Death following partner bereavement: A self-controlled case series analysis.

BACKGROUND: There is mixed evidence that older people bereaved of a spouse or partner are at risk of adverse outcomes. The main difficulty is to take account of other explanatory factors. We tested for an association between a patient's death and the timing of any bereavement of a cohabitee. METHOD: Self-controlled case series study in which each case serves as his or her own control and which thereby accounts for all fixed measurable and unmeasurable confounders. We used the Health Improvement Network (THIN) primary care database to identify patients who died aged 50-99 years during the period 2003 to 2014. We used the household identifier in the database to determine whether they had an opposite sex cohabitee at the start of the observation period. RESULTS: 38,773 men and 23,396 women who had died and who had a cohabitee at the start of the observation period, were identified and included in male and female cohorts respectively. A higher risk of death was found in the 24 months after the death of the cohabitee than in the time classified as unexposed. The greatest risk was during the first 3 months after the death of the cohabitee (age-adjusted incidence rate ratio [IRR] 1.63, 95% CI 1.45-1.83 in the male cohort, and IRR 1.70, 95% CI 1.52-1.90 in the female cohort). CONCLUSION: Risk of death in men or women was significantly higher after the death of a cohabitee and this was greatest in the first three months of bereavement. We need more evidence on the effectiveness of interventions to reduce this increased mortality.

Inequalities in receipt of mental and physical healthcare in people with dementia in the UK.

Background: UK Dementia Strategies prioritise fair access to mental and physical healthcare. We investigated whether there are inequalities by deprivation or gender in healthcare received by people with dementia, and compared healthcare received by people with and without dementia. Methods: we investigated primary care records of 68,061 community dwelling dementia patients and 259,337 people without dementia (2002-13). We tested hypotheses that people with dementia from more deprived areas, and who are women receive more psychotropic medication, fewer surgery consultations, are less likely to receive annual blood pressure, weight monitoring and an annual review, compared with those from less deprived areas and men. Results: only half of people with dementia received a documented annual review. Deprivation was not associated with healthcare received. Compared to men with dementia, women with dementia had lower rates of surgery consultations (adjusted incidence rate ratio (IRR) 0.90, 95% CI 0.90-0.91), of annual blood pressure monitoring (adjusted IRR 0.96, 95% CI 0.95-0.97) and of annual weight monitoring (adjusted IRR 0.91, 95% CI 0.90-0.93). Men with dementia were less likely to be taking psychotropic medication than women with dementia. People with dementia had fewer surgery consultations and were less likely to have their weight and blood pressure monitored at least annually, compared to the non-dementia group. Conclusions: people with dementia, in particular women, appear to receive less primary healthcare, but take more psychotropic medication that may negatively impact their physical health. Reducing these inequalities and improving access of people with dementia to preventative healthcare could improve the health of people with dementia.

Living With an Older Person Dying From Cancer, Lung Disease, or Dementia: Health Outcomes From a General Practice Cohort Study.

CONTEXT: Increasing numbers of people will die from chronic disease. Families contribute significantly to end-of-life care, but their role may not be recognized. OBJECTIVES: To 1) establish the proportion of older cohabitees identified in primary care as "carers"; 2) describe demographic and lifestyle characteristics of cohabitees of people terminally ill with cancer, dementia, and chronic obstructive pulmonary disease (COPD); 3) describe their health a year before and after bereavement; and 4) compare health outcomes between cohabitees of people dying with cancer, COPD, or dementia. METHODS: Retrospective cohort study using a U.K. primary care database (The Health Improvement Network) of 13,693 bereaved cohabitees (a proxy marker for being a carer), aged 60 years or older of people dying from cancer, COPD, or dementia. Characteristics were described one year before and after bereavement. We compared cancer, COPD, and dementia cohabitee outcomes using incidence rate ratios one year before and after bereavement and calculated mortality risk after bereavement. RESULTS: A total of 6.9% of cohabitees were recorded as carers. Health outcomes differed little between the three groups of cohabitees in the year before or after bereavement. The proportion of cohabitees with six or more consultations increased the year after bereavement (cancer cohabitees 16.0% to 18.8%, COPD cohabitees 17.8% to 20.4%, and dementia cohabitees 15.5% to 17.5%). At postbereavement (follow-up median 3 years, interquartile range 1.3-5.4), we found no mortality differences between the three groups. CONCLUSION: Recording of carers of terminally ill people was suboptimal. Cause of bereavement produced few differential effects on health outcomes or mortality.

