Loveleen Bansi

When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study.

BACKGROUND Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 × 10(9) cells/L initiate combined antiretroviral therapy (cART), but the optimal CD4 cell count at which cART should be initiated remains a matter of debate. OBJECTIVE To identify the optimal CD4 cell count at which cART should be initiated. DESIGN Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used to compare cART initiation strategies for CD4 thresholds between 0.200 and 0.500 × 10(9) cells/L. SETTING HIV clinics in Europe and the Veterans Health Administration system in the United States. PATIENTS 20, 971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 × 10(9) cells/L and no previous AIDS-defining illnesses, of whom 8392 had a CD4 cell count that decreased into the range of 0.200 to 0.499 × 10(9) cells/L and were included in the analysis. MEASUREMENTS Hazard ratios and survival proportions for all-cause mortality and a combined end point of AIDS-defining illness or death. RESULTS Compared with initiating cART at the CD4 cell count threshold of 0.500 × 10(9) cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death. LIMITATIONS CD4 cell count at cART initiation was not randomized. Residual confounding may exist. CONCLUSION Initiation of cART at a threshold CD4 count of 0.500 × 10(9) cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 × 10(9) cells/L.

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.

BACKGROUND The 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. METHODS 7916 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. FINDINGS 167 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). INTERPRETATION We 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:  Data describing the incidence and survival of HIV‐related central nervous system diseases (CNS‐D) in recent years are sparse.

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.

Impact of antiretroviral therapy on tuberculosis incidence among HIV-positive patients in high-income countries.

BACKGROUND The lower tuberculosis incidence reported in human immunodeficiency virus (HIV)-positive individuals receiving combined antiretroviral therapy (cART) is difficult to interpret causally. Furthermore, the role of unmasking immune reconstitution inflammatory syndrome (IRIS) is unclear. We aim to estimate the effect of cART on tuberculosis incidence in HIV-positive individuals in high-income countries. METHODS The HIV-CAUSAL Collaboration consisted of 12 cohorts from the United States and Europe of HIV-positive, ART-naive, AIDS-free individuals aged ≥18 years with baseline CD4 cell count and HIV RNA levels followed up from 1996 through 2007. We estimated hazard ratios (HRs) for cART versus no cART, adjusted for time-varying CD4 cell count and HIV RNA level via inverse probability weighting. RESULTS Of 65 121 individuals, 712 developed tuberculosis over 28 months of median follow-up (incidence, 3.0 cases per 1000 person-years). The HR for tuberculosis for cART versus no cART was 0.56 (95% confidence interval [CI], 0.44-0.72) overall, 1.04 (95% CI, 0.64-1.68) for individuals aged >50 years, and 1.46 (95% CI, 0.70-3.04) for people with a CD4 cell count of <50 cells/μL. Compared with people who had not started cART, HRs differed by time since cART initiation: 1.36 (95% CI, 0.98-1.89) for initiation <3 months ago and 0.44 (95% CI, 0.34-0.58) for initiation ≥3 months ago. Compared with people who had not initiated cART, HRs <3 months after cART initiation were 0.67 (95% CI, 0.38-1.18), 1.51 (95% CI, 0.98-2.31), and 3.20 (95% CI, 1.34-7.60) for people <35, 35-50, and >50 years old, respectively, and 2.30 (95% CI, 1.03-5.14) for people with a CD4 cell count of <50 cells/μL. CONCLUSIONS Tuberculosis incidence decreased after cART initiation but not among people >50 years old or with CD4 cell counts of <50 cells/μL. Despite an overall decrease in tuberculosis incidence, the increased rate during 3 months of ART suggests unmasking IRIS.

