Cardiovascular Disease Risk Factor Control in People With and Without HIV.

BACKGROUND: Management of hypertension, dyslipidemia, diabetes and other modifiable factors may mitigate the cardiovascular disease (CVD) risk in people with human immunodeficiency virus (HIV, PWH) compared with people without HIV (PWoH). METHODS: This was a retrospective cohort study of 8285 PWH and 170 517 PWoH from an integrated health system. Risk factor control was measured using a novel disease management index (DMI) accounting for amount/duration above treatment goals (0% to 100% [perfect control]), including 2 DMIs for hypertension (diastolic and systolic blood pressure), 3 for dyslipidemia (low-density lipoprotein, total cholesterol, triglycerides), and 1 for diabetes (HbA1c). CVD risk by HIV status was evaluated overall and in subgroups defined by DMIs, smoking, alcohol use, and overweight/obesity in adjusted Cox proportional hazards models. RESULTS: PWH and PWoH had similar DMIs (80%-100%) except for triglycerides (worse for PWH) and HbA1c (better for PWH). In adjusted models, PWH had an elevated risk of CVD compared with PWoH (hazard ratio [HR], 1.18; 95% confidence interval [CI], 1.07-1.31). This association was attenuated in subgroups with controlled dyslipidemia and diabetes but remained elevated for PWH with controlled hypertension or higher total cholesterol. The strongest HIV status association with CVD was seen in the subgroup with frequent unhealthy alcohol use (HR, 2.13; 95% CI, 1.04-4.34). CONCLUSIONS: Control of dyslipidemia and diabetes, but not hypertension, attenuated the HIV status association with CVD. The strong association of HIV and CVD with frequent unhealthy alcohol use suggests enhanced screening and treatment of alcohol problems in PWH is warranted.

Outcomes and Predictors of Rapid Antiretroviral Therapy Initiation for People With Newly Diagnosed HIV in an Integrated Health Care System.

Background: Rapid antiretroviral therapy (ART) is the recommended treatment strategy for patients newly diagnosed with HIV, but the literature supporting this strategy has focused on short-term outcomes. We examined both long-term outcomes and predictors of rapid ART among patients newly diagnosed with HIV within an integrated health care system in Northern California. Methods: This observational cohort study included adults newly diagnosed with HIV between January 2015 and December 2020 at Kaiser Permanente Northern California. Rapid ART was defined as ART initiation within 7 days of HIV diagnosis. We collected demographic and clinical data to determine short-term and long-term outcomes, including viral suppression, care retention, medication adherence, and cumulative viral burden. Logistic regression models were used to identify predictors of rapid ART initiation. Results: We enrolled 1409 adults; 34.1% initiated rapid ART. The rapid ART group achieved viral suppression faster (48 vs 77 days; P < .001) and experienced lower cumulative viral burden (log10 viremia copy-years, 3.63 vs 3.82; P < .01) but had slightly reduced medication adherence (74.8% vs 75.2%; P < .01). There was no improvement in long-term viral suppression and care retention in the rapid group during follow-up. Patients were more likely to initiate rapid ART after 2017 and were less likely if they required an interpreter. Conclusions: Patients who received rapid ART had an improved cumulative HIV burden but no long-term improvement in care retention and viral suppression. Our findings suggest that rapid ART should be offered but additional interventions may be needed for patients newly diagnosed with HIV.

Fracture Risk and Association With TDF Use Among People With HIV in Large Integrated Health Systems.

BACKGROUND: Greater decline in bone health among people with HIV (PWH) has been documented but fracture risk and the impact of specific antiretroviral therapy (ART) regimens remain unclear. SETTING: Retrospective analyses of electronic health record data from 3 US integrated health care systems. METHODS: Fracture incidence was compared between PWH aged 40 years or older without prior fracture and demographically matched people without HIV (PWoH), stratified by age, sex, and race/ethnicity. Multivariable Cox proportional hazards models were used to estimate fracture risk associated with HIV infection. The association of tenofovir disoproxil fumarate (TDF) use and fracture risk was evaluated in a subset of PWH initiating ART. RESULTS: Incidence of fracture was higher in PWH [13.6/1000 person-years, 95% confidence interval (CI): 13.0 to 14.3, n = 24,308] compared with PWoH (9.5, 95% CI: 9.4 to 9.7, n = 247,313). Compared with PWoH, the adjusted hazard ratio (aHR) for fracture among PWH was 1.24 (95% CI: 1.18 to 1.31). The association between HIV infection and fracture risk increased with age, with the lowest aHR (1.17, 95% CI: 1.10 to 1.25) among those aged 40-49 years and the highest aHR (1.89, 95% CI: 1.30 to 2.76) among those aged 70 years or older. Among PWH initiating ART (n = 6504), TDF was not associated with significant increase in fracture risk compared with non-TDF regimens (aHR: 1.18, 95% CI: 0.89 to 1.58). CONCLUSIONS: Among people aged 40 years or older, HIV infection is associated with increased risk of fractures. Bone health screening from the age of 40 years may be beneficial for PWH. Large cohort studies with longer follow-up are needed to evaluate TDF effect and the potential benefit of early screening.

