Association of pregnancy with engagement in HIV care among women with HIV in the UK: a cohort study.

BACKGROUND: Women with HIV face challenges in engaging in HIV care post partum. We aimed to examine changes in engagement in HIV care through clinic attendance before, during, and after pregnancy, compared with matched women with HIV who had never had a recorded pregnancy. METHODS: In this cohort study, we describe changes in engagement in HIV care before, during, and after pregnancy among women with HIV from the UK Collaborative HIV Cohort (CHIC) study from 25 HIV clinics in the UK with a livebirth reported to the National Surveillance of HIV in Pregnancy and Childhood between Jan 1, 2000, and Dec 31, 2017. To investigate whether changes were specific to HIV, we compared these changes to those over equivalent periods among non-pregnant women with HIV in the UK CHIC study matched for ethnicity, year of conception, age, CD4 cell count, viral suppression, and antiretroviral therapy use. Analyses were via logistic regression using generalised estimated equations with an interaction between case-control status (pregnant women vs non-pregnant women) and pregnancy or pseudo pregnancy (for non-pregnant women) stage. FINDINGS: 1116 matched pairs of pregnant and non-pregnant women were included (median age 34 years [IQR 30-38], 80·1% Black African, 12·5% white). 69 330 person-months of follow-up were recorded, 25 412 in the before stage, 18 897 during, and 25 021 after pregnancy or pseudo pregnancy stages. Among pregnant women, the proportion of time engaged in care increased during pregnancy (8477 [90·5%] of 9371 person-months) and after pregnancy (10 501 [84·6%] of 12 407), compared with before pregnancy (9979 [78·5%] of 12 707). Among non-pregnant women in the control group, engagement in HIV care remained stable across the three equivalent stages (9688 [76·3%] of 12 705 person-months before pseudo pregnancy; 7463 [78·3%] of 9526 during pseudo pregnancy; and 9892 [78·4%] of 12 614 after pseudo pregnancy). The association of engagement in HIV care with pregnancy or pseudo pregnancy stage differed significantly by case-control status (pinteraction<0·0001); the odds of engagement in HIV care were higher during pregnancy (odds ratio [OR] 3·32, 95% CI 2·68-4·12) and after pregnancy (OR 1·49, 1·24-1·79) only among pregnant women, and not among non-pregnant women, when compared with the before pseudo pregnancy stage. INTERPRETATION: Women with HIV and a pregnancy resulting in a livebirth were more likely to engage in HIV care post partum when compared with before pregnancy. A detailed understanding of the reason for this finding could support interventions to maximise engagement in HIV care for all women with HIV. FUNDING: Medical Research Council and National Institute for Health Research.

Differences in HIV clinical outcomes amongst heterosexuals in the United Kingdom by ethnicity.

OBJECTIVE: We investigated differences in clinical outcomes in heterosexual participants, by ethnicity in the UK Collaborative HIV Cohort Study from 2000 to 2017. DESIGN: Cohort analysis. METHODS: Logistic/proportional hazard regression assessed ethnic group differences in CD4+ cell count at presentation, engagement-in-care, combination antiretroviral therapy (cART) initiation, viral suppression and rebound. RESULTS: Of 12 302 participants [median age: 37 (interquartile range: 31-44) years, 52.5% women, total follow-up: 85 846 person-years], 64.4% were black African, 19.1% white, 6.3% black Caribbean, 3.6% black other, 3.3% South Asian/other Asian and 3.4% other/mixed. CD4+ cell count at presentation amongst participants from non-white groups were lower than the white group. Participants were engaged-in-care for 79.6% of follow-up time; however, black and other/mixed groups were less likely to be engaged-in-care than the white group (adjusted odds ratios vs. white: black African: 0.70 (95% confidence interval (CI) 0.63-0.79], black Caribbean: 0.74 (0.63-0.88), other/mixed: 0.78 (0.62-0.98), black other: 0.81 (0.64-1.02)). Of 8867 who started cART, 79.1% achieved viral suppression, with no differences by ethnicity in cART initiation or viral suppression. Viral rebound (22.2%) was more common in the black other [1.95 (1.37-2.77)], black African [1.85 (1.52-2.24)], black Caribbean [1.73 (1.28-2.33)], South Asian/other Asian [1.35 (0.90-2.03)] and other/mixed [1.09 (0.69-1.71)] groups than in white participants. CONCLUSION: Heterosexual people from black, Asian and minority ethnic (BAME) groups presented with lower CD4+ cell counts, spent less time engaged-in-care and were more likely to experience viral rebound than white people. Work to understand and address these differences is needed.

Associations of menopausal age with virological outcomes and engagement in care among women living with HIV in the UK.

