Teresa Hill

Impact of late diagnosis and treatment on life expectancy in people with HIV-1: UK Collaborative HIV Cohort (UK CHIC) Study

Objectives To estimate life expectancy for people with HIV undergoing treatment compared with life expectancy in the general population and to assess the impact on life expectancy of late treatment, defined as CD4 count <200 cells/mm3 at start of antiretroviral therapy. Design Cohort study. Setting Outpatient HIV clinics throughout the United Kingdom. Population Adult patients from the UK Collaborative HIV Cohort (UK CHIC) Study with CD4 count ≤350 cells/mm3 at start of antiretroviral therapy in 1996-2008. Main outcome measures Life expectancy at the exact age of 20 (the average additional years that will be lived by a person after age 20), according to the cross sectional age specific mortality rates during the study period. Results 1248 of 17u2009661 eligible patients died during 91u2009203 person years’ follow-up. Life expectancy (standard error) at exact age 20 increased from 30.0 (1.2) to 45.8 (1.7) years from 1996-9 to 2006-8. Life expectancy was 39.5 (0.45) for male patients and 50.2 (0.45) years for female patients compared with 57.8 and 61.6 years for men and women in the general population (1996-2006). Starting antiretroviral therapy later than guidelines suggest resulted in up to 15 years’ loss of life: at age 20, life expectancy was 37.9 (1.3), 41.0 (2.2), and 53.4 (1.2) years in those starting antiretroviral therapy with CD4 count <100, 100-199, and 200-350 cells/mm3, respectively. Conclusions Life expectancy in people treated for HIV infection has increased by over 15 years during 1996-2008, but is still about 13 years less than that of the UK population. The higher life expectancy in women is magnified in those with HIV. Earlier diagnosis and subsequent timely treatment with antiretroviral therapy might increase life expectancy.

Effect of HIV-1 subtype on virologic and immunologic response to starting highly active antiretroviral therapy.

BACKGROUNDnIt has been proposed that subtype-related human immunodeficiency virus type 1 (HIV-1) variability may influence virologic and immunologic responses to highly active antiretroviral therapy (HAART). Studies to date, however, have described treatment outcomes predominantly in persons with subtype B infection or compared subtype B with diverse non-B subtypes grouped together.nnnMETHODSnWith use of data from the linked UK Collaborative Group on HIV Drug Resistance and the UK Collaborative HIV Cohort Study databases, time to viral load undetectability (viral load, <50 copies/mL), time to virologic rebound (viral load, >1000 copies/mL), and increases in the CD4 cell count were compared for a median of 39 months (interquartile range, 23-67 months) in drug-naive patients infected with subtype B (n=1550), subtype C (n=272), subtype A (n=66), circulating recombinant form AG (n=57), or subtype D (n=41) disease who started HAART.nnnRESULTSnOverall, 1906 (90%) of 2116 patients achieved viral load undetectability within 12 months after they started HAART, of whom 335 (18%) subsequently experienced virologic rebound. In adjusted analyses, viral load suppression occurred more rapidly in patients infected with subtype C (hazard ratio, 1.16; 95% confidence interval, 1.01-1.33; P=.04) and subtype A (hazard ratio, 1.35; 95% confidence interval, 1.04-1.74; P=.02) relative to subtype B infection. The virologic rebound occurred marginally more rapidly in patients with subtype C infection (hazard ratio, 1.40; 95% confidence interval, 1.00-1.95; P=.05), but the hazard of virologic rebound was similar with other subtypes. Although persons with subtype B infection showed higher baseline CD4 cell counts and maintained the advantage throughout therapy, CD4 cell count recovery occurred at similar rates with all subtypes.nnnCONCLUSIONSnPatients infected with prevalent non-B subtypes were as likely to achieve viral load suppression as persons infected with subtype B and showed comparable rates of CD4 cell count recovery. HAART achieves excellent outcomes regardless of the infecting subtype.

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.

Treatment exhaustion of highly active antiretroviral therapy (HAART) among individuals infected with HIV in the United Kingdom: multicentre cohort study