Undiagnosed Cognitive Impairment and Impact on Instrumental Activities of Daily Living Among People With HIV Infection in Primary Care.

Background: Little is known about the prevalence of undiagnosed cognitive impairment and its impact on instrumental activities of daily living (IADL) among people with HIV (PWH) in primary care. Methods: PWH were recruited from an integrated health care setting in the United States. PWH were eligible for recruitment if they were ≥50 years old, taking antiretroviral therapy (ie, ≥1 antiretroviral therapy [ART] prescription fill in the past year), and had no clinical diagnosis of dementia. Participants completed a cognitive screen (St. Louis University Mental Status exam) and a questionnaire on IADL (modified Lawton-Brody). Results: Study participants (n = 47) were mostly male (85.1%), 51.1% White, 25.5% Black, 17.0% Hispanic, and the average age (SD) was 59.7 (7.0) years. Overall, 27 (57.5%) participants were categorized as cognitively normal, 17 (36.2%) as having mild cognitive impairment, and 3 (6.4%) as having possible dementia. Of the 20 participants with mild cognitive impairment or possible dementia, 85.0% were men, the average age (SD) was 60.4 (7.1) years; 45.0% were White, 40.0% were Black, 10.0% were Hispanic, and 30.0% reported difficulty with at least 1 IADL. Most (66.7%) attributed difficulty with IADL primarily (33.3%) or in part (33.3%) to cognitive problems. Conclusions: Undiagnosed cognitive impairment is frequent among ART-treated PWH, with possible elevated risk among Black PWH, and may be accompanied by difficulty with IADL. Efforts are needed to optimize identification of factors contributing to cognitive and IADL difficulties among ART-treated PWH in primary care.

Age group differences in substance use, social support, and physical and mental health concerns among people living with HIV two years after receiving primary care-based alcohol treatment.

Objectives: People living with HIV (PWH) have seen reduction in HIV-associated morbidity and increase in near-normal life expectancy, yet unhealthy alcohol use poses substantial risks to older as well as younger adults. Further research regarding age-associated physical and mental health concerns among PWH who drink alcohol is needed to inform services, given the expanding age range of patients in care.Methods: We compared age group differences (18-34, 35-44, 45-54, ≥55 years old) in two-year patient-reported outcomes and HIV viral control among PWH enrolled in a primary care-based behavioral alcohol intervention trial; with 90% follow up from baseline.Results: Of 553 PWH, 50 (9%) were 18-34, 85 (15%) were 35-44, 197 (36%) were 45-54, and 221 (40%) were ≥55 years old. Most were men (97%) and White (64%). At two years, PWH ≥55 reported less substance use in the prior 30 days, fewer social contacts, and more pain; younger PWH had lower antiretroviral therapy (ART) adherence. In adjusted analyses, PWH ages 18-34 had higher odds of unhealthy alcohol use, tobacco, cannabis, or other substances compared to those ≥55; with higher odds of anxiety among PWH 35-44 compared with those ≥55; and physical quality of life was worse among those ≥55 compared with younger groups.Conclusions: While older PWH report less substance use than younger PWH and have better ART adherence post-treatment, they are more likely to experience limited social support and worse physical quality of life. Findings can inform interventions to address varying needs of PWH across the lifespan.

Impact of the Coronavirus Disease 2019 Pandemic on Antiretroviral Therapy Initiation and Care Delivery for People With Newly Diagnosed HIV in an Integrated Healthcare System.

The coronavirus disease 2019 (COVID-19) pandemic disrupted health systems. For patients newly diagnosed with human immunodeficiency virus, starting immediate antiretroviral therapy (ART) is recommended. For periods before and during the COVID-19 pandemic, Kaiser Permanente Northern California found similar rates of rapid ART initiation and time to viral suppression, concurrent with an increase in telemedicine.

