The association between combination antiretroviral therapy (cART) and cancer risk, especially regimens containing protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs), ...is unclear.
Participants were followed from the latest of D:A:D study entry or January 1, 2004, until the earliest of a first cancer diagnosis, February 1, 2012, death, or 6 months after the last visit. Multivariable Poisson regression models assessed associations between cumulative (per year) use of either any cART or PI/NNRTI, and the incidence of any cancer, non-AIDS-defining cancers (NADC), AIDS-defining cancers (ADC), and the most frequently occurring ADC (Kaposi sarcoma, non-Hodgkin lymphoma) and NADC (lung, invasive anal, head/neck cancers, and Hodgkin lymphoma).
A total of 41,762 persons contributed 241,556 person-years (PY). A total of 1832 cancers were diagnosed incidence rate: 0.76/100 PY (95% confidence interval: 0.72 to 0.79), 718 ADC 0.30/100 PY (0.28-0.32), and 1114 NADC 0.46/100 PY (0.43-0.49). Longer exposure to cART was associated with a lower ADC risk adjusted rate ratio: 0.88/year (0.85-0.92) but a higher NADC risk 1.02/year (1.00-1.03). Both PI and NNRTI use were associated with a lower ADC risk PI: 0.96/year (0.92-1.00); NNRTI: 0.86/year (0.81-0.91). PI use was associated with a higher NADC risk 1.03/year (1.01-1.05). Although this was largely driven by an association with anal cancer 1.08/year (1.04-1.13), the association remained after excluding anal cancers from the end point 1.02/year (1.01-1.04). No association was seen between NNRTI use and NADC 1.00/year (0.98-1.02).
Cumulative use of PIs may be associated with a higher risk of anal cancer and possibly other NADC. Further investigation of biological mechanisms is warranted.
Concerns have arisen about possible effects of protease inhibitors (PIs) on cardiac conductivity. We found no significant association between current or recent PI exposure and sudden death or ...nonhemorrhagic stroke (adjusted rate ratio, 1.22; 95% confidence interval, .95-1.57), whereas cumulative exposure to PIs was associated with an increased risk (adjusted rate ratio, 1.06 per year of exposure; 95% confidence interval, 1.01-1.11).
Whether or not the association between some antiretrovirals used in HIV infection and chronic kidney disease is cumulative is a controversial topic, especially in patients with initially normal renal ...function. In this study, we aimed to investigate the association between duration of exposure to antiretrovirals and the development of chronic kidney disease in people with initially normal renal function, as measured by estimated glomerular filtration rate (eGFR).
In this prospective international cohort study, HIV-positive adult participants (aged ≥16 years) from the D:A:D study (based in Europe, the USA, and Australia) with first eGFR greater than 90 mL/min per 1·73 m(2) were followed from baseline (first eGFR measurement after Jan 1, 2004) until the occurrence of one of the following: chronic kidney disease; last eGFR measurement; Feb 1, 2014; or final visit plus 6 months (whichever occurred first). Chronic kidney disease was defined as confirmed (>3 months apart) eGFR lower than 60 mL/min per 1·73 m(2). The primary outcome was the occurrence of chronic kidney disease. Poisson regression was used to estimate the incidence rate of chronic kidney disease associated with cumulative exposure to tenofovir disoproxil fumarate, ritonavir-boosted atazanavir, ritonavir-boosted lopinavir, other ritonavir-boosted protease inhibitors, or abacavir.
Between Jan 1, 2004, and July 26, 2013, 23,905 eligible individuals from the D:A:D study were included. Participants had a median baseline eGFR of 110 mL/min per 1·73 m(2) (IQR 100-125), a median age of 39 years (33-45), and median CD4 cell count of 441 cells per mm(3) (294-628). During a median follow-up of 7·2 years (IQR 5·1-8·9), 285 (1%) of 23,905 people developed chronic kidney disease (incidence 1·76 per 1000 person-years of follow-up 95% CI 1·56-1·97). After adjustment, we recorded a significant increase in chronic kidney disease associated with each additional year of exposure to tenofovir disoproxil fumarate (adjusted incidence rate ratio 1·14 95% CI 1·10-1·19, p<0·0001), ritonavir-boosted atazanavir (1·20 1·13-1·26, p<0·0001), and ritonavir-boosted lopinavir (1·11 1·06-1·16, p<0·0001), but not other ritonavir-boosted protease inhibitors or abacavir.
In people with normal renal function, the annual incidence of chronic kidney disease increased for up to 6 years of exposure to tenofovir disoproxil fumarate, ritonavir-boosted atazanavir, or ritonavir-boosted lopinavir therapy. Although the absolute number of new cases of chronic kidney disease was modest, treatment with these antiretrovirals might result in an increasing and cumulative risk of chronic kidney disease. Patients on potentially nephrotoxic antiretrovirals or at high risk of chronic kidney disease should be closely monitored.