A Method to Estimate the Size and Characteristics of HIV-positive Populations Using an Individual-based Stochastic Simulation Model.

It is important not only to collect epidemiologic data on HIV but to also fully utilize such information to understand the epidemic over time and to help inform and monitor the impact of policies and interventions. We describe and apply a novel method to estimate the size and characteristics of HIV-positive populations. The method was applied to data on men who have sex with men living in the UK and to a pseudo dataset to assess performance for different data availability. The individual-based simulation model was calibrated using an approximate Bayesian computation-based approach. In 2013, 48,310 (90% plausibility range: 39,900-45,560) men who have sex with men were estimated to be living with HIV in the UK, of whom 10,400 (6,160-17,350) were undiagnosed. There were an estimated 3,210 (1,730-5,350) infections per year on average between 2010 and 2013. Sixty-two percent of the total HIV-positive population are thought to have viral load <500 copies/ml. In the pseudo-epidemic example, HIV estimates have narrower plausibility ranges and are closer to the true number, the greater the data availability to calibrate the model. We demonstrate that our method can be applied to settings with less data, however plausibility ranges for estimates will be wider to reflect greater uncertainty of the data used to fit the model.

Observational cohort study: deprivation and access to anti-dementia drugs in the UK.

BACKGROUND: UK National Dementia Strategies prioritise fair access to dementia treatments for the whole population. We investigated for the first time inequalities in NHS national dementia prescribing and how they have varied between UK countries and over time. METHOD: we investigated the association between Townsend deprivation score and anti-dementia drug prescribing in 77,045 dementia patients from UK primary care records from 2002 to 2013. RESULTS: we included 77,045 patients with recorded dementia diagnosis or anti-dementia drug prescription. Least deprived patients were 25% more likely to be initiated on anti-dementia drugs than the most deprived (adjusted incidence rate ratio 1.25, 95% confidence interval 1.19-1.31). This was driven by data from English practices where prescribing rates were consistently lower in more deprived patients compared with Scotland, Northern Ireland and Wales, where prescribing was not related to deprivation quintile. Compared with English practices, anti-dementia medication was prescribed more often in Northern Irish (1.81, 1.41-2.34) and less in Welsh practices (0.68, 0.55-0.82), with a trend towards more prescribing in Scottish practices (1.14, 0.98-1.32). Drug initiation rates were also higher in younger people and men. CONCLUSION: four years after the English National Dementia Strategy, there is no evidence that the Strategy's key objective of reducing treatment inequalities is being achieved. Higher overall anti-dementia drug prescribing in Scottish and Northern Irish practices, and differing clinical guidelines in Scotland from other UK countries might explain greater equality in prescribing in these countries. Strategies to offer treatment to more deprived people with dementia in England are needed.

Projected Lifetime Healthcare Costs Associated with HIV Infection.