Background: Women ageing with HIV undergo sex-specific changes. There is limited evidence available with regards to how the menopause impacts HIV outcomes.Objective: To investigate whether menopausal age is associated with engagement-in-care (EIC), viral load (VL) suppression and rebound among women living with HIV.Methods: Women were grouped by age (<40, 40-50, >50 years), corresponding to pre-, peri- and post-menopausal stages. EIC, HIV VL suppression (VL < 50 copies/mL) within 12 months of antiretroviral therapy initiation and VL rebound (two consecutive VL > 50 copies/mL) after VL suppression were compared across age groups using logistic/Cox proportional hazards regression. Associations were compared to those seen in heterosexual men.Results: Six thousand four hundred and fifty-five (6455) eligible women (median age 36 [interquartile range: 29-42], 64.4% black African, 19.1% white) contributed 44,226 person-years (PYRS) of follow-up; 29,846, 10,980 and 3,399 PYRS in those aged <40, 40-50 and >50, respectively. Women were engaged-in-care for 79.5% of follow-up time, 3,344 (78.0%) experienced VL suppression and 739 (22.1%) VL rebound. After adjustment, women aged >50 years had lower EIC than those aged <40. Women aged 40-50 were more likely to have VL suppression and were less likely to experience VL rebound than those aged <40 years. Trends in heterosexual men were similar for EIC but with no evidence of a higher VL suppression rate in those aged 40-50 years (pint. 0< .0001) and a stronger protective association between older age and VL rebound (pint. 0< .0001).Conclusion: Our findings warrant further research into the potential impact of the menopause to support women and clinicians through HIV care.

CD4+:CD8+ T Cell Ratio Normalization and the Development of AIDS Events in People with HIV Starting Antiretroviral Therapy.

We identify factors associated with the normalization of the CD4+:CD8+ T cell ratio among UK Collaborative HIV Cohort study participants, and describe the association of the CD4+ and CD8+ T cell counts and the CD4+:CD8+ T cell ratio, with the risk of new AIDS events among individuals who achieve a suppressed viral load. Participants initiating combination antiretroviral therapy (cART) after 2006 with a CD4+:CD8+ T cell ratio <1, and viral suppression within 6 months were included. Cox proportional hazard models were used to examine associations with ratio normalization (ratio ≥1). Poisson regression models were used to investigate factors associated with the development of AIDS after viral load suppression. A total of 13,178 participants [median age: 37 (interquartile range: 31-44)] were followed for 75,336 person-years. Of the 4,042 (32.9%) who experienced ratio normalization, individuals with a high CD4+ T cell count [>500 vs. ≤200 cells/mm3, adjusted hazard ratio (95% confidence interval): 7.93 (6.97-9.01)], low CD8+ T cell count [>1,150 vs. ≤500 cells/mm3: 0.18 (0.16-0.21)], and low CD4+:CD8+ T cell ratio [>0.8 vs. <0.2: 12.36 (10.41-14.68)] at cART initiation were more likely to experience ratio normalization. Four hundred and nineteen people developed a new AIDS event. Most recent CD4+ T cell count [>500 vs. ≤200 cells/mm3: adjusted rate ratio 0.24 (0.16-0.34)] and CD4+:CD8+ T cell ratio [>0.8 vs. <0.2: 0.33 (0.21-0.52)] were independently associated with a new AIDS event. One third of study participants experienced ratio normalization after starting cART. CD4+ T cell count and CD4+:CD8+ T cell ratio are both individually associated with ratio normalization and the development of new AIDS events after cART.

Incidence of and risk factors for tuberculosis among people with HIV on antiretroviral therapy in the United Kingdom.

OBJECTIVE: The United Kingdom has a low tuberculosis incidence and earlier combination antiretroviral therapy (cART) is expected to have reduced incidence among people with HIV. Epidemiological patterns and risk factors for active tuberculosis were analysed over a 20-year period among people accessing HIV care at sites participating in the UK CHIC observational study. DESIGN: Cohort analysis. METHODS: Data were included for individuals over 15 years old attending for HIV care between 1996 and 2017 inclusive, with at least 3 months follow-up recorded. Incidence rates of new tuberculosis events were calculated and stratified by ethnicity (white/Black/other) as a proxy for tuberculosis exposure. Poisson regression models were used to determine the associations of calendar year, ethnicity and other potential risk factors after cART initiation. RESULTS: Fifty-eight thousand seven hundred and seventy-six participants (26.3% women; 54.5% white, 32.0% Black, 13.5% other/unknown ethnicity; median (interquartile range) age 34 (29-42) years) were followed for 546 617 person-years. Seven hundred and four were treated for active tuberculosis [rate 1.3; 95% confidence interval (CI) 1.2-1.4/1000 person-years). Tuberculosis incidence decreased from 1.3 (1.2-1.5) to 0.6 (0.4-0.9)/1000 person-years from pre-2004 to 2011-2017. The decline among people of Black ethnicity was less steep than among those of white/other ethnicities, with incidence remaining high among Black participants in the latest period [2.1 (1.4-3.1)/1000 person-years]. Two hundred and eighty-three participants [191 (67%) Black African] had tuberculosis with viral load less than 50 copies/ml. CONCLUSION: Despite the known protective effect of cART against tuberculosis, a continuing disproportionately high incidence is seen among Black African people. Results support further interventions to prevent tuberculosis in this group.