Variation in Heart Failure Risk by HIV Severity and Sex in People With HIV Infection.

BACKGROUND: HIV is an independent risk factor for heart failure (HF). However, the association of HIV severity with incident HF and the potential interaction with sex are incompletely understood. SETTING: Integrated health care system. METHODS: We conducted a cohort study of people with HIV (PWH) and matched people without HIV (PWoH), all aged ≥ 21 years and with no previous HF. Poisson regression was used to compare incident HF by HIV status, with PWH stratified by severity of HIV infection [defined by recent (<6 months) CD4 count, nadir CD4 count, or recent HIV RNA level]. Models were adjusted for sociodemographic characteristics, substance use, and HF risk factors. Analyses were conducted for men and women combined, then by sex. RESULTS: The study included 38,868 PWH and 386,569 PWoH (mean baseline age = 41.0 ± 10.8 years; 88% men). Compared with PWoH, incident HF risk was higher among PWH with lower recent CD4 [200-499 cells/µL, adjusted rate ratio (aRR) = 1.82, 95% confidence interval (CI) = 1.50 to 2.21 and <200 cells/µL, aRR = 3.26 (2.47 to 4.30)] and a low nadir CD4 [<200 cells/µL, aRR = 1.56 (1.37 to 1.79)] but not among PWH with normal CD4 [≥500 cells/µL, aRR = 1.14 (0.90 to 1.44)]. Higher incident HF risk was observed among PWH at all HIV RNA levels, with greater HF risk at higher HIV RNA levels. The excess HF risk associated with low CD4 (recent or nadir) and high HIV RNA was stronger among women than men (P interactions=0.05, 0.08, and 0.01, respectively). CONCLUSIONS: Given the association of HIV severity with HF, optimizing HIV treatment and management may be important for HF prevention among PWH.

The relationship of smoking and unhealthy alcohol use to the HIV care continuum among people with HIV in an integrated health care system.

INTRODUCTION: Smoking tobacco and unhealthy alcohol use may negatively influence HIV care continuum outcomes but have not been examined in combination. METHODS: Participants were people with HIV (PWH) in Kaiser Permanente Northern California. Predictors included smoking status and unhealthy alcohol use (exceeding daily and/or weekly limits) reported by patients during primary care screening (index date). Outcomes were based on not achieving the following steps in the care continuum: linkage to HIV care (≥1 visit within 90 days of newly identified HIV diagnosis), retention (2+ in-person visits, 60+ days apart) and HIV RNA control (<75 copies/mL). Adjusted odds ratios (ORs) were obtained from separate logistic regression models for each outcome associated with smoking and unhealthy alcohol use independently and combined. RESULTS: The overall sample (N = 8958) had a mean age of 48.0 years; was 91.3 % male; 54.0 % white, 17.6 % Latino, 15.1 % black, and 9.6 % other race/ethnicity. Smoking was associated with higher odds of not being linked to HIV care (OR = 1.60 [95 % CI 1.03-2.48]), not retained (OR = 1.30 [95 % CI 1.13-1.50]), and HIV RNA not in control (OR = 1.91 [95 % CI 1.60-2.27]). Alcohol measures were not independently associated with outcomes. The combination of unhealthy alcohol use and smoking (versus neither) was associated with higher odds of not being linked to care (OR = 2.83 [95 % CI 1.40-5.71]), although the interaction did not reach significance (p = 0.18). CONCLUSIONS: In this large sample of PWH in an integrated health care system, smoking, both independently and in combination with unhealthy alcohol use, was associated with worse HIV care continuum outcomes.

Comparison of dementia risk after age 50 between individuals with and without HIV infection.

OBJECTIVE: To compare risk of dementia after age 50 by HIV status among individuals in a primary care setting. DESIGN: Observational cohort study; participants were identified from 2013 to 2017 and followed through 2019. METHODS: Participants were people with HIV (PWH) on antiretroviral therapy (ART) and demographically similar people without HIV (PWOH), all at least 50 years old and with no prior diagnosis of dementia. The study setting was Kaiser Permanente Northern California, an integrated healthcare delivery system in the United States. Incident dementia diagnoses and baseline data on sociodemographics, smoking, alcohol use, other substance use, and clinical factors were gathered from the electronic health record. Cumulative proportion of incident dementia by HIV status was assessed using Kaplan--Meier curves. Unadjusted and adjusted hazard ratios for incident dementia by HIV status were generated using Cox proportional hazards models with age as the time scale. RESULTS: The study included 5381 PWH and 119 022 PWOH (average age at baseline: 57 and 58 years, respectively). Incident dementia was diagnosed in 117 PWH and 2427 PWOH. By age 80, 25.8% of PWH and 13.8% of PWOH had been diagnosed with dementia, corresponding with an unadjusted hazard ratio of 1.98 (95% CI 1.64-2.39). After adjustment for sociodemographic, substance use, and clinical factors, including frequency of outpatient visits, the risk of dementia among PWH remained elevated (vs. PWOH, adjusted hazard ratio = 1.58, 95% CI 1.31-1.92). CONCLUSION: Compared with PWOH, PWH were at 58% higher risk for dementia despite HIV treatment with ART. Research is needed to investigate the potential benefits of targeted risk factor management or earlier cognitive screening in this population.

