84 weeks. Risk of viral rebound was independently associated with baseline and changes from baseline CD4 cell count. The achieved CD4 cell count was the most important factor for prediction of viral rebound (relative hazard, 5.4 for an updated CD4 cell count of <20 vs. >500 copies/mL; P=.0001). Baseline virus load was not associated with virus load rebound. Lower baseline CD4 cell counts were associated with increased risk of viral rebound; however, this risk was significantly reduced in persons with low baseline CD4 cell counts who experienced substantial increases in CD4 cell counts during follow-up.

Adult↗
PubMed1999

Risk of cancer in patients with HIV disease. London African HIV/AIDS Study Group.

The aim of this study was to compare cancer incidence in a cohort of HIV-infected patients with the incidence rates in the population of South East England. Data collected for a retrospective cohort study of 2048 HIV-infected patients were analysed to examine the incidence of cancer. Cases of cancer occurring in South East England from 1985-1995 were obtained from the Thames Cancer Registry. Standardized incidence ratios were calculated by comparison of the observed number of cases for each cancer type in HIV-infected non-Africans with the numbers expected, calculated from the age and sex specific registration rates for the South East England population using person-years of observation. The crude incidence rates of cancer were calculated for HIV-infected Africans. The incidence of non-AIDS defining cancers such as Hodgkin's disease (standardized incidence ratio 22; 95% CI: 3-80) and anal cancer (standardized incidence ratio 125; 95% CI: 3-697) were significantly increased for non-African males with HIV disease. Anal cancer was also significantly increased for non-African females (standardized incidence ratio 1667; 95% CI: 43-9287). Kaposi's sarcoma (KS) was the commonest cancer among HIV-infected Africans and males had an incidence which was nearly 3 times that of females. There is evidence to suggest that the risks for other non-AIDS defining cancers were significantly increased in persons with HIV disease which may have implications for HIV/AIDS surveillance.

Adult↗
PubMed1999

Risk factors for tuberculosis in patients with AIDS in London: a case-control study.

OBJECTIVE: To identify risk factors for the acquired immune-deficiency syndrome (AIDS) associated with tuberculosis, in patients with AIDS attending 11 of the largest human immunodeficiency virus (HIV)/AIDS Units in London. DESIGN: Case-control study nested in a retrospective cohort of 2048 HIV-1 positive patients. Cases were defined as patients with a definitive diagnosis of tuberculosis, and controls as patients with AIDS and without tuberculosis during follow-up. RESULTS: Of 627 patients diagnosed with AIDS, 121 had a definitive diagnosis of tuberculosis. Significant risk factors for tuberculosis in the univariate analysis were sex, ethnicity, age, HIV exposure category and hospital attended, and in the multiple regression analysis ethnicity, age and hospital attended. African ethnicity was the strongest risk factor for tuberculosis (adjusted odds ratio [AOR] 5.9, 95% confidence interval 3.4-10.2). The risk of tuberculosis was higher in the younger age groups (test for trend P < 0.001). The hospital-associated risk of tuberculosis was more heterogeneous in the non-African group, and non-Africans attending Hospital 1 had an increased risk of tuberculosis which was statistically significant. CONCLUSIONS: The risk factors for AIDS-associated tuberculosis in London are sub-Saharan African origin, younger age group, and, among the non-Africans only, attending one hospital in east London. Different transmission patterns and mechanisms for the development of tuberculosis may operate in different settings depending on the background risk of tuberculous infection. Screening for tuberculosis infection and disease among HIV-positive individuals in London is important for the provision of preventive or curative therapy, and prophylaxis policies need to be designed in accordance with the transmission patterns and mechanisms of disease.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group.

BACKGROUND: The introduction of combination antiretroviral therapy and protease inhibitors has led to reports of falling mortality rates among people infected with HIV-1. We examined the change in these mortality rates of HIV-1-infected patients across Europe during 1994-98, and assessed the extent to which changes can be explained by the use of new therapeutic regimens. METHODS: We analysed data from EuroSIDA, which is a prospective, observational, European, multicentre cohort of 4270 HIV-1-infected patients. We compared death rates in each 6 month period from September, 1994, to March, 1998. FINDINGS: By March, 1998, 1215 patients had died. The mortality rate from March to September, 1995, was 23.3 deaths per 100 person-years of follow-up (95% CI 20.6-26.0), and fell to 4.1 per 100 person-years of follow-up (2.3-5.9) between September, 1997, and March, 1998. From March to September, 1997, the death rate was 65.4 per 100 person-years of follow-up for those on no treatment, 7.5 per 100 person-years of follow-up for patients on dual therapy, and 3.4 per 100 person-years of follow-up for patients on triple-combination therapy. Compared with patients who were followed up from September, 1994, to March, 1995, patients seen between September, 1997, and March, 1998, had a relative hazard of death of 0.16 (0.08-0.32), which rose to 0.90 (0.50-1.64) after adjustment for treatment. INTERPRETATION: Death rates across Europe among patients infected with HIV-1 have been falling since September, 1995, and at the beginning of 1998 were less than a fifth of their previous level. A large proportion of the reduction in mortality could be explained by new treatments or combinations of treatments.