Associations between baseline characteristics, CD4 cell count response and virological failure on first-line efavirenz + tenofovir + emtricitabine for HIV.

OBJECTIVES: The aim of this study was to investigate associations between baseline characteristics and CD4 cell count response on first-line antiretroviral therapy and risk of virological failure (VF) with or without drug resistance. METHODS: We conducted an analysis of UK Collaborative HIV Cohort data linked to the UK HIV Drug Resistance Database. Inclusion criteria were viral sequence showing no resistance prior to initiation of first-line efavirenz + tenofovir disoproxil fumarate + emtricitabine and virological suppression within 6 months. Outcomes of VF (≥200 copies/mL) with or without drug resistance were assessed using a competing risks approach fitted jointly with a model for CD4 cell count recovery. Hazard ratios for each VF outcome were estimated for baseline CD4 cell count and viral load and characteristics of CD4 cell count response using latent variables on a standard normal scale. RESULTS: A total of 3640 people were included with 338 VF events; corresponding viral sequences were available in 134 with ≥1 resistance mutation in 36. VF with resistance was associated with lower baseline CD4 (0.30, 0.09-0.62), lower CD4 recovery (0.04, 0.00-0.17) and higher CD4 variability (4.40, 1.22-12.68). A different pattern of associations was observed for VF without resistance, but the strength of these results was less consistent across sensitivity analyses. Cumulative incidence of VF with resistance was estimated to be <2% at 3 years for baseline CD4 ≥350 cells/µL. CONCLUSION: Lower baseline CD4 cell count and suboptimal CD4 recovery are associated with VF with drug resistance. People with low CD4 cell count before ART or with suboptimal CD4 recovery on treatment should be a priority for regimens with high genetic barrier to resistance.

A continuum of HIV care describing mortality and loss to follow-up: a longitudinal cohort study.

BACKGROUND: The cross-sectional HIV care continuum is widely used to assess the success of HIV care programmes among populations of people with HIV and the potential for ongoing transmission. We aimed to investigate whether a longitudinal continuum, which incorporates loss to follow-up and mortality, might provide further insights about the performance of care programmes. METHODS: In this longitudinal cohort study, we included individuals who entered the UK Collaborative HIV Cohort (CHIC) study between Jan 1, 2000, and Dec 31, 2004, and were linked to the national HIV cohort database (HIV and AIDS Reporting System). For each month during a 10 year follow up period, we classified individuals into one of ten distinct categories according to engagement in care, antiretroviral therapy (ART) use, viral suppression, loss to cohort follow-up and loss to care, and mortality, and assessed the proportion of person-months of follow-up spent in each stage of the continuum. 5 year longitudinal continuums were also constructed for three separate cohorts (baseline years of entry 2000-03, 2004-07, and 2008-09) to compare changes over time. FINDINGS: We included 12 811 people contributing 1 537 320 person-months in our analysis. During 10 years of follow-up, individuals spent 811 057 (52·8%) of 1 537 320 person-months on ART. Of the 811 057 person-months spent on ART, individuals had a viral load of 200 copies per mL or less for 607 185 (74·9%) person-months. 10 years after cohort entry, 3612 (28·1%) of 12 811 individuals were lost to follow-up, 954 (26·4%) of whom had transferred to a non-CHIC UK clinic for care. By 10 years, 759 (5·9%) of 12 811 participants who entered the cohort had died. Loss to follow-up decreased and the proportion of person-months that individuals spent virally suppressed increased over calendar time. INTERPRETATION: Loss to follow-up in HIV care programmes was high and rates of viral suppression were lower than previously reported. Complementary information provided by a longitudinal continuum might highlight areas for intervention along the HIV care pathway, however, transfers outside the cohort must be accounted for. FUNDING: Medical Research Council, UK.

The association between detected drug resistance mutations and CD4+ T-cell decline in HIV-positive individuals maintained on a failing treatment regimen.

