SummaryBackgroundHealth care for people living with HIV has improved substantially in the past two decades. Robust estimates of how these improvements have affected prognosis and life expectancy are of utmost importance to patients, clinicians, and health-care planners. We examined changes in 3 year survival and life expectancy of patients starting combination antiretroviral therapy (ART) between 1996 and 2013.MethodsWe analysed data from 18 European and North American HIV-1 cohorts. Patients (aged ≥16 years) were eligible for this analysis if they had started ART with three or more drugs between 1996 and 2010 and had at least 3 years of potential follow-up. We estimated adjusted (for age, sex, AIDS, risk group, CD4 cell count, and HIV-1 RNA at start of ART) all-cause and cause-specific mortality hazard ratios (HRs) for the first year after ART initiation and the second and third years after ART initiation in four calendar periods (1996–99, 2000–03 [comparator], 2004–07, 2008–10). We estimated life expectancy by calendar period of initiation of ART.Findings88 504 patients were included in our analyses, of whom 2106 died during the first year of ART and 2302 died during the second or third year of ART. Patients starting ART in 2008–10 had lower all-cause mortality in the first year after ART initiation than did patients starting ART in 2000–03 (adjusted HR 0·71, 95% CI 0·61–0·83). All-cause mortality in the second and third years after initiation of ART was also lower in patients who started ART in 2008–10 than in those who started in 2000–03 (0·57, 0·49–0·67); this decrease was not fully explained by viral load and CD4 cell count at 1 year. Rates of non-AIDS deaths were lower in patients who started ART in 2008–10 (vs 2000–03) in the first year (0·48, 0·34–0·67) and second and third years (0·29, 0·21–0·40) after initiation of ART. Between 1996 and 2010, life expectancy in 20-year-old patients starting ART increased by about 9 years in women and 10 years in men.InterpretationEven in the late ART era, survival during the first 3 years of ART continues to improve, which probably reflects transition to less toxic antiretroviral drugs, improved adherence, prophylactic measures, and management of comorbidity. Prognostic models and life expectancy estimates should be updated to account for these improvements.FundingUK Medical Research Council, UK Department for International Development, EU EDCTP2 programme.

Background:Cardiovascular disease and non-AIDS malignancies have become major causes of death among HIV-infected individuals. The relative impact of lifestyle and HIV-related factors are debated.Methods:We estimated associations of smoking with mortality more than 1 year after antiretroviral therapy (ART) initiation among HIV-infected individuals enrolled in European and North American cohorts. IDUs were excluded. Causes of death were assigned using standardized procedures. We used abridged life tables to estimate life expectancies. Life-years lost to HIV were estimated by comparison with the French background population.Results:Among 17 995 HIV-infected individuals followed for 79 760 person-years, the proportion of smokers was 60%. The mortality rate ratio (MRR) comparing smokers with nonsmokers was 1.94 [95% confidence interval (95% CI) 1.56–2.41]. The MRRs comparing current and previous smokers with never smokers were 1.70 (95% CI 1.23–2.34) and 0.92 (95% CI 0.64–1.34), respectively. Smokers had substantially higher mortality from cardiovascular disease, non-AIDS malignancies than nonsmokers [MRR 6.28 (95% CI 2.19–18.0) and 2.67 (95% CI 1.60–4.46), respectively]. Among 35-year-old HIV-infected men, the loss of life-years associated with smoking and HIV was 7.9 (95% CI 7.1–8.7) and 5.9 (95% CI 4.9–6.9), respectively. The life expectancy of virally suppressed, never-smokers was 43.5 years (95% CI 41.7–45.3), compared with 44.4 years among 35-year-old men in the background population. Excess MRRs/1000 person-years associated with smoking increased from 0.6 (95% CI –1.3 to 2.6) at age 35 to 43.6 (95% CI 37.9–49.3) at age at least 65 years.Conclusion:Well treated HIV-infected individuals may lose more life years through smoking than through HIV. Excess mortality associated with smoking increases markedly with age. Therefore, increases in smoking-related mortality can be expected as the treated HIV-infected population ages. Interventions for smoking cessation should be prioritized.

Among HIV-infected patients who initiated antiretroviral therapy (ART), patterns of cause-specific death varied by ART duration and were strongly related to age, sex, and transmission risk group. Deaths from non-AIDS malignancies were much more frequent than those from cardiovascular disease.

AIM To examine the risk to heroin users of also using gabapentin or pregabalin (gabapentoids). DESIGN Multidisciplinary study:- we (a) examined trends in drug related deaths and gabapentoid prescription data in England and Wales to test for evidence that any increase in deaths mentioning gabapentin or pregabalin is associated with trends in gabapentoid prescribing and is concomitant with opioid use; (b) interviewed people with a history of heroin use about their polydrug use involving gabapentin and pregabalin; (c) studied the respiratory depressant effects of pregabalin in the absence and presence of morphine in mice to determine whether concomitant exposure increased the degree of respiratory depression observed. SETTING England and Wales. PARTICIPANTS Interviews were conducted with 30 participants (19 males, 11 female). MEASUREMENTS (a) Office of National Statistics drug-related deaths from 1 January 2004 and 31 December 2015 that mention both an opioid and pregabalin or gabapentin; (b) subjective views on the availability, use, interactions, and effects of polydrug use involving pregabalin and gabapentin; (c) rate and depth of respiration. RESULTS Pregabalin and gabapentin prescriptions increased about 24% per year from 1 million in 2004 to 10.5 million in 2015. The number of deaths involving gabapentoids increased from less than one per year prior to 2009 to 137 in 2015; 79% of these deaths also involved opioids. The increase in deaths was highly correlated with the increase in prescribing (correlation coefficient 0.965; 5% increase in deaths per 100,000 increase in prescriptions). Heroin users described pregabalin as easy to obtain. They suggested that the combination of heroin and pregabalin reinforced the effects of heroin but were concerned it induced ‘black outs’ and increased the risk of overdose. In mice, a low dose of S-pregabalin (20 mg/kg) that did not itself depress respiration reversed tolerance to morphine depression of respiration (resulting in 35% depression of respiration, P<0.05) whereas a high dose of S-pregabalin (200 mg/kg) alone depressed respiration and this effect summated with that of morphine (producing over 50% depression of respiration, P<0.05). CONCLUSIONS For heroin users the combination of opioids with gabapentin or pregabalin potentially increases the risk of acute overdose death through either reversal of tolerance or an additive effect of the drugs to depress respiration.

Virally suppressed HIV-positive individuals on cART who do not achieve a CD4 count >200 cells/µL have substantially increased long-term mortality.