Adult↗
PubMed1998

Predictors of a viral response and subsequent virological treatment failure in patients with HIV starting a protease inhibitor.

OBJECTIVES: To investigate the factors related to viral load becoming undetectable among patients from Southern Alberta who started a protease inhibitor for the first time, and to determine the factors related to subsequent re-emergence of detectable viral load amongst those patients whose viral load initially became undetectable. SUBJECTS AND METHODS: A total of 243 patients from the Southern Alberta Clinic had started a protease inhibitor for the first time and had been followed up for a median time of 32 weeks. Standard survival techniques including Kaplan-Meier techniques and Cox proportional hazards models were used to determine which factors were related to viral load becoming undetectable. RESULTS: At 24 weeks after first exposure to a protease inhibitor, 52.8% of the patients [95% confidence interval (Cl), 45.2-56.6] had achieved an undetectable viral load. In a multivariate analysis, those with a higher initial viral load were less likely to become undetectable [relative hazard (RH), 0.50; 95% Cl, 0.35-0.70; P < 0.0001], whereas those starting more new drugs (RH per new drug, 1.54; 95% Cl, 1.01-2.11; P = 0.048) were significantly more likely to achieve an undetectable viral load. Amongst 111 patients whose viral load became undetectable, Kaplan-Meier analysis indicated that 15.5% of patients experienced re-emergence of detectable viral load at 24 weeks after the first undetectable viral load. A higher CD4 cell count was associated with a lower risk of viral load becoming detectable (RH, 0.73; 95% Cl, 0.53-1.00; P = 0.049), as was treatment with indinavir (versus any other protease inhibitor RH, 0.17; 95% Cl, 0.03-0.86; P = 0.033). CONCLUSIONS: A significant proportion of patients in a routine clinic setting achieved an undetectable viral load measurement after first starting a protease inhibitor; viral load in patients with a higher CD4 cell count was more likely to become and stay undetectable. There was no evidence that patients who were drug-naive experienced significantly worse virological effects than drug-experienced patients, as long as the same number of new drugs was started at the date of first exposure to a protease inhibitor. Further follow-up of these patients is warranted to study the longer term effects of treatment with protease inhibitors.

Adult↗
PubMed1998

The relative prognostic value of plasma HIV RNA levels and CD4 lymphocyte counts in advanced HIV infection.

OBJECTIVE: It has been suggested that the plasma HIV RNA level is a better predictor of AIDS and death than the CD4 lymphocyte count. We assessed whether the prognostic value of plasma virus levels was different according to the CD4 count. DESIGN: Prospective cohort study of HIV-infected patients followed for a median of 2.91 years (range, 0.02-4.54). SETTING: Department of Infectious Diseases at Rigshospitalet, Copenhagen, Denmark. PARTICIPANTS: A group of 255 HIV-infected individuals with an initial measurement of CD4 lymphocyte count and plasma HIV RNA. MAIN OUTCOME MEASURE: Survival time. RESULTS: The plasma HIV RNA (median 101410 copies/ml; range (range 200-7200000) and the CD4 lymphocyte count (median 250 cells x 10(6)/l; range 1-1247) were negatively correlated (Pearson r = -0.53; P < 0.00001). Of the 255 patients, 110 died during follow-up. Overall, a higher HIV RNA level was associated with increased risk of death, but the association was smaller in patients with lower CD4 lymphocyte counts (test for interaction P < 0.0001). In patients with CD4 count below 50 cells x 10(6)/l the association between HIV RNA and risk of death was not statistically significant (relative hazard per 10-fold higher HIV RNA level was 1.53; P = 0.11; adjusted for age and CD4 count) while that between the CD4 count and risk of death was highly significant (relative hazard per 50% lower CD4 count 1.38; P = 0.005; adjusted for age and HIV RNA level). CONCLUSIONS: Patients were relatively lightly treated with antiretroviral drugs both before and during this study. In this situation, it appears that the HIV RNA level has a relatively weak association with risk of death in patients with advanced HIV infection and that the CD4 lymphocyte count is probably more useful in assessing prognosis.

Adult↗
PubMed1998

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.

Biomarkers↗
PubMed1998

Evaluating the effect of year of seroconversion on HIV progression in cohort studies. Italian Seroconversion Study.