BACKGROUND: To analyse the effect of drug resistance mutations (DRM) on CD4+ T-cell (CD4) trends in HIV-positive people maintained on virologically failing antiretroviral therapy (ART). METHODS: Individuals from two large cohorts experiencing virological failure (VF) while maintained on ART with ≥1 CD4 count and ≥1 resistance test were included. CD4 slopes were estimated using linear mixed models. Principal component analysis (PCA) was used to assess the effect of clusters of mutations, defined using extracted component based scores from the PCA, on CD4 decline. RESULTS: 5,357 individuals contributing 7,661 VF episodes were included: any DRM were detected in 88.8% of episodes. After adjustment, CD4 counts declined less steeply during episodes where DRM were detected compared to episodes with no DRM (difference =28 cells/mm3/year, 95% CI =18, 39; P<0.001). Among individuals with at least one DRM, we found evidence that any nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) resistance, the reverse transcriptase (RT) mutations M184V, D67N and T215Y as well as the protease mutations V82A and I54V were associated with reduced CD4 declines. The detection of any non-nucleoside reverse transcriptase inhibitor resistance, the RT mutations V179D and L74V were associated with steeper CD4 declines. The presence of some mutation patterns similar to the clusters identified by the PCA also affected the CD4 decline. CONCLUSIONS: Detection of resistance and of certain DRM during VF of ART has a small but significant favourable effect on CD4 decline.

Growing up with perinatal HIV: changes in clinical outcomes before and after transfer to adult care in the UK.

INTRODUCTION: With improved survival, adolescents with perinatal HIV (PHIV) are transitioning from paediatric to adult care, but there are few published data on clinical outcomes post-transfer. Using linked data from patients in the national UK/Ireland paediatric cohort (CHIPS) and an adult UK cohort of outpatient clinics (UK CHIC), we describe mortality and changes in immunological status post-transfer. METHODS: Participants in CHIPS aged ≥13 years by the end of 2013 were linked to the UK CHIC database. Mixed effects models explored changes in CD4 count before and after transfer, including interactions between time and variables where interaction p < 0.05. RESULTS: Of 1,215 paediatric participants aged ≥13 years, 271 (22%) had linked data in UK CHIC. One hundred and forty-six (53%) were female, median age at last visit in paediatric care was 17 [interquartile range, IQR 16,18] years, median duration in paediatric care was 11.8 [6.6,15.5] years, and in adult care was 2.9 [1.5,5.9] years. At last visit in paediatric care, 74% (n = 200) were on ART, increasing to 84% (n = 228, p = 0.001) at last visit in adult care. In the 12 months before leaving paediatric care, 92 (47%) had two consecutive viral loads >400 copies/mL or one viral load >10,000 copies/mL, and likewise 102 (52%) in the 12 months post-transfer (p = 0.79). Seven (3%) people died in adult care. In multivariable analysis, CD4 declined as patients approached transition with a greater decline in those with higher nadir CD4 count (mean rates of decline of 3, 13, 15, 30 cells/mm3 per year for those with nadir CD4 < 100, 100-199, 200-299 and ≥300 cells/mm3, respectively). Post-transition, CD4 continued to decline in some groups (e.g. black males, -20 (-34, -5) cells/mm3 per year post transition, p = 0.007)) while it improved in others. Overall CD4 was higher with later year of birth (14 (7, 21) cells/mm3 per later year). There was no effect of age at transfer or changing hospital at transfer on CD4. CONCLUSIONS: Our findings suggest that CD4 in adolescents with perinatal HIV in the UK was declining in the period before transition to adult care, and there was some reversal in this trend post-transfer in some groups. Across the transition period, CD4 was higher in those with later birth years, suggesting improvements in clinical care and/or transition planning over time.

Association between engagement in-care and mortality in HIV-positive persons.

OBJECTIVE: To assess associations between engagement in-care and future mortality. DESIGN: UK-based observational cohort study. METHODS: HIV-positive participants with more than one visit after 1 January 2000 were identified. Each person-month was classified as being in or out-of-care based on the dates of the expected and observed next care visits. Cox models investigated associations between mortality and the cumulative proportion of months spent in-care (% IC, lagged by 1 year), and cumulative %IC prior to antiretroviral therapy (ART) in those attending clinic for more than 1 year, with adjustment for age, CD4/viral load, year, sex, infection mode, ethnicity, and receipt/type of ART. RESULTS: The 44 432 individuals (27.8% women; 50.5% homosexual, 28.9% black African; median age 36 years) were followed for a median of 5.5 years, over which time 2279 (5.1%) people died. Higher %IC was associated with lower mortality both before [relative hazard 0.91 (95% confidence interval 0.88-0.95)/10% higher, P = 0.0001] and after [0.90 (0.87-0.93), P = 0.0001] adjustment. Adjustment for future CD4 changes revealed that the association was explained by poorer CD4 cell counts in those with lower %IC. In total 8730 participants under follow-up for more than 1 year initiated ART of whom 237 (2.7%) died. Higher values of %IC prior to ART initiation were associated with a reduced risk of mortality before [0.29 (0.17-0.47)/10%, P = 0.0001] and after [0.36 (0.21-0.61)/10%, P = 0.0002] adjustment; the association was again explained by poorer post-ART CD4/ viral load in those with lower pre-ART %IC. CONCLUSIONS: Higher levels of engagement in-care are associated with reduced mortality at all stages of infection, including in those who initiate ART.