OBJECTIVE: Estimates of healthcare costs associated with HIV infection would provide valuable insight for evaluating the cost-effectiveness of possible prevention interventions. We evaluate the additional lifetime healthcare cost incurred due to living with HIV. METHODS: We used a stochastic computer simulation model to project the distribution of lifetime outcomes and costs of men-who-have-sex-with-men (MSM) infected with HIV in 2013 aged 30, over 10,000 simulations. We assumed a resource-rich setting with no loss to follow-up, and that standards and costs of healthcare management remain as now. RESULTS: Based on a median (interquartile range) life expectancy of 71.5 (45.0-81.5) years for MSM in such a setting, the estimated mean lifetime cost of treating one person was £ 360,800 ($567,000 or € 480,000). With 3.5% discounting, it was £ 185,200 ($291,000 or € 246,000). The largest proportion (68%) of these costs was attributed to antiretroviral drugs. If patented drugs are replaced by generic versions (at 20% cost of patented prices), estimated mean lifetime costs reduced to £ 179,000 ($ 281,000 or € 238,000) and £ 101,200 ($ 158,900 or € 134,600) discounted. CONCLUSIONS: If 3,000 MSM had been infected in 2013, then future lifetime costs relating to HIV care is likely to be in excess of £ 1 billion. It is imperative for investment into prevention programmes to be continued or scaled-up in settings with good access to HIV care services. Costs would be reduced considerably with use of generic antiretroviral drugs.

Use of surveillance data on HIV diagnoses with HIV-related symptoms to estimate the number of people living with undiagnosed HIV in need of antiretroviral therapy.

BACKGROUND: It is important to have methods available to estimate the number of people who have undiagnosed HIV and are in need of antiretroviral therapy (ART). METHODS: The method uses the concept that a predictable level of occurrence of AIDS or other HIV-related clinical symptoms which lead to presentation for care, and hence diagnosis of HIV, arises in undiagnosed people with a given CD4 count. The method requires surveillance data on numbers of new HIV diagnoses with HIV-related symptoms, and the CD4 count at diagnosis. The CD4 count-specific rate at which HIV-related symptoms develop are estimated from cohort data. 95% confidence intervals can be constructed using a simple simulation method. RESULTS: For example, if there were 13 HIV diagnoses with HIV-related symptoms made in one year with CD4 count at diagnosis between 150-199 cells/mm3, then since the CD4 count-specific rate of HIV-related symptoms is estimated as 0.216 per person-year, the estimated number of person years lived in people with undiagnosed HIV with CD4 count 150-199 cells/mm3 is 13/0.216 = 60 (95% confidence interval: 29-100), which is considered an estimate of the number of people living with undiagnosed HIV in this CD4 count stratum. CONCLUSIONS: The method is straightforward to implement within a short period once a surveillance system of all new HIV diagnoses, collecting data on HIV-related symptoms at diagnosis, is in place and is most suitable for estimating the number of undiagnosed people with CD4 count <200 cells/mm3 due to the low rate of developing HIV-related symptoms at higher CD4 counts. A potential source of bias is under-diagnosis and under-reporting of diagnoses with HIV-related symptoms. Although this method has limitations as with all approaches, it is important for prompting increased efforts to identify undiagnosed people, particularly those with low CD4 count, and for informing levels of unmet need for ART.

Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with the general population.

BACKGROUND: Due to the success of antiretroviral therapy (ART), it is relevant to ask whether death rates in optimally treated HIV are higher than the general population. The objective was to compare mortality rates in well controlled HIV-infected adults in the SMART and ESPRIT clinical trials with the general population. METHODS: Non-IDUs aged 20-70 years from the continuous ART control arms of ESPRIT and SMART were included if the person had both low HIV plasma viral loads (≤400 copies/ml SMART, ≤500 copies/ml ESPRIT) and high CD4(+) T-cell counts (≥350 cells/µl) at any time in the past 6 months. Standardized mortality ratios (SMRs) were calculated by comparing death rates with the Human Mortality Database. RESULTS: Three thousand, two hundred and eighty individuals [665 (20%) women], median age 43 years, contributed 12,357 person-years of follow-up. Sixty-two deaths occurred during follow up. Commonest cause of death was cardiovascular disease (CVD) or sudden death (19, 31%), followed by non-AIDS malignancy (12, 19%). Only two deaths (3%) were AIDS-related. Mortality rate was increased compared with the general population with a CD4(+) cell count between 350 and 499 cells/µl [SMR 1.77, 95% confidence interval (CI) 1.17-2.55]. No evidence for increased mortality was seen with CD4(+) cell counts greater than 500 cells/µl (SMR 1.00, 95% CI 0.69-1.40). CONCLUSION: In HIV-infected individuals on ART, with a recent undetectable viral load, who maintained or had recovery of CD4(+) cell counts to at least 500 cells/µl, we identified no evidence for a raised risk of death compared with the general population.