Abstract Objectives To investigate whether there is evidence that an increasing proportion of HIV infected patients is starting to experience increases in viral load and decreases in CD4 cell count that are consistent with exhaustion of available treatment options. Design Multicentre cohort study. Setting Six large HIV treatment centres in southeast England. Participants All individuals seen for care between 1 January 1996 and 31 December 2002. Main outcome measures Exposure to individual antiretroviral drugs and drug classes, CD4 count, plasma HIV RNA burden. Results Information is available on 16 593 individuals (13 378 (80.6%) male patients, 10 340 (62.3%) infected via homosexual or bisexual sex, 4426 (26.7%) infected via heterosexual sex, median age 34 years). Overall, 10 207 of the 16 593 patients (61.5%) have been exposed to any antiretroviral therapy. This proportion increased from 41.2% of patients under follow up at the end of 1996 to 71.3% of those under follow up in 2002. The median CD4 count and HIV RNA burden of patients under follow up in each year changed from 270 cells/mm3 and 4.34 log10 copies/ml in 1996 to 408 cells/mm3 and 1.89 log10 copies/ml, respectively, in 2002. By 2002, 3060 (38%) of patients who had ever been treated with antiretroviral therapy had experienced all three main classes. Of these, around one quarter had evidence of “viral load failure” with all these three classes. Patients with three class failure were more likely to have an HIV RNA burden > 2.7 log10 copies/ml and a CD4 count < 200 cells/mm3. Conclusions The proportion of individuals with HIV infection in the United Kingdom who have been treated has increased gradually over time. A substantial proportion of these patients seem to be in danger of exhausting their options for antiretroviral treatment. New drugs with low toxicity, which are not associated with cross resistance to existing drugs, are urgently needed for such patients.

Risk of extensive virological failure to the three original antiretroviral drug classes over long-term follow-up from the start of therapy in patients with HIV infection: an observational cohort study.

BACKGROUNDnThe long-term durability of viral-load suppression provided by the three original antiretroviral drugs is not well characterised. We estimated the proportion of patients who had extensive triple-class failure during long-term follow-up and examined characteristics associated with an increased rate of failure.nnnMETHODSn7916 patients who started antiretroviral therapy with three or more drugs were followed up from the time that therapy started until the last viral-load measure. Extensive triple-class virological failure was defined by failure of three subclasses of nucleoside reverse transcriptase inhibitors, a non-nucleoside reverse transcriptase inhibitor, and a ritonavir-boosted protease inhibitor.nnnFINDINGSn167 patients developed extensive triple-class failure during 27 441 person-years of follow-up. The Kaplan-Meier estimate for the cumulative risk of extensive triple-class failure was 9.2% by 10 years (95% CI 5.0-13.4). There was evidence that this rate has decreased over time (adjusted hazard ratio 0.86 [0.77-0.96] per year more recent; p=0.006). Of the 167 patients with extensive triple-class failure, 101 (60%) subsequently had at least one viral load less than 50 copies per mL. The risk of death by 5 years from the time of extensive triple-class failure was 10.6% (2.4-18.8, nine deaths).nnnINTERPRETATIONnWe have shown that extensive virological failure of the three main classes of drugs occurs slowly in routine clinical practice. This finding has implications for the planning of treatment programmes in developing countries, where additional drugs outside these classes are unlikely to be available for some time.

Late diagnosis in the HAART era: proposed common definitions and associations with mortality

Objective:To identify a definition of presentation after clinical or immunological disease progression that will reliably identify an individual at high risk of mortality over the first 3 months after HIV diagnosis and that can be adopted as a basis for comparing over time and regions. Design:An observational cohort study. Methods:Individuals seen for the first time at a UK Collaborative HIV Cohort study clinic from 1996 to 2006 were identified. Two immunological (CD4 cell count < 200 cells/μl and CD4 cell count <50 cells/μl) and two clinical (AIDS and severe/moderate AIDS) criteria for presentation with advanced HIV disease were compared, as well as combinations of them. The predictive ability of each diagnosis for identifying individuals who died in the first 3 months after HIV diagnosis was assessed. Results:Fifteen thousand seven hundred and seventy-four patients were included, of whom 1495 (9.5%), 4231 (26.8%), 1523 (9.7%) and 379 (2.4%) had a CD4 cell count below 50 cells/μl, CD4 cell count below 200 cells/μl, AIDS or severe/moderate AIDS at diagnosis; CD4 cell counts were unavailable for 2264 (14.4%) patients. Two hundred and six (1.3%) patients died within the first 3 months. Sensitivities of the individual criteria ranged from 18.0% (severe/moderate AIDS) to 50.5% (CD4 cell count < 200 cells/μl) with specificities ranging from 73.5% (CD4 < 200 cells/μl) to 97.8% (severe/moderate AIDS). Combinations of clinical and immunological criteria increased the sensitivity but decreased the specificity. Conclusion:We propose that presentation with ‘advanced HIV disease’ is presentation with a CD4 cell count below 200 cells/μl or AIDS, whereas ‘late’ presentation is defined as presentation when the CD4 cell count is below that when treatment should be initiated (currently CD4 cell count < 350 cells/μl or AIDS).

HIV-associated central nervous system diseases in the recent combination antiretroviral therapy era

Background and purpose:u2002 Data describing the incidence and survival of HIV‐related central nervous system diseases (CNS‐D) in recent years are sparse.