The risk of viral rebound in the year after delivery in women remaining on antiretroviral therapy.

OBJECTIVE: The objective of this study is to assess the risk of viral rebound in postpartum women on suppressive combination antiretroviral therapy (cART). METHODS: Using data from the UK Collaborative HIV Cohort (UK CHIC) study and the UK and Ireland National Study of HIV in Pregnancy and Childhood (NSHPC), women with HIV-RNA 50 copies/ml or less at delivery in 2006-2011, who started life-long cART during pregnancy (n = 321) or conceived on cART (n = 618), were matched by age, duration on cART and time period, with at least one control (non-postpartum). The cumulative probability of viral rebound (HIV-RNA >200 copies/ml) was assessed by Kaplan-Meier analysis; adjusted hazard ratios (aHRs) for the 0-3 and 3-12 months postdelivery (cases)/pseudo-delivery (controls) were calculated in Cox proportional hazards models. RESULTS: In postpartum women who conceived on cART, 5.9% [95% confidence interval (95% CI) 4.0-7.7] experienced viral rebound by 3 months, and 2.2% (1.4-3.0%) of their controls. The risk of viral rebound was higher in postpartum women than in controls during the first 3 months [aHR 2.63 (1.58-4.39)] but not during the 3-12 months postdelivery/pseudo-delivery. In postpartum women who started cART during pregnancy, 27% (22-32%) experienced viral rebound by 3 months, and 3.0% (1.6-4.4%) of their controls. The risk of viral rebound was higher in postpartum women than in controls during both postdelivery/pseudo-delivery periods [<3 months: aHR 6.63 (3.58-12.29); 3-12 months: aHR 4.05 (2.03-8.09)]. CONCLUSION: In women on suppressive cART, the risk of viral rebound is increased following delivery, especially in the first 3 months, which may be related to reduced adherence, indicating the need for additional adherence support for postpartum women.

Pregnancy is associated with elevation of liver enzymes in HIV-positive women on antiretroviral therapy.

OBJECTIVE: The objective of this study is to assess whether pregnancy is associated with an increased risk of liver enzyme elevation (LEE) and severe LEE in HIV-positive women on antiretroviral therapy (ART). DESIGN: Two observational studies: the UK Collaborative HIV Cohort (UK CHIC) study and the UK and Ireland National Study of HIV in Pregnancy and Childhood (NSHPC). METHODS: Combined data from UK CHIC and NSHPC were used to identify factors associated with LEE (grade 1-4) and severe LEE (grade 3-4). Women starting ART in 2000-2012 were included irrespective of pregnancy status. Cox proportional hazards were used to assess fixed and time-dependent covariates including pregnancy status, CD4 cell count, drug regimen and hepatitis B virus/hepatitis C virus (HBV/HCV) coinfection. RESULTS: One-quarter (25.7%, 982/3815) of women were pregnant during follow-up, 14.2% (n = 541) when starting ART. The rate of LEE was 14.5/100 person-years in and 6.0/100 person-years outside of pregnancy. The rate of severe LEE was 3.9/100 person-years in and 0.6/100 person-years outside of pregnancy. The risk of LEE and severe LEE was increased during pregnancy [LEE: adjusted hazard ratio (aHR) 1.66 (1.31-2.09); severe LEE: aHR 3.57 (2.30-5.54)], including in secondary analyses excluding 541 women pregnant when starting ART. Other factors associated with LEE and severe LEE included lower CD4 cell count (<250 cells/µl), HBV/HCV coinfection and calendar year. CONCLUSION: Although few women developed severe LEE, this study provides further evidence that pregnancy is associated with an increased risk of LEE and severe LEE, reinforcing the need for regular monitoring of liver biomarkers during pregnancy.

Does pregnancy increase the risk of ART-induced hepatotoxicity among HIV-positive women?