Predictors of CD4(+) T-cell counts of HIV type 1-infected persons after virologic failure of all 3 original antiretroviral drug classes.

BACKGROUND: Low CD4(+) T-cell counts are the main factor leading to clinical progression in human immunodeficiency virus type 1 (HIV-1) infection. We aimed to investigate factors affecting CD4(+) T-cell counts after triple-class virological failure. METHODS: We included individuals from the COHERE database who started antiretroviral therapy from 1998 onward and who experienced triple-class virological failure. CD4(+) T-cell counts obtained after triple-class virologic failure were analyzed using generalized estimating equations. RESULTS: The analyses included 2424 individuals with a total of 23 922 CD4(+) T-cell count measurements. In adjusted models (excluding current viral load and year), CD4(+) T-cell counts were higher with regimens that included boosted protease inhibitors (increase, 22 cells/µL [95% confidence interval {CI}, 3.9-41]; P = .017) or drugs from the new classes (increase, 39 cells/µL [95% CI, 15-62]; P = .001), compared with nonnucleoside reverse-transcriptase inhibitor-based regimens. These associations disappeared when current viral load and/or calendar year were included. Compared with viral levels of <2.5 log(10) copies/mL, levels of 2.5-3.5, 3.5-4.5, 4.5-5.5, and >5.5 log(10) copies/mL were associated with CD4(+) T-cell count decreases of 51, 84, 137, and 186 cells/µL, respectively (P < .001). CONCLUSIONS: The approximately linear inverse relationship between log(10) viral load and CD4(+) T-cell count indicates that there are likely immunologic benefits from lowering viral load even by modest amounts that do not lead to undetectable viral loads. This is important for patients with low CD4(+) T-cell counts and few drug options.

Projected life expectancy of people with HIV according to timing of diagnosis.

BACKGROUND AND OBJECTIVES: Effective antiretroviral therapy (ART) has contributed greatly toward survival for people with HIV, yet many remain undiagnosed until very late. Our aims were to estimate the life expectancy of an HIV-infected MSM living in a developed country with extensive access to ART and healthcare, and to assess the effect of late diagnosis on life expectancy. METHODS: A stochastic computer simulation model of HIV infection and the effect of ART was used to estimate life expectancy and determine the distribution of potential lifetime outcomes of an MSM, aged 30 years, who becomes HIV positive in 2010. The effect of altering the diagnosis rate was investigated. RESULTS: Assuming a high rate of HIV diagnosis (median CD4 cell count at diagnosis, 432  cells/µl), projected median age at death (life expectancy) was 75.0 years. This implies 7.0 years of life were lost on average due to HIV. Cumulative risks of death by 5 and 10 years after infection were 2.3 and 5.2%, respectively. The 95% uncertainty bound for life expectancy was (68.0,77.3) years. When a low diagnosis rate was assumed (diagnosis only when symptomatic, median CD4 cell count 140  cells/µl), life expectancy was 71.5 years, implying an average 10.5 years of life lost due to HIV. CONCLUSION: If low rates of virologic failure observed in treated patients continue, predicted life expectancy is relatively high in people with HIV who can access a wide range of antiretrovirals. The greatest risk of excess mortality is due to delays in HIV diagnosis.

Calendar time trends in the incidence and prevalence of triple-class virologic failure in antiretroviral drug-experienced people with HIV in Europe.