Immunodeficiency and renal impairment are risk factors for HIV-associated acute renal failure

Objective:To identify risk factors for acute renal failure (ARF) in HIV-infected patients. Design:Observational cohort study of HIV-infected patients attending a South London HIV centre between January 1999 and December 2008. Methods:ARF was defined as a transient, more than 40% reduction in renal function as assessed by estimated glomerular filtration rate. Multivariate Poisson regression analysis was used to identify baseline and time-updated factors associated with ARF. Results:The incidence of ARF was 2.8 (95% confidence interval 2.41–3.24) episodes per 100 person-years. We observed a stepwise increase in ARF incidence with time accrued at lower CD4 cell count and at lower estimated glomerular filtration rate, with adjusted incidence rate ratios of 1 (reference), 1.56 (0.97–2.48), 2.08 (1.11–3.91), 6.38 (3.18–12.78) and 10.29 (5.11–20.98) for CD4 cell counts of more than 350, 201–350, 101–200, 51–100 and of 50/μl or less, and 1 (reference), 1.46 (0.86–2.51), 4.19 (2.37–7.42) and 27.00 (16.13–44.95) for estimated glomerular filtration rate more than 90, 75–89, 60–74 and less than 60 ml/min, respectively. Ethnicity, hepatitis B or C coinfection, exposure to combination antiretroviral therapy with or without indinavir, tenofovir or atazanavir and HIV viraemia were not associated with ARF. Conclusion:Current levels of immunodeficiency and renal function were independent predictors of HIV-associated ARF.

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.  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 31 765 HIV‐positive individuals seen for care between January 1996 and September 2007, 20 365 (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 14 280/17 872 (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.

Clinical epidemiology of HIV-associated end-stage renal failure in the UK.

Objective:To describe the clinical epidemiology of HIV-associated end-stage renal failure (HIV/ESRF) from 1998 to 2007 in the United Kingdom. Design:Observational cohort study. Setting:Seven leading HIV centres and affiliated renal clinics in the United Kingdom. Participants:A total of 21 951 patients in whom renal function was measured. Main outcome measure:Development of end-stage renal failure (ESRF) as defined by initiation of permanent renal replacement therapy (pRRT). Results:Sixty-eight (0.31%) patients had HIV/ESRF, 44 (64.7%) of whom were black. The prevalence of ESRF in black patients increased over time from 0.26% in 1998–1999 to 0.92% in 2006–2007 (P for trend = 0.001). Overall 5-year survival from starting pRRT was 70.3%, and significantly better for black patients compared to those of other ethnicities (85.2 vs. 43.4%, P = 0.001). In multivariable analysis, black ethnicity was associated with a higher risk of ESRF [HR 6.93, 95% confidence interval (CI) 3.56, 13.48], whereas a higher current CD4 cell count was associated with reduced risk (HR: 0.83, 95% CI 0.76, 0.95) per 50 cells higher). No association was seen between current viral load or current highly active antiretroviral therapy (HAART) status and ESRF. On the basis of these observations, we estimate that 231 HIV-infected patients required pRRT in the United Kingdom in 2007, and an HIV prevalence of 0.51% among the United Kingdom pRRT recipients in that year. Conclusion:The prevalence of HIV/ESRF increased during the HAART era to reach nearly 1% in black patients, in whom favourable survival rates were observed. Earlier HIV diagnosis will be an important strategy to stem the rising trend of HIV/ESRF.

Declining prevalence of HIV-1 drug resistance in antiretroviral treatment-exposed individuals in Western Europe

HIV-1 drug resistance represents a major obstacle to infection and disease control. This retrospective study analyzes trends and determinants of resistance in antiretroviral treatment (ART)-exposed individuals across 7 countries in Europe. Of 20 323 cases, 80% carried at least one resistance mutation: these declined from 81% in 1997 to 71% in 2008. Predicted extensive 3-class resistance was rare (3.2% considering the cumulative genotype) and peaked at 4.5% in 2005, decreasing thereafter. The proportion of cases exhausting available drug options dropped from 32% in 2000 to 1% in 2008. Reduced risk of resistance over calendar years was confirmed by multivariable analysis.