INTRODUCTION: High rates of hepatotoxicity have been observed among HIV-positive pregnant women using antiretroviral therapy (ART). However, the extent to which pregnancy affects the risk of ART-induced hepatotoxicity is unclear since studies in this area have generated conflicting results. MATERIAL AND METHODS: Combined data from the UK Collaborative HIV Cohort (UK CHIC) study and the UK and Ireland National Study of HIV in Pregnancy and Childhood (NSHPC) were used. Alanine aminotransferase (ALT) data were assessed according to the Division of AIDS toxicity guidelines to identify factors associated with liver enzyme elevation (LEE) (grade 1-4). Women starting ART in 2000-11 aged 16-49 years were included irrespective of pregnancy status at ART start. Cox proportional hazards were used to assess the associations between fixed (ethnicity, exposure group, HBV/HCV co-infection, prior ART use, and age, year, pregnancy status, viral load and CD4 count at ART start) and time-dependent covariates (pregnancy status, age, year, CD4 count, viral load, duration on ART) and the risk of LEE. RESULTS: Of the 3426 women included, one-quarter (25.0%, n=857) were pregnant during follow-up and 14.4% (n=492) started ART during pregnancy. The rate of LEE was 15/100 person-years (PY) during pregnancy and 6.1/100 PY outside pregnancy. The risk of LEE was increased during pregnancy (adjusted hazard ratio (aHR) 1.61 [1.26-2.06], p<0.001), including in secondary analysis excluding 493 women pregnant when starting ART. Other factors independently associated with LEE were lower CD4 count (<250 cells/mm(3) vs. 251-350 cells/mm(3) aHR 1.25 [1.02-1.54], p=0.03), HBV/HCV co-infection (aHR 1.94 [1.58-2.39], p<0.001), HIV acquired via injecting drug use (aHR 1.61 [1.15-2.24], p=0.01 vs. heterosexually) and calendar year (aHR 1.05 [1.02-1.08], p<0.001 per one year increase). Three ART drugs were associated with increased risk of LEE (efavirenz aHR 1.27 [1.06-1.50], p-value 0.008; maraviroc 4.19 [1.34-13.1], p=0.01; and nevirapine 1.59 [1.30-1.95], p-value <0.001). Use of zidovudine was associated with decreased risk of LEE (aHR 0.74 [0.63-0.87], p<0.001) as was increasing time on an NNRTI-based regimen (aHR 0.91 [0.86-0.96], p<0.001 per additional year). CONCLUSIONS: Pregnant women were at increased risk of LEE, highlighting the importance of close monitoring of toxicity biomarkers during pregnancy.

Predicted savings to the UK National Health Service from switching to generic antiretrovirals, 2014-2018.

INTRODUCTION: In other disease areas, generic drugs are normally used after patent expiry. Patents on zidovudine, lamivudine, nevirapine and efavirenz have already expired. Patents will expire for abacavir in late 2014, lopinavir/r in 2016, and tenofovir, darunavir and atazanavir in 2017. However, patents on single-tablet regimens do not expire until after 2026. METHODS: The number of people taking each antiretroviral in the UK was estimated from 23,655 individuals in the UK CHIC cohort (2012 database). Costs of patented drugs were taken from the British National Formulary database, assuming a 30% discount. Costs of generic antiretrovirals were estimated using an 80% discount from patented prices, or actual costs where available. Two options were analysed: 1 - all patients use single-tablet regimens and patented versions of drugs; prices remain stable over time; 2 - all people switch from patented to generic drugs when available, after patent expiry (dates shown above). RESULTS: There were an estimated 67,000 people taking antiretrovirals in the UK in 2014, estimated to rise by 8% per year until 2018 (in line with previous rises). The most widely used antiretrovirals in the CHIC cohort were tenofovir (TDF) (75%), emtricitabine (FTC) (69%), efavirenz (EFV) (39%), lamivudine (3TC) (23%), abacavir (ABC) (18%), darunavir (DRV) (21%) and atazanavir (ATV) (16%). The predicted annual UK cost of generic ABC/3TC/EFV (three generic tablets once daily) was £1018 per person-year. Costs of patented single-tablet regimens ranged from £5000 to £7500 per person-year. Assuming continued use of patented antiretrovirals in the UK, the predicted total national costs of antiretroviral treatment were predicted to rise from £425 million in 2014 to £459 m in 2015, £495 m in 2016, £536 m in 2017 and £578 m in 2018. With a 100% switch to generics, total predicted costs were £337 m in 2014, £364 m in 2015, £382 m in 2016, £144 m in 2017 and £169 m in 2018. The total predicted saving over five years from a switch to generics was £1.1 billion. CONCLUSIONS: Systematic switching from patented to generic antiretrovirals could potentially save approximately £1.1 billion in the UK over the next five years, compared with continued use of patented versions: this money could be spent on urgently needed HIV prevention programmes. Similar savings are feasible for other European countries, given parallel patent expiry dates. More detailed economic evaluation is required to show when patented single-tablet regimens provide value for money, compared to bioequivalent generic versions of 3-4 pills once daily.