Health System-Based Unhealthy Alcohol Use Screening and Treatment Comparing Demographically Matched Participants With and Without HIV.

BACKGROUND: Unhealthy alcohol use among persons living with HIV (PLWH) is linked to significant morbidity, and use of alcohol services may differ by HIV status. Our objective was to compare unhealthy alcohol use screening and treatment by HIV status in primary care. METHODS: Cohort study of adult (≥18 years) PLWH and HIV-uninfected participants frequency matched 20:1 to PLWH by age, sex, and race/ethnicity who were enrolled in a large integrated healthcare system in the United States, with information ascertained from an electronic health record. Outcomes included unhealthy alcohol screening, prevalence, provider-delivered brief interventions, and addiction specialty care visits. Other predictors included age, sex, race/ethnicity, neighborhood deprivation index, depression, smoking, substance use disorders, Charlson comorbidity index, prior outpatient visits, insurance type, and medical facility. Cox proportional hazards models were used to compute hazard ratios (HR) for the outcomes of time to unhealthy alcohol use screening and time to first addiction specialty visit. Poisson regression with robust standard errors was used to compute prevalence ratios (PR) for other outcomes. RESULTS: 11,235 PLWH and 227,320 HIV-uninfected participants were included. By 4.5 years after baseline, most participants were screened for unhealthy alcohol use (85% of PLWH and 93% of HIV-uninfected), but with a lower rate among PLWH (adjusted HR 0.84, 95% CI 0.82 to 0.85). PLWH were less likely, compared with HIV-uninfected participants, to report unhealthy drinking among those screened (adjusted PR 0.74, 95% CI 0.69 to 0.79), and among those who screened positive, less likely to receive brief interventions (adjusted PR 0.82, 95% CI 0.75 to 0.90), but more likely (adjusted HR 1.7, 95% CI 1.2 to 2.4) to have an addiction specialty visit within 1 year. CONCLUSIONS: Unhealthy alcohol use was lower in PLWH, but the treatment approach by HIV status differed. PLWH reporting unhealthy alcohol use received less brief interventions and more addiction specialty care than HIV-uninfected participants.

Smoking and cessation treatment among persons with and without HIV in a U.S. integrated health system.

BACKGROUND: Persons with HIV (PWH) are more likely to smoke and are more susceptible to the harmful effects of smoking than persons without HIV. We examined smoking patterns and use of cessation treatment among PWH and persons without HIV in a U.S. integrated health system. METHODS: We identified adults (≥18 years) with HIV and demographically-matched persons without HIV between July 2013 and December 2017. Smoking status and cessation treatment were ascertained from health records. We calculated age-standardized annual prevalence of smoking and evaluated trends using Cochran-Armitage tests and Poisson regression. Factors associated with cessation treatment during the study period, and smoking in the last year of the study, were evaluated by HIV status using multivariable Poisson models. RESULTS: The study included 11,235 PWH and 227,320 persons without HIV. Smoking prevalence was higher among PWH across all years but declined for both groups (from 16.6% to 14.6% in PWH and 11.6% to 10.5% in persons without HIV). Among smokers, PWH were more likely to initiate cessation treatment compared to persons without HIV (17.9% vs. 13.3%, covariate-adjusted prevalence ratio of 1.31, 95% CI = 1.15-1.50), with few differences in cessation treatment across subgroups of PWH. In 2017, smoking prevalence remained higher in PWH, especially among those who were younger or who had diagnoses of depression or substance use disorder. CONCLUSION: In a setting with access to cessation resources, smoking prevalence decreased both in PWH and persons without HIV. PWH had greater uptake of cessation treatment, which is encouraging for smoking reduction and improved health.