The Highly Active Antiretroviral Therapy Oversight Committee.
Abstract
Background
Relations between different measures of human immunodeficiency virus–related immunosuppression and chronic kidney disease (CKD) remain unknown.
Methods
Immunosuppression measures ...included baseline, current, time-lagged and nadir CD4, years and percentage of follow-up (%FU) with CD4 ≤200 cells/μL, and CD4 recovery. CKD was defined as confirmed estimated glomerular filtration rate <60 mL/minute/1.73 m2.
Results
Of 33 791 persons, 2226 developed CKD. Univariably, all immunosuppression measures predicted CKD. Multivariably, the strongest predictor was %FU CD4 ≤200 cells/μL (0 vs >25%; incidence rate ratio IRR, 0.77 95% confidence interval CI, .68–.88), with highest effect in those at low D:A:D CKD risk (IRR, 0.45 95% CI, .24–.80) vs 0.80 95% CI, .70–.93).
Conclusions
Longer immunosuppression duration most strongly predicts CKD and affects persons at low CKD risk more.
While HIV-related immunosuppression duration and severity both predict chronic kidney disease (CKD), the duration association is strongest. CKD risk related to low CD4 count diminishes once immune function is restored, and most strongly affects persons with low estimated CKD risk.
Although earlier protease inhibitors have been associated with increased risk of cardiovascular disease, whether this increased risk also applies to more contemporary protease inhibitors is unknown. ...We aimed to assess whether cumulative use of ritonavir-boosted atazanavir and ritonavir-boosted darunavir were associated with increased incidence of cardiovascular disease in people living with HIV.
The prospective Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study consists of people living with HIV-1 from 11 cohorts in Australia, Europe, and the USA. Participants were monitored from Jan 1, 2009, until the earliest of a cardiovascular event, 6 months after the last visit, or until Feb 1, 2016. The outcome of interest was the incidence of cardiovascular disease in adults (aged ≥16 years) living with HIV who were being treated with contemporary treatments. We defined cardiovascular disease as centrally validated myocardial infarction, stroke, sudden cardiac death, or use of invasive cardiovascular procedures, including coronary bypass, coronary angioplasty, and carotid endarterectomy. We used Poisson regression models to assess the associations between cardiovascular disease and the contempoary protease inhibitors atazanavir and darunavir (both boosted with ritonavir).
49 709 participants were enrolled in the original cohort from 1999 onwards; 35 711 (71·8%) participants with available data on CD4 cell count and viral load at the 2009 baseline were included in the current analysis, and 13 998 (28·2%) participants had insufficent follow-up data after 2009. During a median 6·96 years of follow-up (IQR 6·28-7·08), 1157 people developed cardiovascular disease (incidence rate 5·34 events per 1000 person-years; 95% CI 5·03-5·65). The incidence rate of cardiovascular disease progressively increased from 4·91 events per 1000 person-years (4·59-5·23) in individuals unexposed to ritonavir-boosted darunavir to 13·67 events per 1000 person-years (8·51-18·82) in those exposed to the drug for more than 6 years. The changes associated with ritonavir-boosted atazanavir were less pronounced, showing an incidence rate of 5·03 cardiovascular events per 1000 person-years (4·69-5·37) in unexposed individuals to 6·68 events per 1000 person-years (5·02-8·35) in participants exposed for more than 6 years. After adjustment, keeping factors on the potential causal pathway from boosted protease inhibitor use to cardiovascular disease fixed at baseline, ritonavir-boosted darunavir use was associated with increased risk of cardiovascular disease (incidence rate ratio 1·59; 95% CI 1·33-1·91 per 5 years additional use), but use of ritonavir-boosted atazanavir was not (1·03; 0·90-1·18). This association remained after adjustment for time-updated factors on the potential causal pathway; myocardial infarction and stroke separately; plasma bilirubin concentration; and after stratification by use of ritonavir-boosted darunavir as the first ever protease inhibitor, used in combination with a non-nucleoside reverse transcriptase inhibitor, by previous virological failure, and by those at high risk of cardiovascular disease.
Cumulative use of ritonavir-boosted darunavir, but not of ritonavir-boosted atazanavir, is associated with progressively increasing risk of cardiovascular disease. Causal inference is limited by the observational nature of the D:A:D study. Our findings should prompt investigation into the possible underlying mechanisms of this finding.
The Highly Active Antiretroviral Therapy Oversight Committee.
Background
Expanding statin use may help to alleviate the excess burden of atherosclerotic cardiovascular disease in people living with HIV (PLHIV). Pravastatin and pitavastatin are preferred agents ...due to their lack of substantial interaction with antiretroviral therapy. We aimed to evaluate the cost‐effectiveness of pravastatin and pitavastatin for the primary prevention of atherosclerotic cardiovascular disease among PLHIV in the United States.