Developing an academic and American Indian tribal partnership in education: a model of community health nursing clinical education.

American Indian tribes shoulder a heavy burden in health inequities and recognize the value of partnerships with academic institutions. This article describes a unique education model developed through a partnership between a school of nursing and 2 Pacific Northwest tribes to provide clinical education for students. Over 3 years, students and faculty worked with 2 tribal communities to design research and implement education programs.

Laboratory adverse events and discontinuation of therapy according to CD4(+) cell count at the start of antiretroviral therapy.

OBJECTIVE: Few data describe antiretroviral treatment (ART)-related adverse events when treatment is initiated at CD4(+) cell counts more than 350 cells/µl. We compared rates of laboratory-defined adverse events (LDAEs) according to CD4(+) cell count at ART initiation. DESIGN: Analysis of on-going cohort study. METHODS: ART-naive persons initiating ART from 2000 to 2010 were included. Chi-square, analysis of variance (ANOVA) and Kruskal-Wallis tests compared characteristics among those starting ART with a CD4(+) cell count of 350 or less, 351-499 and at least 500 cells/µl. Time-updated Poisson regression compared rates of LDAE in the three CD4(+) cell strata. Cox proportional hazard models compared risk of ART discontinuation. RESULTS: Nine thousand, four hundred and six individuals were included: median age 37 years, 61% white, 80% men, median viral load 4.8 log copies/ml. Four hundred and forty-seven (4.9%) and 1099 (11.7%) started ART with a CD4(+) cell count at least 500 and 351-499 cells/µl, respectively. One thousand, two hundred and eighty-three (13.6%) patients experienced at least one LDAE. The rate of LDAE did not differ between those starting ART with a CD4(+) cell count 351-499 and less than 350 cells/µl [relative rate 0.90, 95% confidence interval (CI) 0.74-1.09)], but an increased risk of ART discontinuation was observed (hazard ratio 1.58, 95% CI 1.10-2.27). Those starting ART at CD4(+) cell count at least 500 cells/µl had an increased rate of LDAE (relative rate 1.44, 95% CI 1.13-1.82) but were not more likely to discontinue ART (hazard ratio 1.15, 95% CI 0.64-2.09). CONCLUSION: This study demonstrates the need to consider ART-related toxicities when initiating therapy at CD4(+) cell counts at least 500 cells/µl. Whilst evidence from randomized controlled trials is awaited, the timing of ART initiation in terms of benefits and risks of ART remains an important question.

Incomplete reversibility of estimated glomerular filtration rate decline following tenofovir disoproxil fumarate exposure.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) has been linked to renal impairment, but the extent to which this impairment is reversible is unclear. We aimed to investigate the reversibility of renal decline during TDF therapy. METHODS: Cox proportional hazards models assessed factors associated with discontinuing TDF in those with an exposure duration of >6 months. In those who discontinued TDF therapy, linear piecewise regression models estimated glomerular filtration rate (eGFR) slopes before initiation of, during, and after discontinuation of TDF therapy. Factors associated with not achieving eGFR recovery 6 months after discontinuing TDF were assessed using multivariable logistic regression. RESULTS: We observed declines in the eGFR during TDF exposure (mean slopes, -15.7 mL/minute/1.73 m(2)/year [95% confidence interval {CI}, -20.5 to -10.9] during the first 3 months and -3.1 mL/minute/1.73 m(2)/year [95% CI, -4.6 to -1.7] thereafter) and evidence of eGFR increases following discontinuation of TDF therapy (mean slopes, 12.5 mL/minute/1.73 m(2)/year [95% CI, 8.9-16.1] during the first 3 months and 0.8 mL/minute/1.73 m(2)/year [95% CI, .1-1.5] thereafter). Following TDF discontinuation, 38.6% of patients with a decline in the eGFR did not experience recovery. A higher eGFR at baseline, a lower eGFR after discontinuation of TDF therapy, and more-prolonged exposure to TDF were associated with an increased risk of incomplete recovery 6 months after discontinuation of TDF therapy. CONCLUSIONS: This study shows that a decline in the eGFR during TDF therapy was not fully reversible in one third of patients and suggests that prolonged TDF exposure at a low eGFR should be avoided.

Response to antiretroviral therapy (ART): comparing women with previous use of zidovudine monotherapy (ZDVm) in pregnancy with ART naïve women.