Effectiveness of 'catch-up' human papillomavirus vaccination to prevent cervical neoplasia in immunosuppressed and non-immunosuppressed women.

It is unknown whether the HPV vaccine is effective in immunocompromised women during catch-up ages. We performed a case-control study of 4,357 women with incident CIN2+ (cases) and 5:1 age-matched, incidence-density selected controls (N = 21,773) enrolled in an integrated health care system from 2006 to 2014. Vaccine effectiveness was estimated from multivariable conditional logistic regression models, with results stratified by immunosuppression history, defined as prior HIV infection, solid organ transplant history, or recently prescribed immunosuppressive medications. HPV vaccination resulted in a 19% reduction in CIN2+ rates for women without an immunosuppression history but a nonsignificant 4% reduction for women with an immunosuppression history. Further research is needed to evaluate whether catch-up HPV vaccine effectiveness varies by immunosuppression status, especially given the recent approval of the HPV vaccine for adults up to 45 years of age.

Colorectal Cancer Screening in People With and Without HIV in an Integrated Health Care Setting.

BACKGROUND: As people with HIV (PWH) live longer, age-appropriate colorectal cancer (CRC) screening is increasingly important. Limited data exist on CRC screening and outcomes comparing PWH and persons without HIV. SETTING: Large integrated health care system. METHODS: This study included PWH and demographically matched persons without HIV who were aged 50-75 years during 2005-2016 and had no previous CRC screening. We evaluated time to first CRC screening (fecal test, sigmoidoscopy, or colonoscopy). We also assessed detection of adenoma and CRC with sigmoidoscopy or colonoscopy by HIV status, accounting for CRC risk factors including sex, age, race/ethnicity, number of outpatient visits, smoking, body mass index, type-2 diabetes, and inflammatory bowel disease. Among PWH, we evaluated whether CD4 count (<200/200-499/≥500 cells/µL) was associated with adenoma and CRC. RESULTS: Among 3177 PWH and 29,219 persons without HIV, PWH were more likely to be screened (85.6% vs. 79.1% within 5 years, P < 0.001). Among those with sigmoidoscopy or colonoscopy, adenoma was detected in 161 (19.6%) PWH and 1498 (22.6%) persons without HIV, and CRC was detected in 4 (0.5%) PWH and 69 (1.0%) persons without HIV. In adjusted analyses, we found no difference in prevalence of either adenoma or CRC by HIV status (adjusted prevalence ratio = 0.97, 95% confidence interval: 0.83 to 1.12). Lower CD4 count did not increase likelihood of adenoma or CRC. CONCLUSIONS: Within an integrated health care system with an organized CRC screening program, we found no disparities in CRC screening uptake or outcomes among people with and without HIV, and CD4 count did not influence CRC risk among PWH.

Hepatitis C treatment uptake and response among human immunodeficiency virus/hepatitis C virus-coinfected patients in a large integrated healthcare system.

U.S. guidelines recommend that patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) be prioritized for HCV treatment with direct-acting antiviral agents (DAAs), but the high cost of DAAs may contribute to disparities in treatment uptake and outcomes. We evaluated DAA initiation and effectiveness in HIV/HCV-coinfected patients in a U.S.-based healthcare system during October 2014-December 2017. Of 462 HIV/HCV-coinfected patients, 276 initiated DAAs (70% cumulative proportion treated over three years). Lower likelihood of DAA initiation was observed among patients with Medicare (government-sponsored insurance) versus commercial insurance (adjusted rate ratio [aRR] = 0.62, 95% CI = 0.46-0.84), patients with drug abuse diagnoses (aRR = 0.72, 95% CI = 0.54-0.97), patients with CD4 cell count <200 cells/µl versus ≥500 (aRR = 0.45, 95% CI = 0.23-0.91), and patients without prior HCV treatment (aRR = 0.68, 95% CI = 0.48-0.97). There were no significant differences in DAA initiation by age, gender, race/ethnicity, socioeconomic status, HIV transmission risk, alcohol use, smoking, fibrosis level, HIV RNA levels, antiretroviral therapy use, hepatitis B infection, or number of outpatient visits. Ninety-five percent of patients achieved sustained virologic response (SVR). We found little evidence of sociodemographic disparities in DAA initiation among HIV/HCV-coinfected patients, and SVR rates were high. Efforts are needed to increase DAA uptake among coinfected Medicare enrollees, patients with drug abuse diagnoses, patients with low CD4 cell count, and patients receiving first-time HCV treatment.