Methods
We developed a microsimulation model that randomly selected (with replacement) individuals from the Data‐collection on Adverse Effects of Anti‐HIV Drugs study with follow‐up between 2013 and 2016. Our study population was PLHIV aged 40 to 75 years, stable on antiretroviral therapy, and not currently using lipid‐lowering therapy. Direct medical costs and quality‐adjusted life‐years (QALYs) were assigned in annual cycles and discounted at 3% per year. We assumed a willingness‐to‐pay threshold of $100,000/QALY gained. The interventions assessed were as follows: (1) treating no one with statins; (2) treating everyone with generic pravastatin 40 mg/day (drug cost $236/year) and (3) treating everyone with branded pitavastatin 4 mg/day (drug cost $2,828/year). The model simulated each individual’s probability of experiencing atherosclerotic cardiovascular disease over 20 years.
Results
Persons receiving pravastatin accrued 0.024 additional QALYs compared with those not receiving a statin, at an incremental cost of $1338, giving an incremental cost‐effectiveness ratio of $56,000/QALY gained. Individuals receiving pitavastatin accumulated 0.013 additional QALYs compared with those using pravastatin, at an additional cost of $18,251, giving an incremental cost‐effectiveness ratio of $1,444,000/QALY gained. These findings were most sensitive to the pill burden associated with daily statin administration, statin costs, statin efficacy and baseline atherosclerotic cardiovascular disease risk. In probabilistic sensitivity analysis, no statin was optimal in 5.2% of simulations, pravastatin was optimal in 94.8% of simulations and pitavastatin was never optimal.
Conclusions
Pravastatin was projected to be cost‐effective compared with no statin. With substantial price reduction, pitavastatin may be cost‐effective compared with pravastatin. These findings bode well for the expanded use of statins among PLHIV in the United States. To gain greater confidence in our conclusions it is important to generate strong, HIV‐specific estimates on the efficacy of statins and the quality‐of‐life burden associated with taking an additional daily pill.
Improved methods for targeting HIV testing among patients most likely to be infected are required; HIDES I aimed to define the methodology of a European wide study of HIV prevalence in individuals ...presenting with one of eight indicator conditions/diseases (ID); sexually transmitted infection, lymphoma, cervical or anal cancer/dysplasia, herpes zoster, hepatitis B/C, mononucleosis-like illness, unexplained leukocytopenia/thrombocytopenia and seborrheic dermatitis/exanthema, and to identify those with an HIV prevalence of >0.1%, a level determined to be cost effective. A staff questionnaire was performed. From October 2009- February 2011, individuals, not known to be HIV positive, presenting with one of the ID were offered an HIV test; additional information was collected on previous HIV testing behaviour and recent medical history. A total of 3588 individuals from 16 centres were included. Sixty-six tested positive for HIV, giving an HIV prevalence of 1.8% 95% CI: 1.42-2.34; all eight ID exceeded 0.1% prevalence. Of those testing HIV positive, 83% were male, 58% identified as MSM and 9% were injecting drug users. Twenty percent reported previously having potentially HIV-related symptoms and 52% had previously tested HIV negative (median time since last test: 1.58 years); which together with the median CD4 count at diagnosis (400 cell/uL) adds weight to this strategy being effective in diagnosing HIV at an earlier stage. A positive test was more likely for non-white individuals, MSM, injecting drug users and those testing in non-Northern regions. HIDES I describes an effective strategy to detect undiagnosed HIV infection. All eight ID fulfilled the >0.1% criterion for cost effectiveness. All individuals presenting to any health care setting with one of these ID should be strongly recommended an HIV test. A strategy is being developed in collaboration with ECDC and WHO Europe to guide the implementation of this novel public health initiative across Europe.
Ensuring timely access to care for persons with HIV is an important public health goal. To identify factors associated with delayed presentation to medical care after testing HIV-positive or with ...late HIV testing, we studied 968 patients at their first HIV care visit, enrolled in a multicenter study in Italy from 1997-2000. Patients completed a questionnaire on HIV-testing history, sexual behavior, and drug use behavior. Delayed presenters were patients with >6 months between their first HIV-positive test and presentation for HIV care; late testers were patients with CD4 count < 200 /mm or clinically defined AIDS at their first HIV-positive test. Among the study patients, 255 (26.3%) were delayed presenters, and 280 (28.9%) were late testers. In multinomial logistic regression analysis, injection drug use significantly increased (odds ratio OR= 5.04) the probability of delayed presentation but reduced (OR = 0.55) the chance of late testing. A previous HIV-negative test was associated with a reduced risk of both delayed presentation (OR = 0.39) and late testing (OR = 0.36). Unemployment was positively associated with delayed presentation and increasing age with late testing, whereas HIV counseling at the time of first positive HIV test strongly (OR = 0.42) reduced the odds of delayed presentation. Interventions aimed at promoting timely access to care of HIV-infected persons should consider differentiated programs for delayed presentation and late testing.
PDF