BACKGROUND: Short-term zidovudine monotherapy (ZDVm) remains an option for some pregnant HIV-positive women not requiring treatment for their own health but may affect treatment responses once antiretroviral therapy (ART) is subsequently started. METHODS: Data were obtained by linking two UK studies: the UK Collaborative HIV Cohort (UK CHIC) study and the National Study of HIV in Pregnancy and Childhood (NSHPC). Treatment responses were assessed for 2028 women initiating ART at least one year after HIV-diagnosis. Outcomes were compared using logistic regression, proportional hazards regression or linear regression. RESULTS: In adjusted analyses, ART-naïve (n = 1937) and ZDVm-experienced (n = 91) women had similar increases in CD4 count and a similar proportion achieving virological suppression; both groups had a low risk of AIDS. CONCLUSIONS: In this setting, antenatal ZDVm exposure did not adversely impact on outcomes once ART was initiated for the woman's health.

Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy.

OBJECTIVE: The objective of this study is to estimate life expectancies of HIV-positive patients conditional on response to antiretroviral therapy (ART). METHODS: Patients aged more than 20 years who started ART during 2000-2010 (excluding IDU) in HIV clinics contributing to the UK CHIC Study were followed for mortality until 2012. We determined the latest CD4 cell count and viral load before ART and in each of years 1-5 of ART. For each duration of ART, life tables based on estimated mortality rates by sex, age, latest CD4 cell count and viral suppression (HIV-1 RNA <400 copies/ml), were used to estimate expected age at death for ages 20-85 years. RESULTS: Of 21 388 patients who started ART, 961 (4.5%) died during 110 697 person-years. At start of ART, expected age at death [95% confidence interval (CI)] of 35-year-old men with CD4 cell count less than 200, 200-349, at least 350 cells/µl was 71 (68-73), 78 (74-82) and 77 (72-81) years, respectively, compared with 78 years for men in the general UK population. Thirty-five-year-old men who increased their CD4 cell count in the first year of ART from less than 200 to 200-349 or at least 350 cells/µl and achieved viral suppression gained 7 and 10 years, respectively. After 5 years on ART, expected age at death of 35-year-old men varied from 54 (48-61) (CD4 cell count <200 cells/µl and no viral suppression) to 80 (76-83) years (CD4 cell count ≥350 cells/µl and viral suppression). CONCLUSION: Successfully treated HIV-positive individuals have a normal life expectancy. Patients who started ART with a low CD4 cell count significantly improve their life expectancy if they have a good CD4 cell count response and undetectable viral load.

The emergence of drug resistant HIV variants at virological failure of HAART combinations containing efavirenz, tenofovir and lamivudine or emtricitabine within the UK Collaborative HIV Cohort.

BACKGROUND: Lamivudine (3TC) and emtricitabine (FTC) are guideline choices for combination highly active antiretroviral therapy (HAART). 3TC has a shorter intracellular half life than FTC and may be more likely to lead to the development of drug resistant HIV variants. METHODS: In this study we analysed linked data from the observational UK Collaborative HIV Cohort (CHIC) Study and UK HIV Drug Resistance Database (HDRD) to investigate the rate of development of K65R or M184V resistance mutations in patients failing on combinations containing tenofovir (TDF) and efavirenz (EFV) with either 3TC or FTC. Virological failure was defined as 1 viral load >400 copies/ml. Rates were stratified by demographic variables, baseline viral load, current CD4 count, current viral load and year of starting regimen. Significant associations were identified using Poisson regression models and multivariable analyses were performed adjusting for the variables above. Logistic regression was used to determine whether there were any significant associations between type of regimen and detection of resistance mutation. RESULTS: 5455 patients received either (or both) 3TC, TDF and EFV or FTC, TDF and EFV contributing 6465 treatment episodes over 9962 person-years follow up. 47 of these episodes were preceded by resistance tests showing development of K65R or M184V mutation and were hence excluded. The majority of treatment episodes consisted of FTC- (n = 5190) rather than 3TC- (n = 1228) based regimens. 21 cases of K65R were detected over the course of follow up, giving an overall event rate of 0.21 (95% CI: 0.12-0.31)/100 person years follow up (PYFU). The overall event rate for detection of M184V was 0.38 (95% CI: 0.26-0.5)/100 PYFU. 201 patients receiving either regimen for the first time experienced virological failure. Of those receiving 3TC (n = 53), 7 (13.2%), 12 (22.6%) and 15 (28.3%) developed K65R, M184V and either K65R or M184V respectively. Of those receiving FTC (n = 148), 13 (8.8%), 20 (13.5%) and 26 (17.6%) developed K65R, M184V and either K65R or M184V respectively. Although patients on 3TC were more likely to develop resistance, this was not statistically significant in univariable (OR 1.85 (95% CI: 0.89-3.85, p = 0.09)) or multivariable analyses (OR 1.89 (95% CI: 0.89-4.01, p = 0.1)). CONCLUSIONS: We have not found evidence of an increased risk of development of M184V and K65R in patients exposed to 3TC.