BACKGROUND: Despite the increasing success of antiretroviral therapy (ART), virologic failure of the 3 original classes [triple-class virologic failure, (TCVF)] still develops in a small minority of patients who started therapy in the triple combination ART era. Trends in the incidence and prevalence of TCVF over calendar time have not been fully characterised in recent years. METHODS: Calendar time trends in the incidence and prevalence of TCVF from 2000 to 2009 were assessed in patients who started ART from January 1, 1998, and were followed within the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). RESULTS: Of 91,764 patients followed for a median (interquartile range) of 4.1 (2.0-7.1) years, 2722 (3.0%) developed TCVF. The incidence of TCVF increased from 3.9 per 1000 person-years of follow-up [95% confidence interval (CI): 3.7 to 4.1] in 2000 to 8.8 per 1000 person-years of follow-up (95% CI: 8.5 to 9.0) in 2005, but then declined to 5.8 per 1000 person-years of follow-up (95% CI: 5.6 to 6.1) by 2009. The prevalence of TCVF was 0.3% (95% CI: 0.27% to 0.42%) at December 31, 2000, and then increased to 2.4% (95% CI: 2.24% to 2.50%) by the end of 2005. However, since 2005, TCVF prevalence seems to have stabilized and has remained below 3%. CONCLUSIONS: The prevalence of TCVF in people who started ART after 1998 has stabilized since around 2005, which most likely results from the decline in incidence of TCVF from this date. The introduction of improved regimens and better overall HIV care is likely to have contributed to these trends. Despite this progress, calendar trends should continue to be monitored in the long term.

Trends in virological and clinical outcomes in individuals with HIV-1 infection and virological failure of drugs from three antiretroviral drug classes: a cohort study.

BACKGROUND: Limited treatment options have been available for people with HIV who have had virological failure of the three original classes of HIV antiretroviral drugs-so-called triple-class virological failure (TCVF). However, introduction of new drugs and drug classes might have improved outcomes. We aimed to assess trends in virological and clinical outcomes for individuals with TCVF in 2000-09. METHODS: In our cohort study, we analysed data for adults starting antiretroviral therapy from 1998 in cohorts participating in the PLATO II project, which is part of COHERE, a collaboration of European cohorts. TCVF was defined as virological failure to at least two nucleoside reverse transcriptase inhibitors, one non-nucleoside reverse-transcriptase inhibitor, and one ritonavir-boosted protease inhibitor, with virological failure of a drug defined as one viral-load measurement of greater than 500 copies per mL after at least 4 months of continuous use. We used multivariable generalised estimating equation logistic models and Poisson regression models to study trends in virological suppression and incidence of AIDS or death after TCVF. We adjusted for sex, transmission group, age, AIDS status, CD4 cell count, plasma viral loads at TCVF, achievement of virological response (<50 copies per mL), and number of drug failures before TCVF. FINDINGS: 28 of 33 cohorts in COHERE contributed data to the PLATO II project, of which four had no participants eligible for inclusion in this study. 2476 (3%) of 91 764 participants from the remaining 24 cohorts had TCVF and at least one viral load measurement in 2000-09. The proportion of patients with virological response after TCVF increased from 19·5% in 2000 to 57·9% in 2009 (adjusted p<0·0001). Incidence of AIDS decreased from 7·7 per 100 person-years in 2000-02 to 2·3 in 2008 and 1·2 in 2009 (adjusted p<0·0001). Mortality decreased from 4·0 per 100 person-years between 2000 and 2002 to 1·9 in 2007 and 1·4 in 2008 (unadjusted p=0·023), but the trend was not significant after adjustment (p=0·22). INTERPRETATION: A substantial improvement in viral load suppression and accompanying decrease in the rates of AIDS in people after extensive failure to drugs from the three original antiretroviral classes during 2000-09 was probably mainly driven by availability of newer drugs with better tolerability and ease of use and small cross-resistance profiles, suggesting the public health benefit of the introduction of new drugs.

Risk of triple-class virological failure in children with HIV: a retrospective cohort study.