Early Outcomes of a High-Resolution Anoscopy-Based Anal Cancer Screening Program Among People With HIV Enrolled in an Integrated Health Care System.

BACKGROUND: Few studies have examined outcomes of high-resolution anoscopy (HRA)-based screening for people with HIV infection (PWH), a population at increased risk for anal cancer. SETTING: Large integrated health care system. METHODS: Cohort study of 13,552 people with HIV infection, comparing incidences of anal cancer and advanced anal cancer (higher stage, recurrence, death, or surgical salvage) before and after HRA became available (2008). Calendar time was divided as 1998-2007, 2008-2010, and 2011-2012. Rate ratios (RRs) were obtained from Poisson regression models with adjustment for baseline demographic and health variables. Cohort cases during 2008-2012 were included in a nested case-control study, evaluating association of screening with anal cancer (33 cases, 330 controls) and advanced anal cancer (19 cases, 190 controls). Odds ratios (ORs) for receipt of screening were obtained from conditional logistic regression models with adjustment for baseline demographic and health history variables. RESULTS: Compared with 1998-2007 (pre-HRA), 2008-2010 adjusted RRs were 1.32 [95% confidence intervals (CI): 0.77 to 2.27; P = 0.31] for anal cancer and 2.11 (95% CI: 0.99 to 4.48; P = 0.053) for advanced anal cancer; and 2011-2012 adjusted RRs were 0.35 (95% CI: 0.12 to 0.99; P = 0.048) for anal cancer and 0.23 (95% CI: 0.03 to 1.77; P = 0.16) for advanced anal cancer. Individual history of screening did not reach statistical significance for anal cancer (OR 1.7; 0.6-4.6) or advanced anal cancer (OR 0.44; 0.1-3.8). CONCLUSIONS: Despite the possible effect of secular trends, we found 2008-2012 incidence trends for anal cancer and advanced anal cancer that seem consistent with expected findings of a beneficial screening program.

Effectiveness of catch-up human papillomavirus vaccination on incident cervical neoplasia in a US health-care setting: a population-based case-control study.

BACKGROUND: The population effectiveness of human papillomavirus (HPV) catch-up vaccination, defined in the USA as first vaccination at ages 13-26 years, has not been studied extensively. We aimed to assess the risk of cervical intraepithelial neoplasia (CIN) 2, CIN3, adenocarcinoma in situ, or cancer (CIN2+ and CIN3+) by prior HPV vaccination status, age at first dose, and number of doses in women participating in a screening programme within a large integrated health-care system. METHODS: We performed a nested case-control study of women enrolled in Kaiser Permanente Northern California (an integrated health-care delivery system in California, USA). Cases were women with CIN2+ or CIN3+ confirmed by histology between Jan 1, 1995, and June 30, 2014, and incidence density-selected controls were age-matched women without CIN2+ or CIN3+ at the time each case occurred. For each case, we randomly selected five controls. Cases and controls were aged 26 years or younger when the HPV quadrivalent vaccine became available in 2006. Rate ratios (RRs) from conditional logistic regression were estimated by age at time of first HPV quadrivalent vaccine dose (14-17 years, 18-20 years, and ≥21 years), and number of doses (one, two, and three or more doses) compared with no prior vaccination, with adjustment for smoking, hormonal contraceptive prescription, race or ethnicity, sexually transmitted infections, immunosuppression, parity, and number of outpatient visits. FINDINGS: 4357 incident CIN2+ cases and 21 773 matched controls were included in the study. Of these, 1849 were incident CIN3+ cases with 9242 matched controls. The youngest age at time of first vaccination was 14 years. One or more HPV vaccine doses conferred protection against CIN2+ (RR 0·82, 95% CI 0·73-0·93) and CIN3+ (0·77, 0·64-0·94). We found the strongest protection against CIN2+ in women who had received at least three vaccine doses and had received their first dose aged 14-17 years (0·52, 0·36-0·74) or aged 18-20 years (0·65, 0·49-0·88). No significant protection was found in women aged 21 years or older at time of first dose (0·94, 0·81-1·09). Inferences were similar for CIN3+, but with stronger effects for women who received at least three vaccine doses and had received their first dose aged 14-17 years (0·27, 0·13-0·56) or aged 18-20 years (0·59, 0·36-0·97). INTERPRETATION: Catch-up quadrivalent HPV vaccination with three doses was effective against CIN2+ and CIN3+ in girls and women aged 14-20 years at time of first vaccine dose but not for women aged 21 years and older at first dose. FUNDING: US National Cancer Institute.