OBJECTIVES: To show how a spurious association between the calendar year of seroconversion and HIV progression arises as a result of censoring the follow-up of individuals at their last visit, when the individuals' visits are intermittent. DESIGN: A notional cohort of 1140 seroconverters and a cohort study of 1270 HIV-infected individuals seroconverted between 1985 and 1994, and followed up to December 1995 (the Italian Seroconversion Study cohort). METHODS: Failure times and rate of the patients attending the clinic over the study period were simulated for the notional cohort. Three separate scenarios with different probabilities of making a visit were considered. Standard survival analysis techniques were used to assess the effect of the year of seroconversion on HIV progression. The progression to a CD4 cell count of 200 x 10(6)/l according to the calendar year of seroconversion in the Italian Seroconversion Study was assessed using different censoring strategies. RESULTS: A spurious effect of the year of seroconversion consistently appeared in 100 repeated simulations. When ignoring the visits occurring after the first year of follow-up in the Italian Seroconversion Study cohort, results supported the hypothesis of no effect of the year from seroconversion. CONCLUSIONS: The choice of the censoring strategy is crucial when assessing the effect of year of seroconversion using survival analysis in cohort studies with intermittent visit structure. Different censoring strategies should be considered before firmly concluding that more virulent strains or the use of treatment are modifying the natural history of HIV disease from cohort studies of this nature.

Cohort Studies↗
PubMed1998

A practical approach to adjusting for attrition bias in HIV clinical trials with serial marker responses.

OBJECTIVES: To illustrate a simple approach to adjusting for bias due to drop-outs (i.e., attrition bias) when evaluating the effect of a certain therapy in HIV clinical trials using the mean change in plasma viral load. To evaluate its validity and to compare its performance with that of another simple method for handling drop-outs: the last observation carried forward (LOCF) method. DESIGN: Data from a notional treated group of 100 patients followed up to 52 weeks were generated. Attrition bias was introduced by mimicking selective patient drop-out (i.e., more likely in patients doing badly). METHODS: The difference between the true mean change in HIV RNA levels at 52 weeks and the observed mean change because of drop-outs was calculated (attrition bias). The reduction in bias obtained by using the proposed approach was then calculated and compared with that obtained by using the LOCF method. To assess the performance of the methods over the entire follow-up, the mean areas under the curves were considered. RESULTS: Our method reduced the bias by a clinically relevant amount in a variety of different settings. In most of our simulations, bias was reduced by a larger amount than that obtainable from using the LOCF method. CONCLUSIONS: The current situation is that results from trials in HIV infection are invariably presented with no associated attempt to quantify the attrition bias present. Attrition-adjusted plots of mean change in HIV RNA should, we believe, be presented alongside usual plots as a form of sensitivity analysis.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Disease progression and survival following specific AIDS-defining conditions: a retrospective cohort study of 2048 HIV-infected persons in London.

OBJECTIVE: To assess the impact of specific AIDS-defining conditions on survival in HIV-infected persons, with emphasis on the effect of tuberculosis. METHODS: A retrospective cohort analysis of HIV-infected Africans and non-Africans attending 11 specialist HIV/AIDS units in London enrolled for a comparison of the natural history of HIV/AIDS in different ethnic groups. RESULTS: A total of 2048 patients were studied of whom 627 (31%) developed 1306 different AIDS indicator diseases. Pneumocystis carinii pneumonia accounted for 159 (25%) of initial AIDS episodes and tuberculosis for 103 (16%). In patients with HIV disease, tuberculosis had the lowest risk [relative risk (RR), 1.11; 95% confidence interval (CI), 0.75-1.63], and high-grade lymphoma had the highest risk (RR, 20.56; 95% CI, 2.70-156.54) for death. For patients with a prior AIDS-defining illness, the development of subsequent AIDS indicator diseases such as Pneumocystis carinii pneumonia (RR, 1.18; 95% CI, 0.77-1.83) and tuberculosis (RR, 1.36; 95% CI, 0.76-2.47) had the best survival, and non-Hodgkin's lymphoma had the worst survival (RR, 9.67; 95% CI, 1.26-74.33). Patients with tuberculosis had a lower incidence of subsequent AIDS-defining conditions than persons with other initial AIDS diagnoses (rate ratio, 0.47; 95% CI, 0.37-0.59). CONCLUSIONS: Considerable variation exists in the relative risk of death following different AIDS-defining conditions. The development of any subsequent AIDS-defining condition is associated with an increased risk of death that differs between diseases, and this risk should be considered when evaluating the impact of specific conditions. Like other AIDS-defining conditions, incident tuberculosis was associated with adverse outcome compared with the absence of an AIDS-defining event, but we found no evidence of major acceleration of HIV disease attributable to tuberculosis.

AIDS-Related Opportunistic Infections↗