BACKGROUND: In adults with HIV treated with antiretroviral drug regimens from within the three original drug classes (nucleoside or nucleotide reverse transcriptase inhibitors [NRTIs], non-NRTIs [NNRTIs], and protease inhibitors), virological failure occurs slowly, suggesting that long-term virological suppression can be achieved in most people, even in areas where access is restricted to drugs from these classes. It is unclear whether this is the case for children, the group who will need to maintain viral suppression for longest. We aimed to determine the rate and predictors of triple-class virological failure to the three original drugs classes in children. METHODS: In the Collaboration of Observational HIV Epidemiological Research Europe, the rate of triple-class virological failure was studied in children infected perinatally with HIV who were aged less than 16 years, starting antiretroviral therapy (ART) with three or more drugs, between 1998 and 2008. We used Kaplan-Meier and Cox regression methods to investigate the risk and predictors of triple-class virological failure after ART initiation. FINDINGS: Of 1007 children followed up for a median of 4·2 (IQR 2·4-6·5) years, 237 (24%) were triple-class exposed and 105 (10%) had triple-class virological failure, of whom 29 never had a viral-load measurement less than 500 copies per mL. Incidence of triple-class virological failure after ART initiation increased with time, and risk by 5 years after ART initiation was 12·0% (95% CI 9·4-14·6). In multivariate analysis, older age at ART initiation was associated with increased risk of failure (p=0·02). Of 686 children starting ART with NRTIs and either a NNRTI or ritonavir-boosted protease inhibitor, the rate of failure was higher than in adults with heterosexually transmitted HIV (hazard ratio 2·2 [95% CI 1·6-3·0, p<0·0001]). INTERPRETATION: Findings highlight the challenges of attaining long-term viral suppression in children who will be taking life-long ART. Early identification of children not responding to ART, adherence support, particularly for children and adolescents aged 13 years or older starting ART, and ART simplification strategies are all needed to attain and sustain virological suppression. FUNDING: UK Medical Research Council award G0700832.

Death rates in HIV-positive antiretroviral-naive patients with CD4 count greater than 350 cells per microL in Europe and North America: a pooled cohort observational study.

BACKGROUND: Whether people living with HIV who have not received antiretroviral therapy (ART) and have high CD4 cell counts have higher mortality than the general population is unknown. We aimed to examine this by analysis of pooled data from industrialised countries. METHODS: We merged data on demographics, CD4 cell counts, viral-load measurements, hepatitis C co-infection status, smoking status, date of death, and whether death was AIDS-related or not from 23 European and North American cohorts. We calculated standardised mortality ratios (SMRs) standardised by age, sex, and year, stratifying by risk group. Data were included for patients aged 20-59 years who had at least one CD4 count greater than 350 cells per microL while ART naive. All pre-ART CD4 counts greater than 350 cells per microL from January, 1990, to December, 2004, were included. We investigated mortality for four risk groups--men who have sex with men, heterosexual people, injecting drug users, and those at other or unknown risk. The association between CD4 cell count and death rate was investigated by use of Poisson regression methods. FINDINGS: Data were analysed for 40,830 patients contributing 80,682 person-years of follow-up. Of 419 deaths, 401 were used in the SMR analysis: 100 men who have sex with men (SMR 1.30, 95% CI 1.06-1.58); 68 heterosexual people (2.94, 2.28-3.73); 203 injecting drug users (9.37, 8.13-10.75); and 30 in the other or unknown risk category (4.57, 3.09-6.53). Compared with CD4 counts of 350-499 cells per microL, death rate was lower in patients with counts of 500-699 cells per microL (adjusted rate ratio 0.77, 95% CI 0.61-0.95) and counts of 700 cells per microL (0.66, 0.52-0.85). INTERPRETATION: In HIV-infected ART-naive patients with high CD4 cell counts, death rates were raised compared with the general population. In men who have sex with men this was modest, suggesting that a substantial proportion of the increased risk in other groups is due to confounding by other factors. Even though the increased risk is small, new studies of potential benefits of ART in this group are merited. FUNDING: European Commission, FP6. European AIDS Treatment Network (NEAT). Project number LSHP-CT-2006-037570.

Ongoing changes in HIV RNA levels during untreated HIV infection: implications for CD4 cell count depletion.