Incomplete Reversibility of Estimated Glomerular Filtration Rate Decline Following Tenofovir Disoproxil Fumarate Exposure

Background.u2003Tenofovir disoproxil fumarate (TDF) has been linked to renal impairment, but the extent to which this impairment is reversible is unclear. We aimed to investigate the reversibility of renal decline during TDF therapy. Methods.u2003Cox proportional hazards models assessed factors associated with discontinuing TDF in those with an exposure duration of >6 months. In those who discontinued TDF therapy, linear piecewise regression models estimated glomerular filtration rate (eGFR) slopes before initiation of, during, and after discontinuation of TDF therapy. Factors associated with not achieving eGFR recovery 6 months after discontinuing TDF were assessed using multivariable logistic regression. Results.u2003We observed declines in the eGFR during TDF exposure (mean slopes, −15.7 mL/minute/1.73 m2/year [95% confidence interval {CI}, −20.5 to −10.9] during the first 3 months and −3.1 mL/minute/1.73 m2/year [95% CI, −4.6 to −1.7] thereafter) and evidence of eGFR increases following discontinuation of TDF therapy (mean slopes, 12.5 mL/minute/1.73 m2/year [95% CI, 8.9–16.1] during the first 3 months and 0.8 mL/minute/1.73 m2/year [95% CI, .1–1.5] thereafter). Following TDF discontinuation, 38.6% of patients with a decline in the eGFR did not experience recovery. A higher eGFR at baseline, a lower eGFR after discontinuation of TDF therapy, and more-prolonged exposure to TDF were associated with an increased risk of incomplete recovery 6 months after discontinuation of TDF therapy. Conclusions.u2003This study shows that a decline in the eGFR during TDF therapy was not fully reversible in one third of patients and suggests that prolonged TDF exposure at a low eGFR should be avoided.

CD4 counts and the risk of systemic non-Hodgkin’s lymphoma in individuals with HIV in the UK

This very large HIV-positive cohort study examines a number of variables that predispose to the development of lymphoma in the HAART era. Despite a declining incidence of lymphoma, the authors define a close relationship between latest CD4 count and lymphoma risk, and thus advocate early initiation of HAART and more frequent HIV monitoring. Since the introduction of highly active antiretroviral therapy, there has been a decline in the incidence of non-Hodgkin’s lymphoma among HIV-infected individuals. We described trends in the incidence of systemic non-Hodgkin’s lymphoma in the UK CHIC Study from 1996–2006 and evaluated the association between immunosuppression and development of systemic non-Hodgkin’s lymphoma: 286/23,155 (1.2%) individuals developed an AIDS-defining lymphoma (258 systemic). Younger age, receipt of highly active antiretroviral therapy and later calendar year were all independently associated with a reduced risk of systemic non-Hodgkin’s lymphoma. A lower latest CD4 count was strongly associated with systemic non-Hodgkin’s lymphoma, in patients who had (RR per log2(cells/mm3) higher: 0.62) and had not (0.70) received highly active antiretroviral therapy. Associations with other measures of immunosuppression, including nadir CD4 count, experience and duration of severe immunosuppression, were generally weaker. Earlier highly active anti-retroviral therapy initiation and wider access to HIV testing is advocated to reduce the risk of systemic non-Hodgkin’s lymphoma.

The prevalence of hepatitis C virus (HCV) infection in HIV-positive individuals in the UK - trends in HCV testing and the impact of HCV on HIV treatment outcomes

Summary.u2002 We examined the prevalence of hepatitis C virus (HCV) infection among HIV‐positive individuals in the UK, trends in HCV testing and the impact of HCV on HIV treatment outcomes. Trends over time in HCV prevalence were calculated using each patient’s most recent HCV status at the end of each calendar year. Logistic regression was used to identify factors associated with having a HCV antibody test, and Cox regression was used to determine whether HCV status was associated with the time to experiencing an immunological response to highly active antiretroviral treatment (HAART), time to virological response and viral rebound. Of the 31u2003765 HIV‐positive individuals seen for care between January 1996 and September 2007, 20u2003365 (64.1%) individuals were tested for HCV, and 1807 (8.9%) had detectable HCV antibody. The proportion of patients in follow‐up ever tested for HCV increased over time, from 782/8505 (9.2%) in 1996 to 14u2003280/17u2003872 (79.9%) in 2007. Nine thousand six hundred and sixty‐nine individuals started HAART for the first time in or after January 2000, of whom, 396 (4.1%) were HCV positive. Presence of HCV infection did not affect initial virological response, virological rebound or immunological response. The cumulative prevalence of HCV in the UK CHIC Study is 8.9%. Despite UK guidelines, over 20% of HIV‐positive individuals have not had their HCV status determined by 2007. HCV infection had no impact on HIV virological outcomes or immunological response to HIV treatment. The long‐term impact on morbidity and mortality remain to be determined.