BACKGROUND: Understanding of the interplay between plasma HIV RNA level and CD4 cell count depletion in untreated infection remains incomplete. METHODS: We studied 1169 people with HIV seen for care at a major London clinic while naive to antiretroviral therapy. We considered pairs (n = 5940) of consecutive simultaneously measured CD4 cell count and plasma HIV RNA values from patients who had never started therapy. Baseline was the first date when both measures were known. RESULTS: HIV RNA levels increased variably and often substantially from baseline (60% experience an increase of over 50 000 copies/ml by 5 years of follow-up). The current HIV RNA level (i.e. first value of the pair) was strongly associated with the time-standardized change in CD4 cell count, with a mean 106 cells/microl per year greater rate of CD4 cell count decline per log-copy/ml higher current HIV RNA level (P < 0.0001). After adjustment for the current level, higher baseline HIV RNA was not associated with CD4 cell count decline. There was no average CD4 cell count decline with current HIV RNA level below 3.0 log-copies/ml, compared with a 159 cells/microl per year decline for those with HIV RNA at least 5.5 log-copies/ml (P < 0.0001). Further, the current CD4 cell count predicted subsequent changes in HIV RNA level (0.04 log-copies/year greater increases per 100 cells/microl lower CD4 cell count; P < 0.0001). CONCLUSION: The often substantial increases in HIV RNA level observed in untreated HIV infection appear fundamentally linked to CD4 cell count depletion. Research into mechanisms by which HIV RNA levels rise over time should yield insights into the causes of CD4 cell count depletion, as the two processes are intimately linked.

Triple-class virologic failure in HIV-infected patients undergoing antiretroviral therapy for up to 10 years.

BACKGROUND: Life expectancy of people with human immunodeficiency virus (HIV) is now estimated to approach that of the general population in some successfully treated subgroups. However, to attain these life expectancies, viral suppression must be maintained for decades. METHODS: We studied the rate of triple-class virologic failure (TCVF) in patients within the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) who started antiretroviral therapy (ART) that included a nonnucleoside reverse-transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI/r) from 1998 onwards. We also focused on TCVF in patients who started a PI/r-containing regimen after a first-line NNRTI-containing regimen failed. RESULTS: Of 45 937 patients followed up for a median (interquartile range) of 3.0 (1.5-5.0) years, 980 developed TCVF (2.1%). By 5 and 9 years after starting ART, an estimated 3.4% (95% confidence interval [CI], 3.1%-3.6%) and 8.6% (95% CI, 7.5%-9.8%) of patients, respectively, had developed TCVF. The incidence of TCVF rose during the first 3 to 4 years on ART but plateaued thereafter. There was no significant difference in the risk of TCVF according to whether the initial regimen was NNRTI or PI/r based (P = .11). By 5 years after starting a PI/r regimen as second-line therapy, 46% of patients had developed TCVF. CONCLUSIONS: The rate of virologic failure of the 3 original drug classes is low, but not negligible, and does not appear to diminish over time from starting ART. If this trend continues, many patients are likely to need newer drugs to maintain viral suppression. The rate of TCVF from the start of a PI/r regimen after NNRTI failure provides a comparator for studies of response to second-line regimens in resource-limited settings.

Long-term trends in adherence to antiretroviral therapy from start of HAART.

OBJECTIVE: People on antiretroviral therapy are likely to be required to maintain good adherence throughout their lives. We aimed to investigate long-term trends in highly active antiretroviral therapy (HAART) adherence to identify the main predictors and to evaluate whether participants experience periods of low adherence (95% adherence = 1.02 per year; 95% confidence interval (CI) 1.01-1.04; P = 0.0053]. Independent predictors of adherence were age, demographic group, calendar year period, drug regimen and previous virologic failures. The overall rate of at least one period of low adherence was 0.12 per person-year, but this rate decrease markedly over time to 0.01 in 2007/2008. CONCLUSION: Adherence, as measured by drug coverage, does not decrease on average over more than a decade from start of HAART. This is encouraging, because it shows that patients could potentially maintain viral suppression for many years.

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.